SOGC CLINICAL PRACTICE GUIDELINE

It is SOGC policy to review the content 5 years after publication, at which time the document may be re-affirmed or revised to reflect emer-
gent new evidence and changes in practice.

No. 362, July 2018 (Replaces No. 242, May 2010)

No. 362-Ovulation Induction in Polycystic

Ovary Syndrome

This revised Clinical Practice Guideline has been prepared by
the Reproductive Endocrinology and Infertility Committee,
reviewed by the Guideline Management and Oversight
Committee, and approved by Board of the Society of
Obstetricians and Gynaecologists of Canada.
David S. Smithson, MD, Edmonton, AB
Tannys D.R. Vause, MD, Ottawa, ON
Anthony P. Cheung, MD, Vancouver, BC
Disclosure statements have been received from all authors.
Reproductive Endocrinology and Infertility Committee: Belina
Carranza-Mamane, MD, Sherbrooke, QC; Anthony P. Cheung,
MD (co-chair), Vancouver, BC; Catherine Dwyer, RN, Toronto,
ON; James Graham, MD, Victoria, BC; Sarah Healey, MD,
St. John’s, NL; Robert Hemmings, MD, Westmount, QC; Tarek
Motan, MD, Edmonton, AB; Sony Sierra (co-chair), MD, Toronto,
ON; David Smithson, MD, Edmonton, AB; Tannys D.R.Vause,
MD, Ottawa, ON; Marta Wais, MD, Toronto, ON; Benjamin
Chee-Man Wong, MD, Calgary, AB; Bonnie Woolnough, MD,
Edmonton, AB.
Key Words: Polycystic ovary syndrome, ovulation induction, infertility
Abstract
Objective: To review current non-pharmacologic and pharmacologic
options for ovulation induction in women with polycystic ovary
syndrome (PCOS).
Options: This guideline reviews the evidence for the various options
for ovulation induction in PCOS.
Outcomes: Ovulation, pregnancy and live birth rates, risks, and side
effects are the outcomes of interest.
Evidence: Published literature was retrieved through searches of
Medline using appropriate controlled vocabulary and key words
spanning from 2000 to 2016. 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 Grey (unpublished) literature was identified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.
Values: 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.

KEY MESSAGES

J Obstet Gynaecol Can 2018;40(7):978–987 1. Increased knowledge on the use, efficacy and safety of
aromatase inhibitors
https://doi.org/10.1016/j.jogc.2017.12.004 2. Continued support for first line lifestyle modification as
Copyright © 2018 The Society of Obstetricians and Gynaecologists of appropriate
Canada/La Société des obstétriciens et gynécologues du Canada. Pub- 3. Updated information as applicable on previously listed therapies
lished by Elsevier Inc. All rights reserved.

This document reflects emerging clinical and scientific advances on the date issued and is subject to change. The information should not be
construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opin-
ions. They should be well-documented if modified at the local level. None of these contents may be reproduced in any form without prior written
permission of the publisher.
Patients have the right and responsibility to make informed decisions about their care in partnership with their health care providers. To fa-
cilitate informed choice, patients should be provided with information and support that is evidence-based, culturally appropriate, and tailored
to their needs. The values, beliefs, and individual needs of each patient and their family should be sought, and the final decision about the
care and treatment options chosen by the patient should be respected.

