Human Reproduction Update 1999, Vol. 5, No.5 p.

483492 E European Society of Human Reproduction and Embryology

Premature ovarian failure: a systematic review
on therapeutic interventions to restore ovarian
function and achieve pregnancy
Y.M.van Kasteren
1,3
and J.Schoemaker
2
1
Department of Obstetrics and Gynaecology, Medical Center Alkmaar, Wilhelminalaan 12, 1815 JD, Alkmaar, The
Netherlands and
2
Institute for Endocrinology, Reproduction and Metabolism, Medical Center Free University,
Amsterdam, The Netherlands
Infertility is an important issue for patients with premature ovarian failure (POF). Although oocyte donation offers an
alternative method to achieve a pregnancy, many patients seek to reproduce with their own gametes. We performed a
literature search to evaluate the possibility of pregnancy following diagnosis, and the additional value of treatment
strategies. We found 52 case reports, eight observational studies, nine uncontrolled studies and seven controlled trials. Due
to a strong variability in study design, patient selection and mode of intervention, it was not possible to combine the data of
the seven studies to perform a meta-analysis. None of the studies showed a statistically significant difference between both
(or more) study groups. Due to a lack of incorporation of a placebo group, preference of any treatment over no treatment
could not be established. Importantly, the collected data of observational, uncontrolled and controlled studies indicate that
POF patients still have a 510% chance to conceive following diagnosis. Approximately 80% of the reported pregnancies
resulted in the birth of a healthy child. There is no evidence that any treatment can enhance this pregnancy rate.
Key words: ovulation/pregnancy/premature ovarian failure/therapy
TABLE OF CONTENTS
Introduction 483
Reported pregnancies and livebirths in POF patients 485
Effect of treatment in controlled studies 485
Conclusions 489
References 490
Introduction
Premature ovarian failure (POF) is characterized by a
hypergonadotrophic hypo-oestrogenic oligo- or amenorrhoea.
The cessation of ovarian function after puberty and before the
age of 40 years (Coulam, 1982) strongly interferes with fertility
and family planning. Although oocyte donation can fulfil the
desire to create a family, little progress has been made towards
improvement of reproduction with the patients own gametes.
The diagnosis of POF affects around 10% of patients seeking
evaluation of secondary amenorrhoea (Moraes Ruhsen and
Jones, 1967). Table I shows the diverse aetiology of POF
(Rebar, 1982; Anasti, 1998). However, in the majority of POF
patients a cause cannot be identified, and they are diagnosed to
have idiopathic POF. This group probably is still a
heterogeneous one, consisting of patients with early follicular
depletion and patients with the resistant ovary syndrome, in
whom follicles are still present in the ovaries. Since
differentiation between these forms would be essential to
evaluate the benefit of therapeutic interventions, several
authors performed biopsies or wedge resections either by
laparoscopy or by laparotomy (Kinch et al., 1965; Emperaire
et al., 1970; Zarate et al., 1970; Sharf et al., 1972; Starup and
Sele, 1973; Falk, 1977; Duignan, 1978; Board et al., 1979;
Rebar et al., 1982; Russell et al., 1982; Menon et al., 1984;
Miyaka et al., 1987; Rebar and Conolly, 1990; Muechler et al.,
1991). They either found a few (in 30%) or numerous follicles
(in 10%) in about 40% of all patients. However, several authors
reported pregnancies occurring in patients with negative
biopsies (Sutton, 1974; Polansky and Papp, 1976; Shangold
et al., 1977). So to date, biopsies are not helpful in predicting
the potential of a patient to become pregnant.
Subsequently, it was reported that in 4160% of patients
with POF, follicle-like structures may be visualized in the
ovaries with pelvic ultrasonography (Mehta et al., 1992;
Nelson et al, 1994; Conway et al., 1996). It was concluded
3
To whom correspondence should be addressed
484 Y.M.van Kasteren and J.Schoemaker
(Nelson et al., 1994) that these follicles did not function
normally, as there was a poor correlation between serum
oestradiol concentration and follicular diameter. Six patients
subsequently underwent biopsy of the antral follicles, and all
biopsies showed luteinized follicles. Hence, it was postulated
that premature luteinization may be the major
pathophysiological mechanism in idiopathic POF. However,
premature luteinization may be induced by diminished
negative feedback on luteinizing hormone (LH) as a
consequence of poor follicle performance, either in number or
quality. As such, luteinization would not be the central
pathophysiological mechanism, but rather a secondary
phenomenon. Furthermore, as primordial follicles are too small
to be detected with ultrasonography, patients with the resistant
ovary syndrome cannot be identified with ultrasonography.
