Contraception

and infertility

Medicine
on CD-ROM

Whats new in ...

Contraception and
infertility
Anna Glasier MD FRCOG MFFP is Honorary Professor in the School of Clinical Sciences
and Community Health at the University of Edinburgh and in the Department of Public
Health Policy at the University of London School of Hygiene and Tropical Medicine, and
Director of Family Planning and Well Woman Services for NHS Lothian.
Sharon Cameron MD MRCOG is a Lecturer in the School of Clinical Sciences and
Community Health at the University of Edinburgh.
Recent developments in contraception include new methods such as FemCap, Essure,
NuvaRing and a Depo-Provera subcutaneous formulation, and studies on the
side-effects of existing methods and on hormonal contraception and sexually
transmitted infections. Developments in the eld of infertility include methods for
preservation of fertility in cancer patients, and clinical guidelines for fertility treatment.
Contraception

New methods
FemCap

A new contraceptive diaphragm developed in the USA has limited availability in the
UK. FemCap (Figure 1) is a silicone rubber device shaped like an American sailors
hat. The design is intended to make the cap easier to fit and less likely to slip than the
traditional diaphragm. Because it is said to confer less pressure on the surrounding
vaginal walls, it is also supposed to reduce the risk of urinary tract infection (UTI) a
recognized side-effect of diaphragm use. In a randomized multi-centre study comparing
a traditional diaphragm with FemCap,1 the failure rate of FemCap was higher (1.96
times that for diaphragm users). Although FemCap users had a lower risk of UTI (odds
ratio 0.6, 95% CI 0.41.0), they were more likely to find the device difficult to insert and
remove, and much more likely to experience dislodgement. It is unlikely that FemCap
will become available in the UK through the NHS.

1 FemCap

Essure

Essure is a new method of female sterilization that has become available in the USA
and some parts of Europe. It is being provided in some areas of the UK, but is still
under evaluation. The device is an expanding spring measuring 2 mm in diameter and
4 cm in length made of titanium, stainless steel and nickel containing dacron fibres. On
hysteroscopy under local anaesthesia or mild sedation in an out-patient setting, the
device is inserted via the cavity of the uterus into the proximal section of the fallopian

tube (Figure 2). The device induces a local inflammatory response and, eventually,
fibrosis of the intramural tubal lumen. Several studies have evaluated the efficacy,
safety and acceptability of this procedure as an alternative to laparoscopic tubal
sterilization, which usually requires general anaesthesia and hospitalization.2 Bilateral
device placement is achieved in 8595% of patients. Follow-up is currently limited, but
a trial from Australia reported no pregnancies in 111 women followed-up for 2 years.3

2 Essure shown in place on a model.

NuvaRing

NuvaRing is a combined contraceptive vaginal ring marketed in the USA and many
countries in mainland Europe. It remains unavailable in the UK.

Depo-Provera subcutaneous

A new, micronized formulation of Depo-Provera is in development. It is injected

subcutaneously at a dose of 104 mg every 12 weeks, with an efficacy and a delay in
recovery of fertility similar to that seen with the current intramuscular preparation.4 It may
be associated with a lower incidence of amenorrhoea than intramuscular Depo-Provera.
The only clinical advantage of the new preparation is the potential for self-administration.
In a survey of more than 100 women using Depo-Provera and attending a large family
planning clinic Edinburgh, almost 70% were interested in self-administration.5

New data on existing methods

Oral contraception and venous thromboembolism

Combined oral contraceptives (COCs) are associated with an increased risk of venous
thromboembolism (VTE). Pills containing less androgenic progestogens (third-generation
progestogens) appear to carry a higher risk of VTE than pills containing older, more
androgenic progestogens such as levonorgestrel and norethisterone.
The newest pill available in the UK, Yasmin, contains an anti-androgenic
progestogen (drospirenone) that also has antimineralocorticoid properties. Concern
had been expressed that Yasmin may be associated with a higher risk of VTE. The
UK Committee on Safety of Medicines (CSM) recently quoted interim results from a
large observational study of more than 52,000 woman-years of COC use, including
16,000 woman-years of Yasmin.6 These results suggest that the incidence of VTE is no
different from that associated with COCs containing other progestogens. Women with
other recognized risk factors for VTE (including obesity) were included in the study, and
the incidence of VTE was higher than currently quoted in product information. The CSM
reminds providers that caution should be used when prescribing COCs to women with
a body mass index (BMI) of more than 30 kg/m2 or a higher baseline risk of VTE.

Depo-Provera

It has been recognized for some time that use of intramuscular Depo-Provera is
associated with loss of bone mineral density (BMD) compared with that in non-users.7
There are concerns that this issue may be most significant in very young women, who
may not have achieved peak bone mass. Results of cross-sectional studies are limited
and inconsistent, but two prospective studies have reported statistically significant
decreases in BMD over 2 years in Depo-Provera users aged 1221 years compared
with users of non-hormonal contraception.8,9 BMD also seems to be reduced in older
Depo-Provera users compared with non-users, but limited evidence suggests that

women who stop using the method before the menopause can regain lost bone mass.
However, there is concern about women over 40 years of age, who may not recover
normal BMD after stopping Depo-Provera before they inevitably lose more bone when
they reach the menopause. Only one study has examined fracture risk, and this was in
women with a mean age of 21 years.10 There was no significant association between
use of Depo-Provera and the risk of stress fracture after adjusting for baseline BMD. In
response to new data submitted to the US and UK drug regulatory authorities (currently
unpublished), the CSM has recently advised the following.
In adolescents, Depo-Provera may be used as first-line contraception, but only after
other methods have been discussed with the patient and considered to be unsuitable
or unacceptable.
In women of all ages, careful re-evaluation of the risks and benefits of treatment
should be undertaken in those who wish to continue Depo-Provera for more than
2 years.
In women with significant lifestyle and/or medical risk factors for osteoporosis, other
methods of contraception should be considered.
This advice is unlikely to change until there are data showing that bone loss is
reversed when Depo-Provera is stopped, or that there is an increased risk of fracture
associated with Depo-Provera. The CSM does not advise how women who wish to
continue Depo-Provera should be re-evaluated after 2 years. However, the UK Faculty
of Family Planning and Reproductive Healthcare cautions against using BMD scans,
which are unlikely to help in the decision-making process.

Hormonal contraception and sexually transmitted infection (STI)

Several studies undertaken in the late 1980s and early 1990s suggested that use
of hormonal contraception may be associated with an increased risk of Chlamydia
infection and gonorrhoea. However, hormonal contraceptive use and STIs are both
common. Most studies have been cross-sectional in design, have used insensitive
tests for Chlamydia, and have failed to control for potential confounding factors such
as sexual behaviour. A recently published study involving more than 800 women in the
USA suggested that use of Depo-Provera but not oral contraception was significantly
associated with an increased risk of Chlamydia and gonorrhoea after adjusting for
other risk factors (hazard ratio for Depo-Provera 3.6, 1.68.5; HR for oral
contraception 1.5, 0.63.5).11 It has been suggested that, because Depo-Provera
causes hypo-oestrogenism, thinning of the vaginal epithelium may increase the risk
of STI. The authors of this paper carefully discuss the strength and weaknesses of
the study, including several potential biases. Young age, non-white ethnicity, inner city
residence and multiple sexual partners were all independent risk factors for acquiring
STI. Interestingly, no association between the presence of cervical ectopy and infection
was found with either oral contraceptive or injectable contraceptive use. Further studies
must be undertaken to determine whether the link between hormonal contraception
and STIs is causal or merely related to sexual behaviour.

Infertility
Preservation of female fertility
Oocyte cryopreservation

To preserve fertility in women with cancer who are about to undergo life-saving
chemotherapy and/or radiotherapy (which is likely to result in ovarian failure), in vitro
fertilization (IVF) with cyropreservation of embryos may be undertaken. This is feasible
only for women with a long-term partner; for women without a partner, cyropreservation
of mature oocytes (collected after ovarian stimulation) followed by fertilization at a later
date is now becoming a realistic option. There has been widespread publicity about
a few births resulting from the latter technique, but the procedure currently has only
limited success, mainly because of problems with the fragility of oocytes undergoing
the freezing process. Recent results from one centre that has developed considerable
expertise (13 babies born as a result of treatment) show that, though the survival rate
of oocytes following thawing remains low (37%), clinical pregnancy rates are similar to
those achieved using fresh oocytes and standard IVF techniques (22%).12 Furthermore,
the miscarriage rate appears comparable to that in spontaneous conceptions.12
In England and Wales, the number of centres offering oocyte freezing is increasing;
16 clinics are currently licensed by the Human Fertilisation and Embryology Authority
to perform this technique. Safety issues regarding oocyte cryopreservation remain a
major concern, particularly regarding possible damage to the meiotic spindle of the

oocyte, with increased risk of aneuploidy or adverse effects on mitochondrial function.

Before this procedure can become established, improved survival rates of oocytes are
required, in addition to safety data on long-term follow-up of offspring conceived by this
method.

Ovarian cryopreservation

In pre-pubertal girls undergoing cancer treatment, preservation of fertility may be

possible through cyropreservation of ovarian tissue slices taken before the start of
treatment. The ovarian tissue can later be replaced as a graft to restore natural fertility,
or the immature oocytes within the ovarian slices can be matured by in vitro culture
and subsequently inseminated for embryo transfer. Recent advances in this field have
made this prospect a reality.
In March 2004, it was reported that an embryo had been created from IVF performed
on oocytes retrieved from ovarian tissue that had been transplanted beneath the skin of
the abdomen in a 30-year-old survivor of breast cancer.13 The ovarian tissue had been
cryopreserved 6 years earlier, before chemotherapy-induced menopause. The embryo
was transferred to the uterus, but a successful pregnancy did not result.
Several months later, it was reported that a healthy baby had been born from a
frozenthawed ovarian autograft in a 32-year-old woman cured of Hodgkins disease.14
In this case, cryopreservation of ovarian tissue biopsies had been undertaken 7 years
previously, when the woman presented with grade 4 Hodgkins lymphoma. Following
chemotherapy, the patient was amenorrhoeic, and endocrinological assessment was
consistent with ovarian failure. The ovarian strips were replaced into a surgically
created furrow on the peritoneum, beside the native right ovary. Monitoring of serum
gonadotrophins and vaginal ultrasonography confirmed follicular activity in this ovarian
tissue graft. At 11 months post-re-implantation, a pre-ovulatory follicle was evident on
ultrasonography of the graft. Spontaneous conception ensued and a healthy baby girl
was born in September 2004. It is possible that pregnancy could have resulted from
resumption of ovarian activity in the remaining ovaries, but this is believed not to be the
case, because there was no evidence of follicular activity in the ovaries during this time
(based on ultrasonography, laparoscopy and histological assessment).
The woman in the latter report was 25 years old when the ovarian biopsies were
cryopreserved, but this technology is likely to be of most use in pre-pubertal girls and
very young women. The ovaries of older women are largely depleted of primordial
follicles, and oocyte cryopreservation and embryo cryopreservation following IVF are
alternatives in this group. This recent birth shows that cryopreserved primordial follicles
have the potential to develop and to release mature oocytes that can be fertilized
naturally. The doctors who treated this patient believe that the successful outcome
justifies offering ovarian tissue cryopreservation to all young women diagnosed with
cancer. The technique is currently experimental, but it should encourage further
research in the field.

Preservation of male fertility

Semen cyropreservation should be offered to adult men and post-pubertal boys

undergoing cancer treatment, because preservation of fertility following chemotherapy
or radiotherapy cannot be guaranteed.15 In men who are azoospermic, surgical sperm
retrieval from the testis with cryopreservation should be offered, in the hope that, if a
few motile sperm are found, future fertility may be a possibility via intracytoplasmic
sperm injection performed on oocytes retrieved at IVF.
In pre-pubertal boys, sperm banking is not possible because no active
spermato-genesis is present. It is hoped that testicular stem cell cyropreservation with
subsequent transplantation may one day offer hope of future fertility in this group.
This technique has been effective in mice and rats, but remains experimental in
humans.16,17 There are major concerns about the normality of meiosis after freezing
and re-transplantation of stem cells, and a theoretical risk that this technique could
re-introduce cancer cells into a cured patient.16 Optimal storage conditions have not
been established, so viability is a serious concern, and the risks of testicular biopsy
and orchidectomy are not insignificant. Collection and storage of testicular tissue from
pre-pubertal boys is therefore currently not recommended except as part of a research
project.15

Clinical guidelines for fertility treatment

The National Institute for Clinical Excellence recently published clinical guidelines,
applicable to the NHS in England and Wales, on fertility assessment and treatment
in those with fertility problems.18 The guidelines include recommendations on the
diagnostic, medical and surgical management of couples with infertility in primary,

secondary and tertiary care. Some noteworthy recommendations that should result in
improvements in practice include the following.

Investigations

Unless there are known risk factors for tubal obstruction (previous pelvic inflammatory
disease, ectopic pregnancy), fallopian tubal patency should be assessed by
hysterosalpingography (radiographical evaluation following introduction of radiopaque
contrast into the uterine cavity), which is reliable, and less invasive and cheaper than
laparoscopy.

Male infertility

Men found to have a varicocele should not be offered surgical treatment, because this
does not improve pregnancy rates.

Anovulation

Women with anovulatory polycystic ovary syndrome (PCOS) should undergo

ultrasound monitoring of at least their first cycle of treatment with the anti-oestrogen
clomiphene, to ensure that the dose is appropriate. In women with PCOS who fail to
ovulate in response to clomiphene, and who have a BMI of more than 25 kg/m2, the
insulin-sensitizing drug metformin (though not licensed for ovulation induction) should
be added to clomiphene, because this may improve ovulation rates. Laparoscopic
ovarian drilling (application of diathermy to a small number of sites on each ovary)
should also be offered to women who fail to ovulate in response to clomiphene; this is
as effective as gonadotrophin therapy, without the risk of multiple pregnancy.

Endometriosis

Surgical treatment of moderate-to-severe endometriosis and surgical ablation of

minimal/mild endometriosis should be offered, because treatment improves the
likelihood of pregnancy. In contrast, medical treatment of endometriosis does not
improve the likelihood of successful conception and should not be used for fertility
purposes.

Intrauterine insemination (IUI)

IUI involves placement of a preparation of the partners sperm into the uterine cavity
via a fine catheter. Up to six cycles, without ovarian stimulation, should be offered to
couples with unexplained infertility, mild endometriosis or mild male-factor infertility
(based on semen analysis), and may improve the likelihood of pregnancy.

IVF

Couples with an identified cause of infertility, or unexplained infertility of more than

3 years duration, should be offered up to three cycles of IVF (provided the woman
is under 40 years of age at the start of treatment). Because the likelihood of multiple
pregnancy increases with the number of embryos transferred, no more than two
embryos should be replaced in each treatment.

REFERENCES

1 Mauck C et al. A comparative study of the safety and efficacy of FemCap, a new
vaginal barrier contraceptive, and the Ortho All-Flex diaphragm. The FemCap
Investigators Group. Contraception 1999; 60: 7180.
2 Ubeda A et al. Essure: a new device for hysteroscopic tubal sterilization in an
outpatient setting. Fertil Steril 2004; 82: 1969.
3 Kerin J F et al. The safety and effectiveness of a new hysteroscopic method for
permanent birth control: results of the first Essure pbc clinical study. Aust N Z J
Obstet Gynaecol 2001; 41: 36470.
4 Jain J et al. Pharmacokinetics, ovulation suppression and return to ovulation
following a lower dose subcutaneous formulation of Depo-Provera. Contraception
2004; 70: 1118.
5 Lakha F, Glasier A. Contraception 2005; in press.
6 Committee on Safety of Medicines. Curr Prob Pharmacovigilance 2004; 30: 7.
7 Cundy T et al. Recovery of bone density in women who stop using
medroxyprogesterone acetate. BMJ 1994; 308: 2478.
8 Cromer B A et al. A prospective comparison of bone density in adolescent girls
receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel
(Norplant), or oral contraceptives. J Pediatr 1996; 129: 6716.
9 Lara-Torre E et al. Bone mineral density in adolescent females using depot
medroxyprogesterone acetate. J Pediatr Adolesc Gynecol 2004; 17: 1721.

10 Lappe J M et al. The impact of lifestyle factors on stress fractures in female Army
recruits. Osteoporos Int 2001; 12: 3542.
11 Morrison C S et al. Hormonal contraceptive use, cervical ectopy, and the acquisition
of cervical infections. Sex Transm Dis 2004; 31: 5617.
12 Borini A et al. Pregnancies and births after oocyte cryopreservation. Fertil Steril
2004; 82: 6015.
13 Oktay K et al. Embryo development after heterotopic transplantation of
cyropreserved ovarian tissue. Lancet 2004; 363: 83740.
14 Donnez J et al. Livebirth after orthotopic transplantation of cryopreserved ovarian
tissue. Lancet 2004; 364: 140510.
15 Storage of ovarian and prepubert al testicular tissue. Report of a working party.
Royal College of Obstetricians and Gynaecologists. London: RCOG Press, 2000.
16 Tournaye H et al. Preserving the reproductive potential of men and boys with
cancer: current concepts and future prospects. Hum Reprod Update 2004;
10: 52532.
17 Zhang Z, Short R V, Sucessful intra- and inter- specific male germ cell
transplantation in the rat. Biol Reprod 2003; 68: 961.
18 National Institute for Clinical Excellence. Fertility: assessment and treatment for
people with fertility problems. London: NICE, 2004.

Copyright 2005 The Medicine Publishing Company Ltd

Combined Hormonal Contraception

Anna Glasier is Senior Lecturer in the Department of Obstetrics and Gynaecology
at the University of Edinburgh, UK, and Director of Family Planning and Well Woman
Services for Lothian Primary Care NHS Trust. She qualified from the University
of Bristol, and trained in obstetrics and gynaecology, specializing in reproductive
medicine. Her research interests are contraception, including emergency contraception,
and reproductive health care.
The combined oral contraceptive pill was introduced in the early 1960s and is currently
used by more than 60 million women worldwide. In the UK, 35% of women using
contraception take an oral contraceptive pill. The combined pill is popular because of its
efficacy, ease of use and additional health benefits beyond those of contraception.

Available preparations

The combined pill contains both oestrogen (usually ethinylestradiol) and a progestogen
(a synthetic compound that behaves like progesterone).
Oestrogen: the dose of oestrogen used in the combined pill ranges from 20 g to
50 g; most women now use so-called low-dose pills containing 3035 g. Low-dose
pills are potentially safer because the cardiovascular risks of the pill result mainly from
oestrogen. However, the lower the dose of oestrogen, the higher the risk of poor cycle
control, breakthrough bleeding and pregnancy if compliance is poor.
Progestogens used in currently available pills are divided into three groups:
first-generation progestogens (e.g. norethindrone)
second-generation norgestrel derivatives (e.g. levonorgestrel)
third-generation progestogens (e.g. gestodene, desogestrel, norgestimate).
Different progestogens have different potencies and thus contraceptive effectiveness
is achieved at different doses. At equivalent levels of contraceptive efficacy, the
progestogens are said to have slightly different side-effects, but the evidence for
these claims is unconvincing except possibly for side-effects associated with relative
differences in androgenicity (e.g. acne).
Formulations: the pill is taken for 21 days followed by a 7-day break (the pill-free
interval, PFI), when withdrawal bleeding usually occurs. Combined pills are available in
monophasic preparations (in which every pill in the packet contains the same dose of
steroids), and biphasic and triphasic preparations (in which the dose of both oestrogen
and progestogen changes once or twice over the 21-day period).
Biphasic and triphasic pills were introduced to reduce the total dose of
progestogens, and in the belief that a regimen that mimicked the normal cycle would
produce better cycle control. However, there is no evidence for better cycle control,
and some women find such preparations confusing, particularly when they want to take
two packets of pills consecutively to postpone menstruation. In an attempt to improve
compliance, everyday preparations are used widely in the USA and Australia. These
regimens involve the taking of inactive tablets, rather than 7 days without pills.

Mode of action

The combined pill acts mainly by inhibiting ovulation. The oestrogen component inhibits
secretion of pituitary follicle-stimulating hormone, thereby suppressing the development
of ovarian follicles; progestogen inhibits the development of the luteinizing hormone
surge. Other mechanisms of action of the combined oral contraceptive are shown in
Figure 1.

Mechanisms of action of combined oral contraceptives

Inhibition of ovulation
Changes in cervical mucus that interfere with sperm transport
Tubal motility may be altered
Atrophy of endometrium
Uterine receptivity essential for successful implantation may be impaired

In some women, the 7-day PFI is long enough to allow follicle growth; on the
last day of the PFI, 25% of women exhibit ultrasound evidence of follicles of 10 mm
in diameter. If the PFI is extended beyond 7 days, these follicles continue to develop
and, despite restarting the pill, ovulation may occur. In women who appear to have
conceived as a result of a genuine pill failure (rather than as a result of an error in
pill-taking) and who wish to continue using the combined pill after the pregnancy
is over, the PFI can be shortened to 4 or 5 days to ensure suppression of follicular
development.
Because the risks of the combined pill are mainly from oestrogen, manufacturers
have striven to reduce the dose. In recognition of the risk of compromising
contraceptive efficacy, a new formulation (Mircette, currently available only in the
USA) comprises 21 days of 20 g ethinylestradiol in combination with desogestrel, but
includes five daily doses of 10 g ethinylestradiol alone during the pill-free week to
maintain suppression of follicle growth.

