REVIEW ARTICLE

An algorithm for treatment of infertile women with

polycystic ovary syndrome
Jennifer F. Kawwass
a,
*
, Tammy L. Loucks
b,1
, Sarah L. Berga
c,2
a
Emory University School of Medicine, Department of Gynecology and Obstetrics, Resident,
69 Jesse Hill Drive, Atlanta, GA 30303, United States
b
Research Projects, Department of Gynecology and Obstetrics, Emory University, 1639 Pierce Drive,
WMB 4208, Atlanta, GA 30322, United States
c
Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive,
N.E., WMB 4208, Atlanta, GA 30322, United States
Received 9 May 2010; accepted 13 July 2010
KEYWORDS
Polycystic ovary syndrome;
Infertility;
Obesity;
Anovulation
Abstract Polycystic ovary syndrome (PCOS) is a common condition with both a reproductive and
metabolic phenotype. Women with PCOS often seek care because of infertility or menstrual cycle
irregularities that result from chronic anovulation interspersed with occasional ovulatory cycles.
Initially, it is important to delineate a differential diagnosis for oligo- or amenorrhea and to eval-
uate for disorders that may masquerade as PCOS. If fertility is a desired goal, then it is critical to
optimize health conditions that impact fertility and gestation. Lifestyle modications, including
nutritional counseling and weight loss, should be a part of all treatment plans. Even minimal
(5%) weight loss in obese women with PCOS improves both ovulation and pregnancy rates. The
rst line of treatment for ovulation induction remains the selective estrogen receptor modulator
(SERM) clomiphene citrate. The role of insulin sensitizers, particularly metformin, remains unclear.
A recent consensus panel recommended against its routine use in the absence of an elevated glucose
or hemoglobin A1c. If a woman fails to achieve pregnancy after a trial of weight loss and six
*
Corresponding author. Tel.: +1 757 470 9322; fax: +1 678 973
2258.
E-mail addresses: jennifer.kawwass@emory.edu (J.F. Kawwass),
tloucks@emory.edu (T.L. Loucks), sberga@emory.edu (S.L. Berga).
1
Tel.: +1 404 727 9109; fax: +1 404 727 8609.
2
Tel.: +1 404 727 8600; fax: +1 404 727 8609.
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ovulatory cycles induced by clomiphene citrate, then ovulation induction with exogenous gonado-
tropin, with or without timed intrauterine insemination, or in vitro fertilitization, is a reasonable
next step. Women with PCOS are particularly prone to excessive follicle development and are at
increased risk for ovarian hyperstimulation syndrome (OHSS). Although limited data exist compar-
ing approaches to ovulation induction or controlled ovarian stimulation in women with PCOS, the
American Society for Reproductive Medicine recommends the use of step-up or step-down
protocols in which a low dose of exogenous FSH or combined gonadotropins are employed in
an attempt to constrain ovarian responsiveness. In vitro fertilization allows for the transfer of only
one embryo or for cryopreservation of all embryos with subsequent transfer of a single embryo in a
subsequent cycle without ovarian stimulation. Countless questions regarding pathogenesis and
treatment of PCOS create opportunity for basic and clinical research and for renement of existing
therapeutic approaches.
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Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Initial evaluation and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. The role of weight loss and behavioral modication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Lifestyle modication and improved outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Optimal diet to achieve weight loss. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Bariatric surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. The role of clomiphene with or without metformin in ovulation induction and subsequent pregnancy. . . . . . . . . . . . . 00
5.1. Clomiphene citrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Clomiphene resistance or failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Gonadotropin assisted Intrauterine Insemination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Laparoscopic ovarian surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. In vitro fertilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Disclosure of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
9. Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction
Polycystic ovary syndrome (PCOS) is a common condition
whose phenotypic manifestations include reproductive and
metabolic features, including increased gonadotropin releasing
hormone/luteinizing hormone (GnRH/LH) drive that results
in a relative suppression of follicle stimulating hormone
(FSH) and amplication of LH, hyperandrogenism of ovarian
origin, insulin resistance with or without frank hyperglycemia,
lipoprotein abnormalities, and a tendency to gain weight (1).
