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Coexistence of Polycystic Ovary Syndrome and Endometriosis in Women with Infertility

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Abstract

Purpose The aim of this study was to investigate if there is a higher incidence of endometriosis in patients with polycystic ovary syndrome (PCOS), compared with normal fertile controls. Material and methods Women with PCOS according to Rotterdam criteria, with infertility and/or pelvic pain, were identified (n = 104), and together with fertile women seeking bilateral tubal ligation (n = 111), they were submitted to laparoscopy at the Greenville Hospital System or the University of North Carolina at Chapel Hill. A biopsy was performed in 40 patients with PCOS to confirm or not endometriosis. Results Age was similar in both groups (control: 29.7 ± 0.5 years; PCOS: 29.6 ± 0.4). The incidence of suspected endometriotic lesions in controls and PCOS patients was 12.6% (95% confidence interval [95% CI], 7.6%-20%) and 74% (95% CI, 64.8%-81.5%), respectively; with an odds ratio of 19.7 (95% CI, 9.6-40.2) of finding endometriosis in PCOS (p<0.0001). Our results were similar when endometriosis was confirmed by pathology report. Of the PCOS patients with endometriosis, 76% had endometriosis stage I or II, according to the revised American Society for Reproductive Medicine criteria. Conclusions In this case-control study, a significant association between endometriosis and women with PCOS with pelvic pain and/or infertility was found. The majority of endometriotic lesions (76%) were stage I or II.
© 2014 Wichtig Publishing - ISSN 2035-9969
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Journal of Endometriosis and Pelvic Pain Disorders 2014; 6(2): 78-83 DOI: 10.5301/je.5000181
ORIGINAL ARTICLE
Coexistence of polycystic ovary syndrome and
endometriosis in women with infertility
Kristin J. Holoch1, Ricardo F. Savaris2, David A. Forstein1, Paul B. Miller1, H. Lee Higdon, III1,
Creighton E. Likes1, Bruce A. Lessey1
1Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University Medical Group, Greenville
Hospital System, Greenville, South Carolina - USA
2Department of Obstetrics and Gynecology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul -Brazil
Purpose: The aim of this study was to investigate if there is a higher incidence of endometriosis in
patients with polycystic ovary syndrome (PCOS), compared with normal fertile controls.
Material and methods: Women with PCOS according to Rotterdam criteria, with infertility and/or
pelvic pain, were identified (n = 104), and together with fertile women seeking bilateral tubal ligation
(n = 111), they were submitted to laparoscopy at the Greenville Hospital System or the University of
North Carolina at Chapel Hill. A biopsy was performed in 40 patients with PCOS to confirm or not
endometriosis.
Results: Age was similar in both groups (control: 29.7 ± 0.5 years; PCOS: 29.6 ± 0.4). The
incidence of suspected endometriotic lesions in controls and PCOS patients was 12.6% (95%
confidence interval [95% CI], 7.6%-20%) and 74% (95% CI, 64.8%-81.5%), respectively; with an
odds ratio of 19.7 (95% CI, 9.6-40.2) of finding endometriosis in PCOS (p<0.0001). Our results were
similar when endometriosis was confirmed by pathology report. Of the PCOS patients with
endometriosis, 76% had endometriosis stage I or II, according to the revised American Society for
Reproductive Medicine criteria.
Conclusions: In this case-control study, a significant association between endometriosis and
women with PCOS with pelvic pain and/or infertility was found. The majority of endometriotic lesions
(76%) were stage I or II.
Keywords: Endometriosis, Polycystic ovary syndrome
Accepted: April 11, 2014
INTRODUCTION
Endometriosis is an inflammatory, estrogen-dependent
condition characterized by the presence of endometrial
tissue outside of the uterine cavity. Retrograde
menstruation into the pelvic cavity has been proposed
as one of the mechanisms for its etiology. The
prevalence of endometriosis in the general female
population is around 5%, but it is found in 25% to 40%
of those with infertility or pelvic pain (1). The existence
of mild forms of endometriosis and their relationship to
infertility remain controversial (2).