Efficacy

When used correctly, the combined pill is almost 100% effective. The failure rate
during perfect use is 0.1%. In practice, because of errors in pill-taking, the failure rate
associated with typical use is about 3%.

Advantages of the combined pill

In addition to being a highly effective method of contraception that women find

easy to use, the combined pill confers a number of health benefits. Most women
have lighter, shorter and more regular menstrual periods during pill use. Periods also
tend to be less painful and premenstrual symptoms less troublesome. In women
without contraindications to oestrogen, the combined pill is often the first-choice
treatment for menorrhagia, dysmenorrhoea, premenstrual syndrome and anovulatory
dysfunctional uterine bleeding, which is common in adolescence and during the
perimenopause. In developing countries where anaemia is common, combined oral
contraceptive use reduces the incidence of iron deficiency anaemia by decreasing
menstrual blood loss.
Other benefits include reduced incidence (during pill use) of benign breast lumps,
functional ovarian cysts, endometriosis, acne and, possibly, pelvic inflammatory
disease. Women with severe acne often benefit from Dianette, which contains the
anti-androgen cyproterone acetate as the progestogenic agent. Long-term high-dose
cyproterone acetate is associated with liver function changes, but there is no evidence
for any adverse effect of Dianette in young, fit women, and no apparent need to monitor
liver function. However, the manufacturers do not recommend Dianette solely for contraceptive purposes.
There is convincing evidence that combined oral contraceptives protect against
ovarian and endometrial cancer. In a review of the published literature, the WHO
concluded that there is a 50% reduction in the risk of epithelial ovarian cancer after
5 years use of the combined pill that persists for at least 10 years after pill use
stops. The mechanism for the protective effect is unclear, but may be related to the
reduction in the total number of ovulations, and thereby ruptures of the ovarian capsule,
experienced in a lifetime.
In a recent analysis of 25 years follow-up of 46,000 women who took part in the
Royal College of General Practitioners (RCGP) Oral Contraceptive Study (which
compared 517,519 years of pill use with 335,998 years of never-use), the risk of death
from all causes was similar in ever-users and never-users of oral contraception. In
current users and recent users (within 10 years), the relative risk of death from ovarian
cancer was significantly decreased at 0.2. Combined oral contraceptives also reduce
the risk of endometrial cancer; the effect is strongly related to the duration of use (risk
reduction 20% after 1 year, about 50% after 4 years). The protective effect seems to be
sustained for perhaps as long as 15 years after stopping the pill.

Contraindications

Absolute contraindications to the combined pill are listed in Figure 2. Relative

contraindications include the presence of serious or multiple risk factors for
arterial disease, including hypertension, family history, diabetes mellitus, smoking,
age (> 35 years), obesity and migraine.
Women with hyperprolactinaemia who want to avoid pregnancy should be advised
to use progestogen-only contraception (see page 6), because oestrogen stimulates
lactotrophes (prolactin-secreting cells in the pituitary gland), thus increasing the
prolactin concentration.

Absolute contraindications to the combined oral contraceptive pill

Ischaemic heart disease, including cardiomyopathy

Most types of valvular heart disease
Arterial thrombosis
Venous thrombosis or known predisposition to thrombosis
Past cerebral haemorrhage, current transient ischaemic attacks
Vascular malformations of the brain
Pulmonary hypertension
Hyperlipidaemia
Focal and crescendo migraine, migraine requiring ergotamine or sumatriptan
Active liver disease, recurrent cholestatic jaundice, DubinJohnson or Rotor
syndrome
Liver tumour
Known gallstones
Porphyria
History of serious condition known to be affected by steroids (e.g. trophoblastic
disease)
Pregnancy
Undiagnosed genital tract bleeding
Oestrogen-dependent neoplasms (e.g. breast cancer)
Severe hypertension ( 160 mm Hg diastolic, 100 mm Hg systolic

2
Migraine is a common complaint in young women, though this group may often
describe any headache as migraine. A recent case control study has demonstrated
an increased risk of haemorrhagic stroke in young women with a personal history of
both classical (with aura) and simple (without aura) migraine. This risk appears to be
increased further by use of the combined pill. A careful history should be taken from
women who complain of migraine, and the pill prescribed with caution.

Risks and side-effects

The combined pill has an effect on almost every system in the body. Most
side-effects are minor; mood change, weight gain or fluid retention, nausea and
vomiting, headache, chloasma, loss of libido, mastalgia, breast enlargement and
greasy skin are common complaints. Many improve or disappear within 36 months
of starting the pill, but side-effects often lead to discontinuation of the method. Some
side-effects may be alleviated by changing to a different dose of oestrogen or type of
progestogen, and it is therefore worth trying another brand if time alone does not solve
the problem.
Serious side-effects involve mainly the cardiovascular system. The pill affects
both the venous (venous thromboembolism, VTE) and arterial (myocardial infarction,
cerebrovascular accident) circulations. Although the aetiology and epidemiology of
venous and arterial disease differ, in both cases the increased risk appears to be
related to an increased thrombotic tendency. Contraceptive steroids are metabolized
by the liver and affect the metabolism of carbohydrates, lipids, plasma proteins, amino
acids, vitamins and clotting factors. Changes in clotting factors create a tendency to
hypercoagulability, which is partly balanced by an increase in fibrinolysis. The adverse
effect on clotting is related to the dose of oestrogen; low-dose pills are associated with
a reduced risk compared with pills containing 50 g of oestrogen.
In the 25-year RCGP follow-up study, the risk of death from all causes in
women who had never taken the pill was no different from that in ever-users.
In current or recent users, however, there was an increase in the relative risk of
death from two conditions cervical cancer (relative risk 2.5) and haemorrhagic
stroke (1.9).

Venous disease

The combined pill is associated with a threefold increase in the relative risk of VTE.
Risk is unaffected by age, smoking and duration of pill use, but is higher in obese
women (body mass index, BMI > 30 kg/m2) and in women with a history of pregnancyinduced hypertension. Four well-designed studies have also demonstrated a differential
risk of VTE depending on the type of progestogen in the pill. Combined pills containing

the third-generation progestogens gestodene or desogestrel have about a twofold

increased risk of VTE compared with pills containing levonorgestrel. Although the
reason for this difference is unclear, it is known that oral contraceptive use reduces the
efficiency with which activated protein C down-regulates in vitro thrombin formation,
and this phenomenon appears to be more pronounced in women using a pill containing
desogestrel rather than levonorgestrel.
The publication of these studies led to widespread publicity, and in 1995, in the
UK, Germany and Norway, restrictions were placed on the use of pills containing
gestodene or desogestrel. In the UK, third-generation progestogen-containing
pills were recommended as second-line preparations in women who experience
unwanted side-effects with second-generation brands, and were contraindicated
in women with risk factors for VTE including severe varicose veins, obesity and a
family history of VTE. Opinion varies widely on the validity and interpretation of the
original data on the difference in VTE risk between the different types of progestogen,
and some further studies refuted the findings. The debate continues, and is often
confusing and acrimonious. On balance, most experts agree that the difference in
risk of VTE is real but small. The absolute risk of VTE in combined oral contraceptive
users is very low (15/10,000 woman-years) and considerably less than the risk during
pregnancy (60/10,000 woman-years). The risk returns to normal within 3 months of
stopping the pill. In 1999, prescribing restrictions on third-generation pills were lifted
in the UK.
Women with inherited thrombophilias (e.g. factor V Leiden) are at increased risk of
VTE, and a family history of VTE is an indication for testing for various thrombophilias.
Population-level screening is considered neither practical nor economical.

Arterial disease

Arterial disease in pill users is less common but more serious than venous disease.
In the past, the risks have been over-emphasized. There is no increase in the risk of
myocardial infarction in combined pill users of any age, unless they smoke or have
hypertension or diabetes. Hypertension increases the risk of myocardial infarction by
three times and smoking by as much as tenfold.
The risk of stroke attributable to combined oral contraceptive use is small.
The relative risk of haemorrhagic stroke is not increased in women under 35 years,
and is only slightly increased in older women. The risk of ischaemic stroke is slightly
increased (relative risk 1.5) and is also slightly higher in women over 35 years.
Smoking and hypertension increase the risk of stroke by tenfold and threefold
respectively.
The effect of the combined pill on the arterial system is probably related to both the
thrombogenic effect of oestrogen and the adverse effects of progestogens on lipids.
The risk was thought to be lower in users of third-generation progestogen-containing
pills because these confer more cardioprotective lipid profiles (in particular, increased
concentrations of high-density lipoproteins) and may also produce an increased
tendency to fibrinolysis. However, recent data from the UK have shown no difference
in the risk of myocardial infarction in users of third-generation compared with secondgeneration pills.

Breast cancer

Overviews of the risks and benefits of combined oral contraceptives are dominated
by breast cancer (see page 19). Published data are difficult to interpret because pill
formulations and patterns of reproduction (particularly age at first pregnancy) have
changed with time.
In 1996, the Collaborative Group on Hormonal Factors in Breast Cancer reported a
meta-analysis of 54 studies involving more than 53,000 women with breast cancer and
100,000 controls. The group concluded that use of the combined pill was associated
with a small increased risk of breast cancer, and that the increased risk persisted for 10
years after stopping the pill. The relative risk was 1.24 in current users, 1.16 14 years
after stopping, and 1.07 59 years after stopping. After 10 years, the relative risk was
not increased compared with that in never-users. Although the relative risk was higher
in women who started the pill at a young age (because breast cancer is uncommon
in this age group), there was little added effect from the duration of use, or the dose
or type of hormone. Women who had ever used the combined pill were significantly
less likely (relative risk 0.88) than never-users to develop cancer that spread beyond
the breast, even if they had stopped the pill more than 10 years earlier. In the 25-year
RCGP follow-up study, ever-users were not more likely to die from breast cancer than
never-users.

The relationship between the pill and breast cancer is difficult to explain because
the risk appears to increase soon after exposure, does not increase with duration of
exposure, and returns to normal after 10 years of no exposure. It has been suggested
that starting use of the pill may accelerate the appearance of breast cancer in
susceptible women. It is also possible that tumours are diagnosed earlier in women
who are using the pill, though it is difficult to explain why a tendency to earlier diagnosis
would persist for years after stopping. A biological effect of combined hormonal
contraception has not been excluded.

Cervical cancer

Data on the risk of cervical cancer in combined pill users are difficult to interpret
because barrier methods confer some protection and the aetiology of cervical
cancer is connected with sexual activity. More than 5 years of pill use may be
associated with a small increase in the risk of squamous cell carcinoma of the cervix.
In the 25-year follow-up study, the relative risk of dying from cervical cancer was
2.5 in ever-users. However, pill users are a captive population for cervical screening,
except in countries where the combined pill is available over the counter. There may
be an increased risk of adenocarcinoma in long-term users, but this remains an
uncommon tumour.

Liver cancer

Benign hepatic adenoma is an uncommon consequence of combined oral

contraceptive use.
In countries where hepatocellular carcinoma is rare, this disease may occasionally
be associated with the combined pill. In populations where liver cancer is common
(e.g. the Far East), short-term use of combined oral contraceptives does not affect the
incidence of hepatocellular carcinoma; data on long-term use are scarce.

Practical prescribing

History: a full history should be taken to exclude risk factors that might contraindicate
combined pill use or indicate further investigations.
Examination: blood pressure should be measured, and it may be helpful to record
baseline weight. BMI of more than 30 kg/m2 is considered a contraindication to the
combined pill.
Pelvic examination is not routinely indicated at the first (or any) visit unless
gynaecological pathology is suspected. Women do not like pelvic examinations and
some, particularly the young, may be deterred from starting or continuing with the pill if
examination is seen as a necessary prerequisite. Cervical smears should be taken in
accordance with national policy. Breast examination is unnecessary unless the woman
has symptoms of breast disease.
Choice of preparation: new users should usually start with a low-dose (3035 g)
pill containing a second-generation progestogen. If breakthrough bleeding occurs
and persists beyond the first 3 months, and a gynaecological cause is excluded,
a pill containing a higher dose of oestrogen or a different type of progestogen
may be tried.
Women on long-term enzyme-inducing drugs (e.g. some anticonvulsants) should
use a 50 g oestrogen preparation to ensure best efficacy.
Progestogen-only contraception may be considered in women with contraindications
to the combined pill (see page 6).
Information: women should be carefully instructed how to use the pill and what to do
when pills are forgotten (Figure 3). Many women choose (or are advised) to take a
break from using the pill for a few months. Although most cardiovascular risks decrease
when the pill is stopped, they recur as soon as it is started again, and unplanned
pregnancies commonly occur during such breaks; most women who stop the pill
regain normal fertility within 3 months. Secondary, so-called post-pill amenorrhoea is
almost always the result of abnormalities that were present before the pill was started
(e.g. polycystic ovary syndrome) but which were masked by regular combined oral
contraceptive-induced withdrawal bleeds.
There is no evidence of any adverse effect on the fetus as a result of previous
pill use. When conception occurs during pill use, the risk of teratogenesis is low
or non-existent.

Instructions for women who miss pills

Are you less than
12 hours late in taking
one pill?

YES

Are you more than

12 hours late in taking
one pill or more?

YES

Take the delayed pill

now and further pills
as normal
You do not need extra
protection

Take the last missed

pill now
Discard any other
missed pills

Continue further pills

as usual

Use extra precautions

(e.g. condoms) in
addition to your pills for
the next 7 days

Are there seven or more

pills left in the packet
after those you missed?

YES
NO

When you have finished

the packet have the
usual 7-day break before
starting the next one

When you have finished

the packet start the next
one without a break

The future

Combined oestrogenprogestogen injectable contraceptives are now available in some

parts of the world. Injectable methods are popular with women who like hormonal
methods but forget to take pills. However, progestogen-only injectable contraceptives
are associated with a high incidence of amenorrhoea, which is unacceptable in some
cultures. Cyclofem (medroxyprogesterone acetate, 25 mg, and estradiol cypionate,
5 mg) and Mesigyna (norethisterone enantate, 50 mg, and estradiol valerate, 5 mg)
are given monthly and have very low failure rates (0.5/100 woman-years). Vaginal
bleeding occurs about every 35 days. Discontinuation rates as a result of menstrual
irregularity and amenorrhoea are one-half of those associated with progestogen-only
injectable contraceptives.
Non-oral administration of contraceptive steroids avoids the first pass through
the liver, allowing use of lower doses. Constant circulating hormone concentrations
may reduce the incidence of minor side-effects compared with oral administration.
Transdermal patches are in advanced stages of development. Most steroid
hormones are well absorbed through the vaginal mucosa, and soft silastic or vinyl
rings (Figure 4) have been developed that release a combination of oestrogen and
progestogen, and can be worn for 3 weeks and removed for 7 days. Their efficacy is as
good as that of the combined pill, but the user must remember to insert and remove the
ring once each month. These rings are likely to become available within the next
3 years.

4 Contraceptive vaginal ring. (By courtesy of

NV Organon.)

FURTHER READING

Beral V, Hermon C, Kay C, Hannaford P, Darby S, Reeves G. Mortality Associated with

Oral Contraceptive Use: 25 Year Follow Up of a Cohort of 46,000 Women from Royal
College of General Practitioners Oral Contraception Study. BMJ 1999; 318: 96100.
Chang C L, Donaghy M, Poulter N. Migraine and Stroke in Young Women: A Case
Control Study. BMJ 1999; 318: 1318.
Dunn N, Thorogood M, Faragher B et al. Oral Contraceptives and Myocardial
Infarction: Results of the MICA Case Control Study. BMJ 1999; 318: 157984.
OBrien P A. The Third Generation Oral Contraceptive Controversy. BMJ 1999;
319: 7956.
(Evidence for an increased risk of VTE in women using pills containing
third-generation progestogens.)
Rosing J, Middeldorp S, Curvers J et al. Low-dose Oral Contraceptives and Acquired
Resistance to Activated Protein C: A Randomised Cross-over Study. Lancet 1999;
354: 203640.
Skegg D C G. Third Generation Oral Contraceptives. BMJ 2000; 321: 1901.
(Evidence relating to the effects of third-generation pills on the risk of VTE, with a
discussion of the study design and analysis.)
WHO. Improving Access to Quality Care in Family Planning. Medical Eligibility Criteria
for Contraceptive Use. Geneva: WHO, 2000.
WHO. Oral Contraceptives and Neoplasia. WHO Tech Rep Ser 1992; 817.
(A review of the literature on oral contraception and all types of cancer.)
WHO. Cardiovascular Disease and Steroid Hormone Contraception. Report of a
Scientific Group. WHO Tech Rep Ser 1998; 877.
(A review of the literature on oral contraception and all types of cardiovascular
disease.)
Practice points
The combined oral contraceptive pill is extremely safe; mortality in ever-users is no
different from that in never-users 10 years after stopping the pill
The pill is a highly effective method of contraception; the failure rate is only 0.1% when
it is used correctly
The cardiovascular risks of the combined pill are extremely low
Although there is probably a slight increase in the risk of VTE associated with
combined pills containing desogestrel or gestodene, choice of pill should be a matter
for individual
women guided by their doctor
Current and recent users are at increased risk of diagnosis of breast cancer, but the
risk returns to that seen in never-users 10 years after stopping the pill

Copyright 2003 The Medicine Publishing Company Ltd

Progestogen-only Contraceptive Methods

Diana Mansour is a Consultant in Community Gynaecology and Reproductive Health
Care and Head of Service for Contraception and Sexual Health in Newcastle upon
Tyne, UK. She qualified in Cardiff, and trained in obstetrics and gynaecology in London.
Her research interests include long-term methods of contraception and sexual health in
young people.
Progestogen-only contraceptives are available as oral preparations, injectables,
implants and the intrauterine system (IUS).
Indications progestogen-only contraceptives are indicated in:
women with illnesses contraindicating use of the oestrogen in the combined pill
(e.g. hypertension, migraine with focal aura, diabetes with neuropathic or
nephropathic complications, history of venous thromboembolism)
women at increased risk of venous or arterial disease with the combined pill
(e.g. obese women, heavy smokers)
women who suffer oestrogenic side-effects with the combined pill (e.g. breast
tenderness, headaches, nausea)
breast-feeding women
women who prefer to use the method.
Contraindications are:
known or suspected pregnancy
active venous thromboembolic disorder
past or current severe arterial disease
severe hepatic disease
history of progestogen-dependent tumour
recent trophoblastic disease, until -human chorionic gonadotrophin is undetected in
both blood and urine
undiagnosed vaginal bleeding
hypersensitivity to progestogens.

Progestogen-only pills

The combined pill is the most popular hormonal contraceptive method used by women
in the UK. Only 8% of pill-users take the progestogen-only pill (POP), despite the fact
that it is an effective hormonal contraceptive method, particularly in women over
35 years of age with or without medical problems. Current POPs contain low doses
of levonorgestrel, norethisterone, lynestrenol or ethynodiol diacetate (Figure 1).

Types of progestogen in progestogen-only pills

Type
Desogestrel (soon
to be marketed)
Levonorgestrel
Norgestrel
Lynestrenol
(or ethynodiol diacetate)
Norethisterone

Dose
75 g
30 g
75 g (equivalent to
37.5 g of levonorgestrel)
500 g
350 g

1
Mode of action: POPs may suppress ovulation in only 1540% of cycles; their
contraceptive effect also depends on altering the cervical mucus to reduce sperm
penetration, and inducing changes in the endometrium to prevent sperm survival and
implantation of the blastocyst. POPs may affect tubal motility, thereby increasing the
risk of ectopic pregnancy if the POP fails.
The effect on the cervical mucus reaches its peak within 23 hours then decreases
slowly. It is therefore important that POPs are taken regularly at the same time each
day. If a pill is taken more than 3 hours from the normal time, the user should take the
pill that was forgotten and then continue taking the pills regularly. Extra contraceptive

precautions such as condoms are recommended for the next 7 days, before the POP
can be relied on again.
Efficacy: reported failure rates vary, but all POPs are less effective than the
combined pill.
Contraceptive efficacy may be affected by age one study showed a strong
negative trend (3.1 pregnancies/100 woman-years at age 2529 years, 0.3
pregnancies/100 woman-years at age 40 years) (Vessey et al., 1985).
There is debate whether the efficacy of the POP is affected by body weight. A recent
small study investigating sperm penetration of the cervical mucus suggested
that progestogen had little effect on cervical mucus in women with a weight of more
than 75 kg. The Oxford/FPA study also showed that user weight might affect efficacy
(Figure 2), but this was not statistically significant (Vessey et al., 1990).

Failure rates of progestogen-only pill by user weight

Weight (kg)
< 50
5070
> 70

Woman-years
of use
627
3462
318

Pregnancies
(%)
3
2.8
4

Failure
rate
0.5
0.8
1.3

Source: Vessey M, Villard-Mackintosh L, Yeates D. Br J Fam Plann 1990; 16: 79.

2
A POP containing desogestrel is soon to be marketed in Europe. The dose of
progestogen in this POP is sufficient to inhibit ovulation in 97% of treatment periods,
achieving a Pearl Index of 0.14, compared with 1.17 in women taking a levonorgestrel
POP. Restoration of the hypothalamopituitaryovarian axis takes time; therefore,
the margin for error with a delay of up to 12 hours is not expected to affect the
contraceptive efficacy of this POP (Collaborative Study Group).
Side-effects and benefits: the side-effects of the POP are similar to those of other
progestogen-only contraceptive methods (Figure 3). Irregular bleeding is the most
common. Anecdotally, the incidence of amenorrhoea is higher in POP users in their
40s, because the POP is more likely to suppress the luteinizing hormone (LH) surge,
thereby inhibiting ovulation. There are no studies in this area, but it is probable that
follicular development continues in women with POP-induced amenorrhoea, and
therefore endogenous estradiol production is maintained.