Women with PCOS often present with infertility due to oligo-
or anovulation and, after conception, may be at higher risk for
miscarriage and gestational diabetes (2). Despite progress in
understanding the pathobiology of PCOS over the past twenty
years, many questions persist and treatment remains largely
empirical. Herein we critically evaluate and summarize the cur-
rent literature regarding the treatment of infertile women with
PCOS, focusing specically on roles of weight loss, approaches
to ovulation induction, role of metformin, and indications for
in vitro fertilization (IVF).
2. Pathophysiology
The classical PCOS phenotype is a hyperandrogenic but not
virilized obese woman who reports irregular menses. Endome-
trial sloughing may or may not herald an ovulatory cycle and
may be heavy or light depending on the extent of endometrial
stimulation. Whether there is a single underlying cause of
PCOS remains unclear. Regardless, any pathobiologic expla-
nation of PCOS must account for all the cardinal features,
including hyperandrogenism, insulin resistance, increased
GnRH drive, chronic anovulation with polycystic ovarian
morphology, and a proclivity for weight gain. Insulin resis-
tance without frank hyperglycemia may be difcult to detect
in clinical practice and current practice recommends the use
of hemoglobin A1c (HgbA1c) levels rather than fasting blood
glucose or glycemic challenge paradigms.
Insulin resistance is central to the pathobiology of PCOS.
Insulin drives ovarian androgen production by binding to
insulin-like growth factor (IGF) receptors and thereby aug-
menting theca cell androgen production. Insulin also decreases
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levels of both sex hormone binding globulin (SHBG) and IGF
binding protein-1, which in turn increases androgen availabil-
ity at the tissue or cellular level. Insulin action upon the ovary
is augmented by LH. Women with PCOS display increased
GnRH drive, which manifests as an increased LH pulse fre-
quency and amplitude, decreased FSH secretion, and increased
circulatory LH: FSH ratio. The disproportionately elevated
LH stimulates further androgen production from theca cells
and the relatively insufcient FSH prevents adequate follicular
development. In addition, obesity amplies the conversion of
androgens to estrogens, decreases SHBG, and increases insulin
levels. The net result is a hyperandrogenic, insulin-resistant
environment, in the setting of altered gonadotropin dynamics
that result in oligo- or anovulation and phenotypic manifesta-
tions such as hirsutism and acne (1,3,4).
The PCOS phenotype may be better understood by con-
trasting it to another common cause of anovulation, that of
functional hypothalamic amenorrhea (FHA) or stress-induced
anovulation, a condition attributable to increased sensitivity to
the psychogenic challenges of daily living and energetic stress
from undernutrition or excessive energy expenditure. As
shown in Fig. 1, PCOS can be conceptualized as caloric thrift-
iness conferred by hyperandrogenism in a XX genotypic back-
ground, which may confer stress resistance, while FHA reects
increased adrenal activation in the face of commonplace stress-
ors of daily living.
3. Initial evaluation and diagnosis
Appropriate diagnosis and identication of existing concomi-
tant medical conditions guide the therapeutic approach. Many
conditions either mimic or exacerbate PCOS. Diabetes mellitus,
obesity, medication side effects, Cushings syndrome (adrenal
adenoma that constitutively secretes cortisol) and disease
(pituitary ACTH-secreting adenoma), adrenal and ovarian ste-
roidogenic deciencies such as adult congenital adrenal hyper-
plasia, adrenal and ovarian androgen-secreting neoplasms,
hyperprolactinoma, acromegaly, and other rare metabolic dis-
orders may masquerade or mimic the PCOS phenotype (1,5).
Moreover, it is important to diagnose and treat other possible
deleterious endocrine contributors including stress, under- and
overnutrition, subclinical hypothyroidism (TSH > 2.5 mIU/
L), hyperlipidemia, and frank diabetes (HgbA1c > 6.5%).
Finally, one must not forget toperformstandardizedpreconcep-
tional counseling regarding nutrition, vitamin supplementation,
vaccinations such as rubella, and consideration of genetic vari-
ants such as sickle cell trait or cystic brosis.
A formal diagnosis of PCOS demands that all other condi-
tions be excluded. In practice, it is common to assume the diag-
nosis of PCOS based on presentation and the fact that PCOS
is the most common cause of oligomenorrhea. A history of
chronic oligomenorrhea since menarche, clinical evidence of
androgen excess such as hirsutism or acne or laboratory conr-
mation of androgen excess, with or without polycystic ovarian
morphology on ultrasound, suggests the diagnosis of PCOS.