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Benefits, Harms, and Costs: Benefits include weight reduction and
improvements in ovulation, pregnancy, and live birth rates.
Potential harms include medication side effects and multiple
pregnancies.
Validation: These guidelines have been reviewed and approved by
the Reproductive Endocrinology and Infertility Committee of the
SOGC.
Conclusion: First line management of infertility once a diagnosis of
PCOS is made should include weight loss and exercise with goals
to below class 2 obesity (BMI <35 kg/m2) as applicable.
Subsequently, first line medical therapy for ovulation induction
should include aromatase inhibitors (now considered both safe
and effective) and selective estrogen receptor modulators as
available. Insulin sensitizers should not be used as first line
therapy but as adjuncts as appropriate. Referral to a reproductive
endocrinologist should be considered if there is failure or
resistance to these approaches to consider ovulation induction
with gonadotropins or IVF as appropriate.
Sponsor: The Society of Obstetricians and Gynaecologists of
Canada.
Recommendations:
1. Weight loss, with a target of BMI <35 kg/m2 and/or 5% to 10% of
bodyweight if overweight, through exercise and lifestyle modifica-
tions have been shown to be effective in restoring ovulatory cycles
and achieving pregnancy in overweight individuals with polycystic
ovary syndrome and should be the first-line option. However, the
evidence is limited and not yet demonstrated in high-quality studies
(II-3A). Morbidly obese (body mass index ≥40) individuals should
seek expert advice through referral to qualified providers about safe
weight loss strategies and pregnancy risk in this condition (III-A).
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No. 362-Ovulation Induction in Polycystic Ovary Syndrome
2. Clomiphene citrate has been proven effective in ovulation induc-
tion for women with polycystic ovary syndrome and, where
available, should be considered the first-line medical therapy. Pa-
tients should be informed that there is an increased risk of twin
pregnancy or higher order multiples with ovulation induction using
clomiphene citrate (I-A).
3. Recent research has demonstrated both effectiveness and safety
of aromatase inhibitors in their use for ovulation induction in
polycystic ovary syndrome patients, particularly in the obese
population. Where clomiphene citrate is not available, letrozole
should be considered as an oral ovulation-induction agent after
counselling patients on its classification as off-label use by Health
Canada (I-B).
4. Metformin combined with clomiphene citrate may increase ovula-
tion 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 resis-
tance who are both older (age >28) and have visceral obesity (waist
to hip ratio >0.85) (I-A).
5. In cases of polycystic ovary syndrome with anovulatory cycles, go-
nadotropins should be considered second-line therapy for fertility.
Gonadotropin treatment requires ultrasound and laboratory moni-
toring and is associated with high cost, high risk of cancellation due
to higher than acceptable follicular development, risk of multiple births,
and ovarian hyperstimulation syndrome (II-2A).
6. When there are other indications for laparoscopy, laparoscopic
ovarian drilling may be considered in cases of clomiphene and/or
letrozole resistant polycystic ovary syndrome (I-A). The risks of
surgery and decreased ovarian reserve should be considered
(III-A).
7. In vitro fertilization should be reserved for women with polycystic ovary
syndrome who fail gonadotropin therapy or who have other indica-
tions for in vitro fertilization treatment (II-2A).
JULY JOGC JUILLET 2018 • 979
SOGC CLINICAL PRACTICE GUIDELINE

Table 1. Key to evidence statements and grading of recommendations using the ranking of the Canadian Task Force
on Preventive Health Care
Quality of evidence assessmenta Classification of recommendationsb
I: Evidence obtained from at least 1 properly randomized controlled A. There is good evidence to recommend the clinical preventive
trial action
II-1: Evidence from well-designed controlled trials without B. There is fair evidence to recommend the clinical preventive action
randomization C. The existing evidence is conflicting and does not allow to make a
II-2: Evidence from well-designed cohort (prospective or recommendation for or against use of the clinical preventive action;
retrospective) or case-control studies, preferably from more than 1 however, other factors may influence decision-making
centre or research group D. There is fair evidence to recommend against the clinical preventive
II-3: Evidence obtained from comparisons between times or places action
with or without the intervention. Dramatic results in uncontrolled E. There is good evidence to recommend against the clinical
experiments (such as the results of treatment with penicillin in the preventive action
1940s) could also be included in the category I. There is insufficient evidence (in quantity or quality) to make a
III: Opinions of respected authorities, based on clinical experience, recommendation; however, other factors may influence
descriptive studies, or reports of expert committees decision-making
a
The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Pre-
ventive Health Care.
b
Recommendations included in these guidelines have been adapted from the Classification of recommendations criteria described in The Canadian Task Force on
Preventive Health Care.