Ovarian ultrasonography has not proven to be useful in
predicting the potential for pregnancy.
As autoimmunity may play a role in POF, detection of
autoantibodies has also been used as a screening tool. The
assumption that POF might be an autoimmune disease is based
on four observations. Firstly, POF is associated in some
patients with other endocrinopathies with a known auto-
immune cause, e.g. Addisons disease, autoimmune thyroiditis
and myasthenia gravis (Edmonds et al., 1973; Irvine and
Barnes, 1976; Coulam et al., 1981). Secondly, there is a high
prevalence of autoantibodies in POF patients (Mignot et al.,
1989b; Rabinowe et al., 1989; Luborsky et al., 1990; van
Weissenbruch et al., 1991). Thirdly, changes in lymphocyte
subsets have been found (Mignot et al., 1989a; Nelson et al.,
1991; Hoek et al., 1995). Finally, some authors have
demonstrated lymphocyte and plasma cell infiltration around
developing follicles in ovarian biopsies (Gloor and Hulimann,
1984; Sedmak et al., 1987). However, we do not know whether
these phenomena are causative or merely epiphenomena.
Moreover, autoantibodies have no predictive value with respect
to the possibility to conceive. Nonetheless, the presence of
autoantibodies can be helpful in counselling patients, as
autoantibodies against thyroid and adrenal cortex can precede
the autoimmune disease by several years.
Genetic screening can reveal cytogenetic abnormalities,
usually of the X-chromosome. Although this will not predict
pregnancy potential in the index patient, it can be of great
importance with respect to the future fertility of female
relatives, particularly daughters of the index patient (Davison
et al., 1998).
To date, there are no tools available to categorize adequately
the majority of POF patients according to aetiological factors,
the presence of oocytes, or the potential to achieve a pregnancy.
Consequently, therapeutic interventions have been directed
towards a heterogeneous group of POF patients, usually but not
always of idiopathic origin. Numerous case reports have shown
that pregnancy can occur in POF patients (Table II). It is
doubtful, however, whether alleged therapeutic interventions
played a role, as many pregnancies have been reported to occur
spontaneously (Table II). Thus, we searched the literature for
evidence to support a real effect of any therapy, with respect to
resumption of ovulation, and improvement of pregnancy rates
in POF patients.
Table I. Aetiology of premature ovarian failure
Type of condition Cause Effect
Iatrogenic Radiation exposure
1
Chemotherapy
1
Extensive surgery
1
Oocyte pool decreased by
destruction
Infections Severe PID?
1
Mumps in fetus and adult?
1,2
Oocyte pool decreased by
destruction
Enzyme deficiencies Galactose-1-phosphate uridyl-
transferase (galactosaemia)
3,4
17--hydroxylase
5,6
17-20 desmolase
5
Toxic metabolites?
Aberrant FSH?
Lack of substrate
Lack of substrate
Genetic: cytogenetic XO Turner syndrome
7
Mosaicism
Deletions/inversions
8,9
Probably accelerated atresia
Accelerated atresia?
Genetic: gene mutations FSHR gene on 2p
10
FRM1 gene on X
11,12
Non-functional receptor
Unknown
Autoimmune Cell-mediated
13,14
Autoantibodies
15
Destruction
Destruction or blocking FSH/LH
receptor
Idiopathic Migration disturbed?
Proliferation failure?
Accelerated atresia?
Autoimmune related?
1
Conway, 1997;
2
Morrison et al., 1975;
3
Kaufman et al., 1986;
4
Waggoner et al., 1990;
5
Anasti, 1998;
6
Neuwinger et al., 1996;
7
Singh and Carr 1966;
8
Therman et al., 1990;
9
Sala et al., 1997;
10
Aittomaki et al, 1996;
11
Conway et al., 1998;
12
Partington et al., 1996;
13
Gloor and Hulimann, 1984;
14
Sedmak et al., 1987;
15
van Weissenbruch et al., 1991.
