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Overview of ovulation induction

Author:
Bart CJM Fauser, MD, PhD
Section Editors:
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor:
Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2019. | This topic last updated: Oct 16, 2018.

INTRODUCTIONOvulatory disorders can be identified in 18 to 25 percent of couples

presenting with infertility [1]. Most of these women have oligomenorrhea, arbitrarily defined
as menstruation that occurs at intervals of 35 days to six months. While ovulation may
occasionally occur, spontaneous conception is unlikely.

This topic will review the efficacy of the different regimens used for ovulation induction in
women with ovulatory disorders (clomiphene citrate, gonadotropins, pulsatile gonadotropin-
releasing hormone [GnRH] therapy, aromatase inhibitors, and dopamine agonists) and
provide our approach to the management of such women. Some of these drugs are reviewed
in greater detail elsewhere, and assisted reproductive technologies (ART) are also discussed
elsewhere. (See "Ovulation induction with clomiphene citrate" and "Ovulation induction with
letrozole" and "In vitro fertilization".)

WOMEN WITH ANOVULATORY INFERTILITYThe clinical approach to ovulation

induction requires an understanding of the causes of anovulation. The four most common
ovulatory disorders include hypogonadotropic hypogonadism (HA), polycystic ovary
syndrome (PCOS), primary ovarian insufficiency (POI), and hyperprolactinemia (see
"Clinical manifestations and evaluation of hyperprolactinemia"). Most experts have moved
away from the World Health Organization (WHO) terminology which assign women to three
categories of anovulation:

●WHO class 1 – Hypogonadotropic hypogonadal anovulation (hypothalamic amenorrhea

[HA]) (see "Evaluation and management of secondary amenorrhea" and "Functional
hypothalamic amenorrhea: Pathophysiology and clinical manifestations")

●WHO class 2 – Normogonadotropic normoestrogenic anovulation (almost all women in

this category have polycystic ovary syndrome [PCOS]), when using the Rotterdam criteria
for the diagnosis of PCOS [2]. This is the most common cause of anovulation. (see
"Diagnosis of polycystic ovary syndrome in adults", section on 'Diagnosis')

●WHO class 3 – Hypergonadotropic hypoestrogenic anovulation (primary ovarian

insufficiency [POI; premature ovarian failure]) (see "Clinical manifestations and diagnosis of
spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Pathogenesis
and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)")

Hyperprolactinemia did not have a separate WHO category. The use of serum anti-müllerian
hormone (AMH) concentrations may help to further define various patient categories.

Hypogonadotropic hypogonadism — Hypothalamic causes of hypogonadotropic

hypogonadism include functional hypothalamic amenorrhea (FHA) and isolated
gonadotropin-releasing hormone (GnRH) deficiency. Multiple factors may contribute to the
pathogenesis of FHA, including eating disorders (such as anorexia nervosa), exercise, and
stress. Women in this group, which accounts for 5 to 10 percent of anovulatory women,
usually have amenorrhea (although a range of menstrual dysfunction can be seen) [3].

Biochemical findings include low serum estradiol concentrations and low or low-normal
serum follicle-stimulating hormone (FSH) concentrations due to presumed decreased
hypothalamic secretion of GnRH. AMH levels are low to normal under these circumstances.
Reversing the lifestyle factors that contribute to the anovulation (low weight, excessive
exercise, essentially any condition that leads to energy deficiency) should be attempted
before considering ovulation induction with medications. (See "Functional hypothalamic
amenorrhea: Pathophysiology and clinical manifestations" and "Epidemiology and causes of
secondary amenorrhea".)

Although rare, hypogonadotropic hypogonadism presenting as primary amenorrhea can be

due to complete congenital GnRH deficiency. This syndrome is called idiopathic
hypogonadotropic hypogonadism or, if it is associated with anosmia, Kallmann syndrome.
(See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic
hypogonadism)".)

Many infiltrative diseases and tumors of the hypothalamus and pituitary can also result in
hypogonadotropic hypogonadism (due to diminished GnRH release or gonadotropin
deficiency). (See "Causes of primary amenorrhea" and "Epidemiology and causes of
secondary amenorrhea".)

Polycystic ovary syndrome — Women with PCOS constitute the largest group of anovulatory
women encountered in clinical practice (70 to 85 percent of cases). Serum estradiol and FSH
concentrations levels are normal, whereas luteinizing hormone (LH) concentrations may
either be normal or elevated [4]. The criteria for diagnosis have been referred to as the
"Rotterdam criteria" (table 1) [5]. (See "Diagnosis of polycystic ovary syndrome in adults",
section on 'Diagnosis'.)

In obese women with PCOS, weight loss, which may restore spontaneous ovulation in many
women, should be attempted before treatment with ovulation induction agents is considered
[6]. In addition, women with PCOS should be screened for impaired glucose tolerance before
starting ovulation induction because of the associated risk of pregnancy complications [7,8]
(see "Treatment of polycystic ovary syndrome in adults" and "Pregestational diabetes
mellitus: Obstetrical issues and management"). There is ongoing debate regarding the use of
ovulation induction versus assisted reproductive technologies (ART) for the treatment of
infertile women with PCOS. According to the WHO guidelines [9], despite the widespread
clinical use, little scientific evidence would currently support the use of ART as first-line
treatment.

Primary ovarian insufficiency — POI, formerly referred to premature ovarian failure and
defined as menopause before age 40 years, occurs in only 1 percent of all women but
accounts for 5 to 10 percent of cases of anovulation. In most cases, the follicle pool is
exhausted due to accelerated follicle loss of unknown origin (table 2) [10]. Many strategies,
including pretreatment suppression with exogenous estrogen, GnRH agonists, or androgens,
have been proposed with the aim of improving outcomes from ovulation induction, but none
have been successful. The only effective option is in vitro fertilization (IVF) with donor
oocytes. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency
(premature ovarian failure)" and "Management of spontaneous primary ovarian insufficiency
(premature ovarian failure)" and "Oocyte donation for assisted reproduction".)

Women with POI have other important health issues related to their estrogen deficiency,
including an increased risk of osteoporosis and cardiovascular disease if estrogen is not
replaced. This is discussed in detail separately. (See "Management of spontaneous primary
ovarian insufficiency (premature ovarian failure)", section on 'Approach to management'.)

Hyperprolactinemic anovulation — Hyperprolactinemia accounts for 5 to 10 percent of

women with anovulation. These women are anovulatory because hyperprolactinemia inhibits
gonadotropin secretion, presumably by inhibiting GnRH. Most have oligomenorrhea or
amenorrhea. Their serum gonadotropin concentrations are usually normal or decreased. (See
"Clinical manifestations and evaluation of hyperprolactinemia".)

The presence of hyperprolactinemia should always be confirmed by several measurements of

serum prolactin. Magnetic resonance imaging (MRI) of the head should be done in any
woman with hyperprolactinemia in whom the cause is not obvious (eg, neuroleptic drug
therapy, primary hypothyroidism). (See "Clinical manifestations and evaluation of
hyperprolactinemia".)

OVERVIEW OF APPROACH

Goals — The overarching goals of ovulation induction in women with anovulatory infertility
are:

●Induce monofollicular rather than multifollicular development and subsequent ovulation

and, ultimately, a singleton pregnancy and birth of a healthy newborn (figure 1).

●Start with the least invasive, simplest, and cheapest treatment option; subsequent options
should depend upon ovarian response (ovulation and number of follicles) (table 3).

●Maximize the rate of singleton pregnancies, minimize multiple gestation rates.

●Minimize the risk of OHSS in women undergoing gonadotropin therapy, particularly those
with polycystic ovary syndrome (PCOS), who are at higher risk. This could mean canceling
the cycle and refraining from intercourse in case of multiple follicle development. (See
"Prevention of ovarian hyperstimulation syndrome", section on 'Prevention of OHSS'.)