INTRODUCTION Patients who fulfill these criteria often have infertility sec-
ondary to ovulatory dysfunction which, in some individuals
P COS is a heterogeneous endocrine condition that affects
approximately 5% to 10% of women in the reproduc-
tive age group.1–3 Depending on the population being
with PCOS, can be attributed to the effects of
hyperandrogenism. Approaches that have been used for ovu-
lation induction and fertility treatment in PCOS have included
examined, prevalence rates as high as 26% have been the following:
reported.4 Although debate on what constitutes PCOS con-
tinues, the Rotterdam Consensus on Diagnostic Criteria for
• Weight loss, exercise, and lifestyle modifications
PCOS published in 2003 is the most commonly used defi-
• Clomiphene citrate
nition. According to this consensus, PCOS is diagnosed based
• Aromatase inhibitors (most commonly LTZ)
on an individual having at least 2 of the following 3 crite-
• Metformin
ria: oligo-ovulation or anovulation, clinical or biochemical
• Gonadotropins
evidence of hyperandrogenism, and polycystic ovaries on
• Ovarian drilling
ultrasound assessment (>12 small antral follicles in an ovary).
• IVF
Other medical conditions such as congenital adrenal hy-
perplasia, androgen-secreting tumours, hyperprolactinemia, This guideline addresses the sequential steps that should be
or Cushing’s syndrome should be excluded.5 considered, as well as the pregnancy rates, risks, and ben-
efits of each approach.

Weight Loss and Lifestyle Modifications

ABBREVIATIONS Obesity (BMI >30 kg/m2) is strongly associated with PCOS
BMI body mass index and may be present in up to 50% of cases.6–10 Obese indi-
CC clomiphene citrate viduals with PCOS are more likely than thin individuals with
CI confidence interval PCOS to suffer from anovulation.6 This effect on ovula-
FSH follicle stimulating hormone
tion may be secondary to insulin resistance, resulting in
IVF in vitro fertilization
compensatory hyperinsulinemia which is associated with in-
creased androgen production by the ovaries. Intraovarian
LH luteinizing hormone
hyperandrogenism in turn inhibits follicular maturation.10
LOD laparoscopic ovarian drilling
LTZ letrozole A randomized controlled trial comparing dietary modifica-
OR odds ratio tion to exercise in an effort to improve outcomes in patients
PCOS polycystic ovary syndrome with PCOS confirmed that the focus of the primary