Review on therapies to restore ovulation in POF 485
Table II. Case reports
Intervention No. of studies No. of patients pregnant
No therapy
19
9 11
Clomiphene citrate (CC)
10
1 1
Gonadotrophins (HMG)
11
1 1
Oestrogens
7,

1232
23 32
Oral contraceptives
21,33
2 2
Oestrogens + HMG
34
1 1
Oestrogens + CC
35
1 1
GnRH-a
36
1 1
GnRH-a + HMG (IVF-ICSI)
37
1 1
GnRH-a + HMG + oestrogens
38,39
2 1
GHRH + GnRH-a + HMG
40
1 0
Corticosteroids oestrogens
4147
7 3
Hypophysectomy HMG/oestrogens/CC
48,49
2 3
Total 52 59
GHRH = growth hormone-releasing hormone; GnRH-a = gonadotrophin-releasing hormone agonist; HMG = human
menopausal gonadotrophin; ICSI = intracytoplasmic sperm injection; IVF = in-vitro fertilization.
1
Behrman, in Keetel
and Bradbyary, 1964;
2
Wright and Jacobs, 1979;
3
Jeppsson et al., 1980;
4
Hammerstein and Rommler, 1980;
5
Friedman et al.,1983;
6
Alper et al., 1986;
7
Kocijancic and Meden-Vrtovec, 1987;
8
Menashe et al., 1996;
9
Gucer
et al., 1997;
10
Nakai et al., 1984;
11
Johnson and Peterson,1979;
12
Polansky and Papp, 1976;
13
Shapiro and Rubin,
1977;
14
Shangold et al., 1977;
15
Rosenwaks et al., 1978;
16
Starup et al., 1978;
17
Szlachter et al., 1979;
18
Brosens
et al., 1979;
19
Voigt, 1984;
20
Oshawa et al., 1985;
21
Alper et al., 1986;
22
Petsos et al., 1986;
23
Le Pors et al., 1987;
24
Tinga and Lapphon, 1988;
25
Varma and Patel, 1988;
26
Tang and Sawers, 1989;
27
Galache Vega et al., 1989;
28
Lopez et al., 1989;
29
Jacobson et al., 1991;
30
Boulieu and Bully, 1993;
31
Helie et al., 1996;
32
Chen and Chang,
1997;
33
Check et al., 1989;
34
Amos, 1985;
35
Davis and Ravnikar, 1988;
36
Ishizuka et al., 1992;
37
Hellebaut et al.,
1998;
38
Letterie and Miyazawa, 1989;
39
Ishizuka et al., 1997;
40
Busacca et al., 1996;
41
Meldrum et al., 1980;
42
Coulam et al., 1981;
43
Bateman et al., 1983;
44
Finer et al., 1985;
45
Rabinowe et al., 1986;
46
Cowchock et al.,
1988;
47
Taylor et al., 1989;
48
Okuda et al., 1989;
49
Check, 1990.
Reported pregnancies and livebirths in POF
patients
An electronic search was performed on Medline over the
period from January 1966 to February 1999. The search terms
were: premature menopause, premature ovarian failure,
premature gonadal failure, hypergonadotrophic ovarian failure,
hypergonadotrophic amenorrhoea, and hypergonadotrophic
hypogonadism, with controlled, randomized, therapy,
treatment, oestrogens, gonadotrophin-releasing hormone
(GnRH) analogues, LH-releasing hormone analogues, corti-
costeroids, ovulation and pregnancy. In addition, references of
review articles were hand-searched.
We found 52 case reports describing pregnancy or return of
ovulation in patients with POF (Table II). Eight observational
studies mentioned the number of patients that had become
pregnant in a group of POF patients (Table III). Nine
uncontrolled studies reported the number of patients that
became pregnant in association with a specific intervention
(Table IV). Only seven trials appeared to be controlled.