These mild forms may go unrecognized or be
underappreciated (3). Risk factors for endometriosis
include cervical stenosis, delayed childbearing,
Mullerian abnormalities, family history, environmental
causes (4), lack of physical activity (5, 6) and heavy
menses (7). High body mass index (BMI) is not a risk
factor for endometriosis per se (8, 9), but in women with
© 2014 Wichtig Publishing - ISSN 2035-9969
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PCOS and endometriosis
endometriosis, higher BMI is associated with a lesser
stage of disease (10). High BMI has been associated
with polycystic ovary syndrome (PCOS) (11). PCOS is
the most common endocrine disorder of reproductive-
aged women and is associated with both infertility and
pelvic pain (12). Women with PCOS may be at
increased risk to develop endometrial cancer due to
anovulatory cycles with unopposed estrogen and lack
of progesterone (13). These same conditions might
predispose to the development of endometriosis,
especially in the presence of heavy irregular menses
and early menarche, which are attributes of PCOS
women (14). Therefore, we hypothesized that women
with PCOS may have coexisting endometriosis,
especially when infertility persists after ovulation has
been restored or in those with pelvic pain. To
investigate this question, we sought to determine the
incidence of endometriosis in 104 patients with a
diagnosis of PCOS who underwent laparoscopy in our
program for these indications, compared with a fertile
control group undergoing tubal ligation (n = 111).
MATERIALS AND METHODS
Patients
In this retrospective case-control study, all consecutive
patients with the diagnosis of PCOS (ICD-9-256.4),
according to the Rotterdam criteria (15), who were
seen at the Greenville Hospital System, Department of
Obstetrics and Gynecology, Division of Reproductive
Endocrinology and Infertility (REI), in Greenville, South
Carolina, between February 2003 and April 2011, were
considered for inclusion.
Inclusion criteria for PCOS used the Rotterdam criteria
and included 2 out of the following characteristics:
irregular cycles (6 cycles per year), signs of clinical or
biochemical hyperandrogenism, polycystic appearing
ovaries at ultrasound. PCOS women with continuing
infertility and/or pelvic pain who did not go to
laparoscopy were excluded. Fertile controls included
women undergoing laparoscopic bilateral tubal ligation
at the University of North CarolinaChapel Hill (UNC-
CH) between July 1994 and January 2003. A review of
hospital and clinic records identified 316 women who
met the criteria for PCOS based on the Rotterdam
criteria, and 104 were submitted to laparoscopy for
indications of infertility and/or pelvic pain.
All laparoscopies were performed by board-certified
reproductive endocrinology and infertility physicians at
Greenville Health System and UNC-CH. Diagnosis and
staging of endometriosis was based on visual
inspection of suspected lesions, including red, white
and clear peritoneal implants in both groups, according
to the revised American Society for Reproductive
Medicine (ASRM) classifications (16). In 40 cases,
suspicious lesions were biopsied and sent to a
pathologist for analysis.
Statistics and ethical issues
Statistical analysis comparing differences between
groups was performed using unpaired Student’s t-test,
the chisquare test for independence and Fisher’s exact
test. The odds ratio between both groups was
calculated with a 95% confidence interval. GraphPad
Prism (version 6 for Mac; GraphPad Software, La Jolla,
CA, USA) was used for statistical analysis and graphics.
Significance was set at a p value of <0.05. This study
was submitted to and approved by the Greenville
Health System and the University of North Carolina at
Chapel Hill institutional review boards. All subjects
gave written consent to participate in the study.
RESULTS
Details of the studied population are listed in Table I.
