CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 62, Number 2, 271–281

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Contemporary
Management of
Polycystic Ovarian
Syndrome
LILLI D. ZIMMERMAN, MD, ROBERT SETTON, MD,
NIGEL PEREIRA, MD, and ZEV ROSENWAKS, MD
The Ronald O. Perelman and Claudia Cohen Center for
Reproductive Medicine, Weill Cornell Medicine, New York,
New York

Abstract: PCOS remains one of the most intriguing
endocrine disorders that physicians encounter even though
it was first described over 80 years ago. Although the
diagnostic criteria, nomenclature, and ideal therapeutic
strategies are areas of active and ongoing debate, there is
no doubt that we have made tremendous progress in
improving the quality of life and reproductive outcomes of
women who suffer from this wide-ranging disorder.
Key words: PCOS, polycystic ovarian syndrome,
management, fertility
polycystic-appearing ovarian morphol-
ogy. Although it has now been over
80 years since Stein and Leventhal1 first
described this clinical syndrome and it is
one of the most common endocrinopa-
thies encountered by gynecologists, its
pathophysiology is still not completely
understood and it has no universally
accepted definition.

Introduction
Polycystic ovary syndrome (PCOS) is a
heterogeneous and enigmatic disorder
that is typically characterized by the
presence of a combination of ovulatory
dysfunction, hyperandrogenism, and
Correspondence: Nigel Pereira, MD, Weill Cornell Med-
ical College, The Ronald O. Perelman and Claudia Cohen
Center for Reproductive Medicine, 1305 York Avenue, 6th
Floor, New York, NY. E-mail: nip9060@med.cornell.edu
L.D.Z. and R.S. contributed equally.
The authors declare that they have nothing to disclose.
Diagnosis of PCOS
Three expert groups have proposed separate
criteria for the diagnosis of PCOS. The
earliest proposed criteria were by the NIH
in 1990 which required the presence of
oligomenorrhea or amenorrhea and clinical
or laboratory evidence of hyperan-
drogenism.2 These criteria were extended
further in the most widely used diagnostic
criteria, the Rotterdam Consensus Criteria,3
which requires 2 of 3 features: oligom-
enorrhea or amenorrhea, clinical or labora-
tory evidence of hyperandrogenism, and

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 62 / NUMBER 2 / JUNE 2019

www.clinicalobgyn.com | 271
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272 Zimmerman et al
polycystic-appearing ovaries on ultrasound
(defined as > 12 follicles between 2 and 9
mm in diameter in at least one ovary or an
ovarian volume > 10 cm3). Finally, the
2006 Androgen Excess Society requires the
presence of hyperandrogenism and ovarian
dysfunction, which can either be oligome-
norrhea or polycystic-appearing ovaries or
both.4
Notably, in 2012 an NIH consensus
panel recommended that the 2003 Rotter-
dam criteria be adapted but with the
caveat that different phenotypes be utilized
(Phenotype A-D) that are based on which
of the criteria qualify the patient for the
diagnosis of PCOS.5 Furthermore, they
suggested that “the name ‘PCOS’ is a
distraction and an impediment to prog-
ress” and that a new name assignment is
warranted for the syndrome that would
capture its complexity and impact on
metabolism, endocrinology, and reproduc-
tion. Indeed, numerous experts and con-
sensus groups are working on reorganizing
and restructuring the syndrome to devise a
nomenclature and classification that better
fits the spectrum of the disease. Previous
suggestions have included hyperandrogen-
ic chronic anovulation,6 metabolic repro-
ductive syndrome,7 and more recently as
polyfollicular ovarian syndrome with met-
abolic features or polyfollicular syndrome
with metabolic dysfunction and/or hyper-
androgenic manifestations.8
As there are competing diagnostic criteria
for defining PCOS, the incidence of the
disease will vary depending on the criteria
being used. With the widely used and most
expansive and inclusive Rotterdam criteria,
the prevalence ranges from 5% to 20% of
the population.9 Using the 1990 NIH cri-
teria, the prevalence is reported to be 5% to
10% and with using the Androgen Excess
Society the prevalence is 10% to 15%.9
Evaluation of PCOS
Patients with PCOS may clinically present
with a variety of symptoms including
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hyperandrogenism, menstrual disorders,
metabolic dysfunction, and infertility. The
most common presenting feature of hyper-
androgenism is hirsutism. Hirsutism is
identified by the presence of excess terminal
hairs that grow > 5 mm in length in a male-
like pattern of distribution over the body
(upper lip, chin, midsternum, upper and
lower abdomen, upper and lower back,
and buttocks). It can be clinically quanti-
fied using the Ferriman and Gallwey,10 or
a modified Ferriman and Gallwey score
which takes into consideration the patient’s
ethnic background.11,12 In addition to
hirsutism, other manifestations of hyper-
androgenism in women with PCOS may be
acne or, to a lesser degree, androgenic
alopecia.13 Although there is little utility
in obtaining circulating androgen levels in
patients who are overtly hirsute, there is a
value of measuring biochemical androgen
levels in many cases. A total testosterone
level and free testosterone level should be
assessed, and DHEA-S and androstene-
dione levels can be considered as well,14
though care must be taken to interpret
these values appropriately.