The data of the uncontrolled, controlled and observational
studies were analysed to obtain an estimate of the chance of
pregnancy following diagnosis. The data of all reports were
analysed to determine the chance of a livebirth, when
pregnancy was achieved. Only the data of the controlled trials
were used to estimate the additive effect of treatment.
In the observational studies, 4.8% of all women became
pregnant, in the uncontrolled studies 18%, and in the controlled
studies 1.5%. Overall, 6.3% of all women conceived after
diagnosis. About 80% of the authors gave information on
pregnancy results. In total, 112 pregnancies were available for
analysis. Three pregnancies were terminated on request, 19
resulted in a miscarriage, one in a stillbirth at term, one in a
tubal pregnancy, and five were still ongoing. Thus, 104
pregnancies resulted in the birth of 86 healthy children (three
twin pregnancies). We did not find any reports on congenital
malformations or chromosomal aberrations such as trisomy 21.
Effect of treatment in controlled studies
These seven controlled trials were analysed for methodology,
inclusion and exclusion criteria, patient characteristics, type of
intervention, and results.
486 Y.M.van Kasteren and J.Schoemaker
Table III. Observational studies
Reference No. of No. of patients Follow-up Medication
patients pregnant (years)
OHerlihy et al. (1980) 67 6 15 None
Aiman and Smentek (1985) 35 2 ?10 Oestrogens
Kreiner et al. (1988) 86 3 3 Oestrogens
Rebar and Conolly (1990) 115 8 10 Oestrogens 7; None 1
Eden (1993) 75 5 3 Oestrogens
Sauer (1995) 200 5 28 Oestrogens
Fenichel et al. (1997) 47 4 ? Oestrogens
Conway (1997) 135 4 0.56 None 1; IVF 1; HMG 1;
corticosteroids 1
Total 760 37
HMG = human menopausal gonadotrophin; IVF = in-vitro fertilization.
Table IV. Uncontrolled intervention trials
Reference No. of No. of patients No. of patients Follow-up Therapy
patients with ovulation pregnant
Tanaka et al. (1982) 6 2 1 17 cycles HMG
Ylostalo et al. (1982) 5 3 3 518 cycles Oestrogens
Menon et al. (1983) 4 1 0 1 cycle GnRHa
Boyers et al. (1988) 19 0 0 1 cycle HMG
Ledger et al. (1989) 12 0 0 22 weeks GnRHa
Check (1990) 91 34 19 19 cycles Oestrogens + HMG
9 3 0 GnRHa + HMG
Buckler et al. (1993) 8 0 0 20 weeks OC
Blumenfeld et al. (1993) 15 8 15 cycles Corticosteroids
GnRHa and HMG
Corenblum et al. (1993) 11 2 2 4 weeks Corticosteroids
Total 180 33
GnRHa = gonadotrophin-releasing hormone agonist; HMG = human menopausal gonadotrophin; OC = oral contraceptives.
The methodology of these trials is summarized in Table V.
Six studies were randomized, and five of them described the
method of randomization. One study (Surrey and Cedars,
1989) had no clear design. Patients were assigned to each
treatment group by the investigators, and some participated in
two groups. From the four studies with a cross-over design,
only two (Nelson et al., 1992; Anasti et al., 1994) incorporated
a wash-out period between the two treatment periods.
Inclusion and exclusion criteria of the controlled
trials
A summary of the inclusion and exclusion criteria is given in
Table VI. All studies shared the inclusion criterion of a serum
follicle-stimulating hormone (FSH) concentration >40 mIU/ml,
determined on at least two occasions. However, only two studies
(Surrey and Cedars, 1989; Rosen et al., 1992) included patients
with an amenorrhoea of >12 months duration. Four of the other
studies incorporated women with an amenorrhoea of >4 months
duration. In one study (Taylor et al., 1996), a large proportion
(27%) of the women had an amenorrhoea of only 2 months
duration.
Four studies included primary as well as secondary
amenorrhoea, and the other three only secondary amenorrhoea.
Only in one study (Taylor et al., 1996) were several patients
enrolled with an abnormal karyotype. Exposure to radiation,
chemotherapy or extensive surgery (iatrogenic POF) was not
excluded in this study. In summary, we conclude that the
inclusion and exclusion criteria varied widely.