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consultation of overweight PCOS patients should be on life-
style interventions such as dietary advice, exercise, and weight
loss.11 Weight loss through exercise and diet is effective in
restoring ovulatory cycles and achieving pregnancy for many
of these patients.12–14 In obese, anovulatory women with
PCOS, weight loss of even 5% to 10% of body weight often
restores ovulatory cycles.8,9,15,16 Studies also show that over-
weight women are less likely to respond to pharmacologic
ovulation induction methods.8,17
Obese individuals often report difficulty in achieving and
maintaining weight loss. The extent to which their obesity
reflects an inherent metabolic disturbance, making it more
challenging for them to lose weight, remains a question. The
current recommendation is to reduce weight gradually to
increase the chances of maintaining the weight loss. Pref-
erential diet composition has been evaluated in 2 small
studies.18,19 These studies compared a high carbohydrate
(55%), low protein (15%) hypocaloric diet with a low car-
bohydrate (40%), high protein (30%) hypocaloric diet and
found similar weight loss and decrease in circulating an-
drogen and insulin levels. Although the patient sample size
was small and larger confirmatory studies are lacking, these
2 studies suggest that patients can safely pursue either dietary
composition without negatively impacting on androgen and
insulin levels.
Routine exercise is also very important in the reproductive
health of individuals with PCOS. Exercise increases insulin
sensitivity and helps achieve and maintain weight loss.7,20
Once patients have achieved weight loss, they should be en-
couraged to maintain this in the long term and to have
normal weight gain during pregnancy. Obesity contributes
to poor obstetrical outcomes (increased risk of spontane-
ous abortion and preterm labour) and also increases maternal
complications, including gestational hypertension,
gestational diabetes mellitus, thromboembolism, and
wound infection.6 Long-term lifestyle modifications can de-
crease predisposition to health conditions such as Type 2
diabetes mellitus and modify risk factors for cardiovascu-
lar disease.7
Recommendation
1. Weight loss, with a target of BMI <35 kg/m2 and/or
5% to 10% of bodyweight if overweight, through ex-
ercise and lifestyle modifications have been shown to
be effective in restoring ovulatory cycles and achiev-
ing pregnancy in overweight individuals with polycystic
ovary syndrome and should be the first-line option.
However, the evidence is limited and not yet demon-
strated in high-quality studies (II-3A). Morbidly obese
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No. 362-Ovulation Induction in Polycystic Ovary Syndrome
(body mass index ≥40) individuals should seek expert
advice through referral to qualified providers about safe
weight loss strategies and pregnancy risk in this con-
dition (III-A).
Clomiphene Citrate
CC has been used as a first-line ovulation induction agent
for over 40 years.21,22 It is a selective estrogen receptor modu-
lator that stimulates endogenous FSH production and
secretion by interrupting estrogen feedback to the hypo-
thalamus and pituitary. PCOS patients can be sensitive to
ovulation induction medications because of a large number
of antral follicles. This places some of them at risk of ex-
cessive response (greater than 1–2 dominant follicles) with
multiple follicle development and ovarian hyperstimula-
tion. Conversely, others may have a poor response without
development of a dominant follicle despite using higher doses
of CC.
The starting dose of clomiphene citrate is 50 mg per day
for 5 days, commencing between day 2 and 5 of menses.23
Menses may be induced with a progestin if required. If this
dose produces multiple follicle development, the dose can
be lowered to 25 mg. If ovulation is not achieved using 50 mg
per day, the dose can be increased in increments of 50 mg.
The manufacturer does not recommend exceeding 100 mg
per day24; however, many experienced clinicians use doses
up to 150 mg, and some even up to 250 mg per day for 5
days,25 taking into account that alternative treatments such
as gonadotropins have greater risk (see below) and are more
costly.
Cycle monitoring should be considered in at least the first
cycle and when the treatment dose has to be increased
because ovulation has not occurred. Indications of an ovu-
latory response are a biphasic pattern on basal body
temperature charting and a serum progesterone measure-
ment in the expected luteal phase of >10 nmol/L if tested
6 to 8 days before the onset of menses.26 Urinary kits are
readily available and are used to detect the pre-ovulatory LH
surge. In some circumstances, ovarian follicle and endome-
trial assessment with transvaginal ultrasound during the late
follicular phase is more accurate than LH positivity.
Although 60% to 85% of patients will ovulate on CC, only
about one-half will conceive.27,28 Approximately 50% of con-
ceptions will occur on 50 mg, with another 20% to 25% and
10% occurring on 100 mg and 150 mg, respectively.16,29 Lack
of conception despite evidence of ovulation may be due
to anti-estrogenic effects of CC on the endometrium, which
may manifest as a thin endometrium on ultrasound.30 In 1
study, no pregnancies occurred when the endometrium was