Menstrual disorders are commonly de-
scribed as irregular, infrequent, or scant
or absent menstrual bleeding that often is
an extension of postmenarche menstrual
irregularity that never normalized. How-
ever, in some women the menstrual man-
ifestations may present in adulthood as
well. Notably, the presence of regular
menstrual cycles does not exclude PCOS
as cycles may become regular as women
with PCOS age in some cases.15 With
both menstrual dysfunction and hyper-
androgenism, the severity of symptoms
directly correlates with the degree of
insulin resistance.16,17 Infertility ensues
primarily because of anovulation or
oligo-ovulation.
The classical ovarian morphology
(Fig. 1) detected on transvaginal ultra-
sonography is that of an increased num-
ber of antral follicles or an increased
ovarian volume as delineated by the
 Contemporary Management of PCOS
FIGURE 1. Transvaginal ultrasonography highlighting classic polycystic ovarian morphology.
Rotterdam consensus conference as
stated above. It should be emphasized
though that polycystic-appearing mor-
phology alone should not be regarded as
indicative of PCOS as it is frequently
found in otherwise normal young women
in the general population.
A clinical suspicion of PCOS should be
raised in any woman who presents with
signs or symptoms of hirsutism or oligome-
norrhea. The subsequent assessment will
attempt to diagnose the condition based on
the established diagnostic criteria and iden-
tification of the specific phenotype as differ-
ence phenotypes are associated with
varying degrees of metabolic or other types
of dysfunction. The differential diagnosis
of PCOS must include other causes of
androgen excess and ovulatory dysfunction
such as thyroid disease, prolactin disorders,
nonclassical forms of congenital adrenal
hyperplasia, exogenous androgens, andro-
gen-secreting tumors, genetic defects
of insulin action, Cushing syndrome, and
primary hypothalamic and primary ovarian
dysfunction.18
In the evaluation of a patient with
suspected PCOS, a detailed history should
be obtained with emphasis on the onset and
duration of symptoms of menstrual dys-
function and androgen excess, and medi-
cation history. As part of the physical
examination, a waist circumference should
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273
be obtained and a careful body inspection
performed to detect the presence of acne,
hirsutism, central obesity, alopecia, clito-
romegaly, and acanthosis nigricans. Pelvic
examination may reveal ovarian enlarge-
ment. Transvaginal pelvic ultrasonography
is important in the evaluation of women
with suspected PCOS as polycystic-appear-
ing ovaries are a component of most
diagnostic criteria. All women should be
screened for metabolic syndrome which is
defined as: elevated blood pressure ≥ 130/
85 mm Hg, increased waist circumference
≥ 35 inches, elevated fasting glucose ≥ 100
mg/dL, decreased HDL less than or equal
to 50 mg/dL, and elevated triglyceride level
≥ 150 mg/dL.19
The initial laboratory biochemical
evaluation in women or adolescents who
present with symptoms concerning for
PCOS should include a serum total tes-
tosterone, sex hormone binding globulin
(SHBG), and free testosterone. Free tes-
tosterone is more sensitive than total
testosterone for detection of hyperandro-
genism; however, it is only more reliable if
calculated from total testosterone and
SHBG (as opposed to measuring free
testosterone directly by equilibrium dial-
ysis). There are no established androgen
level cutoffs that would suggest an andro-
gen-secreting tumor.20 As PCOS is a
diagnosis of exclusion, a laboratory
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274 Zimmerman et al
work-up for other causes of hyperandro-
genemia and non-androgenic causes of
anovulation is warranted. Obtaining a
serum hCG, FSH, LH, prolactin, and
TSH are appropriate as an initial step,
as well as an early morning follicular
phase 17-hydroxyprogesterone (17-OHP)
to rule out nonclassical congenital
adrenal hyperplasia because of 21-
hydroxylase deficiency in appropriately
selected patients (for example, in at-risk
populations such as Ashkenazi Jews).