BMIwas greater in women without findings of
endometriosis compared with those with suspected
endometriosis (without endometriosis [mean BMI ±
SD]: 37.4 ± 8.7, vs. with endometriosis: 31.3 ± 7.5; p =
0.002). Stage of endometriosis, as based on the
revised ASRM criteria (stages I to IV), was minimal or
mild disease in 76% of cases. Pathological reports
confirmed the diagnosis of endometriosis in 14/14
(100%; 95% CI, 78%-100%) and 28/40 (70%; 95% CI,
54%-82%) of visually suspected lesions in controls and
cases, respectively (Tab. II). Considering all subjects
in each group, the odds ratio based on suspected
endometriotic lesions was 19.76 (95% CI, 9.6-40.26); in
cases with confirmed endometriotic lesions, the odds
ratio was 16.17 (95% CI, 6.7-38.9).
DISCUSSION
Poor reproductive performance in PCOS women has
been an enigma (17). Surprisingly, few studies have
directly
© 2014 Wichtig Publishing - ISSN 2035-9969
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Holoch et al
PCOS = polycystic ovary syndrome; SD = standard deviation.
*Unpaired Student’s t-test
ovulation induction with oral clomiphene citrate (50 to 150 mg daily) or
letrozole (5 mg daily) for five days in the early-follicular phase.
combined oral agents and gonadotropins or recombinant follicle stimulating
hormone (rFSH) 75 to 150 IU for 4 to 5 days)
suggested an association between endometriosis
and PCOS (14, 18, 19). Brincat et al reported that
10% of an infertile population had both
endometriosis and PCOS, representing 48% of all
PCOS patients in that study (18). To improve
success with ovulation induction, McGovern and
colleagues discussed the importance of screening
for other causes of infertility in women with PCOS
(20). One could argue that once ovulatory status
has been restored, then PCOS infertility becomes
otherwise unexplained. Meuleman et al, applying
this logic to women with unexplained infertility,
reported that nearly 50% had endometriosis at
laparoscopy (21).
In our study, we found that the incidence of
endometriotic lesions in women with PCOS was
72% (95% CI, 62%-79%) for suspected
endometriosis and 70% (95% CI, 54%-82%) for
confirmed cases. This incidence is in accordance
with those findings published by Janssen et al in
adolescents with chronic pelvic pain who were
submitted to laparoscopy; these authors found an
incidence of endometriosis of 62% (95% CI, 58.4%-
64.8%) (22), which is in a range similar to that in our
findings. However, our findings were higher than
those of others, where the incidence of
endometriosis in women with PCOS varied between
11% and 16% (95% CI, 7%-25%) (23, 24). Possible
explanations include differences in practice patterns,
patient selection, regional differences in the
incidence of endometriosis (i.e., where laparoscopy
was performed at 2 different institutions and by
different surgeons), possible differences in
thresholds to perform surgery (i.e., infertility
evaluation requires a more detailed visualization of
the peritoneal cavity, while in tubal ligation,
laparoscopy is expeditious and focused, which may
lead to false negative results). In addition, a better
recognition of subtle forms of endometriosis in the
past 10 to 20 years has been observed (2). In
general, women with PCOS are much less likely to
undergo laparoscopy during an infertility workup,
since ovulatory dysfunction is a known primary
cause of diminished fecundity. Further, as assisted
reproductive technologies replace laparoscopy as a
treatment modality, women with PCOS who fail oral
ovulation induction protocols are increasingly
offered in vitro fertilization (IVF) as an alternative
(25, 26). Anovulation is not a common finding
among women with endometriosis (27), and
endometriosis per se is a known risk factor for
infertility (28); thus women with PCOS are not
thought of in terms of heightened endometriosis risk.
Likewise, women with PCOS typically have a higher
BMI, which has been reported to be protective for
the diagnosis of endometriosis (29).