General principles

●The method of ovulation induction selected by the clinician should be based upon the
underlying cause of anovulation and the efficacy, costs, risks, patient burden, and potential
complications associated with each method as they apply to the individual woman.

●Women with ovulatory disorders should undergo conventional ovulation induction

strategies before considering assisted reproductive technologies (ART) because success rates
are good, and if monitored by an experienced clinician, complication rates are low [11-13].

●Induction of ovulation should be differentiated from stimulation of multiple follicle

development in ovulatory women (usually referred to as controlled ovarian
hyperstimulation), as is done with assisted conception techniques, because the patient
population, treatment goals, and clinical outcome are distinctly different.

●PCOS represents a risk factor for developing OHSS following ovarian stimulation with
gonadotropins in any setting. (See "Prevention of ovarian hyperstimulation syndrome",
section on 'Prevention of OHSS'.)

Preconception counseling — Like any couple planning fertility, couples considering

ovulation induction should first undergo preconception counseling. Preconception care is a
broad term that refers to the process of identifying social, behavioral, environmental, and
biomedical risks to a woman's fertility and pregnancy outcome and then reducing these risks
through education, counseling, and appropriate intervention. (See "The preconception office
visit".)

In addition to a medical history and physical examination, the preconception assessment

includes an assessment of rubella immunity and additional laboratory assessment based upon
individual risk factors and local guidelines. (See "The preconception office visit", section on
'Laboratory assessment' and "Prenatal screening and testing for hemoglobinopathy".)

In addition, genetic carrier testing is performed based upon the woman or partner's medical
history or family history of heritable disease. (See "Cystic fibrosis: Carrier screening" and
"Preconception and prenatal carrier screening for genetic disease in the Ashkenazi Jewish
population".)

Serum anti-müllerian hormone (AMH) concentrations appear to be an early, reliable indicator

of declining ovarian function. AMH is expressed by the small (<8 mm) preantral and early
antral follicles, and serum concentrations reflect the size of the primordial follicle pool and
may be the best biochemical marker of ovarian function across an array of clinical situations.
AMH has been used as a predictor of in vitro fertilization (IVF) success; low levels correlate
with reduced ovarian reserve and less than three follicles coinciding with poor IVF outcome,
while high levels correlate with a vigorous response to ovarian stimulation and a higher risk
of ovarian hyperstimulation syndrome (OHSS) (see "Evaluation of female infertility", section
on 'Anti-müllerian hormone (AMH)'). AMH may also be a predictor of ovulation induction
success, but it has not been well validated in this setting.
Patient-specific approach — The approach to ovulation induction depends upon the patient
population; the different approaches are reviewed here briefly and in detail elsewhere:

●Women with hypothalamic amenorrhea (HA) are hypoestrogenemic and are therefore
unlikely to respond to clomiphene citrate, an antiestrogen. However, because clomiphene
citrate is easy to administer, it may seem reasonable to give one course of clomiphene prior to
initiating pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropin therapy. For
those who ovulate, clomiphene citrate can then be continued. For those who do not ovulate,
we suggest pulsatile GnRH as first-line therapy in countries where it is available. If pulsatile
GnRH is unavailable, gonadotropin therapy should be initiated, with both luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) (these women do not respond to FSH
alone). (See 'Pulsatile GnRH therapy' below and 'Gonadotropin therapy' below and "Isolated
gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)",
section on 'Ovulation induction in women'.)

●The approach to women with PCOS starts with exercise and weight loss, if indicated,
followed by ovulation induction. Weight loss should always be attempted in overweight or
obese women with PCOS because ovulation can be restored with a modest amount of weight
loss. For obese, infertile women who are >40 years of age, clinicians need to balance the
health benefits of weight loss against the loss of fertility potential that might occur due to a
delay in initiation of ovulation induction. Fertility potential declines rapidly after 40 years of
age. (See "Treatment of polycystic ovary syndrome in adults", section on 'Weight loss'.)

Letrozole therapy, which results in higher live birth rates than clomiphene citrate in women
with PCOS, is now considered first-line therapy. However, ovulation induction is an off-label
use of letrozole, so some women prefer to use clomiphene citrate. (See 'Letrozole' below.)

●All ovulation induction strategies for women with primary ovarian insufficiency (POI) are
unsuccessful, and we suggest against their use. Women with POI should be offered the option
of IVF with donor oocytes as a successful way to fulfill their wish to have children. (See
"Management of spontaneous primary ovarian insufficiency (premature ovarian failure)" and
"Oocyte donation for assisted reproduction".)

●The treatment of choice for anovulatory women with hyperprolactinemia is dopamine

agonists; this is reviewed in detail separately. (See 'Dopamine agonists' below and
"Management of lactotroph adenoma (prolactinoma) during pregnancy", section on
'Restoration of ovulation'.)

ORAL AGENTS

Letrozole — Letrozole, an aromatase inhibitor, blocks the conversion of testosterone and

androstenedione to estradiol and estrone, respectively (unlike clomiphene, which blocks
estrogen action), thereby reducing negative estrogenic feedback at the pituitary and thus
increasing follicle-stimulating hormone (FSH) output (figure 2). In contrast to clomiphene
citrate, letrozole appears to be free of the adverse effects on endometrial and cervical mucus
attributed to clomiphene citrate [14].

For oligoovulatory women with polycystic ovary syndrome (PCOS) undergoing ovulation
induction, we now suggest letrozole as first-line therapy over clomiphene citrate, regardless
of the patient's body mass index (BMI). Before starting letrozole, the clinician must discuss
that this use of the drug is not US Food and Drug Administration (FDA) approved and that
there is an available alternative (clomiphene citrate). This recommendation is consistent with
current American College of Obstetrics and Gynecology (ACOG) guidelines for choice of
ovulation induction agents in women with PCOS [15].

A randomized trial [16] and a meta-analysis of 14 trials in nearly 3000 anovulatory women
with PCOS [17] have both reported that letrozole results in higher live birth rates compared
with clomiphene therapy. Ovulation induction is an off-label use of letrozole. In contrast,
clomiphene citrate is approved for ovulation induction and has been widely used for over 40
years [18]. Efficacy and safety of letrozole reviewed in detail separately. (See "Ovulation
induction with letrozole".)

Clomiphene citrate — In 1958, the nonsteroidal antiestrogen MER-25 was found to induce
menstruation in an amenorrheic woman receiving the drug as an experimental treatment for
endometrial cancer [19]. The next year, 43 anovulatory women given another antiestrogen,
clomiphene citrate, also ovulated. Clomiphene, like tamoxifen and raloxifene, belongs to the
category of compounds known as selective estrogen receptor modulators (SERMs). These
drugs are competitive inhibitors of estrogen binding to estrogen receptors and have mixed
agonist and antagonist activity, depending upon the target tissue. While they could be used
for ovulation induction, tamoxifen and raloxifene are less effective than clomiphene, so are
not typically used for this purpose.

Clomiphene citrate has been the most widely used agent for ovulation induction for over 50
years. Most, but not all, women with PCOS ovulate in response to clomiphene citrate.
However, clomiphene is no longer considered to be first-line therapy for women with PCOS.
(See 'Letrozole' above and "Ovulation induction with letrozole".)

Sixty to 85 percent of anovulatory women, typically with PCOS, ovulate in response to

clomiphene citrate. Of those who ovulate, approximately 50 percent do so at a dose of 50 mg
daily for five days, often cycle days 3 to 7. Twin and triplet gestations occur in approximately
7 to 9 and 0.3 percent, respectively, of clomiphene-induced pregnancies. The incidence of
miscarriage and birth defects appears to be similar to that in spontaneous pregnancies, and the
rate of ectopic pregnancy is probably not increased. The risk of ovarian hyperstimulation
syndrome (OHSS) is less than 1 percent. (See "Ovulation induction with clomiphene citrate",
section on 'Outcomes'.)