While the traditional polycystic ovarian morphology is not
required to make the diagnosis, its presence helps to conrm
the impression. However, a polycystic ovarian morphology
on ultrasound is not pathognomonic for PCOS (6). In fact, dif-
ferent criteria for polycystic ovary morphology (PCOM) exist.
The Adams criteria, dened as 10 or more follicles arranged in a
peripheral pattern around a dense core of stroma, confer great-
er sensitivity for PCOS, while those of Jonard et al., which
dene PCOMas 12 or more follicles of 29 mm, convey a great-
er specicity (7). Using both follicle number and ovarian vol-
ume is thought to improve the power of discrimination. As a
result, the Rotterdam criteria (Fig. 2) incorporate both follicle
number of 12 or more and/or an ovarian volume of more than
Figure 1 Dichotomized view of determinants of ovarian compromise contrasting polycystic ovary syndrome (PCOS) with stress-induced
anovulation/functional hypothalamic hypogonadism/amenorrhea (FHA).
Rotterdam Criteria for Diagnosis of PCOS
Diagnosis confirmed by 2 of 3 criteria after exclusion of other etiologies:
1. Oligo and/or anovulation
2. Biomchemical and/or clinical signs of hyperandrogenism
- Biochemical: Total T > 70 ng/dL, Androstenedione > 245ng/dL, DHEA-S >248 ug/dL)
- Clinical: Acne, Hirsutism, acanthosis nigrans
3. Polycystic Ovaries:
- > 12 follicles (2-9mm diameter) in each ovary or ovarian volume > 10cc
Figure 2 Rotterdam Criteria for Diagnosis of PCOS (2).
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10 ml as characteristic of PCOM (8). Interestingly, recent evi-
dence suggests that ovarian volume and follicle number de-
crease with age in both women with PCOS and in controls,
suggesting that age-based criteria may be necessary to better
dene polycystic ovarian morphology (PCOM) (9). Further-
more, the androgen excess and polycystic ovary syndrome
(AE-PCOS) Society, has yet another set of dening criteria;
AE-PCOS Society emphasizes the role of androgen excess
and denes PCOS by hyperadrogenism (hirsutism and/or hy-
perandrogenemia) and ovarian dysfunction (oligo-anovulation
and/or polycystic ovaries) after exclusion of other androgen
excess related disorders (5).
4. The role of weight loss and behavioral modication
Women with PCOS likely have an altered underlying meta-
bolic efciency which increases their tendency to gain weight.
Regardless of the cause, obesity likely amplies the existing
polycystic ovary phenotype. However, obesity is not a diag-
nostic criterion for PCOS. In fact, approximately twenty per-
cent of women with PCOS are not obese (1,8). Nonetheless,
available evidence supports the notion that reduced insulin
action plays a role in the pathophysiology of PCOS in both
the obese and non-obese woman. Weight loss can improve
not only circulating androgen and glucose levels, but also ovu-
lation and pregnancy rates in obese women with PCOS, but
weight loss is only recommended for those who are overweight
with a body mass index (BMI) > 2527 kg/m
2
.
4.1. Lifestyle modication and improved outcomes
The link between lifestyle modication and improved out-
comes in PCOS has been documented over the last three dec-
ades. In 1982, Bates et al. placed 18 obese women with PCOS
on a hypocaloric diet. Mean weight fell from 77 to 57 kg and
mean plasma testosterone fell from 0.75 to 0.39 ng/mL. The
authors did not study resumption of ovulation in these patients
(9). In 1994, Guzick et al. determined whether weight loss in
obese, hyperandrogenic, anovulatory women was associated
with resumption of ovulation and/or with changes in insulin,
androgen, and gonadotropin concentrations. There were
signicant reductions in LH, fasting insulin, and testosterone
levels in 6 women who had been placed on a hypocaloric
(10001500 kcal/day) diet (10). Four of the six women who lost
weight resumed ovulation, while none of the controls showed
change in weight, ovulation, or hormone status; conception
was not an endpoint. Similarly, in 1992 Kiddy et al. noted that
among 13 obese PCOS women who lost 5% or more of their
initial body weight, four resumed regular menstrual cycles, an-
other four conceived, and the majority noted a decrease in hir-
sutism (11). These improvements did not occur in those women
in the study who lost less than 5% of their initial weight. In
1999, Huber-Buchholz et al. noted improved insulin sensitivity
and return of ovulatory function in nine of 15 women placed
on a regimen of diet and exercise (12). Notably, there is no
concrete evidence that dietary modication impacts clomi-
phene response rates.