When we performed laparoscopy for infertility
and/or pelvic pain in women with PCOS, suspected
endometriotic lesions were commonly found. This
association, which
© 2014 Wichtig Publishing - ISSN 2035-9969
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PCOS and endometriosis
was highly significant when compared with a fertile
cohort who also underwent laparoscopic inspection
of the pelvis (p<0.0001), demonstrates that
endometriosis and PCOS can coexist. Although the
pathophysiologies of these 2 conditions are distinct,
they overlap in ways that make endometriosis more
likely. Women with PCOS bleed heavily and
irregularly, and as result of anovulation, they have a
progesterone deficiency and unopposed estrogen
that can promote endometrial proliferation and
ectopic endometrial cell growth. Authors have also
suggested a moderate association between
exposure to environmental contaminants and
evidence of PCOS and endometriosis (30).
Inflammation associated with obesity and insulin
resistance may also promote progesterone
resistance in the endometrium in PCOS (31).
In this case-control study, we compared a large
number of fertile controls who underwent
laparoscopic inspection for endometriosis. Our
findings of suspected endometriosis in these fertile
women were within the range reported by others (2).
We also confirmed the epidemiological data
showing that higher BMI is inversely related to
endometriosis.
However, the mean BMI of PCOS patients with
endometriosis (31.3 ± 7.5) was in the obese
category. Finally, we confirmed that women with a
higher BMI tended to have an earlier stage of
endometriosis (10).
The weaknesses of our study included the following:
pathological confirmation of endometriosis was not
possible in all patients with PCOS, especially in
those with minimal disease. As a case-control study,
just an association was shown; that does not mean
a causal effect. Since a significant association was
observed even when only
pathologically confirmed endometriosis was
included, further prospective studies designs are
needed to verify if PCOS is indeed a risk factor for
women with infertility and/or pain.
In summary, our findings support the hypothesis
that PCOS and endometriosis coexist in a
population of women with infertility, dysmenorrhea
and chronic pelvic pain.
These findings will hopefully bring this association
to the attention of practitioners as a topic of clinical
significance. We also believe that women with
PCOS, infertility and/or chronic pelvic pain who fail
to conceive once ovulation is restored should be
offered laparoscopy to investigate the possibility of
coexistence of endometriosis, as has been
suggested by a meta-analysis (32). These findings
highlight the need for further research on causes of
decreased cycle fecundity reported in women with
PCOS (17).
Financial Support: This research was supported by the
Eunice
Kennedy Shriver NICHD/NIH, through cooperative agreement
U54 HD035041, as part of the Specialized Cooperative
Centers Program in Reproduction and Infertility Research,
and the Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq) 240239/2012-1 (RFS).
Conflict of Interest: The authors of this present study report
no
conflict of interest.
Address for correspondence:
Bruce A. Lessey, MD, PhD
890 W. Faris Rd
Suite 470
Greenville, SC 29605, USA
blessey@ghs.org
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... Despite the above evidence, there are conflicting findings for which further research should be conducted, such as coexistence of PCOS and endometriosis in one woman which is probably an exception to the finding on the effect of prenatal testosterone on female fetus or the discrepancies are due to inaccuracy of previous studies (6). ...
... These studies yielded rates of endometriosis that center around 19% (Barbosa et al., 2009;Rawson, 1991;Tissot et al., 2017). Holoch et al. (2014) reported high rates of endometriosis in women with PCOS (>70%), but the PCOS group was subject to ascertainment bias because the women were examined for endometriosis only if they self-reported pelvic pain and/or infertility. Taken together, these studies suggest that, among women without any clear symptoms of endometriosis (pain, heavy bleeding, infertility), the rate of this disorder as determined by laparoscopy is about one-half to one-third lower in women with PCOS than in women with no known reproductive issues. ...
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... Symptoms of these comorbidities are salient in the obtained posteriors (see for example, how the severe phenotype is characterized by painful urination). Furthermore, women with endometriosis are known to exhibit these comorbidities: anxiety, depression, and other mood disorders ( Pope et al., 2015), migraines ( Yang et al., 2012), high blood pressure ( Mu et al., 2017), PCOS ( Holoch et al., 2014), and painful urination/interstitial cystitis ( Chung et al., 2005). ...