Adverse effects in women taking desogestrel or levonorgestrel

progestogen-only pill

Irregular bleeding
leading to discontinuation
Headache
Acne
Breast pain
Nausea
Vaginitis
Dysmenorrhoea

Women reporting event (%)

Desogestrel Levonorgestrel
22.5
18
7.5
3.1
4.0
3.3
3.8
1.2

6.1
4.0
3.1
1.5
2.8
3.4

Source: Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.

Eur J Contracept Repro Health Care 1998: 3: 16978.

Recent studies have suggested that POPs do not increase the risk of venous
thrombosis, cardiovascular disease or cerebral thrombosis (WHO).
Data concerning the return of fertility following discontinuation of the POP are
limited, but suggest that its reversibility is similar to that of the combined pill.

Progestogen-only injectables

One of the first long-acting contraceptive preparations was an intramuscular

progestogen-only depot that gave contraceptive cover for 23 months. The most
commonly used progestogen-only injectable is Depo-Provera, which contains 150 mg
of depot medroxyprogesterone acetate (DMPA) and is administered every 12 weeks
or at intervals of up to 91 days.
The other progestogen-only injectable is Noristerat, which contains 200 mg of
norethisterone enantate (NET-EN). It is licensed for short-term contraceptive use
in the UK and is given every 8 weeks. NET-EN is licensed for use in women whose
partners are undergoing vasectomy, until the vasectomy becomes effective, and in
women receiving immunization against rubella, to prevent pregnancy during the period
of activity of the virus. However, it is generally accepted that NET-EN can be used for
long-term contraception in selected patients after counselling.
Mode of action: both injectables must be commenced within the first 5 days of the
menstrual cycle, and are given by deep intramuscular injection. DMPA and NET-EN
inhibit ovulation by suppressing LH and, to a certain extent, follicle-stimulating hormone,
and are at least as effective as the combined pill.
Efficacy: pregnancy rates at 1 year are 0.4/100 women on the 2-month NET-EN
regimen, and 0.3/100 women with DMPA.
Side-effects with these injectables include irregular vaginal bleeding/amenorrhoea.
NET-EN has less effect on bleeding patterns than DMPA. In a comparative trial,
bleeding episodes in the first 6 months were significantly shorter in NET-EN users than
in DMPA users. Bleeding patterns after 6 months were similar. Amenorrhoea lasting
more than 90 days was significantly less common in NET-EN users. Another study
suggests that more than 55% of DMPA users are amenorrhoeic after 12 months, and
this may increase to 68% by 2 years.
Further disadvantages of progestogen-only injectables include the delay that may
occur in the return to normal fertility after discontinuation of the method. In one study,
former NET-EN users conceived, on average, 11 months after their last injection.
Another study investigated pregnancy rates for 4 years after discontinuation of
DMPA, the combined pill and the IUD. The median time to conception was longer in
former DMPA users (10 months from the date of the last injection) than in both former
combined pill users (3 months) and IUD users (4.5 months). However, almost 70%
of former DMPA users had conceived within the first 12 months of discontinuation,
and more than 90% had conceived within 24 months. Within 3 years of discontinuing
contraception, fertility rates were similar in all groups.
Other side-effects are similar to those seen with other progestogen-only
contraceptives. Recent WHO data suggest that there is no long-term increase in the
risk of breast, cervical or ovarian cancer in DMPA users, though there was a small risk
in one study. There was a marked reduction in the risk of endometrial cancer.
There has been concern that DMPA may adversely affect bone mineral density.
At present, the data are conflicting. Studies suggest that more than 80% of long-term
DMPA users have estradiol levels of less than 150 pmol/litre. There appears to be little
evidence that bone mineral density is affected at the hip, but several studies suggest
that it may be adversely affected at the lumbar spine (36.5% reduction). Whether
this is clinically important is debatable a similar loss occurs in those who drink two
or more units of alcohol per day. There is no evidence of a dose-related response to
DMPA, that duration of DMPA use is important, or that a policy of giving add-back
oestrogen is beneficial.
Some units restrict use of DMPA to women under 45 years of age, to allow
time for recovery of bone density before the menopause. Others balance the risks
of an unplanned pregnancy against any potential risks of continuing an effective
contraceptive with non-contraceptive benefits.
Recent work has reported that progestogen-only injectables do not increase
the risk of acute myocardial infarction, venous thrombosis or stroke. The numbers
involved in this multi-centre study were small, however, and further work is
required (WHO).

History
As early as 1921, it was suggested that extracts from the ovaries of pregnant
animals might be used as hormonal contraceptives. Progesterone and a
number of oestrogens were then isolated from animal sources and investigated.
Unfortunately, large numbers of animals were needed to isolate these products,
making them very expensive. A major breakthrough came in 1943, when
progesterone was produced from diosgenin extracted from wild Mexican yams.
The oral progestogens norethisterone and norethynodrel were then developed in
the early 1950s.
In 1956, Puerto Rican women were recruited to join contraceptive clinical trials
using oral progestogens. These were successful until chemists removed an
impurity in the pills. This led to irregular bleeding and reduced efficacy, because
the impurity was an oestrogen (mestranol). Once the oestrogen was restored to
the preparation, cycle control and contraceptive effectiveness improved.
Over the following years, synthetic progestogens were developed.

Progestogen-only implants
Norplant

Norplant is a highly effective, reversible contraceptive lasting 5 years. It comprises

six small, flexible, sealed silastic capsules, each containing 38 mg of levonorgestrel.
It initially releases 85 g/day, decreasing to 50 g/day by 6 months and 35 g/day by
18 months. It was initially recommended for use in women aged 1840 years because
many of the pre-marketing studies concentrated on this age group, but has been
successfully used in women over 40 years of age.
Mode of action: Norplant suppresses ovulation in about 50% of cycles, particularly in
the first year. It also reduces the sperm penetrability of cervical mucus.
Side-effects: irregular bleeding and other reported side-effects of Norplant are similar
to those seen with other progestogen-only contraceptives.
More than 54,000 women have used Norplant in the UK, but its popularity declined
following adverse media coverage of implant removal and side-effect problems.
Norplant was withdrawn from the UK market for commercial and not safety reasons
much of the dissatisfaction with the method resulted from the actions of untrained or
inexperienced service providers who gave poor pre-insertion counselling, coerced
women to keep the implants, and then attempted removal without the necessary
training/supervision. More recently, a Legal Aid-funded class action in the UK was
unsuccessful.

Implanon

Implanon is a single-rod implant containing 68 mg of etonogestrel (3,keto-desogestrel),

the active metabolite of desogestrel. Insertion and removal are quicker than with
Norplant, and there are fewer reported complications following removal. An Implanon
implant lasts 3 years, and may therefore suit more women than Norplant, which lasts
5 years (Edwards & Moore).
Mode of action: the main contraceptive effect of Implanon is inhibition of ovulation.
It also reduces the sperm penetrability of cervical mucus. Etonogestrel is released
steadily and in a controlled manner over 3 years with no local accumulation. Within
1 day after insertion, serum blood levels of etonogestrel are achieved that inhibit
ovulation (90 pg/ml). Maximum levels are reached after 4 days, and are only about
20% of those achieved with a combined pill containing 150 g of desogestrel.
Efficacy: concerns have been raised that body weight may affect the efficacy of
Implanon. However, serum blood levels, even in women with a high body mass index,
appear to be above the minimum dose required to inhibit ovulation, and at the time
of writing no pregnancies have occurred in studies of Implanon. Although clinical
experience in heavier women is limited, the author would not recommend early removal
or changing of the implant in this group.
The effects of Implanon are immediately reversible more than 90% of women
ovulate within 30 days of removal.

Side-effects of Implanon are similar to those of Norplant.

Irregular bleeding may occur, and the incidence of amenorrhoea is higher than
in Norplant users. Overall, Implanon users experience less bleeding but with a
more variable pattern. Continuation rates for Implanon are similar to those of
Norplant about 80% of users are continuing with the method at 2 years.

Progestogen intrauterine system

Mirena has been available in the UK since May 1995 and has been used by more than
150,000 women. It is a highly effective contraceptive, and users also report reduced
dysmenorrhoea and lighter menses. Studies show an objective blood loss reduction
of 86% after 3 months and 97% after 12 months. The IUS can also be used as the
progestogen component of hormone replacement therapy (HRT).
The IUS is a T-shaped device with a vertical stem containing 52 mg of
levonorgestrel surrounded by a silastic capsule. This allows steady, local release
of 20 g/day over 5 years, with few systemic side-effects. Unlike the copper IUD, the
IUS should be changed every 5 years, even in women over the age of 40 years.
Mode of action: the IUS exerts its contraceptive action by altering the cervical mucus
and uterotubal fluid to inhibit sperm migration. It also causes atrophy of the uterine
endometrium, making the uterine mucosa thin, the stroma swollen, the endometrial
glands atrophic and the epithelial cells inactive. The IUS may also suppress ovulation in
one-third of users, and may reduce the pre-ovulatory LH surge.
Side-effects and benefits: concerns have been raised that women with
oligomenorrhoea or amenorrhoea may be at risk of osteoporosis because their
oestrogen levels are low. However, the incidence of ovulation is similar in menstruating
and amenorrhoeic women using the IUS, and mean plasma estradiol levels were similar
in these two groups.
Partial or complete expulsion of the IUS can occur at any time after insertion, but
particularly if the IUS is inserted when menstrual flow is at its heaviest. Women may
not notice that the IUS has been expelled, but may comment that their periods have
returned or that they have become heavier.
Long-term IUS use prevents endometrial proliferation and may induce regression of
endometrial hyperplasia. The IUS may also regulate and help prevent fibroid growth;
further work is needed. Reported ectopic pregnancy rates are very low in IUS users, so
this contraceptive method is suitable for women with a history of ectopic pregnancy.
The IUS dramatically reduces menstrual blood loss and dysmenorrhoea, but
potential users must be advised that it may cause irregular bleeding, particularly in the
first 3 months. In the first month of use, 20% of users experience prolonged bleeding
(> 8 days), but periods become shorter and only 3% of users experienced prolonged
bleeding during the third month. The duration and amount of bleeding generally
decrease over time with Mirena; 17% of women experience amenorrhoea of 3 or more
months duration in the first year. Studies suggest that women in their 40s report more
periods of amenorrhoea than younger users this is an advantage of this contraceptive
method.
A recent Finnish epidemiological post-marketing survey established that 82% of
women were still using the IUS 3 years after insertion. Swedish data are now available
for women who have used the IUS for 13 years (i.e. they have used three systems).
After the first 5 years, 70% of women reported regular, scanty bleeding, 26% had
amenorrhoea and 4% complained of irregular bleeding. After 10 years continuous use,
60% reported amenorrhoea, 28% had regular scanty bleeding and 12% had irregular
bleeding. Irregular bleeding or spotting did not occur after the second or third IUS was
inserted.
The IUS is the contraceptive method of choice in women who suffer heavy periods,
and may be an alternative to hysterectomy. Recent studies have suggested that more
than two-thirds of women planning hysterectomy cancelled their operations following
IUS insertion (Lahteenmaki et al.). This included several women who had tried other
medical treatments to control their menorrhagia. A comparative study of women
with the IUS and others who underwent transcervical resection of the endometrium
showed no statistical difference in patient satisfaction or efficacy. In the future, the
non-contraceptive benefits of the IUS may help reduce the number of hysterectomies
performed for menorrhagia.
Evidence is now mounting to support the use of the IUS as the progestogen
component of HRT. Research is under way concerning its use in perimenopausal and
post-menopausal women. If used in this manner, the IUS would need to be changed
every 5 years.

REFERENCES

Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill. A

Double-blind Study Comparing the Contraceptive Efficacy, Acceptability and Safety
of Two Progestogen-only Pills Containing Desogestrel 75 mcg/day or Levonorgestrel
30 mcg/day. Eur J Contracept Repro Health Care 1998: 3: 16978.
Edwards J E, Moore A. Implanon A Review of Clinical Studies. Br J Fam Plann 1999;
24: (Suppl.): 116.
Lahteenmaki P, Haukkamaa M, Puolakka J et al. Open Randomised Study of Use of
Levonorgestrel Releasing Intrauterine System as Alternative to Hysterectomy. BMJ
1998; 316: 11226.
Vessey M P, Lawless M, Yeates D, McPherson K. Progestogen-only Oral
Contraception. Findings in a Large Prospective Study with Special Reference to
Effectiveness. Br J Fam Plann 1985; 10: 11721.
Vessey M, Villard-Mackintosh L, Yeates D. Effectiveness of Progestogen Only Oral
Contraceptives. Br J Fam Plann 1990; 16: 79.
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormones.
Cardiovascular Disease and Use of Oral and Injectable Progestogen-only
Contraceptives and Combined Injectable Contraceptives. Results of an International,
Multicenter, Case-control Study. Contraception 1998; 57: 31524.

FURTHER READING

Andrews G, ed. Womens Sexual Health. London: Baillire Tindall, 1997.

(A balanced text for all health professionals, covering contraception, and womens
health issues including STI and common gynaecological problems.)
Glasier A, Winikoff B. Fast Facts Contraception. Abingdon: Health Press, 2000.
(A concise overview of contraceptive methods.)
Kubba A, Sanfilippo J, Hampton N. Contraception and Office Gynaecology. London:
Harcourt, 1999.
(A comprehensive text for postgraduate students, with chapters on contraceptive
methods and gynaecological problems.)

Practice points
When counselling men and women about contraception, remember that there
are many different methods available
Balanced messages, giving the advantages and disadvantages of
progestogen-only contraceptive methods, lead to greater user acceptability
and continuance; emphasis should be placed on the lack of serious long-term
side-effects, but the possibility of irregular bleeding
Training is necessary to insert and remove contraceptive implants or fit the IUS
Progestogen-only methods have non-contraceptive benefits; in the UK, the
IUS is licensed for the treatment of menorrhagia

Copyright 2003 The Medicine Publishing Company Ltd

Non-hormonal Methods of Contraception

Audrey Brown is a Specialist Registrar in Obstetrics and Gynaecology in Edinburgh,
UK. She qualified from the University of Glasgow, and trained in community
gynaecology. Her interests include the development of new methods of contraception
and provision of services for young people.
Non-hormonal methods of contraception have wide-ranging efficacy and popularity,
and include the IUD, male and female sterilization, male and female barrier methods
and natural family planning.
Choice of contraception is affected by many factors, including the age of the couple,
plans for further pregnancies and the availability of the method. In the UK, most
young users of contraception rely principally on hormonal methods more than 50%
of contraceptive users under the age of 30 years use oral hormonal contraception.
However, over the last decade, there has been an increase in the use of the male
condom by younger couples (as the sole method or in combination with a hormonal
method), probably as a result of concerns about HIV and other sexually transmitted
infections (STIs). About one-quarter of UK contraceptive users now rely on the male
condom, but condom use remains low in many areas of the world where HIV and AIDS
are a major threat.
Sterilization is used more commonly in older couples who have completed
childbearing. In the UK, almost one-half of couples over the age of 40 years rely on
sterilization; perhaps surprisingly, men are sterilized as often as women. Worldwide,
sterilization is the most widely used method of contraception; more than 200 million
couples have been sterilized.
The IUD is the second most widely used method worldwide, with about 100 million
users. Most of these women are in China, where more than one-third of contraceptive
users rely on the IUD. In the UK, about 10% of contraceptive users over the age of 25
years use the IUD.
Female barrier methods (diaphragm, cap, sponge and spermicide) and the
various methods of natural family planning are not widely used, but may be important
in those who wish to avoid hormonal methods, or to whom other methods are
unacceptable.

Sterilization

Sterilization is often an excellent choice for couples who have achieved their desired
family size. It is effective, does not require repeated visits to clinics, and does not
involve any ongoing expense. Before undergoing sterilization, the couple should be
counselled, usually by the general practitioner or a family planning professional. This
counselling session should cover:
the methods of sterilization available, and potential risks and side-effects
the effectiveness of the procedure and its intended irreversibility
which partner is to be sterilized
the couples current method of contraception, and the importance of continuing this
until the sterilization is complete
alternative long-acting (and reversible) methods
the stability of the relationship, including any sexual or relationship problems
the possibility of change in family circumstances (e.g. change of partner, loss of
a child).
Despite counselling, some couples (up to 10%) express regret after sterilization,
and about 1/100 seek reversal. Several factors are associated with a higher risk of
regret, and couples should be dissuaded from undergoing sterilization in the following
situations:
young couples (< 25 years)
sterilization immediately after pregnancy (term delivery or abortion)
relationship problems
psychiatric illness
couples without children.

Female sterilization

Methods: sterilization of women is usually performed by occlusion of the fallopian

tubes, or occasionally by bilateral salpingectomy or hysterectomy. Tubal occlusion is
the method of choice, and in the UK is normally performed as a day-case procedure by

laparoscopy under general anaesthesia. Local or regional anaesthesia may

also be used, particularly where facilities for safe general anaesthesia are lacking.
When laparoscopy is not possible, tubal occlusion can be performed by
mini-laparotomy.
Laparoscopic sterilization a pneumoperitoneum is first created by insufflation of
23 litres of carbon dioxide into the peritoneal cavity. The laparoscope is then passed
through a 1 cm subumbilical incision and the pelvic organs are visualized. A second
port is introduced in the iliac fossa or suprapubically; the instrument of choice for
occluding the tubes is then introduced and the sterilization is completed. Three main
methods of tubal occlusion are used in the UK.
Clips are applied over the whole width of the tube to ensure complete occlusion.
The most commonly used types in the UK are the Filshie clip (Figure 1) and the
HulkaClemens clip.
The falope ring (a small ring of silicone rubber) is applied over a loop of the tube,
after elevating the tube with a specially designed applicator.
Bipolar diathermy is now used in preference to the more hazardous unipolar
diathermy. However, cases of thermal damage to surrounding structures are still
reported, and the above mechanical methods are preferable.

1 Clips are applied over the

whole width of the tube to ensure
complete occlusion. In the UK,
the most commonly used type is
the Filshie clip.
Sterilization at delivery women occasionally request sterilization at the time of
Caesarean section. It is essential that such women are counselled fully antenatally, and
that the decision is not made hastily in the emotion of labour and delivery. Sterilization
at the time of delivery has a higher failure rate and leads to greater long-term feelings of
regret. Women should be strongly advised to undergo interval sterilization, which also
provides a time delay during which any immediate health problems that the neonate
may have should become apparent.
When sterilization at the time of delivery is appropriate, it can be achieved by
mechanical occlusive methods, or by surgical division and ligation of the tubes.
Complications of female sterilization are rare.
Visceral or vascular damage at laparoscopy is usually recognized at the time
of injury, and may necessitate laparotomy. Occasionally, the damage is not apparent
during surgery, and there may be delayed presentation with an acute abdomen or
septicaemia.
Death is very rare (< 10/100,000 procedures).
Infection at the wound site is usually minor, and can be managed with wound toilet
and oral antibiotics.
Failure the cumulative rate of failure of female sterilization is about 1/200. Women
must be advised that sterilization is not 100% effective, and that they should seek
a pregnancy test if a menstrual period is delayed. About 5% of pregnancies after
sterilization are ectopic, and this complication must be excluded as soon as possible.
Change in menses women often report a change in menstrual pattern after
sterilization. This is not caused by the sterilization procedure, but by coincidental
changes in contraception. For example, women who used the combined oral
contraceptive pill until sterilization are likely to notice increased menstrual bleeding as a
result of stopping the pill.

Male sterilization

Male sterilization (vasectomy) prevents delivery of sperm into the ejaculate by occlusion
of the vas deferens. Couples considering this method must be advised that it takes
time for the vasectomy to become effective, because the sperm already present in the
distal vas must be ejaculated. This is said to require about 20 ejaculations, though there
is considerable variation. In the UK, men are asked to provide two semen samples 12
and 16 weeks after vasectomy; the vasectomy cannot be considered effective until two
consecutive samples show azoospermia. Couples must be advised about the need for
continuing alternative contraception until given the all-clear.
Methods: vasectomy is most commonly performed under local anaesthesia, but
general anaesthesia can also be used. The vas deferens is approached through a
small skin incision (a single midline incision or two small lateral incisions). The sheath
overlying the vas is divided and carefully stripped back, and the underlying vas is
divided and then occluded. The occlusion may be achieved by ligation with sutures,
with clips, or by diathermy. No-scalpel vasectomy involves the use of two specially
designed instruments, and delivers the vas through a puncture wound rather than a
surgical incision. This method is said to have a lower complication rate, and is now
widely used.
Complications of vasectomy include the following.
Haematoma bruising is expected, but about 2% of men develop a haematoma.
This usually resolves with support and analgesia, but occasionally surgical evacuation
is necessary.
Infection at the wound site occurs in about 5% of men, and may need treatment
with antibiotics.
Sperm granuloma formation is thought to result from leakage of sperm from the
end of the vas. Palpable lumps may form, and there is occasionally significant pain.
Excision may be necessary if the symptoms do not resolve.
Antibody formation most men form antisperm antibodies after vasectomy. This is
of no clinical relevance, unless the man seeks reversal of the vasectomy in the future.
Failure about 12% of vasectomies fail to achieve azoospermia. This may result
from infrequent ejaculation and failure to clear existing sperm from the vas. In some
cases, the vas remains patent and the vasectomy may have to be repeated. Late failure
of vasectomy may occur after initial azoospermia and is presumably caused by late
recanalization. The cumulative rate of failure of male sterilization is about 1/2000; it is
therefore considerably more effective than female sterilization.
Cancer several epidemiological studies have shown an increased incidence of
testicular and prostatic cancer in men who have undergone vasectomy. No biological
explanation for this association has been found, and it is thought that the link is
not causal.