4.2. Optimal diet to achieve weight loss
There is no denitive evidence regarding the most effective diet
for achieving weight loss and improvement in clinical manifes-
tations of PCOS. Ideally, a member of a multidisciplinary team
including a physician, a nutritionist, and a tness professional
would meet with the patient at weekly intervals. When Moran
et al. enrolled obese women with PCOS to a high- versus low-
carbohydrate diet, they found no signicant difference in the
rate of ovulatory dysfunction (13). In contrast, Kasim-Karakas
et al. argued that protein supplementation confers superior fat-
specic weight loss over carbohydrate supplementation in com-
parable low-calorie diets (14). While negative energy balance
carried reproductive benets for women with PCOS, the contri-
bution of restriction of energy intake versus energy expenditure
via exercise to induce weight loss remains to be determined.
Preliminary evidence suggests that the majority of the repro-
ductive benets likely stem from caloric restriction and that
exercise only improves body composition (15). A knowledge
gap exists regarding the optimal type, duration, and frequency
of exercise. Whether exercise and caloric restriction have a neg-
ative impact on the reproductive axis for women with PCOS
also remains unclear and is likely different in women with
PCOS than in controls due to an underlying altered metabolic
efciency and altered central GnRH drive which may be more
resistant to stress-induced suppression by stressors.
4.3. Bariatric surgery
Recently, bariatric surgery has been advocated as a strategy
for weight loss in the morbidly obese. Two primary ap-
proaches, restrictive and combined restrictive and malabsorp-
tive procedures, adjustable gastric binding and the Roux-en-
Y gastric bypass, are commonly performed. Not surprisingly,
in 17 women with PCOS and a mean BMI of 50.7 kg/m
2
, ba-
riatric surgery resulted in an average loss of 41 9 kg in
12 months and improvements in ovulation, insulin resistance,
hyperandrogenism, and hirsutism (16). Similarly, an observa-
tional cohort study comparing 25 obese (BMI P35 kg/m
2
) e-
umenorrheic women without PCOS who underwent bariatric
that resulted in 25% decrease of initial body weight to 14 nor-
mal weight control subjects revealed an improvement but not
complete normalization of previously decient luteal LH and
progesterone 6 months after bariatric surgery (17). Of note,
women who have had bariatric surgery are at increased
risk for nutritional deciencies including protein, iron, vitamin
B
12
, folate, vitamin D, and calcium; however no con-
sensus exists regarding optimal nutritional screening and
supplementation.
Despite the clear improvements in both clinical and endo-
crine parameters in obese women with PCOS who lose as little
as 6% of their initial body weight, the benets of weight loss
and dietary modication in non-obese women with PCOS
are less well-studied and merit further investigation.
5. The role of clomiphene with or without metformin in ovulation
induction and subsequent pregnancy
Preconception counseling for an overweight woman with
PCOS should begin with thorough education regarding life-
style modication including diet, exercise, and weight loss.
Thereafter, the rst line medical therapy for ovulation induc-
tion remains the selective estrogen receptor modulator clomi-
phene citrate. The therapeutic role of the insulin sensitizer
metformin has received considerable scrutiny; a recent consen-
sus statement recommended against its routine use in women
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who do not display evidence of insulin resistance and hypergly-
cemia (18,19).
5.1. Clomiphene citrate
Countless studies demonstrate the benecial effects of
clomiphene citrate as an agent to induce ovulation and sub-
sequent pregnancy. The live birth rate following 6 months
of clomiphene ranged from 20% to 40% (18,20,21). Further-
more, the majority of pregnancies occurred within the rst six
ovulatory cycles following the initiation of treatment (18). A
typical starting dose is 50 mg given orally for 5 days begin-
ning on the 2nd to 5th day of each cycle or following a pro-
gestin-induced withdrawal bleed, although some advocate the
use of a lower dose of 25 mg for 7 days starting on day 3 of
the cycle to more closely mimic the expected early follicular
phase rise in FSH that causes follicular development
(22,23). A subsequent menses is often interpreted as evidence
of adequate estrogen production and ovulation, however,
bleeding may also be due to endometrial destabilization
resulting from uctuating hormone levels and the direct
anti-estrogenic impact of clomiphene upon the endometrium.