Predictors of ovulation in one study included a lower free androgen index (FAI), a calculation
of testosterone not bound to sex hormone-binding globulin (SHBG), lower body mass index
(BMI), presence of oligomenorrhea (as opposed to amenorrhea), and lower ovarian volume
[20]. Of those who ovulate, 30 to 40 percent conceive. In the study noted [20], predictors of
pregnancy with clomiphene included younger age, low BMI, low FAI, and oligomenorrhea
rather than amenorrhea. A nomogram has been developed to help predict chances for live
birth based upon simple, initial screening characteristics (figure 3). There is general
agreement that obese women respond less favorably to clomiphene citrate ovulation
induction.

Ovulation induction with clomiphene is reviewed in greater detail elsewhere. (See "Ovulation
induction with clomiphene citrate" and "Treatment of polycystic ovary syndrome in adults",
section on 'Ovulation induction medications'.)
Metformin — Correction of hyperinsulinemia with metformin has been shown to have a
beneficial effect in anovulatory women with PCOS by increasing menstrual cyclicity and
improving spontaneous ovulation. However, it does not appear to improve live-birth rates
when given alone or in combination with clomiphene citrate. This topic is discussed
separately. There is some experience with the use of another insulin-sensitizing drug,
(myo)inositol. Results of well-designed studies of sufficient sample size should be awaited.
(See "Metformin for treatment of the polycystic ovary syndrome", section on 'Anovulatory
infertility'.)

Dopamine agonists — A dopamine agonist is the treatment of choice for women with
hyperprolactinemic anovulation who are pursuing pregnancy. In women with a lactotroph
adenoma, as an example, a marked reduction in the serum prolactin concentration occurs
within two to three weeks (figure 4). (See "Management of lactotroph adenoma
(prolactinoma) during pregnancy", section on 'Restoration of ovulation'.)

Bromocriptine is still often used to restore ovulation in women with hyperprolactinemia.

However, drugs that bind more specifically to dopamine D2 receptors on the lactotroph cells,
such as cabergoline, are associated with fewer side effects. The fetal safety of bromocriptine
is better established than cabergoline, but cabergoline appears to be safe as well. We typically
let women choose which dopamine agonist they would like to try. Women who are especially
concerned about the possibility of birth defects often choose bromocriptine, and women who
are more concerned about nausea from bromocriptine typically choose cabergoline. (See
"Management of lactotroph adenoma (prolactinoma) during pregnancy", section on 'Choice
of drug'.)

Dopamine agonist regimens and monitoring for ovulation induction are reviewed in detail
separately. Treatment should be stopped once pregnancy has been diagnosed because the
safety of continued usage has not been well established. If the patient has a macroadenoma
and the size increases enough to cause visual field impairment during pregnancy, treatment
can be resumed then, but the need to do so is rare, especially if the patient is advised not to
attempt to become pregnant while the adenoma is near the optic chiasm (table 4) [21]. (See
"Management of lactotroph adenoma (prolactinoma) during pregnancy", section on 'Before
pregnancy'.)

PULSATILE GnRH THERAPYThe pulsatile administration of gonadotropin-releasing

hormone (GnRH) using an infusion pump stimulates the production of endogenous follicle-
stimulating hormone (FSH) and luteinizing hormone (LH). The resulting serum FSH and LH
concentrations remain within the normal range, so the chances of multifollicular development
and ovarian hyperstimulation are low. In comparison, continuous GnRH therapy lowers
gonadotropin release (figure 5).

Indication — Pulsatile GnRH administration is indicated for women with hypogonadotropic

hypogonadism (hypothalamic amenorrhea [HA]) who have normal pituitary function.
Because pulsatile GnRH therapy maintains normal feedback mechanisms, most cycles result
in a single dominant follicle. Therefore, rates of multiple gestation are extremely low, and the
risk of ovarian hyperstimulation syndrome (OHSS) in women with HA is exceedingly low
[12]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic
hypogonadotropic hypogonadism)", section on 'Ovulation induction in women'.)
Pulsatile GnRH has also been used with some success for women with polycystic ovary
syndrome (PCOS). This approach is counterintuitive as women with PCOS typically have an
increased hypothalamic GnRH pulse frequency and high serum LH concentrations. (See
"Treatment of polycystic ovary syndrome in adults", section on 'Ovulation induction
medications'.)

Protocol — The intravenous (IV) route appears superior to the subcutaneous route. In order
to mimic the normal pulsatile release of GnRH, the pulse interval is 60 to 90 minutes. The
most physiologic dose for IV administration is 75 ng/kg [22] (in practice, some clinicians use
2.5 micrograms/pulse for women weighing <50 kg and 5 micrograms/pulse for women
weighing >50 kg; others use doses ranging from 2.5 to 10 mcg per pulse, starting with 2.5
mcg and increasing until the minimum dose to induce ovulation is reached). In published
studies, pulsatile GnRH is continued for the entire cycle. In the clinical setting, pulsatile
GnRH administration may be discontinued after ovulation and the corpus luteum supported
by human chorionic gonadotropin (hCG). A potential regimen for luteal phase hCG
administration that has been used with gonadotropin therapy is 500 units administered on
days 7, 10, and 13 after ovulation.

Women being treated with IV pulsatile GnRH should be seen weekly to monitor the IV site
for swelling, pain, or erythema. We monitor the patient's initial cycles with ultrasound until
we are confident that a dose that will induce ovulation has been reached. Serum estradiol
monitoring is not necessary. Once ultrasound monitoring is stopped, the patient can predict
ovulation in subsequent cycles with urinary LH kits. We confirm ovulation in subsequent
cycles by measuring a luteal phase progesterone concentration.

Results — Ovulation rates of 90 percent and pregnancy rates of 80 percent or higher have
been reported in women treated with pulsatile GnRH [12,23]. Local complications such as
phlebitis may occasionally occur.

Pulsatile GnRH is currently unavailable in the United States but is widely used in other parts
of the world. A smaller infusion device has been introduced.

GONADOTROPIN THERAPYSince their introduction into clinical practice in 1961,

gonadotropins extracted from the urine of postmenopausal women (human menopausal
gonadotropins [hMG]), in which the ratio of luteinizing hormone (LH) to follicle-stimulating
hormone (FSH) bioactivity is 1:1, have assumed a central role in ovulation induction [24].
Refinement of the initially crude preparation resulted in the availability of purified and highly
purified urinary FSH (uFSH). Since 1996, recombinant human FSH (rhFSH, >99 percent
purity) has been available. Recombinant preparations are appealing due to their ease of
administration (subcutaneous rather than intramuscular), purity, and batch-to-batch
consistency.

Candidates — There are several indications for gonadotropin therapy in anovulatory women:

●Women with polycystic ovary syndrome (PCOS) who have not ovulated or conceived with
weight loss, clomiphene, or letrozole therapy (table 3).

●Hypogonadotropic anovulatory women with hypopituitarism or women with hypothalamic

amenorrhea (HA) who do not have access to pulsatile gonadotropin-releasing hormone
(GnRH) therapy. (See 'Pulsatile GnRH therapy' above.)
Preparations

hMG and FSH — The degree to which the type of follicle-stimulating hormone (FSH)
compound employed may influence outcome of ovulation induction has been controversial.
However, in a meta-analysis of 14 trials in 1726 women (10 trials comparing rhFSH and
urinary gonadotropins [FSH-highly purified (HP) or human menopausal gonadotropins
(hMG)] and four trials comparing FSH-purified [P] and hMG or HP-hMG), the following
results were seen [25]:

●There were no differences in clinical pregnancy or live-birth rates for rhFSH and urinary-
derived gonadotropins.