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Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder characterized by irregular menses, hyperandrogenism, and polycystic ovaries. The prevalence of PCOS varies depending on which criteria are used to make the diagnosis, but is as high as 15%-20% when the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine criteria are used. Clinical manifestations include oligomenorrhea or amenorrhea, hirsutism, and frequently infertility. Risk factors for PCOS in adults includes type 1 diabetes, type 2 diabetes, and gestational diabetes. Insulin resistance affects 50%-70% of women with PCOS leading to a number of comorbidities including metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes. Studies show that women with PCOS are more likely to have increased coronary artery calcium scores and increased carotid intima-media thickness. Mental health disorders including depression, anxiety, bipolar disorder and binge eating disorder also occur more frequently in women with PCOS. Weight loss improves menstrual irregularities, symptoms of androgen excess, and infertility. Management of clinical manifestations of PCOS includes oral contraceptives for menstrual irregularities and hirsutism. Spironolactone and finasteride are used to treat symptoms of androgen excess. Treatment options for infertility include clomiphene, laparoscopic ovarian drilling, gonadotropins, and assisted reproductive technology. Recent data suggest that letrozole and metformin may play an important role in ovulation induction. Proper diagnosis and management of PCOS is essential to address patient concerns but also to prevent future metabolic, endocrine, psychiatric, and cardiovascular complications.
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BACKGROUND Endometriosis associated with pain symptoms in adolescents has been extensively reported, but the exact prevalence is unclear because pain symptoms may be atypical and endometriosis can only be diagnosed by laparoscopy. The aim of this paper is to provide a systematic review of the prevalence of endometriosis diagnosed by laparoscopy in adolescents.METHODSA systematic literature search was carried out for relevant articles published between 1980 and 2011 in the databases PUBMED and EMBASE, based on the keywords 'endometriosis', 'laparoscopy', 'adolescents' and 'chronic pelvic pain (CPP)'. In addition, the reference lists of the selected articles were examined.RESULTSBased on 15 selected studies, the overall prevalence of visually confirmed endometriosis was 62% (543/880; range 25-100%) in all adolescent girls undergoing laparoscopic investigation, 75% (237/314) in girls with CPP resistant to treatment, 70% (102/146) in girls with dysmenorrhea and 49% (204/420) in girls with CPP that is not necessarily resistant to treatment. Among the adolescent girls with endometriosis, the overall prevalence of American Society of Reproductive Medicine classified moderate-severe endometriosis was 32% (82/259) in all girls, 16% (17/108) in girls with CPP resistant to treatment, 29% (21/74) in girls with dysmenorrhea and 57% (44/77) in girls with CPP that is not necessarily resistant to treatment. Due to the quality of the included papers an overestimation of the prevalence and/or severity of endometriosis is possible.CONCLUSIONS About two-thirds of adolescent girls with CPP or dysmenorrhea have laparoscopic evidence of endometriosis. About one-third of these adolescents with endometriosis have moderate-severe disease. The value of early detection of endometriosis in symptomatic adolescents and the indications for laparoscopic investigation in adolescents require more research.
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Polycystic ovary syndrome (PCOS), the most common endocrinopathy of reproductive-aged women, is characterized by ovulatory dysfunction and hyperandrogenism. The aim was to compare gene expression between endometrial samples of normal fertile controls and women with PCOS. We conducted a case control study at university teaching hospitals. Normal fertile controls and women with PCOS participated in the study. Endometrial samples were obtained from normal fertile controls and from women with PCOS, either induced to ovulate with clomiphene citrate or from a modeled secretory phase using daily administration of progesterone. Total RNA was isolated from samples and processed for array hybridization with Affymetrix HG U133 Plus 2 arrays. Data were analyzed using GeneSpring GX11 and Ingenuity Pathways Analysis. Selected gene expression differences were validated using RT-PCR and/or immunohistochemistry in separately obtained PCOS and normal endometrium. ANOVA analysis revealed 5160 significantly different genes among the three conditions. Of these, 466 were differentially regulated between fertile controls and PCOS. Progesterone-regulated genes, including mitogen-inducible gene 6 (MIG6), leukemia inhibitory factor (LIF), GRB2-associated binding protein 1 (GAB1), S100P, and claudin-4 were significantly lower in PCOS endometrium; whereas cell proliferation genes, such as Anillin and cyclin B1, were up-regulated. Differences in gene expression provide evidence of progesterone resistance in midsecretory PCOS endometrium, independent of clomiphene citrate and corresponding to the observed phenotypes of hyperplasia, cancer, and poor reproductive outcomes in this group of women.