IUD

The IUD is the most commonly used reversible method of contraception worldwide.
Historically, a number of materials including ivory, gold and even lead have been
introduced into the uterine cavity in an attempt to control fertility. At present, all
devices used in the UK are copper-bearing, and most are based on a plastic frame
with fine copper wire around the stem, sometimes with a copper sleeve (Figure 2).
The frameless GyneFix comprises six copper beads crimped onto a single thread
(Figure 3), which is embedded into the myometrium with a knot.

2 The IUD is based on a plastic frame with

fine copper wire around the stem.

3 The frameless Gynefix

comprises six copper beads
crimped onto a single thread.
The IUD and its introducer are
shown here.
IUDs are licensed for use for up to 10 years (Figure 4). All IUDs are more than 99%
effective at 1 year; devices containing more than 300 mm of copper are even more
effective. When an IUD is fitted in a woman over the age of 40 years, it may be retained
until she is beyond the menopause and no longer requires contraception, without any
loss of efficacy.

Duration of use of IUDs currently available in the UK

Device
Nova T 200
Nova T 380
Ortho-Gynae T
Multiload Cu 250
Multiload Cu 375
Flexi-T 300
GyneFix

Licensed duration of use

5 years
5 years
10 years
3 years
5 years
5 years (3 years in under-35s)
5 years

4
IUDs were originally thought to act by preventing implantation of the fertilized
ovum. However, more recent work has shown an additional true antifertilization effect.
Infiltration of inflammatory cells within the uterus and fallopian tubes directly inhibits
sperm transport and fertilization. In addition, the high concentration of copper ions is
thought to be toxic to gametes. If fertilization were to occur, prevention of implantation
would prevent pregnancy.
The benefits of the IUD are:
safety (mortality after insertion is 1/500,000)
immediate contraception
coitus-independent
not user-dependent, cannot be forgotten
reversible
can be used as a post-coital contraceptive up to 120 hours after intercourse
(page 17).
Side-effects: the IUD has several potential risks and side-effects, and these should
be fully explained to potential users before insertion. Contraindications to IUD use are
summarized in Figure 5.

Contraindications to the IUD

Absolute
Pregnancy
Undiagnosed abnormal
vaginal bleeding
Current or recent STI
Distorted uterine cavity
Copper allergy
Wilsons disease

Relative
Menstrual problems
High risk of STI
Valvular heart disease
Immunosuppression
Anticoagulants
Previous ectopic pregnancy

5
Menstrual problems most women using the IUD have heavier and more
prolonged menses: if troublesome, this can usually be improved with a non-steroidal
anti-inflammatory drug such as mefenamic acid. Some women also report an increase
in dysmenorrhoea.
Infection there is an increased risk of pelvic infection in the first 3 weeks after
IUD insertion. It is thought that this results from carriage of micro-organisms from the
cervix into the uterine cavity during fitting. If the woman is thought to be at higher risk of
infection (e.g. < 25 years old, recent change of sexual partner), pre-insertion screening
for STI should be performed.
Expulsion of the IUD occurs in 35% of cases, and is most common in the first
year of use. IUDs used in the UK have a thread that is trimmed to 23 cm in length
beyond the cervix. This thread enables easy removal of the IUD (by gentle traction),
and its presence confirms that the device is in place. When the thread cannot be seen,
presence of the device can be confirmed by ultrasonography or radiography.
Perforation of the uterus is rare (about 1/1000 cases).
Vagal response manipulation of the cervix during the fitting of an IUD can
cause a vagal response, with occasional bradycardia and even asystole. It is therefore
essential that IUDs are inserted by appropriately trained staff in clinics where there are
facilities for resuscitation.
Failure pregnancy is rare in women with a correctly inserted IUD. If it does occur,
there is an increased risk of miscarriage and ectopic pregnancy. The IUD should be
removed if possible, and ultrasonography should be performed to exclude ectopic
pregnancy.

Barrier methods

Barrier methods of contraception act by preventing sperm from reaching the upper
genital tract of the female partner. They may be mechanical or chemical, or a
combination of the two.

Male condom

Condoms have been in use for hundreds of years; materials such as sheep bladder
and linen have been used. At present, most condoms are made from latex, have a
spermicidal lubricant, and protect against both pregnancy and STI, including HIV.
The efficacy of condoms in preventing pregnancy is variable different series have
reported rates of 8599%. Success depends on the experience and motivation of
the couple. Young people must be taught how to use condoms safely and effectively,
and demonstration of condoms is now part of many sex education courses. Condom
use is central to the practice of safe sex, and many couples opt to use them solely
for protection against STI, using the combined contraceptive pill to protect against
pregnancy (the Double-Dutch method).
Condoms have the advantage of being widely available in various outlets,
and can be easily obtained without consulting a health professional. This may be
particularly important in teenagers, who may be too embarrassed or afraid to consult
a doctor. Condoms can be obtained free of charge from many clinics and health advice
centres, but GPs are unable to provide them free on prescription. They are
now available in various sizes and shapes. Polyurethane condoms (e.g. Avanti)
are available for those who are sensitive to latex, and non-spermicidally lubricated
condoms for those with nonoxyl-9 sensitivity. Despite these advances, however,
disadvantages remain.
Condoms interfere with the spontaneity of sexual intercourse.
Some users complain of loss of sensation.
Oil-based lubricants such as baby oil and Vaseline reduce the strength of condoms,
as do various antifungal and hormonal vaginal medicines.

Female condom

The female condom is available in the UK as Femidom (Figure 6), which can
be purchased over the counter. The condom is made of polyurethane and is
non-spermicidally lubricated, thus avoiding allergy problems, and provides
protection against STI. It is less likely to split than the male condom, and is not
damaged by oil-based lubricants. Reported failure rates of 520% are likely to
reflect user motivation and experience.

6 The female condom is available

in the UK as Femidom.
Femidom allows greater sexual spontaneity than the male condom because it can
be inserted in advance of intercourse and can be left in place for some time afterwards,
but it is not a widely used method of contraception. Many users dislike its appearance
and size, and others complain that it is noisy during intercourse. However, it is a
valuable alternative to the male condom in the practice of safe sex, particularly for
women who have difficulty negotiating male condom use.

Diaphragms and caps

The diaphragm (Dutch cap) is a circular, sprung device that is fitted in the vagina
between the posterior fornix and the symphysis pubis, covering the cervix. It is usually
used in conjunction with a spermicide; thus, the method uses both mechanical and
chemical barriers. Diaphragms range in size from 55 mm to 95 mm in diameter
(Figure 7); the correct size is chosen after examination by the doctor or family
planning nurse. The woman is then taught how to insert and remove the device.

7 Diaphragms range in size from

55 mm to 95 mm.
The diaphragm can be inserted up to 3 hours before intercourse. The woman
applies spermicide to the surface then compresses the device into an eliptical shape
and inserts it into her vagina. She can confirm it is correctly positioned by checking that
the cervix is covered. After intercourse, the diaphragm must be left in place for at least
6 hours, to ensure that the spermicide has killed all sperm. After removal, the device
is washed in warm water and left to dry. Each diaphragm lasts for up to 1 year. It must
be refitted after pregnancy, or when the womans weight has changed significantly. The
contraceptive efficacy of the method is very user-dependent; failure rates of 418%
have been reported. Sensitivity of either partner to the latex or the spermicide is
occasionally problematic.
Vault and cervical caps are smaller than diaphragms and are designed to fit over the
vaginal vault and cervix respectively. They are available in several different sizes, and
should be used in conjunction with a spermicide.
A spermicidally impregnated sponge has recently become available again in the UK,
but failure rates are high.

Spermicides

Some individuals use spermicide as the sole method of contraception. Failure rates of
up to 25% can be anticipated, and such an approach cannot usually be recommended.
However, in those with a background of much reduced fertility (e.g. in the climacteric),
spermicide alone may be adequate. Spermicides (usually nonoxyl-9) are available
in various preparations including gels, pessaries and aerosols. They have the
benefit of providing additional vaginal lubrication, and may offer some protection
against STI.

Natural family planning

Natural family planning is based on awareness of the fertile time of the menstrual
cycle, and depends on avoidance of intercourse during this phase. Various methods
can be used to determine the fertile phase; all aim to identify indicators of ovulation
(Figure 8). Many couples use a combination of natural family planning methods, and
very motivated couples who do not break the rules have reported success rates of up
to 98%. However, in practice, many couples take chances, and the actual effectiveness
may be as low as 80% with some methods.
Natural family planning
Calendar method (rhythm method)
Cycle length is monitored over several months
Subtract 20 days from the shortest cycle
this day is the start of the fertile phase
Subtract 11 days from the longest cycle
this day is the end of the fertile phase
Couple must abstain between these days
Temperature method
Basal body temperature rises by 0.20.4C
after ovulation
Check temperature every day
Once temperature rise has been sustained for
3 days, fertile phase is over
Signals only the end of the fertile phase;
when this method is used alone, couples must
abstain throughout the entire follicular phase of
the cycle
Billings method

Fertile cervical mucus is elastic and can be

stretched between the fingers
The woman checks the consistency of her
mucus daily
Couple must abstain from the first day
of fertile mucus until 3 days after the
peak day
Cervical method
Under stimulation from rising oestrogen levels
in the approach to ovulation, the cervix rises in
the pelvis and the cervical os opens a little

The Persona device (Unipath) is available in the UK to assist couples who wish to
practice natural family planning. It measures the urinary metabolites of estradiol and
luteinizing hormone, and uses a series of red lights (fertile, abstinence) and green lights
(infertile, may have intercourse) to guide the couple. About 810 red days per cycle
are expected for the average couple. The method is said to be about 94% effective. It
is not available on prescription, and must be purchased at a cost of about 50, plus an
additional 10 per month for urinary testing sticks.

Breast-feeding

Worldwide, breast-feeding is a commonly used method of delaying or spacing

childbirth. The lactational amenorrhoea method is up to 98% effective when the
following criteria are fulfilled.
The child is under 6 months of age.
The child is fully or almost fully breast-fed.
The child suckles at least every 6 hours.
The mother is amenorrhoeic.
In addition, breast-feeding provides many other benefits to both mother and child
(Labbok et al.).

REFERENCES

Chi I-C, Jones D B. Incidence, Risk Factors and Prevention of Poststerilization Regret
in Women: An Updated International Review from an Epidemiological Perspective.
Obstet Gynecol Surv 1994; 49: 72232.
Labbok M H, Perez A, Valdez V et al. The Lactational Amenorrhoea Method (LAM):
A Postpartum Introductory Family Planning Method with Policy and Programme
Implications. Adv Contracept 1994; 10: 93109.
Royal College of Obstetricians and Gynaecologists. Male and Female Sterilisation.
Evidence-based Clinical Guidelines No.4. London: RCOG, 1999.
WHO. Intrauterine Devices. Technical and Managerial Guidelines for Service. Geneva:
WHO, 1997.

FURTHER READING

Glasier A, Gebbie A. Handbook of Family Planning and Reproductive Healthcare. 4th

ed. Edinburgh: Churchill Livingstone, 2000.
(A comprehensive textbook detailing all methods of contraception, and many other
aspects of sexual health.)
Guillebaud J. Contraception: Your Questions Answered. 3rd ed. Edinburgh: Churchill
Livingstone, 1999.
(Very chatty and readable question-and-answer format.)
Tomlinson J. ABC of Sexual Health. London: BMJ Books, 1999.
(An excellent introduction to sexual function and dysfunction.)

Practice points
Non-hormonal methods of contraception are widely used; sterilization and the
IUD are the principal methods worldwide
Sterilization is an effective method of contraception requiring no ongoing
motivation or contact with health professionals, but it is designed to be
irreversible, and adequate counselling before the procedure is required to
prevent later regret
The IUD provides safe, effective, long-acting and reversible contraception
Barrier methods and natural family planning have the benefit of client control,
but depend on user motivation for efficacy

Copyright 2003 The Medicine Publishing Company Ltd

Emergency Contraception
Anna Graham is Clinical Research Fellow in the Division of Primary Health Care at
the University of Bristol, UK. She qualified from University College and the Middlesex
Hospital Medical School, London, and trained in general medicine, general practice
and epidemiology. Her research interests include evaluating means of improving young
peoples understanding of emergency contraception, and young womens views on its
deregulation.
Women request emergency contraception when their contraceptive method has failed
or no method was used. Hormonal emergency contraception was prescribed 800,000
times in the UK in 1999/2000, by general practitioners in about two-thirds of cases and
in family planning clinics in one-third. A management plan for emergency contraception
is shown in Figure 1.

Methods of emergency contraception

Emergency contraceptive methods include hormonal methods and the insertion of a

copper IUD.
Until recently, the combined morning-after pill (Yuzpe regimen) was the most widely
used preparation in the UK. Each tablet contains 50 g of ethinylestradiol and 500 g of
norgestrel. Two tablets are taken within 72 hours of intercourse, followed by two tablets
12 hours later.
A progestogen-only emergency contraceptive became available in the UK in 2000.
This comprises two tablets of 750 g of levonorgestrel taken 12 hours apart, the first
dose within 72 hours of intercourse.
Both hormonal methods are safe and effective. A recent large multi-centre
study suggests that the progestogen-only method is more effective and has fewer
side-effects than the combined pill version, and is the treatment of choice. The only
disadvantage at present is its greater cost. From January 2001, the progestogen-only
emergency contraceptive became available over the counter in the UK, at a cost of
20. It has been available in this way in France, Norway and Portugal for longer.

Hormonal emergency contraception

How does emergency contraception work?

The precise mode of action of both the hormonal preparations and the IUD as
post-coital contraceptives is unknown. It probably depends on when in the cycle
the method is used. The IUD produces changes in the endometrium, making it
unsuitable for implantation; it does not inhibit ovulation. Hormonal methods may delay
or inhibit ovulation if given in the first half of the cycle. There is no evidence (clinical
or theoretical) that post-coital methods are abortifacient, because they act before
implantation of the fertilized ovum.

How effective is hormonal emergency contraception?

In a meta-analysis of ten published studies, it was calculated that the Yuzpe regimen
would prevent three out of four pregnancies (Trussell et al.). In a WHO randomized
controlled trial comparing the Yuzpe method with the progestogen-only method, the
latter prevented 85% of expected pregnancies when treatment was initiated within
72 hours of unprotected sex, compared with 57% for the combined preparation
(Task Force on Postovulatory Methods of Fertility Regulation). The efficacy of both
methods improved, and the difference between them decreased, when protocol
violations were removed from the analysis (i.e. women who did not use the method
correctly, women who had intercourse before the next period after taking emergency
contraception).
Both hormonal methods are effective if treatment is initiated within 72 hours, but
evidence from the WHO trial suggests that they are better at preventing pregnancy
when the first dose is taken within 24 hours of unprotected sex (Figure 2).

Contraindications to hormonal methods

Pregnancy is the only absolute contraindication to hormonal emergency contraception.

Raised blood pressure or previous thromboembolic events are relative contraindications
because the risks of pregnancy far outweigh the risks of the contraception. Women who
suffer focal migraines should be offered the progestogen-only method or the IUD.

Management of a request for emergency contraception

1 Estimate the likely date of ovulation and the risk of pregnancy by
recording the following
Usual length of cycle
Did the last period start at the expected time? Was it shorter or lighter
than usual?
Timing of all inadequately protected intercourse (on which days in the
current cycle)
2 Calculate the number of hours elapsed since the first episode of
unprotected intercourse
3 Identify any contraindications to emergency contraceptive methods,
and conditions requiring consideration and/or precautionary measures
NB: Pelvic examination is not justified. When pregnancy is suspected, a pregnancy
test should be performed.
4 Explain the options
If < 72 hours since unprotected sex
Offer emergency contraceptive pills or copper IUD and explain the following points
Mode of action
Efficacy
Risks and possible side-effects
If emergency contraceptive pills are used, the woman must abstain from sex
or use a barrier method for the remainder of the cycle
Follow-up is important if the womans next period does not start within 7 days
of the expected date
There is no evidence that emergency contraceptive methods carry any risk
of teratogenicity, but a normal outcome to any pregnancy cannot be
guaranteed
If oral hormonal emergency contraception is chosen
Explain when the pills should be taken
Advise the woman what to do if either dose of pill is vomited within 2 hours
Consider use of anti-emetic (domperidone recommended)
If > 72 hours since unprotected sex
Offer copper IUD and explain its use
5 Document, sign and date an accurate record
6 Discuss ongoing contraception, and STI screening and prevention; offer
follow-up
Reassure patient that repeat use of emergency contraception is safe
Source: Faculty of Family Planning and Reproductive Health Care of the Royal College
of Obstetricians and Gynaecologists. Emergency Contraception: Recommendations for
Clinical Practice. London: RCOG, 2000.

Side-effects

Nausea is the most common side-effect of hormonal emergency contraception. In

the WHO study, 50% of women taking the Yuzpe regimen felt sick and 20% vomited.
Of those ran-domized to receive the progestogen-only method, 23% felt sick and
only 6% vomited. Women who have experienced sickness on previous use of these
methods may be helped by the provision of an anti-emetic; the recommended drug
is domperidone, 10 mg taken with each dose of hormone. If vomiting occurs within
2 hours of taking either dose, another dose should be taken with domperidone, or, if
appropriate, use of the IUD discussed.

Pregnancy rates following emergency contraception

Coitus-to-treatment
interval

Pregnancy rate
(95% CI)

72 hours
Combined pill
Progestogen-only

Proportion of
expected
pregnancies
prevented (%)

3.2 (2.24.5)
1.1 (0.622.0)

57
85

24 hours
Combined pill
Progestogen-only

2.0 (0.93.7)
0.4 (0.11.6)

77
95

2548 hours
Combined pill
Progestogen-only

4.1 (2.36.6)
1.2 (0.33.0)

36
85

4972 hours
Combined pill
Progestogen-only

4.7 (1.99.4)
2.7 (0.96.1)

31
58

Data from a multi-centre randomized controlled trial involving 1998 women

randomized to receive the combined pill or progestogen-only emergency
contraception
Source: Task Force on Postovulatory Methods of Fertility Regulation. Lancet 1998; 352:
42833.

What if hormonal emergency contraception fails to work?

Women should be advised to take a pregnancy test if their period is more than 1 week
late; if this is positive, they should be counselled as for any woman who becomes
pregnant accidentally. There is no evidence that these emergency methods are
teratogenic, but a normal outcome to any pregnancy cannot be guaranteed.

Is it safe to use hormonal emergency contraception repeatedly?

Each dose of hormonal emergency contraception is equivalent to 1 week of low-dose

combined pill, so anxiety about repeat use is unjustified. Women can be prescribed
hormonal emergency contraception more than once in the same cycle, but should
be advised that this is not as effective in preventing pregnancy as other methods of
contraception.

Emergency IUD

The IUD is the most effective post-coital method available. It is particularly appropriate
in women who wish to use the method longer term. A copper IUD is inserted up to
5 days (120 hours) after unprotected intercourse, or up to 5 days after the earliest
possible ovulation day in the current cycle.
It is good practice to take swabs before fitting an emergency IUD. Antibiotic cover
at the time of insertion may be appropriate; the most likely infection is Chlamydia. To
ensure compliance, a single dose of azithromycin, 1 g, may be given. Women who have
an infection must be followed-up, and contact-tracing should be undertaken (probably
best performed by the local genitourinary medicine department).
If the woman wishes, the IUD can be removed at the next menstruation.

Is emergency contraception necessary after missing

oral contraceptive pills?

Emergency contraception is recommended when two or more combined pills

are missed from the first seven pills in a packet, or three or more pills are missed
mid-packet.
When two or more pills are missed from the last seven pills in a packet, emergency
contraception is unnecessary provided the pill-free interval is omitted.

 Emergency contraception should be offered when one or more progestogen-only

pills are taken more than 3 hours after the usual pill-taking time, or are missed.

Availability of emergency contraception

Emergency contraception is not available worldwide. Few family planning associations

provide the method in developing countries, though in many such areas conditions may
be favourable for its introduction. In Mexico, for example, oral contraceptives are sold
without prescription, and hence emergency contraception is available to women who
obtain their own supplies.

REFERENCES

Ellertson C, Winikoff B, Armstrong E, Camp S, Senanyake P. Expanding Access

to Emergency Contraception in Developing Countries. Stud Fam Plann 1995;
26: 25163.
Glasier A. Emergency Post-coital Contraception. N Eng J Med 1997; 337: 105864.
NHS Contraceptive Services, England: 19992000. London: HMSO, 2000.
Senanyake P. Emergency Contraception: The International Planned Parenthood
Federations Experience. Int Fam Plann Perspect 1996; 22: 6970.
Task Force on Postovulatory Methods of Fertility Regulation. Randomised Controlled
Trial of Levonorgestrel versus the Yuzpe Regimen of Combined Oral Contraceptives
for Emergency Contraception. Lancet 1998; 352: 42833.
Trussell J, Ellerson C, Stewart F. The Effectiveness of the Yuzpe Regimen of
Emergency Contraception. Fam Plann Perspect 1996; 28: 5864.