●There also were no differences between hMG preparations and urinary FSH-P.

●After pooling the data, there were no differences in the rates of ovarian hyperstimulation
syndrome (OHSS) between rhFSH and urinary-derived gonadotropins.

●The evidence for all outcomes was of very low quality.

Purified uFSH has some LH activity, but rhFSH does not. The experience with rhFSH in
hypogonadotropic hypogonadal women indicates that those women who have very low serum
LH concentrations (<0.5 international units/L) need exogenous human chorionic
gonadotropin (hCG) (or 75 international units/day subcutaneous recombinant LH) to maintain
adequate estradiol biosynthesis and follicle development [26].

Long-acting rhFSH preparations are currently registered in some countries for use in in vitro
fertilization (IVF) [27], but their use is not advised for ovulation induction.

Ovulatory triggers — hCG is used to trigger ovulation when the ovarian follicles are mature.
Both urinary and recombinant hCG preparations are available. A dose of 250 mcg of
recombinant hCG appears to be equivalent to the standard doses of urinary hCG (5000 to
10,000 units) [28].

Other ovulatory triggers, such as recombinant LH, are discussed elsewhere. (See "In vitro
fertilization".)

Protocols — The aim of ovulation induction with gonadotropins, as with clomiphene, is the
formation of a single dominant follicle. In spontaneous cycles, this is achieved at the
beginning of the cycle by a transient increase in serum FSH concentrations above the
threshold value (figure 1) [29]. The concentrations then decrease due to negative feedback,
preventing more than one follicle from undergoing preovulatory development (figure 6).
Because ovarian sensitivity to FSH stimulation varies among individual women, specific
treatment and monitoring protocols are needed to achieve development of a single follicle
when exogenous gonadotropin is administered.

In the conventional gonadotropin protocol, the starting dose of FSH is 150 international
units/day. However, this regimen is associated with a multiple pregnancy rate of up to 36
percent, and ovarian hyperstimulation occurs in up to 14 percent of treatment cycles [29].
In patients with PCOS, who are at particular risk for complications, this approach has been
largely abandoned in favor of a low-dose, step-up protocol [30] designed to allow the FSH
threshold to be reached gradually, minimizing excessive stimulation and therefore the risk of
development of multiple follicles. In this protocol, the initial subcutaneous or intramuscular
dose of FSH is 37.5 to 75 international units/day. It is recommended that the dose be
increased only if, after 14 days, no response is documented on ultrasonography and serum
estradiol monitoring. Increments of 37.5 international units then are given at weekly intervals
up to a maximum of 225 international units/day (figure 7). The optimal interval for increasing
the dose has not been well studied in PCOS patients.

The detection of an ovarian response is an indication to continue the current dose [31-33]
until hCG can be given to trigger ovulation, as described below. (See 'Preparations' above.)

The low-dose, step-down protocol of ovulation induction mimics more closely the
physiology of normal cycles [34]. Therapy with 150 international units FSH/day is started
shortly after spontaneous or progesterone-induced bleeding and continued until a dominant
follicle (>10 mm) is seen on transvaginal ultrasonography. The dose is then decreased to
112.5 international units/day followed by a further decrease to 75 international units/day
three days later, which is continued until hCG is administered to induce ovulation. The
appropriate starting dose can be determined by using the low-dose, step-up regimen for the
first treatment cycle [35]. The robustness of the step-down regimen in everyday practice
remains to be evaluated, and hence, the low-dose, step-up regimen should be considered the
first choice treatment.

Monitoring — The ovarian response to gonadotropin therapy is monitored using

transvaginal ultrasonography to measure follicular diameter. The scans during the late
follicular phase, usually performed every two or three days, should be focused on identifying
follicles of intermediate size.

hCG is given as an ovulatory trigger on the day that at least one follicle appears to be mature.
The criteria for follicle maturity are a follicle diameter of 18 mm and/or a serum estradiol
concentration of 200 pg/mL (734 pmol/L) per dominant follicle. Available hCG preparations
are reviewed in the preceding section. (See 'Preparations' above.)

If three or more follicles larger than 15 mm are present, stimulation should be stopped, hCG
withheld, and use of a barrier contraceptive advised in order to prevent multiple pregnancies
and ovarian hyperstimulation. Measurements of serum estradiol are useful; preovulatory
concentrations above the normal range may predict ovarian hyperstimulation. (See
"Prevention of ovarian hyperstimulation syndrome" and "Strategies to control the rate of high
order multiple gestation" and "Neonatal complications, outcome, and management of
multiple births".)

Serum progesterone measurements are sometimes useful before administration of hCG to

determine if a premature LH surge has occurred, although we do not suggest routine
progesterone measurements.

Outcomes

Pregnancy — A series of 225 women with PCOS treated over a 10-year period in one center
found rates of ovulation and pregnancy of 72 percent and 45 percent, respectively, after use
of the low-dose, step-up protocol [30]. Multiple folliculogenesis and ovarian
hyperstimulation are less common than that seen with the standard protocol, and pregnancy
rates appear similar [36-38]. However, the results of the low-dose, step-up protocol are
negatively influenced by age and obesity.

Gonadotropin therapy after clomiphene treatment has failed has been the "classical" approach
to ovulation induction for anovulatory infertility. Using this sequential approach, cumulative,
singleton live-birth rates of 71 percent (only 7 percent multiples) over 24 months have been
reported (figure 8) [11]. These results suggest that conventional approaches offer an effective
means of treating the majority of women with anovulatory infertility before proceeding to
more aggressive treatments such as IVF.

Ovulation induction is sometimes combined with intrauterine insemination (IUI). In the

absence of male factor infertility, this clinical approach is not based on sound clinical
evidence. If both anovulatory and male factor infertility are causing the couple's infertility,
then combined ovulation induction with IUI is a useful approach.

Obesity and insulin resistance (but not an elevated serum LH concentration) are associated
with lower success rates [11,39,40].

Multiple gestation — The risk of multiple gestation is increased with clomiphene citrate but
to a much greater extent with gonadotropin therapy. The reasons for multiple gestation and
strategies to lower risk are described in detail elsewhere [41]. (See "Strategies to control the
rate of high order multiple gestation", section on 'Limiting the multiple gestation risk of
ovulation induction and superovulation' and "Neonatal complications, outcome, and
management of multiple births".)

Ovarian hyperstimulation syndrome — OHSS is a potentially life-threatening complication of

ovulation induction. Its most severe manifestations include massive ovarian enlargement and
multiple cysts, hemoconcentration, and third-space accumulation of fluid; these changes may
be complicated by renal failure, hypovolemic shock, thromboembolic episodes, acute
respiratory distress syndrome, and death [42-47]. This topic is reviewed in detail elsewhere.
(See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation
syndrome" and "Prevention of ovarian hyperstimulation syndrome" and "Management of
ovarian hyperstimulation syndrome".)

Adjuvant treatment — Adjuvant GnRH agonists or antagonists are commonly used for
women with ovulatory infertility undergoing "ovarian hyperstimulation" with gonadotropins
in the setting of IVF. The goal is to suppress pituitary gonadotropins to optimize control of
the cycle and prevent a premature rise of endogenous LH prior to full maturation of the
cohort of ovarian follicles. (See "In vitro fertilization", section on 'GnRH agonist (long)
protocol'.)