Review on therapies to restore ovulation in POF 487
Table V. Methodology of seven controlled studies
Reference Design Randomization Blinded Intervention Study duration
Surrey and Cedars
(1989)
Mixed No No HMG after cyclic HRT
versus HMG+oestrogens
versus HMG+GnRHa
512 weeks
Nelson et al.
(1992)
Cross-over Yes, described Yes Rebound phase after
GnRHa+cyclic HRT
versus placebo+cyclic HRT
12 months
Rosen et al.
(1992)
Cross-over Yes, described No HMG versus no therapy
in the rebound phase
after cyclic HRT
89 weeks
Anasti et al.
(1994)
Cross-over Yes, described Yes Rebound phase after
danazol versus combined
HRT
12 months
van Kasteren et al.
(1995)
Parallel-group Yes, described Yes GnRHa + HMG
versus placebo + HMG
15 weeks
Taylor et al.
(1996)
Cross-over Yes, no details No Oestradiol versus
no therapy
12 weeks
van Kasteren et al.
(1999)
Parallel-group Yes, described Yes Corticosteroids + HMG
versus placebo + HMG
2 weeks
GnRHa = gonadotrophin-releasing hormone agonist; HMG = human menopausal gonadotrophin;
HRT = hormone replacement therapy.
Table VI. Inclusion and exclusion criteria of seven controlled studies
Reference Serum FSH/
oestradiol concn
Amenorrhoea Normal karyotype
inclusion criteria
Exclusion of
iatrogenic POF
Surrey and Cedars (1989) >40 mIU/ml Primary + secondary
>12 months
No, <30 years normal
>30 years unknown
Not described
Nelson et al. (1992) >40 mIU/ml Primary + secondary
>4 months
Yes Yes
Rosen et al. (1992) >40 mIU/ml <40 pg/ml Secondary >12 months Yes Not described
Anasti et al. (1994) >40 mIU/ml Primary + secondary
>4 months
Yes Yes
van Kasteren et al. (1995) >40 mIU/ml Secondary >4 months Yes Yes
Taylor et al. (1996) >40 mIU/ml Primary + secondary
>2 months
No, abnormal
karyotype included
No
van Kasteren et al. (1999) >40 mIU/ml Secondary >4 months Yes Yes
FSH = follicle-stimulating hormone; POF = premature ovarian failure.
Patient characteristics in the controlled trials
The characteristics of the patients included in the studies are
presented in Table VII. The mean age ranged from 31 to 34
years between the studies. The median age ranged from 30 to
35 years.
The interpretation of the duration of amenorrhoea is rather
difficult. In two studies (Nelson et al., 1992; Anasti et al.,
1994), this was given as the time between diagnosis and
study-entry, which would be an unreliable estimate in cases
where a long period had elapsed from the start of amenorrhoea
until diagnosis. Nevertheless, we accepted this as an estimate
for the duration of amenorrhoea. The estimate from one study
(Surrey and Cedars, 1989) was calculated by us from their data.
Other authors (van Kasteren et al., 1995, 1999) gave duration
of amenorrhoea as such, meaning the time elapsed since the last
menstrual period; therefore, in their studies oligomenorrhoeic
patients were listed as having an amenorrhoea of 0.3 years,
even if they had been oligomenorrhoeic for many years. In
contrast, in another study (Taylor et al., 1996) the mean
duration of irregular menses (46.6 months) and the duration of
elevated FSH concentration (14.9 months) were clearly stated.
Obviously, a considerable proportion of the study subjects were
only just entering the climacteric, and were not truly
postmenopausal. For the present study, we took the duration of
elevated FSH concentration as the estimate for duration of
amenorrhoea.
488 Y.M.van Kasteren and J.Schoemaker
Table VII. Characteristics of the patients in seven controlled studies
Reference Mean age (years) Mean (range) duration
of amenorrhoea (years)
No. of patients (%) with antibodies
Non-specific Specific
Surrey and Cedars (1989) 32.4 (34
a
) 4.5 (114) 0 2 (14)
Nelson et al. (1992) 33
a
2
a
(0.312) 11 (48) 12 (52)
Rosen et al. (1992) 32 1.4 (12) ND 0
Anasti et al. (1994) 32
a
2
a
(0.410) 24 (52) 8 (17)
van Kasteren et al. (1995) 30.8 (30
a
) 2.6 (0.312) 13 (43)
Taylor et al. (1996) 33.7 1.2 21 (57)
van Kasteren et al. (1999) 33.8 (35.5
a
) 3 (0.314) 19 (53)
a
Values are medians.