A truly elevated 17-OHP should be
followed-up with an ACTH stimulation
test.21 Rare disorders such as Cushing
syndrome or acromegaly can be consid-
ered in the appropriate clinical context.
A slightly elevated LH to FSH ratio is
common in PCOS because of increased
LH concentrations and low-normal FSH
concentrations.22 The increase in serum
LH is a consequence of an abnormal LH
secretory mechanism in which there is an
increase in LH pulse frequency and am-
plitude in patients who are anovulatory.
The decreased in FSH is because of a
concurrent increase in GnRH pulse fre-
quency and negative feedback effects of
elevated estrogen levels derived from pe-
ripheral aromatization and from in-
creased inhibin B levels. Abnormal
thyroid function may alter testosterone
levels by altering SHBG levels and ele-
vated prolactin may be caused by a
prolactinoma. DHEA-S is another useful
biochemical marker as when it is elevated
it suggests an androgen-secreting tumor
most likely originating from the adrenal
gland. Although elevated AMH levels
have been associated with PCOS, there
are no cutoff values that are currently
established that would aid in the diagnosis
of PCOS.
Insulin resistance and an abnormal
compensatory hyperinsulinemia are key
features of the pathophysiology of PCOS
and these features result in an increased
risk of impaired glucose tolerance
and type 2 diabetes mellitus in these
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patients.23 As such, women with a diag-
nosis of PCOS should be screened for
impaired glucose tolerance and type 2
diabetes with a fasting glucose level fol-
lowed by a 2-hour oral glucose tolerance
test after administration of a 75 g glucose
load. Women with PCOS should also
be screened for dyslipidemia because of
the increased risk of metabolic syndrome
and its subsequent cardiovascular risk.
Rescreening for features of the metabolic
syndrome and cardiovascular risk should
be done periodically as there is a nearly
20% risk of developing impaired glucose
tolerance yearly in patients with PCOS.24
In addition to long-term consequences
of insulin resistance, metabolic syndrome,
diabetes, and cardiovascular disease in
women with PCOS, there are several
more conditions for which these women
are at risk. As patients with PCOS are
typically obese, conditions associated
with obesity and anovulation have a
higher prevalence in this population
such as endometrial cancer, endometrial
hyperplasia, obstructive sleep apnea,
nonalcoholic fatty liver disease, and
mood disturbances including anxiety and
depression.25 Obesity and hirsutism
have also been associated with a reduced
quality of life.26
Nonpharmacologic Therapies
The association between PCOS and in-
sulin resistance, and thus risk of develop-
ing metabolic syndrome and type II
diabetes, has been clearly established.
No prospective studies thus far have
documented a clear link between PCOS
and cardiovascular events, though some
studies with premenopausal women have
suggested a relation between increasing
level of oligomenorrhea and independent
cardiovascular risk factors, such as in-
creased prevalence of subclinical athero-
sclerosis compared to controls.27–29 It is
still unclear how and why women with
PCOS do not seem to exhibit a higher
 Contemporary Management of PCOS
incidence of myocardial infarctions de-
spite the increased prevalence of abnor-
mal vasculature.