Because of its hypothalamic site of action, clomiphene will be
ineffective in a woman who is hypoestrogenic due to hypo-
thalamic hypogonadism. No clinical or laboratory parameter
accurately predicts the dose at which a patient will most
likely respond, however, the majority of women who re-
sponded to clomiphene did so at either 50 mg (52%) or
100 mg (22%) (21). No clear evidence suggests benet with
higher doses. Similarly, no specic guidelines exist regarding
the number of attempts at a low dose prior to increasing to
the next tier; it is reasonable to increase the clomiphene dose
after 12 anovulatory cycles. Although unusual, if a patient
hyperstimulates at 50 mg, a 12.525 mg/day dose for 7 days
may be offered (22,23). The goal is for FSH to just barely ex-
ceed the threshold needed to elicit follicular development to
the FSH-independent stage. While the maximum Food and
Drug Administration approved daily dose is 150 mg, higher
doses (150250 mg) may sometimes succeed when lower doses
fail. Use of these higher doses does, however, require height-
ened awareness of a possible increased risk of drug-related
side effects such as visual changes and of OHSS; the absolute
risk remains low. Moreover, although ultrasound monitoring
is unnecessary to ensure a good outcome, many centers mon-
itor at least one cycle to evaluate ovarian response, conrm
follicular develop, and adjust the dose (18). Similarly, a timed
progesterone (day 21) greater than 3 ng/ml conrms ovula-
tion; higher progesterone levels and having more than one
follicle develop indicate that the clomiphene is having the in-
tended effect. Because other therapies exist and the probabil-
ity of conception declines if conception does not occur within
six ovulatory cycles, it is unreasonable to continue
clomiphene indenitely. Additionally, questions persist
regarding both the impact of clomiphene on the endometrium
and the long-term sequelae to both the woman and her fetus;
metabolites of the drug are detectable for as long as 6 weeks
after administration. After 36 cycles without conception,
particularly in a woman over 35 years of age, it is prudent
to recommend more aggressive interventions. Of note, other
anti-estrogens such as letrozole and tamoxifen appear equally
effective as clomiphene for ovulation induction in preliminary
trials. However, neither of these drugs is approved for use for
infertility and their use for ovulation induction should be
considered off-label use that merits further investigative
prospective randomized controlled trials (1,24).
5.2. Metformin
The rationale for use of metformin either alone or in conjunc-
tion with clomiphene for ovulation induction stems from a
1998 randomized control trial by Nestler et al. in which obese
women (BMI > 28) with PCOS were randomized to metfor-
min or placebo in Phase 1 and received clomiphene in Phase
2 if they failed to ovulate during the rst phase. Ninety percent
of the metformin plus clomiphene citrate group ovulated com-
pared to only 8% of the group receiving clomiphene alone
(25). A study by Glueck et al. in 1999 supported the benecial
effects of metformin; 91% of a cohort of oligomenorrheic,
infertile women reported the resumption of regular menses
after 612 months of metformin (26). A randomized control
trial performed by El-Biely and Habba in 2001 compared com-
bination clomiphene and metformin to metformin alone in 90
patients. Combination therapy conferred a pregnancy rate of
29% versus 8% in the single therapy group (27). In addition,
a 2003 Costello and Eden meta-analysis of nine observational
trials comprising mostly obese women revealed statistically sig-
nicant overall improvement in menstrual regularity with met-
formin compared to placebo. Notably, individual trial
participants were selected independent of insulin resistance.
In addition, there was no evidence of overall increased preg-
nancy rates in this analysis (28). Moreover, Palomba et al. per-
formed a randomized trial (n = 100) comparing clomiphene
and metformin. The live birth rate was 26/50 (52%) after
6 months of metformin alone compared to 9/50 (18%) after
therapy with clomiphene alone. Of note, this study excluded
women with a BMI >30 kg/m
2
or who were greater than
34 years old (29).