ND = not determined.
Table VIII. Results of seven controlled studies on the restoration of ovarian function in premature ovarian failure patients
Reference Patients
included (n)
Cycles,
including
placebo (n)
Patients
ovulating
(n)
Ovulatory
cycles
therapy (n)
Ovulatory
cycles
placebo/ alternative(n)
Pregnancies (n)
Surrey and Cedars (1989) 14 20 1 1 0 0
Nelson et al. (1992) 23 46 4 3 2 1
Rosen et al. (1992) 8 16 3 2 2 0
Anasti et al. (1994) 46 92 10 8 4 0
van Kasteren et al. (1995) 30 30 3 3 0 0
Taylor et al. (1996) 37 70 17 13 11 2
van Kasteren et al. (1999) 36 36 0 0 0 0
Total 194 310 38 30 19 3
In one study (Surrey and Cedars, 1989), only antibodies
against thyroid and adrenal tissue were tested for, while in
another report (Rosen et al., 1992) only patients without
antibodies against thyroid tissue were included. All other
authors tested for a range of organ-specific and non-specific
autoantibodies. The percentage of patients that tested positive
did not vary widely. With regard to the role of autoimmune
phenomena, the patients in these studies seemed to be compar-
able between studies.
In summary, patient characteristics varied with regard to age
at study entry, and duration of amenorrhoea.
Description of the intervention protocol of the
controlled trials
In one study (Surrey and Cedars, 1989), three protocols were
compared: cyclic conjugated oestrogens/medroxy progesterone
acetate (MPA), versus cyclic ethinyloestradiol/MPA, versus the
GnRH agonist (GnRH-a) histerelin. In all three protocols the
dose was increased until adequate suppression of FSH
concentrations (<20 mIU/ml) was reached. As serum oestradiol
concentration was used to monitor follicular activity, cyclic
conjugated oestrogens were discontinued at the start of ovulation
induction with human menopausal gonadotrophin (HMG;
Pergonal

). Ethinyloestradiol was continued at the same dose,

and the GnRH-a at a lower dose. Gonadotrophin therapy was
commenced at 150300 IU daily, increasing to a maximum of
450 IU. The authors evaluated the effect of gonadotrophin
therapy after restoration of a normogonadotrophic status.
In another study (Nelson et al., 1992), a fixed suppression
protocol was used in both treatment groups. One group received
the GnRH-a deslorelin with cyclic oestradiol/MPA for 4 months,
and the other group placebo received cyclic oestradiol/MPA.
Ovarian function was monitored by weekly oestradiol
measurements during a period of 8 weeks after discontinuing all
medication. The authors were interested in a spontaneous
restoration of follicular function as a rebound effect after pituitary
suppression.
In addition, the difference between spontaneous resumption
of ovulation and ovulation induction in the rebound phase after
GnRH-a therapy was evaluated (Rosen et al., 1992). Both
patients groups received increasing doses of leuprolide acetate
until serum FSH was suppressed to <25 mIU/ml. One group
was then started on gonadotrophins (Pergonal

), 150 IU daily,
increasing to 300 IU after 5 days if necessary. Patient
monitoring comprised weekly serum oestradiol measurements.
The spontaneous resumption of ovulation after pituitary
suppression was investigated with a fixed protocol (Anasti et al.,
1994). Patients received either combined oestradiol/MPA or 800
Review on therapies to restore ovulation in POF 489
mg danazol for 4 months. Monitoring consisted of weekly
oestradiol measurements during a period of 8 weeks after
stopping medication. The aim of the study was to examine
differences between pure endocrine suppression
(oestradiol/MPA) and combined endocrine and immune
suppression (danazol) with regard to restoration of ovarian
function.