Similar strategies have been proposed to improve outcomes in anovulatory women

undergoing ovulation induction with gonadotropins. However, insufficient data are available
to conclude whether GnRH agonists may improve pregnancy or OHSS rates [48]. Similarly,
there are insufficient data to draw conclusions regarding the possible role of GnRH
antagonists as adjuvant therapy.
LAPAROSCOPIC OVARIAN DIATHERMYLaparoscopic ovarian diathermy ("ovarian
drilling") represents an alternative second-line therapy for women with polycystic ovarian
syndrome (PCOS). In women who are still anovulatory despite an adequate trial of
clomiphene citrate, another therapeutic option next to gonadotropins is laparoscopic surgery
with electrocautery or laser. This topic is reviewed in detail elsewhere. (See "Laparoscopic
surgery for ovulation induction in polycystic ovary syndrome".)

CANCER RISKS

●Ovarian cancer – In some early studies, it appeared that the use of fertility drugs was
associated with neoplasia, particularly borderline ovarian tumors [49-51]. Subsequent studies
and meta-analyses have not confirmed an excess risk of ovarian cancer with infertility
treatment (clomiphene or gonadotropin therapy), but in some reports, infertility itself was an
independent risk factor [51-59]. Thus, the initial observation that fertility drug use was linked
to epithelial ovarian cancer appears to be explained by the fact that these drugs are more
likely to be used in infertile women [50,60]. This hypothesis is supported by the observation
that nulliparous women with refractory infertility may harbor a particularly high risk of
epithelial ovarian cancer, irrespective of their use of fertility drugs [58,60-63].

The best evidence for a lack of association comes from a systematic review of 11 case-
control studies and 14 cohort studies that included a total of 182,972 women. In this analysis,
there was no convincing evidence of an excess risk of invasive ovarian tumors with fertility
drug therapy [59]. However, there was a possible excess risk of borderline ovarian tumors in
subfertile women undergoing in vitro fertilization (IVF), but there were methodological
limitations, including a high risk of bias and small number of cases.

●Breast cancer – There does not appear to be an increased risk of breast cancer in women
treated with fertility drugs [53,54,64-68]. However, interpretation of the available data is
limited by several factors, such as survey information, small subgroup numbers, lack of
evaluation by drug type/dose or cause of infertility, and confounding by the presence of other
risk factors for breast cancer. (See "Factors that modify breast cancer risk in women".)

One relatively large, case-control study showed that infertile women with breast cancer were
more likely to have been treated with human menopausal gonadotropin (hMG) for more than
six cycles than infertile women without breast cancer; no increased risk was noted for
clomiphene citrate [69]. However, this study was subject to many of the limitations noted
above.

In contrast, in a prospective cohort study of 116,671 women with 1357 incident cases of
breast cancer, women who reported infertility due to an ovulatory disorder had a lower risk of
breast cancer than women who did not report infertility (hazard ratio [HR] 0.75) [70]; women
who had received clomiphene citrate were at lowest risk (HR 0.60). In a sister-matched, case-
control study among approximately 1400 women with and 1600 sisters without breast cancer,
those who had used clomiphene citrate or exogenous follicle-stimulating hormone (FSH) but
did not conceive were at lower risk of breast cancer compared with nonusers (odds ratio [OR]
0.62, 95% CI 0.43-0.89). Those who used fertility drugs and did conceive (at least a 10-week
pregnancy) had the same breast cancer risk as women who had never taken fertility drugs
[71].
Thus, women taking infertility drugs can be reassured that these drugs probably do not
increase their risk of breast cancer, although it is not clear whether some subgroups may be at
increased risk. Further investigation is required.

●Other ovulation induction drugs – Other ovulation induction therapies discussed below
(including pulsatile gonadotropin-releasing hormone [GnRH] and dopamine agonists) have
not been linked to ovarian or breast cancer risk.

●Other cancers – In a retrospective, cohort study, neither clomiphene nor gonadotropin use
appeared to be associated with an increased risk of melanoma or thyroid, cervical, or colon
cancers [72]. In contrast, the same investigators reported that clomiphene use may be
associated with a greater risk of endometrial cancer. However, one explanation for these
findings is that infertile women who used clomiphene were more likely to have underlying
chronic anovulation, which is a strong risk factor for development of endometrial cancer,
than infertile women not exposed to clomiphene. (See "Ovulation induction with clomiphene
citrate", section on 'Cancer risks'.)

●Risk in offspring – A large, population-based study found that childhood tumor risk was
not increased in children conceived following ovulation induction [73]. Ongoing monitoring
of the long-term effects of these drugs is warranted since the number of cases was small.
However, congenital malformation risk does not appear to be increased with oral ovulation
induction agents (see "Ovulation induction with clomiphene citrate"). Pregnancy outcome
after assisted reproductive technologies (ART) is discussed in detail elsewhere. (See
"Pregnancy outcome after assisted reproductive technology".)

SOCIETY GUIDELINE LINKSLinks to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society
guideline links: Polycystic ovary syndrome" and "Society guideline links: Female
infertility".)

INFORMATION FOR PATIENTSUpToDate offers two types of patient education materials,

"The Basics" and "Beyond the Basics." The Basics patient education pieces are written in
plain language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for patients
who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Infertility treatment with gonadotropins
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Ovulatory disorders are a common cause of infertility, which in most cases is treatable with
ovulation induction agents. The goal of therapy in these women is monofollicular
development and subsequent ovulation. This approach should be differentiated from
stimulation of multiple follicle development in ovulatory women, as is done with assisted
reproductive technologies (ART). (See 'General principles' above.)

●The method of ovulation induction selected by the clinician should be based upon the
underlying cause of anovulation and the efficacy, costs, risks, burden of treatment, and
potential complications associated with each method as they apply to the individual woman.
(See 'General principles' above.)

●For women with hypogonadotropic amenorrhea, we suggest pulsatile gonadotropin-

releasing hormone (GnRH) as first-line therapy in women with intact pituitary function in
countries where it is available (Grade 2C). Because clomiphene citrate is easy to administer,
it is reasonable to give one course of clomiphene prior to initiating pulsatile GnRH. However,
very few women in this group respond. If pulsatile GnRH is unavailable, gonadotropin
therapy should be initiated, with both luteinizing hormone (LH) and follicle-stimulating
hormone (FSH) (these women do not respond to FSH alone). The low-dose, step-up regimen
is considered to be the first-choice treatment. (See 'Patient-specific approach' above and
'Protocols' above.)

●For oligoovulatory women with polycystic ovary syndrome (PCOS) undergoing ovulation
induction, we suggest letrozole as first-line therapy over clomiphene citrate, regardless of the
patient's body mass index (BMI) (Grade 2B). Before starting letrozole, the clinician must
discuss that this use of the drug is not approved for ovulation induction. (See "Ovulation
induction with letrozole", section on 'Suggested approach'.)

●For obese women with PCOS, we also suggest lifestyle changes and weight loss as an initial
strategy to restore ovulatory cycles (Grade 2B). (See "Ovulation induction with letrozole",
section on 'Suggested approach'.)

●Doses, regimens, and monitoring for clomiphene and letrozole use in women with PCOS
are discussed in detail elsewhere (see "Ovulation induction with clomiphene citrate" and
"Ovulation induction with letrozole"). Other strategies are available as well for clomiphene-
resistant patients.

●If oral ovulation induction agents are unsuccessful in women with PCOS, then gonadotropin
therapy should be started (in this case, FSH alone is sufficient). Strict attention to follicle
number is essential to avoid multiple gestation and ovarian hyperstimulation. (See
'Gonadotropin therapy' above.)

●To minimize the risk of multiple gestation and ovarian hyperstimulation syndrome (OHSS)
in PCOS, gonadotropin treatment should be stopped if there are an excess number of follicles
or extremely high serum estradiol concentrations. (See 'Monitoring' above and "Prevention of
ovarian hyperstimulation syndrome".)