JULY JOGC JUILLET 2018 • 981
SOGC CLINICAL PRACTICE GUIDELINE
<6 mm at midcycle,31 but others studies have not found a
similar association.32 Nevertheless, alternatives for ovula-
tion induction should be considered if the periovulatory
endometrium is persistently thin on CC therapy. Similarly,
if pregnancy does not occur within 6 ovulatory cycles,
another ovulation induction method should be considered.
Other drawbacks of CC include an increased rate of twin
(7%–9%) and triplet (0.3%) pregnancy, and side effects such
as vasomotor hot flashes.33 Unusual visual symptoms (visual
blurring or persistent after-images) are also noted in 1% to
2% of patients taking CC, which are likely related to anti-
estrogenic effects of CC on the visual cortex.34
Although more studies are required, it is best to limit a pa-
tient’s lifetime exposure to CC to 12 treatment cycles, as
additional cycles may place the patient at increased risk of
borderline ovarian tumours, though studies have not been
able to prove this to any conclusive level of risk due to small
numbers of cases reported.35 In addition, another therapy,
LTZ, is evolving as an alternative first-line medical therapy
(see below). Due to current industry considerations around
the production of clomiphene citrate and its lack of avail-
ability in Canada, LTZ may become the new first-line oral
agent at least for the foreseeable future.
Recommendation
2. Clomiphene citrate has been proven effective in ovu-
lation induction for women with polycystic ovary
syndrome and, where available, should be consid-
ered the first-line medical therapy. Patients should be
informed that there is an increased risk of twin preg-
nancy or higher order multiples with ovulation
induction using clomiphene citrate (I-A).
Aromatase Inhibitors
Aromatase inhibitors have been used for the last decade as
adjunctive treatments in breast cancer.36 They block the con-
version of testosterone and androstenedione to estradiol and
estrone, respectively, and hence inhibit the estrogen-
negative feedback on the hypothalamic–pituitary axis. This
leads to increased gonadotropin secretion, which in turn leads
to ovarian follicular growth and development.36
The use of aromatase inhibitors in ovulation induction was
first introduced in 2001.37 Ovulation and pregnancy rates
with aromatase inhibitors, such as LTZ and anastrozole,
appear to be promising. Although these agents seem to have
less anti-estrogen effect on the endometrium, the evi-
dence on endometrial effects is conflicting, and most studies
show equivalence with clomiphene citrate.36–39 In 2005, Health
Canada and the manufacturing company of LTZ issued a
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“Physician Warning Letter” on the off-label use of LTZ for
fertility given the possibility of embryotoxicity, fetotoxicity,
and teratogenicity as found in rats following a scientific ab-
stract based on preliminary data.40 In a clinical retrospective
analysis, Biljan et al.41 compared congenital malformations
in babies conceived with LTZ, with or without gonadotro-
pins, with those in babies born to a low-risk population of
women without known fertility treatments, and found a
higher incidence of both cardiac and bone abnormalities
in the LTZ group.41 A more recent study,42 retrospectively
evaluated 911 newborns from LTZ and CC pregnancies and
found no increase in the risk of congenital malformations
and chromosomal abnormalities (2.4% in the LTZ group
versus 4.8% in the CC group, compared with a back-
ground population risk of 2%–3%).42
Since then, a large, multi-centred, randomized controlled trial
published in 2014 compared LTZ with CC. The 2 dosing
regimens were CC 50 mg or LTZ 2.5 mg for 5 days start-
ing on day 3. If the patient was anovulatory, then the dose
was increased in successive cycles to CC 100 mg to a
maximum of CC 150 mg and, similarly, LTZ 5 mg then a
maximum of 7.5 mg as required.
Their findings demonstrated both higher live-birth rates and
higher ovulation rates among the cohort of women with
PCOS who took LTZ. This was even more pronounced with
respect to diminishing time to live birth amongst women
with BMI >30.3. Further, their study demonstrated that there
were no significant differences in congenital anomalies when
comparing CC with LTZ (P = 0.65), nor were there any sig-
nificant differences in pregnancy loss. LTZ also demonstrated
a tendency towards mono-ovulation in cases of anovula-
tory patients when compared with CC. With respect to side
effects, CC was associated with a higher incidence of hot
flushes, while LTZ was associated with higher incidence of
fatigue and dizziness.43
This is persuasive and clear evidence based on a well-
conducted, multicenter trial that LTZ should be considered
first-line medical therapy for ovulation induction. However,
given Health Canada’s original letter of warning for phy-
sicians published in 2005 with no further updates, patients
should continue to be counselled on the off-label use of LTZ
for fertility. 44 Despite this, the Canadian Fertility and
Andrology Society in a statement made March 2015 docu-
mented its confidence in LTZ as a safe and even more
effective treatment for oral ovulation induction (than CC?).
Recommendation
3. Recent research has demonstrated both effectiveness
and safety of aromatase inhibitors in their use for