In a later study (van Kasteren et al., 1995), the effect of
pituitary suppression with a GnRH-a (buserelin) on the ovarian
response to gonadotrophins (Metrodin

) was evaluated. The

GnRH-a or placebo was continued at the same fixed dose
during gonadotrophin therapy, the dose of gonadotrophins
being increased weekly from 150 IU with 150 IU to 450 IU in 3
weeks. The authors evaluated the effect of creating a
normogonadotrophic state before and during ovulation
induction with gonadotrophins.
Subsequently, a study was performed (Taylor et al., 1996) to
address the widely held belief that oestrogen replacement
therapy would enhance resumption of ovulation, and thereby
the chance of pregnancy. Patients received either 2 mg
oestradiol or no therapy at all for 6 weeks. Monitoring
consisted of weekly serum oestradiol measurements and pelvic
ultrasonography.
The effect of immune suppression with corticosteroids on
the ovarian response to gonadotrophin therapy was also studied
(van Kasteren et al., 1999). Patients received either 9 mg
dexamethasone daily, or placebo daily, for 1 week. In the
second week the dose was tapered. Gonadotrophin therapy was
started on day 5 of the immune suppression. Monitoring was
performed with serum oestradiol measurements on alternate
days, and pelvic ultrasonography when a rise occurred in serum
oestradiol concentrations.
Results of the controlled studies
The results of the studies in terms of ovulation and pregnancy
are summarized in Table VIII. None of the studies showed a
statistically significant difference between both (or more) study
groups. Therefore, the results of both groups are depicted in
combined form, except for the number of ovulatory cycles.
The primary endpoint for all studies was ovulation, as
determined by serum progesterone concentration. In one study
(Surrey and Cedars, 1989), the concentration of serum
progesterone was not defined, while in others (Nelson et al.,
1992; Rosen et al., 1992; Anasti et al., 1994) a serum
progesterone concentration >3 ng/ml was regarded as proof of
ovulation. In a later study (Taylor et al., 1996), a concentration
of 4 ng/ml was taken as evidence of ovulation; this group had
chosen a lower concentration than usual in their research
(6 ng/ml) because of the weekly observations. Ovulation was
defined according to urinary pregnanediol excretion of
>3 mol/24 h by one group (van Kasteren et al., 1995), but in a
subsequent study, the criteria for ovulation were not described
as there was a total lack of ovarian response (van Kasteren
et al., 1999).
The criteria for ovulation varied in such a way that
luteinization of unruptured follicles could have been mistaken as
proof of ovulation. Progesterone concentrations in two ovulatory
cycles of 4.2 and 3.2 ng/ml were reported in one study (Rosen
et al., 1992), while in a later study (Anasti et al., 1994) eight
ovulations were found after danazol, compared with four
ovulations after combined hormone replacement therapy (HRT).
However, in eight of these ovulatory cycles (five in the danazol
group, one in the combined HRT group), progesterone
concentrations ranged between 3 and 4 ng/mlconcentrations
which would not have been accepted as proof of ovulation by
many researchers (e.g. Taylor et al., 1996).
In one study (Nelson et al., 1994), one pregnancy resulting
in a miscarriage was reported, while in another study (Taylor
et al., 1996) two pregnancies were reported which occurred
within the study period. Three other women conceived within 8
months after initiation of the study, but after the study was
closed. After 8 months, no other pregnancies ensued (total
follow-up 48 months). Data on the outcome of five pregnancies
in the study by Taylor et al. (1996) were not available.
Conclusions
Due to a strong variability in study design, patient selection and
mode of intervention, it is not possible to combine the data of
the seven studies to perform a meta-analysis. However, some
conclusions can be drawn from these studies. The data again
stress the importance of randomization in trials evaluating
therapeutic intervention, since ovulations occurred almost
always in both study groups. It can be argued that the power of
the studies often was only sufficient to detect large differences
of around 30%. However, most of the studies did not show a
trend, that might have become a significant difference if the
number of patients included had been expanded.
It is striking that, apart from one study (Taylor et al., 1996), a
placebo-only group was not incorporated in any of the studies.
Consequently, we can only conclude that several types of
intervention are equally ineffective. We do not know whether or
not these interventions should be preferred to no therapy at all.