Though reproductive and metabolic
implications may seem to have two dis-
parate focuses, the general principle of
therapy in PCOS is to optimize health
first, before commencing treatment for
infertility. Nonpharmacologic lifestyle
changes have been shown to attenuate
some of the metabolic perils associated
with PCOS and can additionally lead to a
sense of better physical well-being in these
women.30 An increase in exercise com-
bined with dietary changes, particularly
caloric restriction, has consistently been
shown to reduce the risk of developing
type II diabetes equal to or better than
pharmacologic agents.31 Up to 80% of
women with PCOS are overweight or
obese. In this population, even modest
weight loss—as little as 5% body weight
change—has been associated with en-
hancements in overall health including
improved glucose and lipid levels. In the
obese PCOS population, weight loss itself,
regardless of modality—be it medication,
gastric bypass, or diet and exercise—has
been associated with improved pregnancy
rates as well as decreased hirsutism.32–35
Although much of the focus on therapy
for women with PCOS appropriately
centers on enhancing metabolic manage-
ment and fertility treatments, cosmetic
medical issues may profoundly impact
the quality of life and psychological
well-being of women with PCOS and in
fact are the most common reason for
women presenting for medical care.
Hirsutism and acne are the most common
physical manifestations of hyperandro-
genism. Although there is no clear
first-line treatment for hirsutism, lifestyle
interventions to improve this condition
primarily center around mechanical
hair removal including shaving, plucking,
waxing, electrolysis, and laser vaporiza-
tion; depilatory creams are also
often utilized. The combination of an
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275
FDA-approved topical pharmacologic
agent, Eflornithine, an inhibitor of the
enzyme ornithine decarboxylase, used 2
times daily in combination with laser
therapy has been shown to be superior
to laser alone in the treatment of
hirsutism.36 The treatment of acne centers
primarily around pharmacologic inter-
ventions aimed at decreasing circulating
androgens in addition to topical treat-
ments by dermatologists.
Surgical Interventions
Although most treatments for fertility
related to anovulation or oligo-ovulation
in women with PCOS focus on pharma-
cologic intervention, surgical interven-
tions have been attempted as an
alternative to restore ovulatory cycles.
Ovarian wedge resection was the earliest
surgical intervention proposed, first de-
scribed by Stein and Cohen in 1935.37
Although many studies showed this
technique to be successful in terms of
ovulation induction, wedge resection is
associated with significant adhesion for-
mation which itself is fraught with poten-
tial fertility implications. As a surgical
alternative, laparoscopic ovarian drilling
(LOD) was first described by Gjönnaess38
in 1984 and has been widely used since
that time. LOD typically employs mo-
nopolar or bipolar electrocautery, or la-
ser, to effectively drill an undefined
number of holes into the ovarian
cortex.39,40 This surgical procedure is
currently recommended only as a sec-
ond-line therapy in clomiphene-resistant
women with anovulatory infertility.18
A Cochrane review of 25 randomized
controlled trials found that LOD was
equivalent to other pharmacologic ovula-
tion induction therapies in terms of
live birth rate, long-term cost, and quality
of life, however notably resulted in
a lower rate of multiple pregnancy.41
Despite the improvement in risk of multi-
ple pregnancy, this procedure is not
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276 Zimmerman et al
recommended first line given the under-
lying surgical risks in addition to risk of
periovarian adhesion formation.
Pharmacologic Therapies
Pharmacologic therapies are routinely
utilized alongside nonpharmacologic in-
terventions to manage the overall health
of women with PCOS. The specific inter-
ventions and medications employed to
manage this condition will differ among
patients based on their individual charac-
teristics and goals of treatment. Pharma-
cologic treatments may be divided into
treatment for counteracting hyperandro-
genism, managing endometrial effects
of ovulatory dysfunction, improving
metabolic status, and treatment of
infertility via ovulation induction.
COMBINED ORAL CONTRACEPTIVES
Unless otherwise contraindicated, combi-
nation low-dose oral contraceptive pills
(OCPs) are regarded as first line therapy
in women with PCOS who are not ac-
tively attempting to become pregnant.