ovulation induction in polycystic ovary syndrome pa-
tients, particularly in the obese population. Where
clomiphene citrate is not available, letrozole should be
considered as an oral ovulation-induction agent after
counselling patients on its classification as off-label use
by Health Canada (I-B).
Insulin Sensitizing Agents
The recognition of an association between PCOS and insulin
resistance has led to the use of insulin-sensitizing agents in
ovulation induction. Metformin, the most widely studied
agent used in PCOS, is a biguanide insulin-sensitizing agent
that acts by inhibiting hepatic glucose production and in-
creasing peripheral glucose uptake.45 It does not stimulate
secretion of insulin or cause hypoglycemia.
Many earlier studies examining the use of metformin alone
or in conjunction with CC in ovulation induction showed
promising results,46–52 but most of these studies had rela-
tively small sample sizes. A 2003 meta-analysis of 13
randomized controlled trials by Lord et al.53 concluded that
metformin was more effective in achieving ovulation in
women with PCOS compared with placebo (OR 3.88; 95%
CI 2.25–6.69) and that metformin and CC were more ef-
fective than CC alone (OR 4.41; 95% CI 2.37–8.22).
Pregnancy rates were not significantly better with metformin
than with placebo (OR 2.76; 95% CI 0.85–8.98), but an im-
provement in pregnancy rates was seen with metformin plus
CC over CC alone (OR 4.4; CI 1.96–9.85).53 In specific cases
of documented insulin resistance, a 2017 meta-analysis sug-
gested that there may be value in using metformin alone
initially as first-line therapy, though the evidence for this is
limited.54
A 2008 meta-analysis published 55 comparing CC and
metformin, both alone and in combination, found that
metformin alone increased the odds of ovulation com-
pared with placebo (OR 2.94; 95% CI 1.43–6.02) but did
not result in a statistically significant difference in preg-
nancy rates (OR 1.56; 95% CI 0.74–3.33). When CC and
metformin were compared with CC alone, both ovulation
and pregnancy rates were statistically increased with ORs
of 4.39 (95% CI 1.94–9.96) and 2.67 (95% CI 1.45–4.94),
respectively. A 2012 Cochrane Review yielded similar results
regarding increased ovulation rates but not in live birth rates.
The reduction of fasting insulin levels as well as of andro-
gens was seen with metformin therapy but only in the context
of BMI <30. 56
Ng et al.57 in 2001 compared metformin and placebo in 20
women and found that women who received metformin were
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No. 362-Ovulation Induction in Polycystic Ovary Syndrome
less likely to achieve a live birth, although this difference did
not reach statistical significance (OR 0.44; 95% CI 0.03–
5.88). Four of the included trials examined live birth rates
with CC and metformin versus CC alone.51,58–60 Collec-
tively, the combination of CC and metformin suggested an
increase in live birth rate over CC alone, but this increase
was not statistically significant (OR 1.74; 95% CI 0.79–
3.86). The only trial adequately powered to assess live birth
rates was the large randomized controlled trial published by
Legro et al. in 2007.58 This trial included 626 patients and
demonstrated that although the live birth rate following up
to 6 months of treatment with metformin and CC was in-
creased (26.8%), it was not significantly different from that
with CC alone (22.5%). Live birth rates using CC alone or
with metformin were significantly higher than rates with
metformin alone (7.2%).
The evidence supports the use of clomiphene citrate over
metformin as first-line pharmacologic therapy following life-
style modification in women with PCOS. However, there
may be a role for the addition of metformin to CC in women
who are clomiphene-resistant. Siebert et al.61 examined 6 trials
in which metformin was randomized with either placebo
or CC in clomiphene-resistant patients and found a signifi-
cant improvement in ovulation with combination therapy
(OR 6.82; 95% CI 3.59–12.96). Further, a recent study also
suggested that women with PCOS who are older (age >28)
and have increased visceral obesity (waist to hip ratio of
>0.85) may benefit from the additional use of metformin.62
Side effects of metformin may include nausea, bloating,
cramps, and diarrhea. Patients should be counselled to start
with 250 mg to 500 mg orally daily and increase as toler-
ated to the optimal daily dose of 500 mg to 750 mg 3 times
daily with food. Metformin can also be dosed 850 mg orally
twice daily to improve compliance.
Although some studies have shown that continuing
metformin in pregnancy may decrease the spontaneous abor-
tion rate,52,63–65 none of these are prospective, randomized
trials. Randomized controlled trials are needed in this area
before sustained metformin treatment throughout preg-
nancy can be recommended.
Recommendation
4. Metformin combined with clomiphene citrate may in-
crease ovulation and pregnancy rates but does not
significantly improve the live birth rate over that of clo-
miphene citrate alone (I-A). Metformin may be added
to clomiphene citrate in women with clomiphene re-
sistance who are both older (age >28) and have visceral