Despite initial evidence favoring the use of metformin for
ovulation induction in women with PCOS, more recent nd-
ings suggest that the insulin-sensitizing agent does not signif-
icantly improve pregnancy rates and is poorly tolerated due
to gastrointestinal side effects. The tide began to turn against
the universal use of metformin in 2006 when Moll et al. pub-
lished a trial comparing pregnancy rates in patients random-
ized to receive clomiphene plus metformin or clomiphene plus
placebo. The results revealed no signicant differences in
rates of ovulation, ongoing pregnancy, or spontaneous abor-
tion (29). Subsequently, in 2007 Legro et al. published the
largest randomized control trial to date comparing the two
drugs taken alone or in combination. This was a multi-center,
NIH-funded trial of 626 women with PCOS at 14 centers in
the United States and was conducted with the goal of deter-
mining the independent effects of metformin and clomiphene
in women with PCOS. Live births were signicantly higher in
the group taking only clomiphene (47/209, 22.5%) than in
those taking only metformin (15/208, 7.2%), and the addition
of metformin to clomiphene therapy did not signicantly im-
prove outcome (56/209, 26.8%). Of note, there was a 6% rate
of twin gestation in the clomiphene alone group and 0% in
the metformin alone group (18). In 2008, Moll et al. con-
rmed the NIH network trial ndings in a double-blind ran-
domized control trial. The investigators evaluated pregnancy
rates in 225 patients randomized to receive clomiphene plus
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metformin or clomiphene plus placebo. There was no overall
added benet with metformin-containing therapy; however
subgroup analysis did reveal higher pregnancy rates in the
clomiphene plus metformin arm in women over 28 years
old with increased waist-hip-ratio (P0.85), likely reecting
the relationship between pre-existing insulin resistance and
efcacy of insulin-sensitization therapy (20). Support for
widespread metformin use continued to decrease following
the Zain et al. 2008 analysis of 150 Asian women with newly
diagnosed PCOS. This 3-arm randomized control trial (met-
formin alone, clomiphene alone, or metformin + clomiphene)
powered to show a 15% difference in ovulation rate reported
higher, statistically signicant increases in ovulation in both
the clomiphene alone (59%, p = .002) and metformin plus
clomiphene (68%, p = .001) groups as compared to the met-
formin arm (24%); adding metformin increased the ovulation
rate but not in a statistically signicant manner (p = .74)
(21). Moreover, pregnancy (PR) and live birth rates (LBR)
in the metformin plus clomiphene arm (PR = 21.1%,
LBR = 18.4%) and clomiphene arm (PR = LBR = 15.4%)
as compared to the metformin arm (PR = LBR = 7.9%)
were increased but not statistically signicantly so; admittedly
the study was not powered to detect differences in pregnancy
and live birth rates. Furthermore, a 2010 Cochrane review re-
vealed no difference in live birth rate when metformin was
used either alone or in combination with other drugs to in-
duce ovulation (19).
In summary, clomiphene remains the rst-line agent for wo-
men with PCOS seeking fertility; there is minimal evidence to
support the use of metformin alone for ovulation induction in
women with PCOS, particularly when the desired goal is preg-
nancy and not simply resumption of menses. An argument ex-
ists for the addition of metformin in some women, namely
those with clinically signicant insulin resistance and hypergly-
cemia (Hgb A1c > 6.5 or impaired fasting serum glucose
100125 mg/dl). Given these considerations, it is not surprising
that a 2008 consensus published in Fertility and Sterility rec-
ommended against the routine use of metformin except in wo-
men with elevated glucose or Hgb A1c (24).
6. Clomiphene resistance or failure
6.1. Gonadotropin assisted Intrauterine Insemination
If a woman with PCOS fails to achieve pregnancy after a
trial of weight loss and six cycles of clomiphene citrate,
exogenous gonadotropin induction with or without intra-
uterine insemination is a reasonable next step. Women with
PCOS have a larger cohort of FSH sensitive follicles com-
pared to those without PCOS. Thus, women with PCOS
are particularly prone to excessive follicle development and
are at increased risk for ovarian hyperstimulation syndrome
(OHSS) (30). Because of this risk, the American Society for
Reproductive Medicine (ASRM) recommends low-dose gon-
adotropin protocols. Low-dose protocols may be step-up
or step-down or combination regimens. Step-up ovulation
induction protocols initiate treatment with a lower dose of
FSH (37.550 IU/day) and gradually increases the dose over
a 14 day period until the FSH threshold needed to initiate
folliculogenesis is exceeded as evidenced by follicular activity
on ultrasound and rising estradiol levels. Step-down proto-
cols begin with a higher initial dose of FSH aimed at sur-
passing the FSH threshold needed for folliculogenesis and
then gradually reducing FSH below the threshold once fol-
licular production is noted. Initially both protocols were
shown to produce comparable rates of monofollicular devel-
opment, however, the largest studies to date suggested that
the step-up regimen may be safer with regards to monofol-
licular development and may be easier to monitor (31,32).