We presume that this phenomenon may be partly related to the
urge to offer more than monitoring alone. Most patients and
physicians would regard no therapy or placebo treatment
combined with monitoring of no additive value to the standard
strategy of expectant management. However, continuous
monitoring of ovarian function in experimental settings may
enhance timed intercourse, and thereby improve the chance of
pregnancy.
The study referred to above (Taylor et al., 1996) did,
however, incorporate a no therapy group, but due to the
liberal inclusion criteria would have needed a larger patient
population and a longer observation period to detect
differences between the groups. In this study, 46% of all
490 Y.M.van Kasteren and J.Schoemaker
patients ovulated, and 14.4% became pregnant during, or at
some time after, the study. Even if one were to consider these
patients as having merely incipient ovarian failure, this seems
to be a high percentage compared with the other data (Scott and
Hofmann, 1995), which referred to an overall pregnancy rate of
5% in patients with an abnormal clomiphene citrate challenge
test and regular cycles in a follow-up of 45 months.
It was found (Taylor et al., 1996) that 10/10 patients with an
amenorrhoea of <2 months duration ovulated (100%), while only
seven of 27 patients (26%) with an amenorrhoea of >3 months
duration did so. This difference was statistically significant (P <
0.001). A trend to fewer ovulations with longer duration of
amenorrhoea could also be observed in the other six studies of
this review.
In the observational studies, 4.9% of all women became
pregnant, compared with 18% in the uncontrolled intervention
studies and 1.5% in the controlled studies. The low pregnancy
rate found in the controlled studies may result, at least partly,
from the short duration of these trials. The statistically significant
higher pregnancy rate in the uncontrolled studies compared with
the observational studies could be attributed mainly to two
studies (Check et al., 1990; Blumenfeld et al., 1993), without
which the difference was not significant (9% versus 4.9%). These
studies each showed a long follow-up, indicating that monitoring
may have had a beneficial effect on the chance to conceive.
However, monitoring per se has not been a subject in controlled
trials. Furthermore, these data probably suffer from a strong
positive publication bias, as uncontrolled studies with negative
results are not likely to be published.
Nevertheless, the combined data of the observational,
uncontrolled and controlled studies tentatively indicate that POF
patients have a 510% chance of conceiving at some time after
diagnosis. The pregnancy loss in these studies was 20%, which is
quite similar to that of the normal population. There is no
evidence that any treatment can improve this pregnancy rate. The
widely held belief, that oestrogens enhance pregnancy in POF
patients, is not substantiated. However, oestrogens certainly do
not seem to be harmful to the reproductive potential.
The controlled studies performed until now have dealt with
most of the theoretically useful approaches. Four out of six
studies have suppressed gonadotrophins in one way or another.
Hence, if premature luteinization were to be the central
mechanism, these studies should have shown better results. Two
studies focused on immunomodulation, though without success.
Nonetheless, corticosteroids may be useful in autoimmune
oophoritis, characterized by the presence of autoantibodies
against steroid-producing cells (Hoek et al., 1997). However, this
form of POF is rare, and it would be practically impossible to
collect enough patients to perform a randomized trial.
Future studies in this area should use strict inclusion criteria.
POF patients represent a heterogeneous group, though this
heterogeneity may be reduced by excluding primary
amenorrhoea, iatrogenic causes, genetic causes, and causes
known to reduce or destroy oocytes, as in galactosaemia. It is
probable that we can only start to select patients adequately when
a reliable method has been found to determine the presence of
oocytes in the ovary. Studies should incorporate a placebo-only
group and, as the data suggest that POF patients do not ovulate
every month, the treatment period should last at least several
months. The primary endpoint should be pregnancy rate rather
than ovulation, because restoration of ovarian endocrine function
may not automatically imply improvement of oocyte quality.
Henceforth, these studies would require a large number of
participating patients in order to have adequate power.
In practical terms, a study which fulfils all these prerequisites
can be executed only in a multicentre setting. More importantly,
we should attempt to explore the factors that determine the
dynamics of the oocyte pool and the quality of the oocyte in
terms of its capacity to produce a healthy child.
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Received on February 15, 1999; accepted on May 28, 1999