obesity (waist to hip ratio >0.85) (I-A).
JULY JOGC JUILLET 2018 • 983
SOGC CLINICAL PRACTICE GUIDELINE
Gonadotropins
Use of intramuscular gonadotropins began in the 1960s.
These preparations, extracted from the urine of postmeno-
pausal women, contained both FSH and LH, but could be
purified to reduce the LH content. For over 2 decades, re-
combinant human FSH preparations are also available. Both
urinary gonadotropin preparations and recombinant FSH
are administered subcutaneously.66 Gonadotropins are used
when PCOS patients fail either to ovulate or to conceive
with oral ovulation inducing medications.
Daily gonadotropin injections are combined with concur-
rent blood and ultrasound monitoring with the aim of
monofollicular growth and development. Calaf Alsina et al.
described a low-dose step up protocol recommended in the
first cycle, with incremental dose adjustments following a
minimum of 7 days at the starting dose.67 Over the years,
several step-up or step-down protocols have been intro-
duced in an effort to achieve monofollicular growth, but
despite these efforts, given the inherent nature of exog-
enous gonadotropin treatment, multifollicular development
is not uncommon. Once the dominant follicle has reached
the appropriate size, human chorionic gonadotropin is ad-
ministered to trigger ovulation, with cancellation if a
dominant follicle is not achieved.
Injectable gonadotropins are costly and require frequent
monitoring with serum estradiol and ultrasound assess-
ments. Pregnancy rates with gonadotropins are 20% to
25% per cycle.66 Because of the high number of antral
follicles in women with PCOS, it may be necessary to
cancel treatment to minimize the occurrence of multiple
pregnancy and potential ovarian hyperstimulation syndrome68
or, if available, convert to IVF followed by elective
single embryo transfer. Other risks of gonadotropin
treatment include multiple pregnancy, with some studies
stating up to 20% versus 5% risk in oral induction agent
treatment, and ovarian hyperstimulation syndrome. Go-
nadotropins should be administered by physicians with
specific training in reproductive medicine and with ready
access to ultrasound monitoring and rapid hormone
testing.
Recommendation
5. In cases of polycystic ovary syndrome with anovula-
tory cycles, gonadotropins should be considered
second-line therapy for fertility. Gonadotropin treat-
ment requires ultrasound and laboratory monitoring
and is associated with high cost, high risk of cancel-
lation due to higher than acceptable follicular
development, risk of multiple births, and ovarian hy-
perstimulation syndrome (II-2A).
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Ovarian Drilling
Surgical ovarian wedge resection by open laparotomy was
a treatment for PCOS-associated anovulation before the avail-
ability of ovulation-induction medications.69 It was thought
to induce ovulation by decreasing the ovarian theca and thus
reducing androgen production. Because of the operative
morbidity of the procedure and the risk of postoperative
adhesions,70 ovarian wedge resection by laparotomy has
largely been abandoned as more effective medical thera-
pies for ovulation induction have become available. With
the popularity of minimally invasive surgery, LOD has been
introduced as an alternative to wedge resection of the ovaries
and is thought to be less destructive to the ovary and has a
lower risk of adhesion formation. LOD uses either cautery
or laser to create approximately 10 superficial perforations
per ovary.71
A 2007 Cochrane review examined 16 randomized con-
trolled trials evaluating ovulation induction in clomiphene-
resistant PCOS with LOD. The dose at which clomiphene
resistance was defined ranged from 100 mg to 200 mg in
the various studies. Approximately 80% of PCOS patients
became ovulatory after LOD. There was no difference found
in the rates of miscarriage, ongoing pregnancy, or live birth
between patients who underwent LOD and patients treated
with gonadotropins for ovulation induction. There were sig-
nificantly fewer multiple pregnancies in the LOD than in
the gonadotropin treatment groups (1% vs. 16%; OR 0.13;
95% CI 0.03–0.59).71 In 1 of the included trials, adjuvant
therapy with CC or gonadotropins was required to achieve
equivalent pregnancy and live birth rates in patients remain-
ing anovulatory 8 weeks after LOD or those who
subsequently became anovulatory.72
There are concerns about the effects of LOD on postop-
erative adhesion formation and ovarian reserve,73 although
it has been shown that in women who respond to this treat-
ment, the rate of cessation of ovulation is low.74 A 2012
Cochrane Review Update suggested that future research into
the risk of long-term effects on ovarian reserve after LOD
should be performed.75
Recommendation
6. When there are other indications for laparoscopy, lapa-
roscopic ovarian drilling may be considered in cases
of clomiphene and/or letrozole resistant polycystic
ovary syndrome (I-A). The risks of surgery and de-
creased ovarian reserve should be considered (III-A).
In Vitro Fertilization
IVF, with or without intracytoplasmic sperm injection, is the
next treatment option for individuals with PCOS who fail