FURTHER READING

Faculty of Family Planning and Reproductive Health Care of the Royal College of
Obstetricians and Gynaecologists. Emergency Contraception: Recommendations for
Clinical Practice. London: RCOG, 2000.

Practice points

Hormonal emergency contraception or the copper IUD can be used after sex
when contraception fails or no method is used
There are few contraindications to hormonal emergency contraception, which
can be used as often as necessary
Progestogen-only hormonal emergency contraception is probably more
effective, and has fewer side-effects, than the combined pill version; both
hormonal methods are more effective when given earlier after unprotected sex
Post-coital contraception is not abortifacient because it acts before
implantation of the fertilized ovum
Emergency contraception is now available in pharmacies without prescription
in several countries in Europe, including the UK, France, Portugal and Norway

Copyright 2003 The Medicine Publishing Company Ltd

Contraception in Adolescence
and the Perimenopause
Kate Weaver is a Staff Grade Doctor in Family Planning and Reproductive Healthcare.
She qualified from the University of Edinburgh, and is currently training in family
planning and reproductive health care. Her research interest is contraceptive
development.
Most women are particularly keen to avoid pregnancy at the extremes of reproductive
life. Factors other than contraceptive efficacy often determine the choice of
contraceptive; for example, side-effects such as weight gain can deter adolescents
from effective contraceptive options, whereas women in the perimenopause often
welcome side-effects such as amenorrhea.

Adolescence

It often seems difficult for teenagers to use contraception effectively. The ideal method
would be effective, convenient, discreet, safe, free of side-effects and protective against
sexually transmitted infections (STIs). Achieving this is a challenge, requiring accessible
services and often a combination of methods.
It is good practice to suggest that adolescents discuss sexuality with a parent.
However, adolescents must be assured they have the same right to confidentiality as
adults. Adolescents can consent to treatment (including contraception and abortion)
if they understand that treatment and its implications.
Adolescents need to know about STIs and their potential risks to fertility and health,
and need help to find contraceptive strategies that minimize the dangers. Dedicated
young peoples clinics are more acceptable and effective than general family planning
clinics. Contraceptive consultations need not be unduly medicalized. Blood pressure
should be monitored in pill-users, but other examinations or investigations are
performed only when indicated. Cervical smears are seldom indicated in teenagers.

Choice of method

Combined oral contraceptive pill is popular, and is reliable in those who use it
carefully. Adolescents need to know what to do about missed pills and other factors that
reduce the efficacy of this method, and need ready access to condoms and emergency
contraception.
Few adolescents have medical contraindications to the pill; more worrying to most
users are minor side-effects such as weight gain and acne. The pill will not be used
well (or at all) if these side-effects are unacceptable. These concerns must be handled
sympathetically. Third-generation pills (see page 1) are more skin-friendly, and patient
preference outweighs any small increased risk of venous thromboembolism. Dianette
is sometimes used for effective contraception with beneficial effects on acne.
Third-generation pills can usually be satisfactorily substituted after a year or two.
Injectable progestogen-only contraception is often a good option because it does
not have to be taken daily. It is important to discuss possible side-effects, which can
be slow to resolve. Weight gain is often feared, but is not inevitable. Amenorrhoea is
common and often welcome, but is not acceptable to all users many adolescents (and
their mothers) value regular periods to confirm that they are not pregnant.
Reduced bone mass is a theoretical concern. Women reach peak bone mass in
their 20s, and might not achieve this if they are hypo-oestrogenic on Depo-Provera for
a prolonged period in adolescence. There is evidence that the rate of accumulation of
bone mass is reduced, but the clinical consequences, if any, are unknown. This is
not a contraindication to the use of Depo-Provera in adolescents, but the method is
probably best avoided in young women with other risk factors for osteoporosis such
as weight loss-related amenorrhoea or exposure to corticosteroids (e.g. for juvenile
rheumatoid arthritis).
Progestogen-only contraceptive implant: insertion of Implanon causes initial
bruising, but the rod is unobtrusive. It produces anovulation, but ovarian activity
remains sufficient to maintain physiological oestrogen levels and therefore should not
have any detrimental effect on bone mass. The possibility of menstrual irregularity or
amenorrhoea must be discussed with the patient.

Progestogen-only pill (mini-pill) is usually unsuitable in adolescents because it

requires careful compliance with regular pill-taking, and the failure rate is relatively high.
Barrier methods: condoms should always be considered, as part of a strategy to
prevent both pregnancy and STIs. Adolescents must be taught how to use condoms
correctly, and the local availability of emergency contraception should be discussed, in
case of condom failure.
Diaphragms are often unacceptable to young women, and have a high failure rate.
IUD: the copper IUD is a reliable, user-independent method. It is not an ideal choice
for many adolescents, but is not absolutely contraindicated. Concerns about facilitating
ascent of STIs with subsequent pelvic infection have probably been exaggerated.
However, in contrast, barrier methods confer protection, and even hormonal methods
thicken the cervical mucus, giving some protection against ascending infection.
Insertion of the IUD in young, nulliparous women may be problematic because the
uterus is small. Pre-existing infection may be spread at time of insertion, and
pre-insertion screening for Chlamydia is prudent.
Periodic abstinence and natural family planning: all these methods (including
Persona, see page 14) have very high failure rates. The demands of periodic
abstinence are best met by settled couples who are committed to using the method
together. They provide no protection against STIs.
Emergency contraception: progestogen-only emergency contraception is the
first-choice method; it has fewer side-effects and is comparable in efficacy to
combined hormonal methods. The IUD is not a popular choice, but is very effective
when inserted up to 5 days after the likely date of ovulation (e.g. day 19 of a regular
28-day cycle). It is prudent to screen for Chlamydia and to give prophylactic antibiotics
before insertion. The IUD can be removed at the next period. If the patient decides to
keep it, the importance of safe sex must be emphasized.
There is no limit to the frequency or number of times that hormonal emergency
contraception can be safely used. Consultations for emergency contraception are an
opportunity to promote more reliable contraception and safe sex, but it is important not
to make the adolescent feel irresponsible.

Perimenopause

In this period of fluctuating ovarian activity, many women experience 2 or 3 years

of menstrual disruption, and the physical and emotional symptoms associated with
decreasing oestrogen levels. Fertility is declining, but unexpected pregnancy remains
a possibility. Lifestyle and contraceptive choice may have become settled, but there
may be medical reasons or personal reasons (e.g. a new relationship) to change a
long-standing method. The issue of STI protection may seem less important, but
cannot be neglected.
Contraceptive hormones can be used to control the immediate symptoms of the
perimenopause, particularly menstrual disruption. Contraceptive decisions also begin
to involve issues such as hormone replacement therapy (HRT) and post-menopausal
health concerns, including osteoporosis and breast cancer.

When to stop contraception

By convention, if a woman has her last spontaneous period before 50 years of age,
she should continue to use contraception until she has remained amenorrhoeic for
2 years. If her last spontaneous period occurs after 50 years, she should continue
to use contraception until she has been amenorrhoeic for 1 year. The latest natural
conception recorded in the UK was in a woman aged 54 years.

Choice of method

Combined oral contraceptive pill: by this age, some women have cardiovascular
contraindications to combined oral contraception, but healthy, migraine-free
non-smokers may use the method up to the age of 50 years. There are considerable
benefits manageable bleeding pattern, bone protection and control of many
gynaecological conditions. However, the risk of breast cancer (Figure 1) demands
careful discussion. The relative risk of breast cancer in all pill-users is 1.24, decreasing
to the population risk (that of never-users) over 10 years after stopping the pill. The
absolute risk is multiplied by a higher background risk in older women. There is no good
evidence that a family history of breast cancer further multiplies the risk.

Excess cases of breast cancer associated with 5 years combined oral

contraceptive use
300

Estimated number of cases

(per 10,000 women)

Never took combined oral contraceptive

262

Used combined oral contraceptive for 5 years

230

200

181
160

100

100

48.7

44

4.5

4
0

< 20

16

111

17.5

2024

2529

3034

3539

4044

50

55

Took the pill at age (years)

30

35

40

45

Cancer found up to age (years)

Source: Curr Prob Pharmacovigilance 1998; 24: 2 3.

1
Menopausal status cannot be determined in women taking the combined pill.
Commonly, women change to barrier methods or the progestogen-only pill at the age
of 50 years and monitor their menopausal symptoms or have their gonadotrophin levels
checked.
Progestogen-only pill: many women change to this method when the combined
pill becomes contraindicated. In older women, the contraceptive reliability of the
progestogen-only pill approaches that of the combined pill, and a settled lifestyle often
allows more reliable pill-taking. The bleeding pattern is unpredictable, but amenorrhea
is perhaps more likely, implying anovulation and greater efficacy. Menopausal status
can be assessed without stopping the progestogen-only pill. Beyond the age
of 50 years, follicle-stimulating hormone levels above 30 IU/ml on two occasions
1 year apart confirm that the menopause is over and contraception can be stopped.
Alternatively, the progestogen-only pill can be continued until the age of 55 years, when
all contraception can be safely stopped. Another advantage is that women can take
cyclical HRT while using this method.
Depo-Provera is a highly reliable contraceptive with few contraindications, but there
are concerns that profound ovarian suppression can lead to hypo-oestrogenism
in perimenopausal women. A minority of women exhibit bone loss, and there is
(unsubstantiated) concern about increased risk of osteoporotic fractures in later life.
Insufficient data exist to establish firm guidelines, but it is probably sensible to change
to another method after the age of 45 years, to allow endogenous oestrogen levels to
rise and restore bone mass.
Progestogen-only contraceptive implant: this low-dose progestogen-only method is
suitable in women of any age who desire long-term contraception. Women who use it
are anovulatory, but oestrogen levels are in the normal range.
Barrier methods: condom use is prudent whenever there is a risk of STI. Condoms
are a reasonably reliable contraceptive method, and experienced couples are less likely
to have accidents. Emergency contraception is a safe option when such accidents
occur.
Caps and diaphragms are not the most reliable of methods but can give acceptable
contraceptive protection in women with declining natural fertility. Vaginal dryness in
the perimenopause may make insertion of these devices unpleasant, but the use of
spermicide may provide welcome extra lubrication during intercourse.
IUD: an IUD inserted after the age of 40 years remains reliable until after the
menopause. The main concern is possible menorrhagia.

In women with pre-existing menorrhagia, the hormone-releasing intrauterine system

(IUS) is an excellent option. Most users experience lighter bleeding or amenorrhea,
but some exchange predictable heavy periods for unpredictable frequent spotting,
and careful discussion of possible bleeding patterns is important. Suspicious bleeding
patterns must always be investigated, regardless of the presence of an IUS.
The efficacy of the IUS is comparable with that of sterilization, and this should be
mentioned to couples who are seeking sterilization.
Sterilization is popular in older couples. Vasectomy is safer and more reliable than
female sterilization and has a lower failure rate.
Natural family planning methods become even less reliable with the irregular cycles
of the perimenopause.

REFERENCES

Clements S, Stone N, Diamond I, Ingham R. Modelling the Spatial Distribution of

Teenage Conception Rates within Wessex. Br J Fam Plann 1998; 24: 6171.
Collaborative Group on Hormonal Factors in Breast Cancer. Breast Cancer and
Hormonal Contraceptives: Collaborative Reanalysis of Individual Data of 53,297
Women with Breast Cancer and 100,239 Women without Breast Cancer from
54 Epidemiological Studies. Lancet 1996; 347: 171327.
WHO. Cardiovascular Disease and Steroid Hormone Contraception. Report of a
Scientific Group. WHO Tech Rep Ser 1998; 877.

FURTHER READING

Glasier A, Gebbie A. Handbook of Family Planning and Reproductive Healthcare.

4th ed. Edinburgh: Churchill Livingstone, 2000.
(Includes chapters on broader aspects of the menopause and adolescent
reproductive health.)
Grimes D A. Intrauterine Device and Upper Genital Tract Infection. Lancet 2000;
356: 101319.
(A review of the quality of evidence linking the IUD with upper genital tract infection.)
Kane R, Wellings K. Reducing the Rate of Teenage Conceptions. An International
Review of the Evidence: Data from Europe. London: Health Education Authority,
1999.
(Comparative data on teenage pregnancy and possible associated factors across
Europe.)
Killick S, ed. Contraception in Practice. London: Martin Dunitz, 2000.
Meirik O. Hormonal Contraception and Bone Mass. IPPF Med Bull 2000; 34(5): 12.
(Evidence linking bone mass with hormonal contraceptives.)

Practice points

At all ages, it is important to discuss safe sex and to find strategies that
combine protection against pregnancy with protection from STIs
Contraception is often as much a lifestyle choice as a medical decision, and
women of all ages must be helped to make their own choice of method
Dedicated contraceptive services for young people are effective; adolescents
value confidentiality, discretion and respect for their views
In the perimenopause, contraceptive hormones often have therapeutic sideeffects, particularly on menstrual dysfunction

Copyright 2003 The Medicine Publishing Company Ltd

Infertility: Introduction
Anthony J Rutherford is Consultant Gynaecologist and Director of Reproductive
Medicine at Leeds General Infirmary, Leeds, UK. He qualified from the University of
London, and trained in reproductive medicine at the Hammersmith Hospital, London.
His research interests include preservation of fertility in cancer patients, in vitro
maturation of oocytes and pre-implantation genetic diagnosis.
Osama H Salha is a Subspecialist Trainee in Reproductive Medicine at Leeds
General Infirmary and St Jamess University Hospital, Leeds, UK. He qualified in
Ireland, and trained in obstetrics and gynaecology at the Hammersmith Hospital,
London, UK. His research interests include cryopreservation and in vitro maturation
of oocytes.
Infertility is best defined as an inability to conceive after 1 year of unprotected
intercourse. About 1/6 couples seek specialist help at some time in their reproductive
lives because of difficulty conceiving; the numbers trying for first and second
pregnancies are almost equal. There is no evidence for an increase in the prevalence
of infertility, but the number of couples seeking help has increased greatly during the
last decade because they are aware that effective treatment is now available.

Normal fertility

Normal human fertility is relatively poor. The average monthly likelihood of conception
in healthy couples of proven fertility is only 2025%; 10% of fertile couples fail to
conceive in the first year of trying, and 5% after 2 years. Thus, it is important to
appreciate that effective treatments can be expected to achieve pregnancy rates of only
2530% per cycle, and it may be necessary to repeat treatment several times before
success is achieved.

Causes of infertility

Any of the key requirements for conception can fail:

ovulation
oocyte uptake and transport by the fallopian tubes
timed coital delivery of sperm
sperm motility (to reach the fallopian tubes)
fertilization (in the fallopian tube)
uterine receptivity and implantation of the embryo.
Disorders of ovulation are discussed on page 28, other female causes of infertility on
page 34, and male infertility on page 23.

Compounding variables

Age has a profound effect on the fertility of women; fertility begins to decrease in
the early 30s, and decreases more rapidly from the age of 37 years. This is related to
a reduction in the pool of oocytes available for selection and the quality of the oocyte
released. This effect can most readily be seen in women treated with donor sperm, in
whom the live birth rate per cycle of treatment decreases from 1012% in women under
30 years of age, to 34% in those over 40 years.
Sperm counts may decrease with age, but male fertility does not seem to be
appreciably affected.
Weight in women, body mass can have a significant effect on fertility.
Underweight women can lose their menstrual cycles completely, and even if ovulation
is restored, the risk of pregnancy loss is increased if their weight is not corrected.
Over-exercising can have a similar effect. Obese women respond less well to most
fertility treatments, and the risk of early pregnancy loss is increased.
Smoking and alcohol cigarette smoking can dramatically reduce a womans
natural fertility some studies suggest a reduction of 22% in women who smoke
more than one packet per day. Alcohol also appears to affect female fertility in a
dose-dependent manner; those who drink more than 10 units per week are less likely to
conceive than those who drink 5 units per week or less.
Lifestyle factors sperm count can be reduced in men who wear tight underpants
or take very hot baths or showers factors that cause testicular hyperthermia.
Reproductive history women who have already had a pregnancy are almost
twice as likely to conceive again as those who have never been pregnant.

Investigation of infertile couples

All the key functional requirements for conception must be investigated. The couple
should be seen together, and investigations should be undertaken within the framework
of a locally developed guideline. Figure 1 lists tests that could be arranged in primary
care and those that should be reserved for secondary care. Secondary care should be
undertaken in a dedicated infertility clinic with an appropriately trained multidisciplinary
team. Written information should be readily available to supplement the advice given
during the consultation.

Investigations in primary and secondary care

Primary care
Women
General screening tests
Cervical smear
Cervical swab for Chlamydia antigen
Rubella antibodies
Specific infertility tests
Mid-luteal phase progesterone
Early follicular phase (days 15)
Follicle-stimulating hormone
Luteinizing hormone
Estradiol
Women with oligomenorrhoea/amenorrhoea (cycle absent or > 6 weeks)
Prolactin
Testosterone
Thyroid function tests
Men
Semen analysis x 2
Secondary care
Women
Tubal patency
Hysterosalpingography
Laparoscopy with dye insufflation
Selective hysterosalpingography
Women with oligomenorrhoea/amenorrhoea (cycle absent or > 6 weeks)
Ovarian ultrasonography
Men
Follicle-stimulating hormone
Men with oligospermia/azoospermia
Luteinizing hormone
Karyotype
Testosterone
1
Diagnoses of infertility
Seminal defect
22%
Tubal defect
17%
Unexplained
14%
Ovulation defect
30%
Other disorder
12%
Endometriosis
5%
Source: Taylor P J, Collins J A. Unexplained Infertility. Oxford: Oxford
University Press, 1993.

History

A detailed history should be taken from both partners, with particular reference to the
duration of infertility, any previous pregnancies and their outcome, past contraceptive
use, coital frequency, the womans menstrual history, both partners medical and
surgical histories, and possible exposure to toxins and drugs (including a history of
smoking and assessment of alcohol intake). Occupation is also relevant.

Examination

During physical examination of the female partner, attention should be paid to signs of
endocrine disturbance such as galactorrhoea and hirsutism. Weight and height should
be recorded and body mass index (kg/m2) calculated. Pelvic examination should be
performed, looking for uterine abnormalities, ovarian and tubal masses, uterosacral
nodularity, pelvic organ mobility, and the presence of pain. Cervical swabs should be
taken for Chlamydia. Examination of the male partner is required only when the history
suggests pathology or semen analysis is abnormal.

Investigations

Women: a history of regular menstrual cycles is consistent with ovulation. This can
be confirmed by measuring luteal phase serum progesterone in samples taken 710
days pre-menstrually. Many clinics advocate measurement of early follicular phase
follicle-stimulating hormone levels, usually in combination with luteinizing hormone and
estradiol, to obtain an assessment of the number of recruitable follicles present in the
ovaries. There is evidence that this test is valuable in scheduling super-ovulation as part
of in vitro fertilization, but its usefulness in the routine assessment of infertile couples
remains to be confirmed. Pelvic ultrasonography should be performed to substantiate a
diagnosis of polycystic ovary syndrome and to exclude ovarian and adnexal cysts.
In women with a clearly defined cause of infertility unrelated to tubal disease and/or
in whom the suspicion of abnormality is low, hysterosalpingography (injection of a
non-irritant radiopaque material through the cervix into the uterus and fallopian tubes)
can be used to confirm tubal patency. However, the gold-standard investigation of
the pelvis is laparoscopy and the dye test, in which methylene blue dye is injected
through the cervix, and visualized filling and spilling from the fimbrial end of the
tubes. In addition to confirming tubal patency, this technique has the advantage of
identifying the presence of endometriosis or intrapelvic adhesions, which can often be
treated effectively at the time of the diagnostic procedure. A senior surgeon, who can
accurately grade the severity of the tubal damage or endometriosis, should perform the
laparoscopy.
Investigations not considered of routine value in the assessment include a
post-coital test, serum prolactin, and invasive procedures such as hysteroscopy and
endometrial biopsy.
Men: as discussed on page 25, two fresh semen samples taken at least 1 month
apart should be assessed in an accredited laboratory and the results expressed in
the standard WHO format, including ejaculate volume, sperm count and motility, rate
of progression, and the proportion of abnormal forms. More complex evaluation is
necessary only when a discrete abnormality is suspected, and should be restricted to
patients referred to tertiary care.

Acknowledgement

We thank Mr Dickinson B Cowan, Medical Director of the Portland Hospital Fertility

Unit, London, UK, for reviewing the contributions to the infertility section of this
issue of MEDICINE.

Copyright 2003 The Medicine Publishing Company Ltd

Male Infertility: Causes and Management

D Stewart Irvine is a Clinical Scientist in the MRC Human Reproductive Sciences
Unit and Honorary Consultant Obstetrician and Gynaecologist at the Royal Infirmary,
Edinburgh, UK. He qualified from the University of Edinburgh, and trained in Edinburgh
and Aberdeen. His research interests include male reproductive health, particularly
male infertility.
Infertility is a common problem affecting 1417% of couples, but it is difficult to
establish the relative contribution of the male partner because of difficulties in the
accurate diagnosis of male infertility. Most studies have used the conventional criteria of
semen quality promulgated by the WHO to define the male factor, but these criteria are
of limited diagnostic value. A significant proportion of men with semen of normal quality
are infertile because of defects in sperm function, and many with abnormal semen
have normal sperm function. Nevertheless, in many studies, male factor infertility is the
single most common diagnosis.