OCPs increase circulating levels of sex
hormone binding globulin (SHBG) and
decrease ovarian androgen secretion,
leading to decreased levels of circulating
androgens. They also suppress luteinizing
hormone secretion from the pituitary, and
additionally may stabilize the endome-
trium to minimize the risk of endometrial
hyperplasia.14,18
ANTIANDROGENS
Specific antiandrogens are often employed
to target androgenic hirsutism, acne, and
alopecia. Spironolactone, an androgen re-
ceptor blocker and inhibitor of androgen
biosynthesis, is the preferred first-line treat-
ment specifically for hirsutism. Flutamide,
another androgen receptor blocker, and
finasteride, a 5α-reductase inhibitor are
alternative treatments for hirsutism, with
finasteride also often used to treat for
androgenic alopecia. These antiandrogens
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can be combined for synergistic effect with
one another because of different mecha-
nisms of action and combined with OCPs. If
not being used simultaneously with OCPs,
patients must be counseled on the need for
effective contraception during use as they
have been shown to be teratogenic.42,43
PROGESTINS
Because of chronic oligo-ovulation or an-
ovulation, women with PCOS are at in-
creased risk for endometrial hyperplasia
and thus endometrial carcinoma. To min-
imize this risk, regular administration of
progestins are recommended in patients
not actively attempting to become preg-
nant. No one regimen has been deemed
superior to others, but options for manage-
ment include cyclic or continuous oral
progestins, progestin-containing intrauter-
ine devices, and injectable progestins such
as depot medroxyprogesterone acetate.18
METFORMIN
For metabolic management of this dis-
ease, first line therapy is lifestyle inter-
ventions including weight loss along with
diet changes and exercise as discussed
previously. In women with evidence of
glucose intolerance, elevated insulin lev-
els, or strong family history of diabetes,
medical management with insulin sensi-
tizers, most commonly metformin, is
often dually warranted. In addition to its
metabolic impact on improved insulin
sensitivity and glucose tolerance, metfor-
min also decreases circulating androgen
levels. Furthermore, metformin has
been suggested to improve ovulatory
function.44 A meta-analysis in 2004 found
that metformin was better than placebo
for menstrual cycle regulation in non-
infertile PCOS patients, as well as better
than placebo for ovulation induction in
the infertile PCOS population.45 How-
ever, this same study revealed that preg-
nancy rates were not improved using
metformin. Further studies revealed infe-
riority of metformin when compared
 Contemporary Management of PCOS 277

directly to other oral ovulation inductions
such as clomiphene citrate and letrozole
in terms of ovulation, pregnancy rates,
and live birth rates in women with
PCOS.39,46 Given these findings, metfor-
min is not recommended alone as a first
line drug for fertility treatment, but is
used in this population largely for its
metabolic benefits. In addition, combina-
tion therapy of metformin plus clomi-
phene may be considered in women who
are resistant to clomiphene alone, though
there remains insufficient evidence of an
increase in live birth rates in this setting.46
CLOMIPHENE CITRATE
For women with PCOS seeking ovulation
induction for pregnancy, the most widely
used first-line therapy has traditionally
been the oral antiestrogenic agent clomi-
phene citrate. Clomiphene is a selective
estrogen receptor modulator (SERM),
blocking estradiol receptors in the hypo-
thalamus and inducing a change in
GnRH pulse frequency, leading to an
increased release of FSH from the ante-
rior pituitary and subsequent follicular
development.39 The original multicenter
pregnancy in polycystic ovary syndrome
(PPCOS I) trial showed a clear benefit
of clomiphene compared to metformin
alone in achieving live birth, however also
confirmed that a higher risk of multiple
births is a complication (Fig. 2).46 In the
practical administration of clomiphene
citrate, the starting dose is typically 50
mg for 5 days in the early follicular phase,
with a stair step approach for lack of
response up to a dose of 150 mg. Patient
weight must be considered when consid-
ering a starting dose.