to conceive with sequential clomiphene and/or LTZ and/
or gonadotropin treatment or in the presence of other
indications for advanced reproductive technologies. In IVF,
gonadotropins are administered to achieve intentional
multifollicular development for oocyte retrieval and gen-
eration of embryos for transfer into the uterus. Pregnancy
rates can approach 40% to 50% per cycle with IVF, but, as
with fertility in general, success is significantly influenced
by the women’s age.66 PCOS patients achieve pregnancy and
live birth rates similar to those of non-PCOS patients during
conventional IVF cycles. Side effects include multiple births
when multiple embryos are transferred, and a higher risk
of ovarian hyperstimulation; however, the risk of multiple
births is more easily controlled with IVF than with ovula-
tion induction with gonadotropins because the number of
embryos transferred into the patient’s uterus can be limited
and surplus good quality embryos cryopreserved for future
transfer.
Recommendation
7. In vitro fertilization should be reserved for women with
polycystic ovary syndrome who fail gonadotropin
therapy or who have other indications for in vitro fer-
tilization treatment (II-2A).
CONCLUSION
Patients with polycystic ovary syndrome commonly present
with a history of infertility due to oligo-ovulation or an-
ovulation. First-line management of infertility should always
include weight loss and exercise and lifestyle modifica-
tions in the overweight patient with a target weight to be
below the threshold of class 2 obesity (BMI <35 kg/m2).
Behavioural modification and weight loss reduction strat-
egies are beneficial in the patient’s overall health, may lead
to spontaneous ovulation, and may improve response to
ovulation-induction medications. CC has been used for many
years and remains the first-line medication despite poten-
tial anti-estrogenic effects on the endometrium and cervical
mucus. New research on aromatase inhibitors, in particu-
lar LTZ, has shown efficacy and safety despite historic rat
studies suggesting teratogenesis and its continued off-
label classification by Health Canada. More recent data,
including that from a large randomized controlled trial, pro-
vides safety and effectiveness evidence to support LTZ as
an alternative first-line medication. Recent evidence indi-
cates that insulin-sensitizing agents should not be used as
a first-line therapy, although they may be beneficial in PCOS
patients who are older and who have increased visceral
obesity as assessed by increased waist-to-hip ratios, and in
those who have failed to ovulate on CC or on LTZ alone.
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No. 362-Ovulation Induction in Polycystic Ovary Syndrome
LOD may be considered in individuals with PCOS who are
resistant to CC or who fail LTZ treatment because of the
lower risk of multifetal gestation compared with gonado-
tropin therapy.
Clinicians should always consider a patient’s age and dura-
tion of infertility as they progress through the different
treatment options available. If a patient does not become
pregnant in a timely manner, referral to a fertility clinic with
reproductive specialist expertise and resources including go-
nadotropins and IVF are effective options.
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