Causes of male infertility

The WHO has proposed a scheme for the classification of male infertility (Figure 1).
This approach is valuable as a basis for standardization and for comparative
multi-centre studies, but many of the categories are descriptive (e.g. idiopathic
oligozoospermia) or of controversial clinical relevance (e.g. male accessory gland
infection, varicocele). Furthermore, recent advances in understanding of the causes of
male infertility, particularly genetic problems, mean that this classification may already
require review.

Diagnostic categories of male causes of infertility

Sexual and/or ejaculatory dysfunction

Immunological cause
No demonstrable cause
Isolated seminal plasma abnormalities
Iatrogenic cause
Systemic cause
Congenital abnormalities
Acquired testicular damage
Varicocele
Male accessory gland infection
Endocrine cause
Idiopathic oligozoospermia
Idiopathic asthenozoospermia
Idiopathic teratozoospermia
Idiopathic cryptozoospermia
Obstructive azoospermia
Idiopathic azoospermia

Source: Rowe P J, Comhaire F H, Hargreave T B,

Mahmoud A M A. WHO Manual for the Standardized Investigation and Diagnosis and
Management of the Infertile Male. Cambridge:
Cambridge University Press, 2000; Rowe P J, Comhaire F H, Hargreave T B, Mellows
H J. WHO Manual for the Standardized Investigation and Diagnosis of the Infertile
Couple. Cambridge: Cambridge University Press, 1993.

Genetic causes

Traditionally, genetic causes of male infertility have been sought at the level of
chromosomal abnormalities, which are detected in 2.18.9% of men attending infertility
clinics. The prevalence of chromosomal abnormalities increases with lower sperm
concentrations; abnormal karyotypes are found in about 15% of azoospermic men
(mainly Klinefelters syndrome, 47XXY), but in only about 4% of oligozoospermic
patients. More recent studies have defined a family of genes on the Y chromosome that

are involved in spermatogenesis (including RBM, DAZ, DFFRY, DBY and CDY), and it
has become clear that about 10% of cases of non-obstructive azoospermia may result
from deletions affecting these genes.

Cryptorchidism

Undescended testes is presumed to have an intrauterine origin. It is significantly

associated with an increased risk of impaired spermatogenesis in later life, and with an
increased risk of testis cancer. Testes that are not situated in a low scrotal position by
the age of 2 years are histologically abnormal; spontaneous descent seldom occurs
after 1 year, and there is little evidence that surgical orchidopexy after 2 years of age
improves fertility. For these reasons, treatment should ideally be undertaken at age
12 years.

Orchitis

Symptomatic mumps orchitis is a complication in 2730% of males who suffer mumps

after the age of 1011 years. In 17% of cases, the orchitis is bilateral, and seminiferous
tubular atrophy is a common sequel. The prevalence of infertility after mumps orchitis is
unknown, but fertility should be significantly impaired only when the orchitis is bilateral
and occurs after puberty.

Varicocele

Diagnosis of varicosity of the pampiniform plexus (varicocele) is not difficult

when the patient is examined in a standing position. The condition may be visible
(grade 3), palpable (grade 2) or subclinical (grade 1, detected only during the
Valsalva manoeuvre). Prevalences of 525% have been reported in surveys of
healthy men, but varicocele affects 11% of men with normal semen, and 25% of
men with abnormal semen attending infertility clinics. However, it has been difficult
to establish with certainty whether varicocele affects spermatogenesis, and whether
treatment of varicocele improves fertility. It seems clear that varicocele is associated
with abnormal semen quality, and most appropriately designed controlled studies
suggest that treatment is associated with an improvement in semen quality. However,
when pregnancy is used as the end point, some studies find treatment to be effective
whereas others suggest it is of no benefit.

Occupational and environmental factors

Data on occupational hazards to male reproduction remain controversial. Exposure

to heavy metals such as cadmium, lead, arsenic and zinc has been reported to impair
spermatogenesis, though the data are conflicting. Certain pesticides and herbicides
and some organic chemicals have more clearly been shown to be toxic. There is
clear evidence that occupational or environmental exposure to heat adversely affects
spermatogenesis and prolongs time to pregnancy, but there is conflicting evidence that
wearing tight clothing has a significant effect. Recreational drugs such as cigarettes,
alcohol and cannabis have all been linked with lower semen quality.
There has been much recent data demonstrating that male reproductive health
is deteriorating, with evidence of a secular decline in semen quality and increased
incidences of congenital malformation of the male reproductive tract and testicular
cancer. It has been hypothesized that these changes may result from perinatal
exposure to environmental xenooestrogens, but there is currently no evidence that
these are affecting the prevalence of male infertility.

Iatrogenic infertility

Many general medical disorders are associated with male infertility directly
(e.g. Kartageners syndrome), indirectly as a consequence of systemic disturbance
(e.g. diabetes), or as a result of medical or surgical treatments. Some drugs can impair
sperm production; the most common example in clinical practice is sulfasalazine
administered for the treatment of inflammatory bowel diseases. Cytotoxic treatments
for cancer damage differentiating spermatogonia, and many patients become
azoospermic. Radiation exposure also destroys germ cells with little likelihood of
recovery. A dose of 14 Gy leads to complete cessation of spermatogenesis and only
some stem spermatogonia survive, though there may be some recovery after 1236
months. Doses above 6 Gy are sterilizing.

Genital tract obstruction

Azoospermia, normal testicular volume and normal follicle-stimulating hormone

(FSH) are the hallmarks of genital tract obstruction. Congenital and post-vasectomy

obstruction are most common, but in some parts of the world infectious causes
(particularly gonorrhea and tuberculosis) are of greater importance. Of the specific
congenital abnormalities, the most common is agenesis or malformation of the
corpus/cauda epididymis, vas deferens or seminal vesicles. Congenital bilateral
absence of the vas deferens is associated with CFTR mutations and is found in about
2% of men with obstructive azoospermia.

Male accessory gland infection

Infection in the lower genital tract can be a treatable cause of male infertility. It is clear
that symptomatic sexually transmitted infections, particularly those causing epididymitis
or orchitis, may damage male fertility, but there is doubt about the relevance of
subclinical infection; there is little consensus on diagnostic criteria, and little evidence to
support a genuine role for occult infections in male infertility. There is thus no place for
microbiological screening investigations unless there is clinical suspicion of infection.

Immunological causes

Immunological infertility is suspected in 3% of couples, on the basis of the finding

(using assays such as the immunobead test and the mixed antiglobulin reaction) that
10% or more of motile spermatozoa are coated with antibody. The effect on fertility is
difficult to determine. Some studies suggest that antibody-positive couples conceive at
a lower rate than those without immunological problems. However, antibodies to sperm
surface antigens are also found in fertile control populations, and current techniques do
not permit clear selection of couples with autoimmunity to epitopes which are critical to
the process of fertilization in vivo.

Gonadotrophin deficiency

Secondary testicular failure as a result of gonadotrophin deficiency is rare. Recognition

of this condition is important because it is the only category of male infertility that is
consistently treatable by hormone replacement. The diagnosis is prompted by clinical
evidence of androgen deficiency, and confirmed by low or undetectable levels of
gonadotrophin associated with subnormal testosterone.

Coital disorders

Inadequate coital technique (including use of vaginal lubricants with spermicidal

properties) and frequency, and faulty timing of intercourse, may contribute to infertility
but are seldom the only factor. Erectile and ejaculatory failure may occur as a result
of psychosexual dysfunction, depression, spinal cord injuries, retroperitoneal or
bladder neck surgery, diabetes mellitus, multiple sclerosis, vascular insufficiency,
adrenergic-blocking antihypertensive agents, psychotropic drugs, alcohol abuse
or chronic renal failure. Primary endocrine disorders such as androgen deficiency,
hyperprolactinaemia and hypothyroidism seldom present with infertility without
diminished libido and clinical features specific to the hormonal disturbance.

Idiopathic impairment of semen quality

This descriptive label continues to be required for a substantial proportion of men

attending infertility clinics. Failure of seminiferous tubular function to the extent
of azoospermia (no sperm in the ejaculate) or severe oligozoospermia (< 5 x 106
spermatozoa/ml) is usually associated with small (< 15 ml) and soft testes and
elevated FSH. Asthenozoospermia is the term applied to impaired sperm motility, and
teratozoospermia is used to describe altered morphology. Surface morphology directly
reflects the maturity and functional integrity of the spermatozoa, and morphological
analysis of ejaculated sperm is an important means of assessing spermatogenesis
in the testis. Some authorities believe that sperm morphology is the best predictor of
spontaneous fertility or the outcome of in vitro fertilization (IVF).

Investigation of the male partner

History and examination

The essence of clinical management of infertility is to assess the prognosis and to

advise the couple about treatments that should improve this. This advice is based on a
sound knowledge of the causes of infertility and the treatments available.
It is important to recognize that a number of factors influence couples fertility; for
example, the age of the female partner is a major determinant, and fertility is reduced
following a long period of infertility, even allowing for age. Recent advances in assisted
conception technology have revolutionized the management of couples with male

factor infertility, but have paradoxically encouraged a minimalist clinical approach to the
diagnosis of men with fertility problems, given the limited range of effective therapeutic
options. However, history and examination are important, and are summarized in
Figures 2 and 3.

Key features in the history of potentially infertile men

Primary or secondary infertility

Duration of infertility
Medical history diabetes, respiratory/neurological disease, cystic fibrosis
Medical treatment drug history
Recent (6 months) pyrexial illness
Previous surgery hypospadias, urethral strictures, prostate, bladder neck,
vasectomy, inguinal hernia
Urinary tract infection
Sexually transmitted infection syphilis, gonorrhoea, Chlamydia
Epididymitis
Pathology causing testicular damage orchitis, mumps orchitis, injury, torsion
Varicocele/treatment for varicocele
Cryptorchidism/treated cryptorchidism
Occupational/environmental factors heat, toxin exposure
Excess alcohol/drug abuse/tobacco

Source: Rowe P J, Comhaire F H, Hargreave T B,

Mahmoud A M A. WHO Manual for the Standardized Investigation and Diagnosis and
Management of the Infertile Male. Cambridge:
Cambridge University Press, 2000.

Key features in the physical examination of potentially infertile men

Height, weight, blood pressure

Signs of virilization hypoandrogenism
Gynaecomastia
Penis normal, scars, plaques, hypospadias
Testis palpable, location, normal
Testis volume reference range 1230 ml
Epididymis present, thickened, tender, cystic
Vas deferens present, thickened
Scrotal swelling hydrocele, hernia
Varicocele grade 1/2/31
Inguinal region lymph nodes, scars
Rectal examination2 prostate, seminal vesicles

Grade 1, detectable on Valsalva manoeuvre; grade 2, palpable; grade 3, visible and

palpable
2
If indicated by symptom
1

Source: Rowe P J, Comhaire F H, Hargreave T B, Mahmoud A M A. WHO Manual for

the Standardized Investigation and Diagnosis and Management of the Infertile Male.
Cambridge: Cambridge University Press, 2000.

Semen analysis

A standard semen analysis, performed according to WHO guidelines, provides

information about sperm number, motility and morphology, and the physical
characteristics of the ejaculate. It is important that the laboratory undertaking this
analysis is conversant with WHO methodology and participates in external quality
control. The key features of a WHO semen profile and recognized normal values are
listed in Figure 4.

Semen analysis: key features and commonly used criteria for normality
Parameter
Volume
pH
Sperm concentration
Total sperm count
Motility

Morphology
Viability
WBCs
Mixed antiglobulin
reaction
Immunobead test

Normal value
2.0 ml
7.2
6
20 x 106 spermatozoa/ml
40 x 10 spermatozoa per ejaculate
50% with forward progression or 25%
with rapid linear progression within 60 minutes
after collection
Not currently defined
75% or6 more live
< 1 x 10 /ml
< 50% motile spermatozoa
with adherent particles
< 50% motile spermatozoa with adherent
beads

Source: WHO. WHO Laboratory Manual for the Examination of Human Semen and SpermCervical Mucus Interaction. 4th ed. Cambridge: Cambridge University Press, 1999.

4
Two semen samples should be collected for initial evaluation, after a minimum
of 48 hours and not longer than 7 days sexual abstinence, and between 7 days
and 3 months apart, to take account of the effects of interejaculate variability and
duration of abstinence. The sample should be collected by masturbation into a clean,
wide-mouthed glass or non-toxic plastic container, and should be delivered to the
laboratory within 1 hour of collection if it is not possible for the patient to produce the
sample there.

Hormone measurements

In men with azoospermia or oligozoospermia, measurement of FSH is of value.

Elevated FSH, particularly with re-duced testicular volume, is evidence of severe
and usually irreversible seminiferous tubular damage. Low or undetectable FSH
(usually associated with low luteinizing hormone (LH) and testosterone, with clinical
evidence of androgen deficiency) is suggestive of hypogonadotrophism. Conversely,
azoospermia with normal FSH and normal testicular volume usually indicates genital
tract obstruction.
Testosterone and LH measurements are indicated when there is clinical suspicion of
androgen deficiency, sex steroid abuse or a steroid-secreting lesion.
Hyperprolactinaemia is not a common cause of male infertility, but prolactin should
be measured when there is clinical evidence of sexual dysfunction (particularly reduced
libido) or pituitary disease leading to secondary testicular failure.

Chromosome analysis

Chromosome karyotyping should be undertaken in patients with azoospermia or

severe oligospermia with reduced testicular volume and elevated FSH. Cytogenetic
abnormalities (most commonly Klinefelters syndrome) may be detected in about 10%
of this group, and are of importance if intracytoplasmic sperm injection (ICSI) is being
contemplated.

Testicular biopsy

With the use of plasma FSH to differentiate primary testicular failure and obstructive
lesions, the need for testicular biopsy in the investigation of male infertility has been
largely superseded, though it has a role in the surgical retrieval of sperm for ICSI.

Management of infertile men

Management of male infertility is often a difficult and unsatisfactory experience for

both patient and doctor. In many patients, there is no recognizable or reversible cause,
and doctors often fail to appreciate that normal semen values do not establish fertility.
However, there have been several recent advances in therapy, and it is therefore
important to attempt to improve semen quality and to treat factors that impair fertility.

General measures

Much has been written about the nature of the general advice that should be given, but
objective evidence for its efficacy is lacking. Commonly raised issues include avoidance
of stress, a healthy diet and exercise. Use of recreational drugs such as cannabis,
cigarette smoking and excessive alcohol consumption should be avoided, as should
situations that may chronically elevate testicular temperature. Medications that interfere
with fertility should be avoided if possible.

Medical treatment

It is important to note that empirical treatments for idiopathic oligozoospermia

(e.g. anti-oestrogens, androgens, bromocriptine) have not been shown to be
effective in the treatment of men with abnormal semen, and should not be used
in this situation.
Free radicals have a role in male infertility, but few centres measure these routinely
and there is no evidence that anti-oxidant treatments used on an empirical basis are
effective.
Endocrine treatment is effective only in the presence of specific endocrine
disturbances, which are rare.
Any infection of the male genital tract should be treated, but there is little evidence
that this improves fertility.
Antisperm antibodies may be a cause of male factor infertility, but the use of systemic
corticosteroids for treatment remains controversial and can be recommended only
in the context of further research the evidence of benefit is conflicting and there
are potentially serious side-effects. Commonly, treatment by assisted conception is
recommended.
Sexual problems inability of the man to achieve vaginal penetration and
ejaculation because of erectile difficulties may be overcome by various pharmacological
approaches. Options include the intracavernous agents papaverine and alprostadil,
and oral sildenafil. Absent emission or retrograde ejaculation caused by sympathetic
denervation may respond to sympathomimetic drugs.

Surgical treatment

Surgery on the male genital tract should be undertaken only in centres with appropriate
facilities and trained staff. Reversal of vasectomy is effective in men who want to
reverse their sterilization, and surgical correction of epididymal blockage can be
considered in obstructive azoospermia. Testicular biopsy should be performed only
where there are facilities for sperm recovery and cryostorage.
Varicocele treatment of varicocele remains controversial. When interpreting the
available evidence and deciding whether and when to treat, it is wise to remember that
many other factors affect couples fertility. There is no evidence that treating varicocele
is beneficial in men with semen of normal quality. Available evidence suggests that
such treatment in men with oligozoospermia improves semen quality, but it is unclear
whether this will result in pregnancy, probably because heterogeneous populations
have been studied. It is clear that there is no substantial benefit, and in many cases
(particularly when the female partner is > 35 years of age, the duration of the couples
infertility is prolonged or the deficit in semen quality is severe), assisted conception
techniques have more to offer.

Assisted conception and male infertility

Early developments in IVF focused on couples with female factor infertility, particularly
bilateral tubal occlusion. Conventional IVF rapidly became established as an effective
treatment in couples with tubal disease or unexplained infertility, but it soon became
apparent that it yielded poor pregnancy rates in couples with male factor infertility.
There was much discussion in the literature on the fine-tuning of IVF for such couples,
but management options for those with poor-quality semen remained limited until the
advent of effective micro-assisted fertilization, culminating in the introduction of ICSI
in 1992. This approach involves injection of a single spermatozoon directly into the
cytoplasm of the oocyte through the intact zona pellucida, and produces superior
results.
In the UK, all such treatments are licensed by the Human Fertilisation and
Embryology Authority (HFEA) under the terms of the Human Fertilisation and
Embryology Act (1990). The authoritys most recent annual report indicated that use of
ICSI has increased from 244 cycles/year in 1992/93, to more than 10,000 cycles/year
at present.

Glossary
Azoospermia
Oligozoospermia
Severe oligozoospermia
Asthenozoospermia
Teratozoospermia

No sperms in ejaculate
Low sperm count (< 20 x 106/ml)
Very low sperm count
(< 5 x 106/ml)
Poor sperm motility
(< 50% of sperms show
progressive motility)
Abnormal sperm morphology

ICSI with surgically retrieved spermatozoa: initially, clinical ICSI was used when
the male partner had substantially abnormal semen, but it was then applied to the
significant numbers of men who present with no sperm in their ejaculates.
In men with obstructive azoospermia, spermatozoa can be taken from the
epididymis by microsurgical or percutaneous epididymal sperm aspiration. In
non-obstructive azoospermia, sperm can be taken from the testis. Non-obstructive
azoospermia is a heterogeneous condition, and testicular histology reveals foci of
apparently normal spermatogenesis adjacent to seminiferous tubules devoid of germ
cells. Surgical sperm recovery from men with non-obstructive azoospermia has
become a routine part of clinical infertility practice, as has cryopreservation of
testis-derived spermatozoa.
There is interest in the possibility of using less mature cells (commonly elongating
or round spermatids) to achieve fertilization for men from whom mature spermatozoa
cannot be recovered. Animal models suggests that this may be a viable approach,
and there are a number of clinical case reports in the literature. At present, however,
uncertainties about the safety and efficacy of this approach confine its use to
clinical trials.
Success rates with ICSI: ICSI has become well established as an effective treatment
for couples with male factor infertility. In the last year for which data are available
(1998/99), the HFEA reported 10,630 cycles of ICSI and 23,254 cycles of IVF; thus,
31% of assisted conception treatments in the UK are for severe male factor infertility.
In the same year, the reported live birth rate with ICSI was 21.8% per cycle, compared
with 16.9% per cycle with IVF. The multiple birth rate with ICSI was high (> 25%), and
the age of the female partner was a major determinant of success (2025% per cycle in
women in their early 30s, < 5% per cycle in the over-40s).
Outcomes of ICSI: ICSI is effective, but is it safe? Directly injecting individual
spermatozoa into a mature oocyte bypasses the natural physiological processes
of normal sperm selection, raising concerns about the potential risk of congenital
malformations and genetic defects in children born after ICSI.
Several large cohort studies have been reported, and as the size of the database
of ICSI offspring increases, the available evidence on the short-term health of
these offspring is generally reassuring. However, it is important to appreciate the
important role of genetic factors in male subfertility, and the ability of ICSI to promote
transgenerational transmission of genetic defects causing gametogenic failure. The
significantly increased risk of chromosomal abnormalities in men with impaired semen
quality is easily managed by investigation and counselling before treatment. It is less
easy to respond to the available evidence on microdeletions of the Y chromosome in
men with severely impaired semen quality.

REFERENCES AND FURTHER READING

Campbell A J, Irvine D S. Male Infertility and Intracytoplasmic Sperm Injection (ICSI).

Br Med Bull 2000; 56(3): 61629.
Hargreave T B. Genetics and Male Infertility. Curr Opin Obstet Gynaecol 2000;
12: 20719.
Irvine D S. Male Reproductive Health: Cause for Concern? Andrologia 2000;
32: 195208.
Rowe P J, Comhaire F H, Hargreave T B, Mahmoud A M A. WHO Manual for the
Standardized Investigation and Diagnosis and Management of the Infertile Male.
Cambridge: Cambridge University Press, 2000.