LETROZOLE
Letrozole, an aromatase inhibitor, is also
known to be effective for ovulation in
women with PCOS. This medication is
administered similarly to clomiphene, for
5 days in the early follicular phase, start-
ing with a dose of 2.5 mg and increasing in
a stepwise manner as needed for lack
of response to a maximum dose of 7.5
mg. A large follow-up study to PPCOS I,
the PPCOS II trial, compared clomiphene
citrate directly to letrozole in the infertile
PCOS population, and reported an in-
creased live birth rate and ovulation rate
in this population (Fig. 3).47,48 It is worth
noting however that the mean BMI in this
study was above 35 kg/m2, and thus the
current recommendation for the utiliza-
tion of letrozole as a first-line treatment
over clomiphene should apply to the
obese PCOS population. Further studies
are needed to elicit if there is a benefit of
one oral agent over another in the non-
obese PCOS population. In addition,

FIGURE 2. Comparison of live birth rates with clomiphene citrate alone, metformin alone or
clomiphene citrate with metformin reported in the PPCOS I trial. PPCOS indicates pregnancy in
polycystic ovary syndrome.

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278 Zimmerman et al
FIGURE 3. Comparison of live birth rates with clomiphene citrate or letrozole reported in the
PPCOS II trial. PPCOS indicates pregnancy in polycystic ovary syndrome.
there has more recently been suggestion
that perhaps a combination of letrozole
and clomiphene may act synergistically to
improve ovulation rates in women with
PCOS49; however, sample size in a recent
study was limited and more studies are
needed to examine this finding and
whether this correlates with enhanced live
birth rates.
GONADOTROPINS
In patients resistant to oral ovulation
induction agents or after failures of ther-
apy, injectable gonadotropin therapy may
be used as second-line treatment. Gona-
dotropin therapy has been associated with
a clear increased risk of multiple preg-
nancy, as well as an increased risk of
ovarian hyperstimulation syndrome
(OHSS), a risk amplified in the PCOS
population. OHSS is generally an iatro-
genic condition except in rare cases, and is
a serious and potentially life-threatening
condition involving increased capillary
permeability, third spacing of fluid with
resultant ascites, pulmonary edema, renal
failure, risk of venous thromboembolism,
as well as obstetric complications
including increased risk of spontaneous
abortion.50 This disease state generally
occurs as the result of controlled ovarian
hyperstimulation with gonadotropins for
either ovulation induction or in vitro
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fertilization (IVF). Although the under-
lying etiology of polyfollicular ovaries
and thus inherent risk of OHSS exists,
there are strategies that we can employ
during treatment to minimize the inci-
dence of this disease state.
The risk of OHSS can be attenuated by
gentle stimulation with gonadotropins
along with close monitoring of estradiol
levels in addition to transvaginal ultra-
sound throughout stimulation. The em-
ployment of a low-dose sliding scale hCG
trigger, or use of a GnRH agonist, namely
Leuprolide, either alone or in combina-
tion with hCG as part of a dual trigger
can significantly attenuate this risk and
should always be considered.50,51
In women with PCOS undergoing IVF,
there is evidence suggesting that live birth
rates may be higher and the risk of OHSS
lower when frozen, rather than fresh,
embryo transfer is performed. A multi-
center trial of over 1500 infertile women
with PCOS undergoing day three embryo
transfer of up to two embryos revealed a
higher rate of live birth, along with a
lower risk of OHSS and lower frequency
of miscarriage in these patients compared
with women who underwent fresh embryo
transfer immediately following IVF
stimulation.52 This is proposed to be
because of the interval “rest” period
allowing the hyperstimulated ovary to
 Contemporary Management of PCOS
return to a baseline size, as well as the
hormonal milieu to return to a less stimu-
lated state. Interestingly, the women in
the frozen embryo transfer cohort had a
higher incidence of preeclampsia later in
pregnancy. These findings suggest a po-
tential benefit for this population of in-
fertile women with PCOS to undergo
embryo cryopreservation cycles upfront
after IVF stimulation with gonadotro-
pins, with an interval plan for frozen
embryo transfer to both improve preg-
nancy rates and minimize the medical risk
of OHSS.
Conclusions
PCOS remains one of the most intriguing
endocrine disorders that physicians en-
counter even though it was first described
over 80 years ago. Although the diagnos-
tic criteria, nomenclature, and ideal ther-
apeutic strategies are areas of active and
ongoing debate, there is no doubt that we
have made tremendous progress in im-
proving the quality of life and reproduc-
tive outcomes of women who suffer from
this wide-ranging disorder.
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