●For women with primary ovarian insufficiency (POI; premature ovarian failure) no
ovulation induction strategy has been shown to be effective. However, in vitro fertilization
(IVF) with donor oocytes has high success rates. (See "Oocyte donation for assisted
reproduction".)
●For women with hyperprolactinemic anovulation, we suggest ovulation induction with
dopamine agonists. We suggest either bromocriptine or cabergoline (Grade 2C). (See
'Dopamine agonists' above.)

●While there has been concern about a possible increased risk of ovarian cancer with
ovulation induction drugs, it appears that the risk may be due to the infertility itself rather
than the medications used to treat it. However, because one study suggested an increase after
12 cycles of clomiphene citrate, women should not receive more than 12 cycles. There does
not appear to be an increased risk of breast cancer with ovulation induction drugs. (See
'Cancer risks' above.)

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REFERENCES
1. Hull MG, Glazener CM, Kelly NJ, et al. Population study of causes, treatment, and
outcome of infertility. Br Med J (Clin Res Ed) 1985; 291:1693.
2. Daan NM, Louwers YV, Koster MP, et al. Cardiovascular and metabolic profiles
amongst different polycystic ovary syndrome phenotypes: who is really at risk? Fertil
Steril 2014; 102:1444.
3. De Souza MJ, Miller BE, Loucks AB, et al. High frequency of luteal phase deficiency
and anovulation in recreational women runners: blunted elevation in follicle-
stimulating hormone observed during luteal-follicular transition. J Clin Endocrinol
Metab 1998; 83:4220.
4. Laven JS, Imani B, Eijkemans MJ, Fauser BC. New approach to polycystic ovary
syndrome and other forms of anovulatory infertility. Obstet Gynecol Surv 2002;
57:755.
5. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised
2003 consensus on diagnostic criteria and long-term health risks related to polycystic
ovary syndrome (PCOS). Hum Reprod 2004; 19:41.
6. Norman RJ, Davies MJ, Lord J, Moran LJ. The role of lifestyle modification in
polycystic ovary syndrome. Trends Endocrinol Metab 2002; 13:251.
7. Boomsma CM, Eijkemans MJ, Hughes EG, et al. A meta-analysis of pregnancy
outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006;
12:673.
8. de Wilde MA, Veltman-Verhulst SM, Goverde AJ, et al. Preconception predictors of
gestational diabetes: a multicentre prospective cohort study on the predominant
complication of pregnancy in polycystic ovary syndrome. Hum Reprod 2014;
29:1327.
9. Balen AH, Morley LC, Misso M, et al. The management of anovulatory infertility in
women with polycystic ovary syndrome: an analysis of the evidence to support the
development of global WHO guidance. Hum Reprod Update 2016; 22:687.
10. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010;
376:911.
11. Eijkemans MJ, Imani B, Mulders AG, et al. High singleton live birth rate following
classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2).
Hum Reprod 2003; 18:2357.
12. Martin KA, Hall JE, Adams JM, Crowley WF Jr. Comparison of exogenous
gonadotropins and pulsatile gonadotropin-releasing hormone for induction of
ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab 1993; 77:125.
13. Veltman-Verhulst SM, Fauser BC, Eijkemans MJ. High singleton live birth rate
confirmed after ovulation induction in women with anovulatory polycystic ovary
syndrome: validation of a prediction model for clinical practice. Fertil Steril 2012;
98:761.
14. Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in
patients with an inadequate response to clomiphene citrate. Fertil Steril 2001; 75:305.
15. ACOG Committee Opinion No. 738: Aromatase Inhibitors in Gynecologic Practice.
Obstet Gynecol 2018; 131:e194. Reaffirmed 2019.
16. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for
infertility in the polycystic ovary syndrome. N Engl J Med 2014; 371:119.
17. Franik S, Eltrop SM, Kremer JA, et al. Aromatase inhibitors (letrozole) for subfertile
women with polycystic ovary syndrome. Cochrane Database Syst Rev 2018;
5:CD010287.
18. Fauser BC. Reproductive endocrinology: revisiting ovulation induction in PCOS. Nat
Rev Endocrinol 2014; 10:704.
19. KISTNER RW, SMITH OW. Observations on the use of a non-steroidal estrogen
antagonist: MER-25. Surg Forum 1960; 10:725.
20. Imani B, Eijkemans MJ, te Velde ER, et al. A nomogram to predict the probability of
live birth after clomiphene citrate induction of ovulation in normogonadotropic
oligoamenorrheic infertility. Fertil Steril 2002; 77:91.
21. Weil C. The safety of bromocriptine in hyperprolactinaemic female infertility: a
literature review. Curr Med Res Opin 1986; 10:172.
22. Martin K, Santoro N, Hall J, et al. Clinical review 15: Management of ovulatory
disorders with pulsatile gonadotropin-releasing hormone. J Clin Endocrinol Metab
1990; 71:1081A.
23. Filicori M, Flamigni C, Dellai P, et al. Treatment of anovulation with pulsatile
gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles.
J Clin Endocrinol Metab 1994; 79:1215.
24. Lunenfeld B. Historical perspectives in gonadotrophin therapy. Hum Reprod Update
2004; 10:453.
25. Weiss NS, Nahuis M, Bayram N, et al. Gonadotrophins for ovulation induction in
women with polycystic ovarian syndrome. Cochrane Database Syst Rev 2015;
:CD010290.
26. European Recombinant LH Study Group. Human recombinant luteinizing hormone is
as effective as, but safer than, urinary human chorionic gonadotropin in inducing final
follicular maturation and ovulation in in vitro fertilization procedures: results of a
multicenter double-blind study. J Clin Endocrinol Metab 2001; 86:2607.
27. Devroey P, Boostanfar R, Koper NP, et al. A double-blind, non-inferiority RCT
comparing corifollitropin alfa and recombinant FSH during the first seven days of
ovarian stimulation using a GnRH antagonist protocol. Hum Reprod 2009; 24:3063.
28. Ludwig M, Doody KJ, Doody KM. Use of recombinant human chorionic
gonadotropin in ovulation induction. Fertil Steril 2003; 79:1051.
29. Fauser BC, Van Heusden AM. Manipulation of human ovarian function:
physiological concepts and clinical consequences. Endocr Rev 1997; 18:71.
30. White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose
gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225
women. J Clin Endocrinol Metab 1996; 81:3821.
31. Balen AH, Braat DD, West C, et al. Cumulative conception and live birth rates after
the treatment of anovulatory infertility: safety and efficacy of ovulation induction in
200 patients. Hum Reprod 1994; 9:1563.
32. Homburg R, Levy T, Ben-Rafael Z. A comparative prospective study of conventional
regimen with chronic low-dose administration of follicle-stimulating hormone for
anovulation associated with polycystic ovary syndrome. Fertil Steril 1995; 63:729.
33. Hedon B, Hugues JN, Emperaire JC, et al. A comparative prospective study of a
chronic low dose versus a conventional ovulation stimulation regimen using