Rowe P J, Comhaire F H, Hargreave T B, Mellows H J. WHO Manual for the

Standardized Investigation and Diagnosis of the Infertile Couple. Cambridge:
Cambridge University Press, 1993.
Royal College of Obstetricians and Gynaecologists. The Initial Investigation and
Management of the Infertile Couple. 1998, 2001. www.rcog.org.uk/
Royal College of Obstetricians and Gynaecologists. The Management of Infertility in
Tertiary Care. 1999, 2001. www.rcog.org.uk/guidelines/tertiary.html
Royal College of Obstetricians and Gynaecologists. The Management of Infertility in
Secondary Care. 2000, 2001. www.rcog.org.uk/guidelines/secondary.html
Templeton A. Infertility and the Establishment of Pregnancy Overview. Br Med Bull
2000; 56(3): 57787.
Templeton A, Morris J K, Parslow W. Factors that Affect Outcome of in-vitro Fertilisation
Treatment. Lancet 1996; 348: 14026.
WHO. WHO Laboratory Manual for the Examination of Human Semen and
Sperm-Cervical Mucus Interaction. 4th ed. Cambridge: Cambridge University
Press, 1999.
WHO. The Influence of Varicocele on Parameters of Fertility in a Large Group of Men
Presenting to Infertility Clinics. Fertil Steril 1992; 57: 128993.

Copyright 2003 The Medicine Publishing Company Ltd

Disorders of Ovulation and their

Management
Susan Ingamells is Subspeciality Registrar in Reproductive Medicine at the Princess
Anne Hospital, Southampton, UK. She qualified from the University of Southampton,
and trained in obstetrics and gynaecology in Southampton and Salisbury.
Iain T Cameron is Head of the Department of Obstetrics and Gynaecology at the
University of Southampton, UK. He qualified from the University of Edinburgh,
and trained in obstetrics, gynaecology and reproductive medicine in Edinburgh, in
Melbourne, Australia, and in Cambridge, UK.
A regular ovulatory menstrual cycle requires a functional and integrated feedback
system involving the hypothalamus, the anterior pituitary and the ovary (Figure 1).
In the normal menstrual cycle, periods occur at regular intervals of 2135 days
and bleeding lasts for up to 7 days. Disorders of ovulation usually cause menstrual
disturbance and present with irregular periods (oligomenorrhoea) or absent periods
(amenorrhoea). These disorders account for one-quarter of couples presenting with
infertility. Anovulation may be classified by the anatomical location of the defect in the
hypothalamopituitaryovarian axis (Figure 2).
The hypothalamopituitaryovarian axis
Hypothalamus

Gonadotrophin-releasing
hormone

Pituitary
Folliclestimulating
hormone

Luteinizing
hormone

Progesterone
Estradiol

Ovary

Inhibin
Androgens

Anatomical classification of anovulation

Hypothalamic
Functional (weight loss, exercise)
Drugs
Tumours (e.g. craniopharyngioma)
Kallmanns syndrome
Pituitary
Hypopituitarism (e.g. Sheehans syndrome)
Tumours (adenoma, prolactinoma)
Ovary
Polycystic ovary syndrome
Ovarian failure (genetic, autoimmune, chemotherapy, viruses)
Others
Adrenal hyperplasia
2

Normal ovulation

At the time of puberty, the human ovary contains about 400,000 germ cells in the form
of primordial follicles. Follicle-stimulating hormone (FSH), which is released from the
anterior pituitary in response to pulses of gonadotrophin-releasing hormone (GnRH)
from the hypothalamus, promotes the development of Graaffian follicles from the pool
of primordial follicles.
The process of follicular development and differentiation lasts several months, but
by the start of each menstrual cycle a cohort of FSH-sensitive antral follicles is present.
Normally, only one of these recruited follicles is selected to become the dominant
pre-ovulatory follicle (Figure 3). The dominant follicle ruptures and releases the oocyte
(ovulation) in response to the mid-cycle surge of luteinizing hormone (LH) from the
pituitary. Inhibin is involved in both intra-ovarian paracrine signalling and in regulating
suppression of FSH during the late follicular and luteal phases of the ovarian cycle.

Folliculogenesis
Initiation

Selection

Ovulation

Pre-ovulatory

Ovulatory

20

10

Months

Early antral

Secondary

Primary

Primordial

25 days

Antral

Follicle diameter (mm)

15

45 days

15 days

Time
Source: Gougeon A. Endocr Rev 1996; 17: 28598.

History and examination

Gynaecological history: the menstrual pattern provides information about ovarian

activity because endometrial proliferation and shedding occur in response to steroids
produced by the ovary. If menstruation is absent, it is important to record whether the
amenorrhoea is primary or secondary (secondary amenorrhoea implies past exposure
of the endometrium to sex steroids and a previously patent outflow tract), and whether
there are any associated hot flushes. Hot flushes usually occur only following ovarian
failure in women who have previously been exposed to oestrogens. The patient should
be asked specifically about galactorrhoea, hirsutism and acne.
Details of recent weight change and exercise history should be obtained and any
psychological stress identified. A positive family history of autoimmune disease and
endocrine disorders such as Hashimotos thyroiditis may be relevant. Psychotrophic
drugs including phenothiazines, and reserpine and some recreational drugs are known
to interfere with hypothalamopituitary function.
Examination: particular note should be made of the body mass index (BMI),
secondary sexual characteristics and the presence of galactorrhoea. Development
of breasts and normal female body contours results from production of estradiol by
developing follicles in the ovaries of pubertal girls. Adrenal androgens are responsible
for pubic and axillary hair growth. A pelvic examination should exclude significant
abnormalities of the genital tract.

Laboratory and diagnostic assessment

In women with oligomenorrhoea or amenorrhoea, an endocrine profile should be

obtained to assess the serum concentration of FSH, LH, thyroid-stimulating hormone,
prolactin, estradiol and testosterone. Ultrasonography can confirm whether the
pelvic organs are normal. Karyotype should be determined in women with primary
amenorrhoea, and in those with an abnormal phenotype. MRI or CT of the pituitary
fossa should be performed in women with hyperprolactinaemia, to identify pituitary
tumours.
Oestrogenic status can be assessed by three further means:
clinical examination of the lower genital tract (including the presence of cervical and
vaginal secretions)
ultrasound measurement of endometrium thickness
progestogen challenge.
When a progestogen (e.g. medroxyprogesterone acetate, 10 mg b.d. for 7 days) is
administered to women with sufficient endogenous oestrogen to cause endometrial
proliferation, withdrawal of the progestogen results in endometrial shedding and vaginal
bleeding. If the woman is hypo-oestrogenic, a withdrawal bleed does not occur.
Assessment of oestrogen status has practical importance, because women who are
hypo-oestrogenic are unlikely to respond to induction of ovulation with anti-oestrogens
such as clomiphene citrate (see below).

Detection of ovulation

Women with regular, monthly menstrual cycles usually ovulate on a regular basis. Some
women experience pain at ovulation (mittelschmerz) and others are aware of typical
mid-cycle changes in their cervical mucus.
Presumed ovulation is often assessed biochemically by measuring the circulating
concentration of progesterone in the mid-luteal phase of the cycle. It is crucial that this
test is timed 7 (510) days before the next period, rather than 21 days after the last
period, to take account of variations in cycle length and to avoid an incorrect diagnosis
of anovulation.
Ultrasonography can also be used to track the growth and collapse of the dominant
follicle. Daily measurement of basal body temperature is not always a reliable marker of
ovulation. Urinary LH kits (available from pharmacies) can also be used.

Disorders of ovulation
Ovarian

Polycystic ovary syndrome (PCOS) accounts for 80% of women who present with
oligomenorrhoea or amenorrhoea, and is the most common cause of anovulatory
infertility. It produces a range of symptoms that may occur singly or in combination,
including menstrual cycle disturbances, obesity, hirsutism (including male pattern
hair loss, Figure 4), acne and infertility. Diagnosis of PCOS is based on the
clinical picture, supported in some women by biochemical abnormalities (low sex
hormone-binding globulin (SHBG) and raised androgen and LH) and/or polycystic
ovaries on ultrasonography (increased number of subcapsular follicles 28 mm in
diameter, in an enlarged ovary with a dense stroma, Figure 5).

4 Male pattern balding in a woman with

polycystic ovary syndrome.
(Reproduced by permission of Professor
S Franks and the Department of Audiovisual
Services, Imperial College School of
Medicine, London, UK.)

5 Ultrasound scan of a polycystic

ovary showing multiple small
peripheral follicles and dense stroma.

The precise pathogenesis of PCOS remains uncertain, but the intra-ovarian and
extra-ovarian abnormalities suggest both dysregulation of the relationship between
the hypothalamus, pituitary and ovary, and a disorder of ovarian folliculogenesis,
leading to failure to produce a dominant follicle. Additional extra-ovarian abnormalities
observed in some individuals are adrenal hyperactivity, dysregulation of pituitary growth
hormone and prolactin secretion, and changes in liver function. Hyperandrogenaemia
appears to be important in preventing normal folliculogenesis a reduction in the
circulating concentration of free androgen is often associated with improvement in
menstrual cyclicity and ovulation. However, in some women, a condition of excessive
insulin secretion resulting in insulin resistance underlies these abnormalities.
Hyperinsulinaemia in women with PCOS appears to be associated with an increased
risk of type 2 diabetes and ischaemic heart disease in later life.
Ageing: the number of oocytes in the gonad decreases from 12 million at 20 weeks
gestation, to 400,000 at puberty, to only 10,000 by the age of 37 years. With further
reductions in oocyte number, pregnancy rates decrease, and when only 1000 oocytes
remain, menstrual regularity is lost and ovulation becomes infrequent. The circulating
FSH concentration rises gradually in the 5 years preceding the menopause, and this
has been used as a crude marker of the biological age of the ovary, or of the likely
ovarian responsiveness to stimulation. Inhibin B (the predominant form of inhibin in
the pre-ovulatory follicle) has been suggested as an alternative marker of ovarian age,
because low concentrations of inhibin B are observed in women with depleted ovarian
reserve.
Ovarian failure is characterized by amenorrhoea, raised FSH and low estradiol
concentrations. Premature ovarian failure is defined as amenorrhoea for 6 months
or more before the age of 40 years, in association with increased gonadotrophin
concentrations. This condition is seen in 1% of the female population. Unexplained
ovarian failure may be a consequence of the development of a reduced population of
germ cells in the gonad during intrauterine life. Other possible causes are as follows.
Genetic causes are implicated when ovarian failure occurs before puberty. A sex
chromosome abnormality such as Turners syndrome or XY gonadal dysgenesis is
usually present. Mutations of genes encoding proteins vital for ovarian development
may produce a spectrum of phenotypes, from ovarian dysgenesis to early menopause.
Family-based genetic studies have suggested variable patterns of inheritance involving
both maternal and paternal transmission. Dominant and recessive patterns exist, with
expression in females only.
Acquired causes include damage by viruses and toxins, and iatrogenic causes
including pelvic surgery, irradiation and cytotoxic treatment. It has been estimated that
1/1000 population have survived treatment for cancer in childhood or as a young adult.
The precise effect of radiotherapy and chemotherapy on the ovary is unclear, but the
risk of ovarian failure is linked to both the treatment dose and the age of the patient.
The damage results in a reduction in the number and size of antral follicles
and depletion of primordial follicles.

Autoimmune serum antibodies to hormone-producing cells including the

ovary and the adrenal, thyroid and parietal glands are present. Within the ovary, IgG
antibodies and an inflammatory cell infiltrate are seen around developing and antral
follicles, causing degenerative changes. Primordial follicles are unaffected, and normal
fertile cycles are occasionally observed in some women, suggesting that the oocytes
remain healthy.
Resistant-ovary syndrome in this condition, the hypothalamopituitary axis
functions normally, but the primordial follicles within the ovary are resistant to
gonadotrophin stimulation. The precise cause is unknown. The syndrome may be
reversible.

Hypothalamic

The pulsatile release of hypothalamic GnRH has a pivotal role in normal reproductive
physiology. Any factor that disrupts the normal pattern of GnRH release is likely to lead
to disordered ovulation.
The most common cause of hypothalamic dysfunction is idiopathic (probably
resulting from input into the hypothalamus from higher centres in the brain); stress,
psychological factors and weight change also contribute (see below). Structural
lesions either disrupt the normal pathway of dopamine and cause hyperprolactinaemia,
or compress and destroy hypothalamic and pituitary tissue. These lesions include
craniopharyngiomas, germinomas and gliomas. Secondary hypogonadotrophic
hypogonadism may result from systemic conditions including sarcoidosis, or from head
injury, Sheehans syndrome or cranial irradiation. Deficiency of GnRH secretion leading
to failure of pubertal development and subsequent failure to ovulate is seen in Kallmans
syndrome. Patients with this syndrome may also have an impaired sense of smell and
colour blindness.
Weight-related amenorrhoea and anorexia: women with a BMI of less than
19 kg/m2 or more than 35 kg/m2 do not usually have a regular menstrual cycle. Fat
mass appears to be critical for a normally functioning hypothalamopituitarygonadal
axis. Undernutrition and obesity decrease GnRH release from the hypothalamus,
reducing pituitary LH release. The adipocyte-derived cytokine leptin appears to act
as a signal linking the degree of adiposity with hypothalamic function. High circulating
concentrations of leptin are seen in obesity, and decrease rapidly with weight reduction.

Endocrine disorders

Thyroid disease: both hyperthyroidism and hypothyroidism may result in menstrual

disturbances and ovulatory failure. In the past, menstrual irregularities were seen in
more than 50% of women with thyroid disease. However, recent improvement in the
detection of thyroid dysfunction and earlier treatment have reduced the observed
prevalence of menstrual abnormalities to about 20%. Severe hyperthyroidism and
hypothyroidism are usually associated with anovulation, and often amenorrhoea,
though women with mild hypothyroidism often ovulate normally. These women also
have normal conception rates, but may be at increased risk of miscarriage and
prematurity.
Hyperprolactinaemia is a common cause of anovulation, menstrual cycle disturbance
and infertility. It impairs gonadotrophin release by interfering with pulsatile GnRH.
Elevated prolactin concentrations are normal in pregnancy, during lactation and at
times of stress. Prolactin concentrations are abnormally elevated in the presence
of prolactinomas, renal failure, hepatic dysfunction, hypothyroidism or medication
with phenothiazine. A moderate increase in the concentration of prolactin can
also be seen in women with PCOS. Because prolactin secretion from the anterior
pituitary is under the inhibitory control of dopamine, disease processes that affect the
synthesis or release of dopamine or its passage to the anterior pituitary also result in
hyperprolactinaemia.

Management

Treatment options for disorders of ovulation depend on the clinical presentation,

the underlying cause and the womans wishes. Those who seek fertility require
treatment to induce ovulation, and this treatment should be offered in conjunction
with assessment of other factors relevant to fertility, including semen analysis
and the exclusion of pelvic pathology. Ovulation should not be induced in women
who do not wish to conceive. These women usually seek a diagnosis and cycle control.
This is best achieved using cyclical progestogens or an oestrogenprogestogen

pill, and treatment choice depends on the womans oestrogen status and her
contraceptive needs.
Hypothalamic disorders caused by stress, psychological factors, weight loss or
low body weight should first be managed by addressing the underlying cause. If this
approach does not result in resumption of normal menstruation, induction of ovulation
may be necessary. These women are usually hypo-oestrogenic, so often require
gonadotrophins rather than anti-oestrogens to stimulate follicle growth. Surgical
treatment, with or without additional radiotherapy, is the treatment of choice for primary
hypothalamic tumours.
PCOS: obese patients should be advised to reduce their BMI by diet and exercise.
Weight loss of as little as 5% improves menstrual cyclicity, hirsutism, and rates of
ovulation and pregnancy. Hirsutism can be treated effectively using cyproterone acetate
given in combination with estradiol (Dianette), with advice on the use of depilatory
creams, electrolysis, bleaching, shaving and waxing.
A regular menstrual pattern can be achieved in women with oligomenorrhoea
or amenorrhoea using a combined oral contraceptive pill. (Stimulation of SHBG by the
oestrogen also reduces the free androgen index and improves acne and
hirsutism.) In women with anovulatory cycles, the action of unopposed oestrogen on
the endometrium can cause irregular uterine bleeding with the potential to induce
endometrial hyperplasia or adenocarcinoma. This problem can be avoided by
prescription of progestogens (cyclically or in an oestrogenprogestogen preparation)
after the irregular bleeding has been fully investigated.
Hyperprolactinaemia warrants investigation to exclude a physiological or medical
cause. Imaging of the hypothalamic region should be performed to determine
the presence and location of a tumour. In patients with microprolactinoma or
macroprolactinoma, control of hyperprolactinaemia and tumour shrinkage is achieved
using a dopaminergic agonist. Bromocriptine remains the most commonly used agent,
and induces tumour shrinkage within 6 weeks in 90% of cases. Cabergoline is a good
alternative. This drug is equally effective and has a longer duration of action; it therefore
needs to be taken only once or twice weekly instead of daily, and is often better
tolerated, causing less gastrointestinal upset than bromocriptine. Large non-functional
tumours and tumours that fail to shrink sufficiently may require surgery.
When the dopaminergic agonist alone does not achieve a normal cycle in a
woman who wishes to conceive, it may be necessary to add clomiphene citrate
(or gonadotrophins if the woman remains hypo-oestrogenic). When pregnancy is
not desired, the woman should be made aware that her fertility may return as
her prolactin concentration falls. Some authorities have suggested that, if fertility
is not sought, the best treatment might be not a dopaminergic agonist, but a
combined oestrogenprogestogen pill (for oestrogen replacement, cycle control
and contraception), combined with pituitary surveillance by clinical, biochemical and
radiological means.

Oocyte donation

Oocyte donation can be used to treat infertile women with premature ovarian failure
in whom in vitro fertilization has failed or who are carriers of genetic disorders. The
success rate is related to the age of the woman who donates the egg.

Induction of ovulation

Clomiphene citrate: in anovulatory women with PCOS who desire fertility, an

anti-oestrogen such as clomiphene citrate or tamoxifen is the usual first-line treatment.
Although the primary cellular mechanism of action of clomiphene citrate is debated,
it acts mainly on the hypothalamus and pituitary to increase gonadotrophin release,
leading to follicular recruitment and growth. Clomiphene citrate is administered during
the early follicular phase of the menstrual cycle (e.g. 50 mg daily on days 26) and
induces ovulation in about 85% of women. It has been suggested that ovulation
induction with anti-oestrogens should be monitored by ovarian ultrasonography to
assess the development of a dominant follicle, and to avoid overstimulation resulting
in multiple folliculogenesis and multiple pregnancy. The cumulative pregnancy rate
increases over 10 cycles and then appears to reach a plateau. Concern about the
possible risks of ovarian cancer has led to recommendations that treatment with
clomiphene should be limited to 12 months duration (Royal College of Obstetricians
and Gynaecologists guidelines).

Gonadotrophins: exogenous LH and FSH (originally extracted from the urine

of post-menopausal women, and now synthesized in a highly purified form
or by recombinant technology) are given by daily injection from the beginning of the
cycle. The dose is titrated against the individual response and monitored by serum
estradiol concentrations and ultrasound assessment of follicular size and number.
Ovulation is usually triggered by an injection of human chorionic gonadotrophin (hCG)
(which binds to the LH receptor) when ultrasonography has shown an adequate
response.
Exogenous GnRH is administered subcutaneously or intravenously in a pulsatile
manner using an infusion pump to stimulate release of FSH and LH from the pituitary.
In patients with a functioning pituitary, spontaneous ovulation occurs following the
endogenous LH surge. Patients with a non-functional pituitary require a bolus dose of
hCG to induce ovulation, followed by booster doses on days 3/4 and 6/8 post-ovulation,
to maintain progesterone secretion from the corpus luteum.
Metformin: recent studies have suggested that insulin-sensitizing drugs such as
metformin, troglitazone and rosi-glitazone may lead to resumption of normal ovulatory
cycles and amelioration of hirsutism and acne in women with oligomenorrhoea or
amenorrhoea caused by PCOS. These out-comes appear to be independent of
an action of the drugs on BMI, and the effect is also seen in the absence of insulin
resistance. The results of large-scale randomized controlled trials should be awaited
before insulin-sensitizing agents become widely adopted for ovulation induction and
cycle control.
Ovarian drilling effectively treats anovulation in women with clomiphene-resistant
PCOS. A laser or diathermy needle is used laparoscopically to make multiple small
holes in the surface of the ovary. The mechanism by which this acts is uncertain. It
may restore ovulatory cycles by increasing the sensitivity of the ovary to gonadotrophin
stimulation by modifying autocrine and paracrine factors in the ovary. Spontaneous
ovulation occurs in more than two-thirds of women.
Treatment with ovarian drilling does not increase the risk of ovarian hyperstimulation
or multiple pregnancy, and does not require intensive monitoring. However, laparoscopy
has inherent surgical and anaesthetic risks, and care must be taken to avoid
compromising fertility further by the development of pelvic adhesions as a consequence
of surgery.
In vitro fertilization (IVF) is an effective treatment for ovulation disorders in
infertile women, provided oocytes can be obtained and embryos created. It may
be recommended in women in whom ovulation induction with clomiphene or
gonadotrophins has been unsuccessful, or when there is an associated male or tubal
cause of infertility.

Adverse outcomes of ovulation induction

Multiple pregnancy

Multiple pregnancy is a major clinical problem resulting in significant perinatal

morbidity and mortality, and long-term disabilities as a result of preterm delivery and
congenital abnormalities. The use of ovulation induction agents is associated with an
increase in the multiple pregnancy rate of triplet and higher-order pregnancies, 17%
arise following ovulation induction with clomiphene. Follicle tracking and low-dose
gonadotrophin regimens may reduce but cannot abolish the risk.