Additionally, the two protocols can be combined by gradu-
ally increasing the dose of gonadotropins until a response is
observed, and then decreasing the dose once a dominant fol-
licle has emerged. Once a follicle or follicles have reached a
sufciently mature stage, the granulosa cells and follicular
apparatus become FSH independent and LH dependent. In
a proof of principle, Sullivan et al. demonstrated during
controlled ovarian stimulation that switching from FSH to
LH once the follicle or follicles exceeded 14 mm in size al-
lowed only the larger follicles to continue to develop (33).
This variation of a step-down approach elegantly minimizes
the risk of OHSS because the decrement in FSH deprives
only the smaller follicles and the larger follicle or follicles
continue to develop to the pre-ovulatory stage, when ovula-
tion can be triggered by exogenous LH, GnRH agonist, or
hCG. However, this latter approach has not been tested in
large-scale trials in women with PCOS.
Unlike clomiphene induction, gonadotropin induction re-
quires close ultrasound monitoring to detect follicle growth
and to thereby minimize the risk of OHSS and multiple
gestation. The recommended threshold for cycle cancella-
tion has grown more stringent with time. Current recom-
mendations suggest withholding human chorionic
gonadotropin (hCG) administration in the presence of more
than two follicles >16 mm or more than one follicle
>16 mm and two additional follicles >14 mm or if serum
estradiol levels are between 1000 and 2500 pg/mL, particu-
larly in women <38 years old without any other infertility
factors (24). Overall, low-dose regimens resulted in a mono-
follicular ovulation rate of approximately 70%, a pregnancy
rate of 20% per cycle and a multiple live birth rate of
5.7% while maintaining a low incidence of multiple preg-
nancies (<6%) and OHSS (<1%) (34,35). Conversely, clo-
miphene resulted in an ovulation rate of approximately
80%, an overall pregnancy rate of 3043%, and a twin rate
of 510% (36).
6.2. Laparoscopic ovarian surgery
Of note, in clomiphene insensitive women who are unable to
comply with the close monitoring necessary for gonadotropin
administration, bilateral laparoscopic ovarian surgery (LOS)
with monopolar electrocautery or laser is an acceptable alter-
native; both modalities confer similar results (37). Approxi-
mately 50% of anovulatory women with PCOS treated with
LOS will ovulate within 12 weeks; the remaining 50% will re-
quire adjuvant therapy with clomiphene (38). Of note, a 2009
randomized control trial (n = 72) comparing LOS to clomi-
phene in anovulatory, treatment-naive women with PCOS
showed increased though not statistically signicant pregnancy
rates in the clomiphene group (44% clomiphene v. 27% LOS,
p = 0.13). Of note, the study was not adequately powered sec-
ondary to loss of 7 patients who conceived prior to enrollment
(36).