recombinant human follicle stimulating hormone in anovulatory infertile women.
Hum Reprod 1998; 13:2688.
34. van Santbrink EJ, Donderwinkel PF, van Dessel TJ, Fauser BC. Gonadotrophin
induction of ovulation using a step-down dose regimen: single-centre clinical
experience in 82 patients. Hum Reprod 1995; 10:1048.
35. Imani B, Eijkemans MJ, Faessen GH, et al. Prediction of the individual follicle-
stimulating hormone threshold for gonadotropin induction of ovulation in
normogonadotropic anovulatory infertility: an approach to increase safety and
efficiency. Fertil Steril 2002; 77:83.
36. Buvat J, Buvat-Herbaut M, Marcolin G, et al. Purified follicle-stimulating hormone in
polycystic ovary syndrome: slow administration is safer and more effective. Fertil
Steril 1989; 52:553.
37. Shoham Z, Patel A, Jacobs HS. Polycystic ovarian syndrome: safety and effectiveness
of stepwise and low-dose administration of purified follicle-stimulating hormone.
Fertil Steril 1991; 55:1051.
38. Calaf Alsina J, Ruiz Balda JA, Romeu Sarrió A, et al. Ovulation induction with a
starting dose of 50 IU of recombinant follicle stimulating hormone in WHO group II
anovulatory women: the IO-50 study, a prospective, observational, multicentre, open
trial. BJOG 2003; 110:1072.
39. Mulders AG, Eijkemans MJ, Imani B, Fauser BC. Prediction of chances for success
or complications in gonadotrophin ovulation induction in normogonadotrophic
anovulatory infertility. Reprod Biomed Online 2003; 7:170.
40. Mulders AG, Laven JS, Imani B, et al. IVF outcome in anovulatory infertility (WHO
group 2)--including polycystic ovary syndrome--following previous unsuccessful
ovulation induction. Reprod Biomed Online 2003; 7:50.
41. Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation
for subfertility treatment. Lancet 2005; 365:1807.
42. Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation
syndrome (OHSS): a review. Hum Reprod Update 2002; 8:559.
43. Delvigne A, Dubois M, Battheu B, et al. The ovarian hyperstimulation syndrome in
in-vitro fertilization: a Belgian multicentric study. II. Multiple discriminant analysis
for risk prediction. Hum Reprod 1993; 8:1361.
44. Navot D, Relou A, Birkenfeld A, et al. Risk factors and prognostic variables in the
ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1988; 159:210.
45. Delvigne A. Symposium: Update on prediction and management of OHSS.
Epidemiology of OHSS. Reprod Biomed Online 2009; 19:8.
46. Enskog A, Henriksson M, Unander M, et al. Prospective study of the clinical and
laboratory parameters of patients in whom ovarian hyperstimulation syndrome
developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil
Steril 1999; 71:808.
47. Lewis CG, Warnes GM, Wang XJ, Matthews CD. Failure of body mass index or body
weight to influence markedly the response to ovarian hyperstimulation in normal
cycling women. Fertil Steril 1990; 53:1097.
48. Nugent D, Vandekerckhove P, Hughes E, et al. Gonadotrophin therapy for ovulation
induction in subfertility associated with polycystic ovary syndrome. Cochrane
Database Syst Rev 2000; :CD000410.
49. Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile
women. N Engl J Med 1994; 331:771.
50. Shushan A, Paltiel O, Iscovich J, et al. Human menopausal gonadotropin and the risk
of epithelial ovarian cancer. Fertil Steril 1996; 65:13.
51. Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian
cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002; 155:217.
52. Bristow RE, Karlan BY. Ovulation induction, infertility, and ovarian cancer risk.
Fertil Steril 1996; 66:499.
53. Venn A, Watson L, Bruinsma F, et al. Risk of cancer after use of fertility drugs with
in-vitro fertilisation. Lancet 1999; 354:1586.
54. Modan B, Ron E, Lerner-Geva L, et al. Cancer incidence in a cohort of infertile
women. Am J Epidemiol 1998; 147:1038.
55. Calderon-Margalit R, Friedlander Y, Yanetz R, et al. Cancer risk after exposure to
treatments for ovulation induction. Am J Epidemiol 2009; 169:365.
56. Kashyap S, Moher D, Fung MF, Rosenwaks Z. Assisted reproductive technology and
the incidence of ovarian cancer: a meta-analysis. Obstet Gynecol 2004; 103:785.
57. Brinton LA, Lamb EJ, Moghissi KS, et al. Ovarian cancer risk after the use of
ovulation-stimulating drugs. Obstet Gynecol 2004; 103:1194.
58. Brinton LA, Lamb EJ, Moghissi KS, et al. Ovarian cancer risk associated with
varying causes of infertility. Fertil Steril 2004; 82:405.
59. Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with
ovarian stimulating drugs for infertility. Cochrane Database Syst Rev 2013;
:CD008215.
60. Rodriguez C, Tatham LM, Calle EE, et al. Infertility and risk of fatal ovarian cancer
in a prospective cohort of US women. Cancer Causes Control 1998; 9:645.
61. American College of Obstetricians and Gynecologists. Management of infertility
caused by ovulatory dysfunction. ACOG practice bulletin #34. American College of
Obstetricians and Gynecologists, Washington, DC 2002.
62. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk:
collaborative analysis of 12 US case-control studies. IV. The pathogenesis of
epithelial ovarian cancer. Collaborative Ovarian Cancer Group. Am J Epidemiol
1992; 136:1212.
63. Rossing MA, Tang MT, Flagg EW, et al. A case-control study of ovarian cancer in
relation to infertility and the use of ovulation-inducing drugs. Am J Epidemiol 2004;
160:1070.
64. Ricci E, Parazzini F, Negri E, et al. Fertility drugs and the risk of breast cancer. Hum
Reprod 1999; 14:1653.
65. Rossing MA, Daling JR, Weiss NS, et al. Risk of breast cancer in a cohort of infertile
women. Gynecol Oncol 1996; 60:3.
66. Doyle P, Maconochie N, Beral V, et al. Cancer incidence following treatment for
infertility at a clinic in the UK. Hum Reprod 2002; 17:2209.
67. Brinton LA, Scoccia B, Moghissi KS, et al. Breast cancer risk associated with
ovulation-stimulating drugs. Hum Reprod 2004; 19:2005.
 68. Gauthier E, Paoletti X, Clavel-Chapelon F, E3N group. Breast cancer risk associated
with being treated for infertility: results from the French E3N cohort study. Hum
Reprod 2004; 19:2216.
69. Burkman RT, Tang MT, Malone KE, et al. Infertility drugs and the risk of breast
cancer: findings from the National Institute of Child Health and Human Development
Women's Contraceptive and Reproductive Experiences Study. Fertil Steril 2003;
79:844.
70. Terry KL, Willett WC, Rich-Edwards JW, Michels KB. A prospective study of
infertility due to ovulatory disorders, ovulation induction, and incidence of breast
cancer. Arch Intern Med 2006; 166:2484.
71. Fei C, Deroo LA, Sandler DP, Weinberg CR. Fertility drugs and young-onset breast
cancer: results from the Two Sister Study. J Natl Cancer Inst 2012; 104:1021.
72. Althuis MD, Scoccia B, Lamb EJ, et al. Melanoma, thyroid, cervical, and colon
cancer risk after use of fertility drugs. Am J Obstet Gynecol 2005; 193:668.
73. Brinton LA, Krüger Kjaer S, Thomsen BL, et al. Childhood tumor risk after treatment
with ovulation-stimulating drugs. Fertil Steril 2004; 81:1083.