Ovarian hyperstimulation syndrome (OHSS)

OHSS is uncommon. It results from multiple follicular development and ovarian

enlargement. It is most often seen in IVF cycles (see page 36), in which the incidence
is about 1%, and is triggered by hCG. An exaggerated ovarian response to stimulation
is observed; multiple follicles form, and extra-vascular accumulation of fluid (which
when severe may lead to ascites and pleural effusion) causes abdominal distension,
nausea and breathing difficulties. The resultant haemo-concentration can lead to
thromboembolism.
The mechanism of OHSS is thought to be secondary to a gross increase
in estradiol concentration that results in changes such as activation of the ovarian
reninangiotensin pathway and excessive secretion of vascular endothelial growth
factor (a potent stimulant of vascular permeability). Severe OHSS is rare; it is

potentially fatal, but the incidence may be reduced by appropriate monitoring of

gonadotrophin therapy using ultrasonography and serum estradiol assessments.
If the response is excessive ovarian folliculogenesis, hCG should be withheld
because this triggers OHSS. OHSS may also be exacerbated by hCG following
conception.

Ovarian carcinoma

Epidemiological studies have suggested that women who have undergone

ovulation induction may be at increased future risk of ovarian malignancy. It is
difficult to determine cause and effect. It is known that nulliparity doubles the risk
of ovarian carcinoma, and that pregnancy and drugs that suppress ovulation
(e.g. the combined oral contraceptive pill) reduce the risk. There is no direct
evidence that agents used to induce ovulation cause ovarian cancer, but it has been
suggested that long-term prescription should be avoided. The potential risks should
be discussed with couples before treatment, and long-term follow-up should be
considered.

REFERENCES

Clark A M, Ledger W, Galletly C et al. Weight Loss Results in Significant Improvement

in Pregnancy and Ovulation Rates in Anovulatory Obese Women. Hum Reprod
1995; 10: 270512.
Dahlgren E, Johansson S, Linstedt G et al. Women with Polycystic Ovary Syndrome
Wedge Resected in 1956 to 1965: A Long-term Follow-up Focusing on Natural
History and Circulating Hormones. Fertil Steril 1992; 57: 50313.
Dunaif A. Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and
Implications for Pathogenesis. Endocr Rev 1997; 18: 774800.
Hileman S M, Pierroz D D, Flier J S. Leptin, Nutrition, and Reproduction: Timing is
Everything. J Clin Endocrinol Metab 2000; 85: 8047.
Lockwood G M. The Role of Inhibin in Polycystic Ovary Syndrome. Hum Fertil 2000;
3: 8693.
Krassas G E. Thyroid Disease and Female Reproduction. Fertil Steril 2000;
74: 106370.
Oberfield S E. Metabolic Lessons from the Study of Young Adolescents with Polycystic
Ovary Syndrome Is Insulin, Indeed, the Culprit? J Clin Endocrinol Metab 2000;
85: 35205.
Whittemore A S, Harris R, Itnyre J et al. Characteristics Relating to Ovarian Cancer
Risk: Collaborative Analysis of 12 US Case Control Studies. Invasive Epithelial
Ovarian Cancers in White Women. Am J Epidemiol 1992; 136: 1184203.

FURTHER READING

Barbieri R L. Induction of Ovulation in Infertile Women with Hyperandrogenism and

Insulin Resistance. Am J Obstet Gynecol 2000; 183: 141218.
(An up-to-date and detailed review of the role of insulin resistance in polycystic ovary
syndrome, including data on the use of metformin.)
Jacobs H S. Polycystic Ovary Syndrome. In: OBrien P M S, ed. Yearbook of Obstetrics
and Gynaecology. London: RCOG, 2000: 2709.
(A succinct review of current knowledge about polycystic ovary syndrome.)
Nugent. D. Ovarian Neoplasia and Subfertility Treatments. Br J Obstet Gynaecol 1998;
105: 58491.
(A review of the theories and evidence linking induction of ovulation with cancer of
the ovary.)
Royal College of Obstetricians and Gynaecologists. Evidence-based Clinical
Guidelines No. 3. The Management of Infertility in Secondary Care. London:
RCOG, 1998.
(An essential clinical text detailing the evidence base for the management of
infertility.)
Soule S G, Jacobs H S. Prolactinomas: Present Day Management. Br J Obstet
Gynaecol 1995; 102: 17881.
(A comprehensive overview of current recommendations in all aspects of the
management of hyperprolactinaemia.)

Practice points
PCOS accounts for 80% of women with oligomenorrhoea/amenorrhoea
Treatment options for disorders of ovulation depend on whether the woman
desires cycle control or pregnancy; ovulation induction should normally be
considered only in women who wish to conceive
Lifestyle modifications to achieve a normal BMI are an important first-line
treatment
Other potential contributions to infertility (male factor, tubal status) should be
considered before commencing treatment to induce ovulation
Ovulation induction should be initiated and coordinated in units equipped to
monitor and treat the adverse consequences of multiple folliculogenesis
The outcomes of large-scale randomized controlled trials should be awaited
before insulin-sensitizing agents are widely adopted as first-line treatments for
ovulation induction or cycle control

Copyright 2003 The Medicine Publishing Company Ltd

Female Infertility: Other Causes

Anthony J Rutherford is Consultant Gynaecologist and Director of Reproductive
Medicine at Leeds General Infirmary, Leeds, UK. He qualified from the University of
London, and trained in reproductive medicine at the Hammersmith Hospital, London.
His research interests include preservation of fertility in cancer patients, in vitro
maturation of oocytes and pre-implantation genetic diagnosis.
Osama H Salha is a Subspecialist Trainee in Reproductive Medicine at Leeds General
Infirmary and St Jamess University Hospital, Leeds, UK. He qualified in Ireland, and
trained in obstetrics and gynaecology at the Hammersmith Hospital, London, UK. His
research interests include cryopreservation and in vitro maturation of oocytes.
In all women with infertility, a careful history and examination (see page 21) is essential.
It is also important to determine whether the woman has a disorder of ovulation, as
discussed on page 28. This contribution focuses on causes other than disorders of
ovulation.

Management
Tubal factor infertility

The most common cause of tubal disease is pelvic inflammatory disease, followed by
endometriosis and iatrogenic damage. Congenital tubal abnormalities are rare. Tubal
damage ranges from subtle epithelial damage to severe distortion with destruction of
the epithelium and complete occlusion to form bilateral hydrosalpinges. There may be
accompanying damage to the pelvic anatomy, with adhesions and pseudocyst formation.
The ovaries may be wrapped in adhesions, making ovum release or capture impossible.
The likelihood of spontaneous pregnancy is low in women with tubal disease.
Surgery is still considered a reasonable option in carefully selected patients with
relatively mild damage; pregnancy rates of up to 44% are quoted after 2 years
follow-up. However, there is good evidence to support the view that this surgery
should be performed only in centres with experienced surgeons.
There are several grading systems used to assess the extent of tubal damage
(Figure 1 shows an example); these take into account the degree of epithelial damage,
the extent of dilatation of the tube, if it is completely blocked, and the nature of the
fibrosis of the tubal wall. The more severe the tubal damage, the worse the prognosis
with surgery (Figure 2). Minimally invasive procedures such as selective tubal
catheterization may be used to identify women with less severe proximal tubal disease.
Other factors to consider in the selection process include age (in vitro fertilization (IVF)
should be considered earlier in older patients) and concomitant pathology (IVF may be
more appropriate).

Grading of distal tubal disease

Stage I
Thin-walled hydrosalpinx with little or no fibrosis
Mucosa in folds with no flattened areas
Any adhesions flimsy and limited to ampulla and ovary
Ovary present and mainly free
Stage II
Thick-walled hydrosalpinx with good mucosa
Mucosa flattened with attenuated or few folds, but thin-walled tube
Mucosal folds markedly adherent in the lumen
Fibrous, thick adhesions involving tube and/or ovary
Stage III
Combination of thick-walled hydrosalpinx with marked mucosal damage or thick, fibrous adhesions
Clean hydrosalpinx with thin wall, but nodularity of patent isthmus
Ovary incarcerated against pelvic side wall or absent on that side
Stage IV
Tubo-ovarian mass or fibrous, adherent hydrosalpinx with incarcerated ovary and/or isthmic damage
Source: Winston R M, Margara R A. Br J Obstet Gynaecol 1991; 98(7): 63742.

Live birth rates in tubal disease after surgery

45
40

Live births (%)

35
30
25
20
15
10
5
0

Stage 1
(mild)

Stage 2

Stage 3

Stage 4
(severe)

Source: Winston R M, Margara R A. Br J Obstet Gynaecol 1991;

98(7): 63742.

2
Evidence suggests that microsurgery is preferable to laparoscopic surgery for distal
tubal disease, but these methods are equally effective when the principal problem is
peritubal adhesions. IVF is the most appropriate treatment in severe tubal disease
and when additional causes of infertility are present, but the choice between IVF and
surgery in moderate disease is not straightforward. If surgery is performed, recourse to
IVF is suggested if pregnancy is not achieved within 1 year.
Complications: ectopic pregnancy is a complication of both tubal surgery and IVF
treatment for tubal disease. It is more common with tubal surgery in women with
proximal damage (12% of pregnancies) than in those with distal disease. In the latest
statistics released from the UK Human Fertilisation and Embryology Authority (HFEA),
there were 183 ectopic pregnancies in a total of 7550 clinical pregnancies (2.4%). Most
of the ectopic pregnancies following IVF occur in patients with manifest tubal disease.

Endometriosis

Using the American Society of Reproductive Medicine system, endometriosis is

classified as minimal, mild, moderate or severe.
Whether minimal or mild endometriosis is a true cause of subfertility (and thus
whether its treatment improves the likelihood of conception) is debated. Results from
meta-analyses show that medical treatment with danazol, medroxyprogesterone
acetate, gestrinone or gonadotrophin-releasing hormone analogue does not
improve pregnancy rates. In all these cases, differences in pregnancy rate between
experimental and control groups were found to be non-significant.
The UK Royal College of Obstetricians and Gynaecologists suggests that surgical
ablation of minimal or mild endometriosis improves fertility. A comparison of therapeutic
laparoscopy with diagnostic laparoscopy as the control in a group of patients with
minimal or mild endometriosis showed higher pregnancy rates within 9 months after
laparoscopic surgery (30.7% compared with 18% in the control group) (Marcoux
et al.). Nevertheless, surgery may not overcome all of the factors by which
endometriosis may cause subfertility, given the low monthly fecundity rate (6.1%).
There is evidence to suggest that mild ovarian stimulation combined with intrauterine
insemination may be an effective option for this group; the birth rate is up to 5.6-fold
greater than in untreated controls (Tummon et al.).
In moderate and severe endometriosis, surgery may improve fertility. IVF may be
considered as an alternative, or as a secondary treatment following unsuccessful
surgery. There are no systematic reviews analysing the effectiveness of IVF alone in
this group of patients, but they appear to fare favourably compared with those with
other conditions treated with IVF.

Unexplained infertility

Even after thorough investigation, the reasons for a couples infertility may remain
obscure. This so-called unexplained infertility accounts for about 28% of infertile
couples in the UK.

The most important prognostic factors in unexplained infertility are age and duration
of infertility. The spontaneous cumulative live birth rate is high if the duration of
subfertility is short (< 3 years). Various reviews and prognostic models have reported
spontaneous live birth rates at 3 years of 33.365%; this broad range may reflect
differences between studies in patient selection, level of health care and diagnostic
protocols. The likelihood of pregnancy without treatment is reduced considerably when
couples have been subfertile for more than 3 years and no specific cause has been
detected.

Treatment for unexplained infertility

The principal treatments for unexplained infertility include expectant observation with
timed intercourse, ovulation induction with or without intrauterine insemination (IUI),
IVF, and gamete intrafallopian tube transfer (GIFT).
Expectant management: the likelihood of pregnancy without treatment in couples with
unexplained infertility is less than that of normally fertile couples, but greater than zero.
Studies of couples with unexplained infertility who are followed without treatment report
cumulative pregnancy rates of 3080% over 3 years follow-up (Figure 3). This variation
results from differences in the age of the female partner and the duration of infertility.
In women under 35 years, there is little to be gained from medical interference.
However, if the duration of infertility exceeds 3 years, the consensus is that expectant
management should be abandoned in favour of active treatment.

Couples conceiving spontaneously (%)

Spontaneous conception in couples with

unexplained infertility
90
80
70
60
50
40
30
20
10
0
1

10

13

16

19

22

Months (cycles)
Duration of unexplained infertility
12 years

23 years

35 years

> 5 years

Source: Hull M G, Glazener C M, Kelly N J et al. BMJ 1985; 291: 16937.

3
IUI and intracervical insemination: IUI has been used for several years. Many
trials have studied its efficacy compared with timed or untimed intercourse, or with
intracervical insemination. The results are variable and inconclusive, or provide
conflicting information. It appears that IUI alone may confer a slightly greater fecundity
than intracervical insemination. However, this treatment is seldom used in isolation.
Ovulation induction with IUI or timed intercourse: in the last 1015 years, there
has been a marked increase in the use of superovulation, with or without IUI, in the
treatment of unexplained infertility. Both clomiphene citrate and gonadotrophins have
been used. The rationale for administering medication to stimulate ovulation in women
with unexplained infertility (who by definition have regular ovulatory cycles) is that it
may overcome a subtle defect in ovulatory function, or may increase the likelihood
of pregnancy by increasing the number of eggs available for fertilization. The use
of clomiphene citrate with timed intercourse has been evaluated in four randomized
controlled trials; the overall effect was small but significant one additional pregnancy
in 40 treatment cycles (95% CI) compared with untreated control cycles.
In a recent meta-analysis comparing superovulation and timed intercourse with
superovulation and IUI, the IUI group showed a significant improvement in clinical

pregnancy rate (Zenyneloglu et al.). This meta-analysis assessed the outcome of 980
superovulation cycles in prospective randomized studies; there were 49 pregnancies in
432 cycles of timed intercourse (11.4%), compared with 110 pregnancies in 549 cycles
of IUI (20.0%). It therefore appears that couples with unexplained infertility can benefit
from the addition of IUI to superovulation for up to four cycles.
GIFT and IVF: the rationale for superovulation and IUI involves the assumption that
oocytes are being released by the ovary and picked up by the fallopian tube, and that
motile sperm reach the oocyte inside the fallopian tube in concentrations adequate
to achieve fertilization. On the basis that these assumptions may be incorrect, GIFT
should theoretically increase the likelihood of pregnancy above that achieved with
superovulation and IUI; this appears to be confirmed in practice. (GIFT involves oocyte
aspiration, then placement of up to three oocytes and an alioquot of prepared sperm
in the fallopian tube.) However, GIFT requires laparoscopy, which increases expense,
discomfort and risk with no clear benefit over IVF. Furthermore, better diagnostic
information is obtained following IVF, because clear information is available on the rate
of fertilization of the eggs.
Existing evidence emphasizes that prolonged unexplained subfertility that persists
after conventional treatment is a clear indication for IVF. In a retrospective cohort study
comparing couples with untreated unexplained infertility with those treated with IVF,
monthly pregnancy rates with IVF were 20-fold higher than those without treatment
(Donderwinkel et al.). This difference was statistically significant despite the fact that
only a limited number of IVF cycles could be performed per year, compared with
monthly attempts in the untreated cohort.

Principles of assisted conception

In the UK, all forms of assisted conception that involve manipulation of sperm and eggs
are subject to the Human Fertilisation and Embryology Act (1990). Legislation dictates
that such treatments can be performed only in licensed centres that adhere to a strict
code of practice established by the HFEA. National statistics for all licensed centres are
compiled by the HFEA and published annually.
Superovulation: assisted conception techniques such as IVF and intracytoplasmic
sperm injection (see below) rely on the recruitment and development of a cohort
of follicles, a process termed superovulation. Most modern protocols use a
gonadotrophin-releasing hormone agonist or antagonist (Figure 4). These compounds
suppress endogenous release of luteinizing hormone (LH), which can induce
resumption of meiosis at an inappropriate time. Follicular recruitment is achieved by use
of exogenous follicle-stimulating hormone, which is continued for 1012 days. Human
chorionic gonadotrophin (hCG), which has actions similar to those of LH, is used to
trigger the final maturation of the oocytes, about 36 hours before collection.

In vitro fertilization using gonadotrophin-releasing hormone agonist

Start gonadotrophin-releasing hormone agonist mid-luteal phase
Down-regulation assessment 12 days later; if satisfactory, add daily
follicle-stimulating hormone
Assess stimulation by ultrasonography after 8 and 10 days follicle-stimulating
hormone; plan administration of human chorionic gonadotrophin
Oocyte collection 36 hours after human chorionic gonadotrophin
Embryo transfer 48 hours after oocyte collection
Luteal support with progesterone for 15 days until outcome of the cycle is
known

In vitro fertilization using gonadotrophin-releasing hormone

antagonist
Start daily follicle-stimulating hormone on day 2 of menstrual cycle
Add gonadotrophin-releasing hormone antagonist on day 6
Assess stimulation with ultrasonography after 8 and 10 days follicle-stimulating
hormone; plan administration of human chorionic gonadotrophin
Oocyte collection 36 hours after human chorionic gonadotrophin
Embryo transfer 48 hours after oocyte collection
4

Oocyte collection is usually performed as a day-case procedure under a mixture of

sedation and local anaesthesia. The stimulated, enlarged ovaries lie close to the top of
the vagina and are easily reached using a transvaginal ultrasound-guided needle. The
follicular fluid is drained using fixed suction pressure and the oocytes are identified.
They are inseminated 40 hours after administration of hCG, placed in an incubator
overnight, and inspected 16 hours later for signs of fertilization. Normally, about 60% of
oocytes have been fertilized.
Embryo transfer: embryos are placed in the uterine cavity using a narrow catheter 48
or 72 hours after oocyte collection, at the four-cell or eight-cell stage respectively. They
are graded according to morphological appearance; usually, the best two are selected
for transfer. There is seldom any indication for transfer of more than two embryos;
transfer of three has little beneficial effect on pregnancy rate, and substantially
increases the risk of triplet pregnancy. Following transfer, the luteal phase is supported
with exogenous progesterone.
About 30% of patients have sufficient spare embryos for cryopreservation for future
use, should the initial cycle fail. Only high-quality embryos with intact blastomeres
(individual cells) survive the freezethaw process.
Success rates: the live birth rate following fresh IVF treatment (Figure 5) varies little,
irrespective of the cause of infertility, and appears not to have improved substantially
over the last decade (14% per cycle in 1992 to 16.9% per cycle in 1999). Age is a major
determining factor of success (Figure 6); live birth rates vary from 20.7% per cycle in
women under 28 years of age, to less than 3% in those over 43 years. About 25% of
pregnancies are twins.
Live births in in vitro fertilization and
intracytoplasmic sperm injection
25

IVF
ICSI

Live births (%)

20

15

10

9192

9293

9394

9495

9596

9697

9798

9899

Year
Human Fertilisation and Embryology Authority, 2000

5
Live births in in vitro fertilization and
intracytoplasmic sperm injection decrease with the
age of the woman
30

IVF

Live births (%)

25

20

ICSI
15

10

0
< 27

2728 2930 3132 3334 3536 3738 3940 4142 4344

Age (years)
Human Fertilisation and Embryology Authority

> 45

Selection of the most appropriate embryos for transfer is thought to be the key
to improving success rates, and a number of techniques have been tried. Delaying
transfer until day 5, when the embryo has reached the blastocyst stage, has been
advocated; early claims suggest that, by the natural process of selection, embryos
replaced at the blastocyst stage should achieve higher implantation rates. However,
blastocysts require more exacting culture conditions, including sequential media to
match the changing needs of the embryo, and large clinical studies to confirm this
early promise are lacking. In some patients, the embryos appear to have an abnormally
thickened zona pellucida (the thick glycoprotein coat around the egg). Mechanical
disruption of the zona before transfer is thought to be of benefit in such individuals,
though there are no good clinical trials.
Using multicolour fluorescent in situ hybridization, it is now possible to analyse up to
seven chromosomes in two cells taken from embryos at the eight-cell stage, replacing
those with a normal chromosome complement. This technique (aneuploidy screening)
has been used successfully to improve the outcome in older patients and in those who
have suffered recurrent failure of IVF. It has recently been licensed for use in the UK,
though further research is needed to confirm its effectiveness.

REFERENCES

Donderwinkel P F, van der Vaart H, Wolters V M, Simons A H, Kroon G, Heineman

M-J. Treatment of Patients with Long-standing Unexplained Subfertility with in vitro
Fertilisation. Fertil Steril 2000; 73: 3347.
Marcoux S, Maheux R, Berube S. Canadian Collaborative Group on Endometriosis
Laparoscopic Surgery in Infertile Women with Minimal or Mild Endometriosis. N Engl
J Med 1997; 337: 21722.
Royal College of Obstetricians and Gynaecologists. Evidence-based Clinical
Guidelines No. 3. The Management of Infertility in Secondary Care. London: RCOG,
1998.
Tummon I S, Asher L J, Martin J S B, Tulandi T. Randomised Controlled Trial of
Superovulation and Insemination for Infertility Associated with Minimal or Mild
Endometriosis. Fertil Steril 1997; 68: 812.
Zenyneloglu H B, Arici A, Olive D L, Duleba A J. Comparison of Intrauterine
Insemination with Timed Intercourse in Superovulated Cycles with Gonadotrophins:
A Meta-analysis. Fertil Steril 1998; 69: 48691.

Copyright 2003 The Medicine Publishing Company Ltd