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Reason for Withdrawal This review has been replaced by a review entitled 'Laparoscopic surgery for endometriosis', published in issue 4 of The Cochrane Library, 2014. To view the published versions of this article, please click the 'Other versions' tab.
Data
Objective: To determine the prevalence of histologically proven endometriosis in a subset of infertile women. Design: Retrospective case series with electronic file search and multivariable logistic regression analysis. Setting: Tertiary academic fertility center. Patient(s): Two hundred twenty-one infertile women without previous surgical diagnosis for infertility with reg-ular cycles (variation, 21–35 days) whose partners have a normal semen analysis. Intervention(s): Diagnostic laparoscopy and, if necessary, operative laparoscopy with CO 2 laser excision. Main Outcome Measurement(s): The prevalence of endometriosis and of fertility–reducing nonendometriotic tubal and/or uterine pathology. Result(s): The prevalence of endometriosis was 47% (104/221), including stage I (39%, 41/104), stage II (24%, 25/104), stage III (14%, 15/104), and stage IV (23%, 23/104) endometriosis, and was comparable in patients with (54%, 61/113) and without (40%, 43/108) pelvic pain. The prevalence of fertility-reducing nonendometriotic tubal and/or uterine pathology was 29% in all patients (15% in women with and 40% in women without endometriosis). A multivariate logistic regression model including pain, ultrasound data, age, duration of infertility, and type of fertility was not or not sufficiently reliable for the prediction of endometriosis according to the revised American Fertility Society (rAFS) classifications I–II and rAFS III–IV, respectively. Conclusion(s): Reproductive surgery is indicated in infertile women belonging to the study population, regardless of pain symptoms or transvaginal ultrasound results, since half of them have endometriosis and 40% of those with-out endometriosis have fertility-reducing pelvic pathology.
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STUDY QUESTION Is there a relationship between body mass index (BMI), body shape and endometriosis? SUMMARY ANSWER Endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. WHAT IS KNOWN ALREADY The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth. STUDY DESIGN, SIZE, DURATION Prospective cohort study using data collected from 116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, METHODS AND SETTING Cases were restricted to laparoscopically confirmed endometriosis. Weight at age 18 and height were reported at baseline, and current weight was updated every 2 years. Waist and hip measurements were first taken in 1993 and updated in 2005. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models with time-varying covariates. MAIN RESULTS AND THE ROLE OF CHANCE A total of 5504 incident cases of endometriosis were reported during 1 299 349 woman-years (incidence rate = 385 per 100 000 woman-years). BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P-value, test for linear trend
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To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS). This guideline reviews the evidence for the various options for ovulation induction in PCOS. Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies. These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC. The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS 1. Weight loss, exercise, and lifestyle modifications have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A) Morbidly obese women should seek expert advice about pregnancy risk. (III-A) 2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate. (I-A) 3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.(I-A) Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity. (I-A) 4. Gonadotropin should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A) 5. Laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, particularly when there are other indications for laparoscopy. (I-A) Surgical risks need to be considered in these patients. (III-A) 6. In vitro fertilization should be reserved for women with PCOS who fail gonadotropin therapy or who have other indications for IVF treatment. (II-2A).