Topic 7407 Version 25.0

GRAPHICS
The Rotterdam consensus meeting criteria for definition of PCOS
2 out of 3 of the following:
1. Oligo and/or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries
PCOS: polycystic ovary syndrome.
Data from: The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group.
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic
ovary syndrome (PCOS). Hum Reprod 2004; 19:41.
Graphic 54308 Version 2.0
Major causes of primary ovarian insufficiency (premature ovarian failure) in women
Accelerated follicular atresia
Genetic defects
Turner syndrome
Fragile X premutations
X chromosome deletions and translocations
Galactosemia
Ovarian toxins
Chemotherapeutic drugs (especially alkylating agents)
Radiation
Mumps or cytomegalovirus infection
Autoimmune injury
Isolated or part of polyglandular autoimmune syndromes
Abnormal follicular stimulation
Intraovarian modulators
BMP15
Steroidogenic enzyme defects
CYP17 deficiency, StAR mutation
Aromatase gene mutations
Gonadotropin receptor function
FSH receptor mutations
Gs alpha subunit gene mutations
FSH: follicle-stimulating hormone.
Graphic 74029 Version 4.0
Human follicle development

Schematic representation of human follicle development during the follicular phase of the
menstrual cycle. There are two major events in this process: increased sensitivity of a
maturing follicle and selection of a single dominant follicle. In spontaneous cycles, this is
achieved at the beginning of the cycle by a transient increase in serum FSH concentrations
above some threshold value; the concentrations then decrease, preventing more than one
follicle from undergoing preovulatory development.
E2: estradiol; FSH: follicle-stimulating hormone.
Fauser, BC, Van Hevsdeau, AM, et al. Manipulation of human ovarian function:
Physiological concepts and clinical consequences. Endocr Rev 1997; 18:71.
Graphic 61116 Version 2.0
Multistep approach to treatment of anovulatory infertility associated with polycystic ovary
syndrome
Treatment Cost Multiple pregnancy risk
Weight loss for high body mass
First line Low Not increased
index
Letrozole (alternative: clomiphene
First line Low Low
citrate)
Second Follicle-stimulating hormone
High High, includes high-order multiples
line injections
Second
Ovarian drilling High Not increased
line
 Very High but reducible with single
Third line In vitro fertilization
high embryo transfer
Graphic 56718 Version 12.0
Aromatase inhibitor treatment

Clomiphene citrate: (Day 5) Administration of CC from days 3 to 7 results in ER depletion

at the level of the pituitary and mediobasal hypothalamus. As a result, estrogen negative
feedback centrally is interrupted and FSH secretion increases from the anterior pituitary
leading to multiple follicular growth. (Day 10) By the late follicular phase, because of the
long tissue retention of CC, there continues to be ER depletion centrally and increased E2
secretion from the ovary is not capable of normal negative feedback on FSH. The result is
multiple dominant follicle growth and multiple ovulation.
Aromatase inhibitor: (Day 5) Administration of an AI from 3 to 7 days results in
suppression of ovarian E2 secretion and reduction in estrogen negative feedback at the
pituitary and mediobasal hypothalamus. Increased FSH secretion from the anterior pituitary
results in stimulation of multiple ovarian growth. (Day 10) Later in the follicular phase, the
effect of the AI is reduced and E2 levels increase as a result of follicular growth. Because AIs
do not affect ERs centrally, the increased E2 levels result in normal negative feedback on
FSH secretion and follicles less than dominant follicle size undergo atresia, with resultant
monofollicular ovulation in most cases.
CC: clomiphene citrate; ER: estrogen receptor; FSH: follicle-stimulating hormone; E2:
estradiol; AI: aromatase inhibitor.
Graphic 81745 Version 6.0
Live birth following clomiphene citrate

A two-step nomogram predicting chances for live birth following clomiphene citrate on the
basis of initial screening characteristics.
BMI: body mass index; FAI: free androgen index; T: testosterone; SHBG: sex hormone-
binding globulin.
Reproduced with permission from: Imani, B, Eijkemans, MJ, te Velde, ER, et al. A
nomogram to predict the probability of live birth after clomiphene citrate induction of
ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril 2002; 77:91.
Copyright © 2002 American Society for Reproductive Medicine.
Graphic 81180 Version 2.0
Dopamine agonist drugs lower serum prolactin concentrations in lactotroph adenoma
(prolactinoma)
Serum prolactin concentrations in women with hyperprolactinemic amenorrhea treated with
bromocriptine and cabergoline. Both drugs lowered serum prolactin concentrations into the
normal range (upper limit of normal equals 20 mcg/L).
Data from: Webster J, Piscitelli MD, Polli A, et al. A comparison of cabergoline and
bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative
Study Group. N Engl J Med 1994; 331:904.
Graphic 72539 Version 4.0
Approximate ovulation and pregnancy rates following ovulation induction
Treatment Ovulation rate, percent Cumulative pregnancy rate, percent
Clomiphene 80 50
Gonadotropins 72 50
Pulsatile GnRH* 90 80
¶
Dopamine agonists 80 70
GnRH: gonadotropin-releasing hormone; WHO: World Health Organization.
* Indicated only for women with hypogonadotropic hypogonadal anovulation (WHO class 1).
¶ Indicated only for women with hyperprolactinemia-induced anovulation.
Graphic 68772 Version 3.0
Importance of the pattern of GnRH secretion

Serum LH and FSH concentrations in an ovariectomized monkey. Pulsatile administration

(given for six minutes every hour) of GnRH maintains serum FSH and LH concentrations. In
comparison, a continuous infusion of GnRH (middle panel) leads to rapid and reversible
suppression of both LH and FSH release.
FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone; LH: luteinizing
hormone.
Data from: Belchetz PE, Plant TM, Nakai Y, et al. Hypophysial responses to continuous and
intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science 1978;
202:631.
Graphic 51212 Version 3.0
FSH threshold and follicular development

The intercycle rise in serum FSH concentrations exceeds the threshold for recruitment of
follicles for further development. The number of follicles recruited is determined by the time
("window") in which the serum FSH is above the threshold at which recruitment occurs.
FSH: follicle-stimulating hormone.
Graphic 60133 Version 2.0
Step-up protocol for ovulation induction
Schematic representation of the low-dose, step-up protocol of gonadotropin administration
for ovulation induction. The initial subcutaneous or intramuscular dose of FSH is 37.5 to 75
IU/day; the dose is increased only if, after 14 days, no response is documented on
ultrasonography and serum estradiol monitoring. Increments of 37.5 IU then are given at
weekly intervals up to a maximum of 225 IU/day. Detection of an ovarian response is an
indication to continue the current dose until hCG can be given to stimulate ovulation.
FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; IU: international
units.
Graphic 58611 Version 2.0
Cumulative singleton rate

Cumulative pregnancy rate resulting in singleton live birth of a consecutive series of 240
normogonadotrophic anovulatory infertile women undergoing classical ovulation induction
(clomiphene citrate as first therapy, followed by FSH as second-line therapy if required),
calculated by the Kaplan-Meier method, with 95 percent confidence interval.
FSH: follicle-stimulating hormone.
Eijkemans, MJ, Imani, B, Mulders, AG, et al. High singleton live birth rate following
classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum
Reprod 2003; 18:2357.
Graphic 66367 Version 2.0

Contributor Disclosures
Bart CJM Fauser, MD, PhDGrant/Research/Clinical Trial Support: Child Health University
Medical Center Utrecht [Women’s health]; Dutch Heart Foundation [Women’s
health/cardiovascular medicine]; ZonMw [PCOS/pregnancy complications].
Consultant/Advisory Boards: Ferring Pharmaceuticals Inc [Infertility (Recombinant FSH)];
Finox Biotech [Infertility]; Gedeon Richter/PregLem [SPRM]; Teva Pharmaceutical
Industries Ltd [Infertility care]; Myovant Sciences Ltd [Benign gynecology]; Pantarhei
Bioscience [Contraception]; COGI [Congress co-chair]. Employment: Reproductive
BioMedicineOnline [Editor-in-chief]; ZonMw [Board member]; London Women's Clinic
[Visiting Professor].Robert L Barbieri, MDNothing to discloseWilliam F Crowley, Jr,
MDConsultant/Advisory Boards: Dare Bioscience [Endocrinology (Transvaginal drug
delivery systems)]; Quest Diagnostics [Reproductive endocrinology]. Equity
Ownership/Stock Options: Dare Bioscience[Endocrinology (Transvaginal ring delivery
systems)].Kathryn A Martin, MDNothing to disclose

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