6 J.F. Kawwass et al.
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7. In vitro fertilization
Because of the increased risk of multiple gestation (up to 10%)
with gonadotropin induction in anovulatory women with
PCOS, IVF is a reasonable alternative for women seeking
pregnancy. IVF with single embryo transfer signicantly re-
duced the risk of multiple gestation (39). In vitro fertilization
allows the placement of only one embryo or for cryopreserva-
tion of all embryos with transfer of a single embryo in a sub-
sequent cycle with endometrial but not ovarian stimulation
IVF. Several stimulation protocols have been published for
the treatment of patients with PCOS undergoing IVF includ-
ing combinations or isolated use of clomiphene, human meno-
pausal gonadotropins (hMG), recombinant FSH, GnRH
agonists, and GnRH antagonists (4042). According to the
2008 ASRM consensus conference, the most commonly em-
ployed protocol is a long FSH desensitization protocol in
which an agonist is started in the early, mid-, or late luteal
phase in the preceding cycle or in the follicular phase until
hCG administration. Stimulation with gonadotropins is
started when pituitary and ovarian suppression has been
achieved (24). Clearly, additional randomized controlled trials
(RCTs) comparing the relative risks and merits of various
induction protocols are warranted to elucidate which protocols
are better in general or for determining which patient factors
should guide the choice of protocols. As a general principle
of study design, RCTs should defend in advance what will
be considered a clinically signicant difference and then the
study should be powered to detect that difference. Unfortu-
nately, most studies do not meet these criteria and this explains
why we have a large body of largely uninterpretable informa-
tion that leaves clinicians and patients alike without reliable
guidance. In the absence of reliable knowledge, clinicians run
the risk of dogmatism and therapies run the risk of empiricism.
Algorithm for Treatment of Infertile Woman with PCOS
Woman with
oligomenorrhea &
infertility
Exclude all other etiologies
Screen: Diabetes (Intervene if Hgb A1C >6.5)
Consider metformin if A1C elevated
Hyperlipidemia
Hypothyroidism (Goal: TSH <2.5)
Optimize lifestyle
Routine prenatal counseling and vaccination
Obese woman
with PCOS
Weight loss (diet and exercise) if BMI >27 kg/m
2
Routine infertility evaluation
Evaluate and correct abnormalities:
Tubal patency, endometrial cavity, male factors
If oligo-ovulation,
initiate ovulation induction
Clomiphene citrate up to 6 cycles
If high risk for OHSS
IVF
If develops OHSS
If fails LOS or Gnt
enous
Gonadotropins
If clomiphene-resistant
Laparoscopic Exog
Ovarian
Surgery IUI
Figure 3 Algorithm for treatment of infertility in women with polycystic ovary syndrome (PCOS). IUI = intrauterine insemination,
IVF = in vitro fertilization, LOS = laparoscopic ovarian surgery, COH = controlled ovarian hyperstimulation, OHSS = ovarian
hyperstimulation syndrome. Gnt = gonadotropin induction of ovulation.
An algorithm for treatment of infertile women with polycystic ovary syndrome 7
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8. Conclusion
When treating obese women with polycystic ovary syndrome
who desire fertility, a basic step-wise protocol can be fol-
lowed (Fig 3). The primary aim is to utilize the least technol-
ogy necessary to achieve the desired result. Technology is
favored when it is the only option or when its use will min-
imize risks while maximizing outcomes. Cost often plays a
role in the decision analysis. Direct costs are those which
can be readily identied during the course of treatment.
Undocumented costs include the general risks such as prema-
turity from multiple gestation and the long-term sequelae of
prematurity to offspring and society. Ideally, patients should
focus on weight loss, diet, and lifestyle modication regard-
less of the next therapeutic steps to promote overall health,
including prenatal health. The eld of fetal origins of adult
disease has revealed a multiplicity of mechanisms through
which maternal state has profound consequences for the later
adult health of the fetus (15), so optimizing health in advance
of conception makes sense. Once the patient has been given a
chance to optimize her and her partners health, treatment
can progress to ovulation induction with clomiphene citrate
for up to six months. In clomiphene-resistant patients, the
next step could include exogenous gonadotropin administra-
tion followed by either intrauterine insemination or in vitro
fertilization or laparoscopic ovarian diathermy. Despite a
multiplicity of guidelines, the wise practitioner remembers
that a patient-tailored approach requires a nuanced under-
standing of the patients health to delineate appropriate op-
tions. Countless questions regarding the pathogenesis and
treatment of polycystic ovary syndrome persist making fur-
ther research and clinical trials imperative if we are to im-
prove existing guidelines.
Disclosure of interests
No interests to disclose.
Acknowledgements
Dr. Bergas research related to this review was supported in
part by grants to SLB from NIMH/NIH R01-MH50748, from
NICHD/NIH as part of the Specialized Cooperative Centers
Program in Reproduction Research through cooperative
agreement U54 HD08610 (Project I-PI SLB, Program Director
Tony Plant), and by grant NIH RR-00056 to the General
Clinical Research Center of the University of Pittsburgh.
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