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Annales dEndocrinologie 71 (2010) 225227

Journes Klotz 2010

Treatment of infertility in women with polycystic ovary syndrome


Traitement de linfertilit chez les femmes souffrant dun syndrome des ovaries polykystiques
P. Bouchard
Endocrinology, Hpital Saint-Antoine, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France
Available online 14 April 2010

Rsum
Le traitement de linfertilit dans le syndrome des ovaires polykystiques (SOPK) associe des modifications du style de vie et lutilisation de
mdicaments inducteurs de lovulation. Dans cet objectif, le citrate de clomifne (CC) doit tre utilis en premire intention, suivi si ncessaire par de
faibles doses de gonadotrophines en seconde ligne. Dans de rares cas, en cas dchec du CC, un drilling ovarien, i.e. une chirurgie laparoscopique
ovarienne, ou enfin une technique de procration mdicalement assiste peut tre utilise. Finalement, linduction dovulation (reprsente par le
CC et les gonadotrophines) savre trs efficace avec un taux cumul de naissances vivantes uniques de 72 %. Lusage dinsulino-sensibilisateurs
cest--dire de metformine dans le SOPK doit tre rserv aux femmes prsentant une intolrance au glucose et/ou une rsistance linsuline.
Compte-tenu des rcents travaux, lutilisation en routine de ce mdicament de facon isole pour induire une ovulation nest pas recommande.
2010 Publie par Elsevier Masson SAS.

Mots cls : Infertilit ; Syndrome des ovaires polykystiques ; Citrate de clomifne ; Gonadotrophines ; Drilling ovarien ; Technique de reproduction mdicalement
assiste ; Metformine

Abstract
The treatment of infertility in polycystic ovary syndrome (PCOS) associates lifestyle measures, and the use of drugs to induce ovulation. In
this endeavour, clomifene citrate (CC) should be used as the first line of treatment, followed eventually by low dose gonadotrophin stimulation,
as a second line. In rare cases, in case of failure of the CC treatment, ovarian drilling i.e. laparoscopic ovarian surgery (LOS), and finally assisted
reproduction techniques can be used, if needed. Overall, ovulation induction (representing the CCgonadotrophin paradigm) is highly effective
with a cumulative singleton live birth rate of 72%. The use of insulin sensitizers i.e. metformin in PCOS should be restricted to women with glucose
intolerance and/or insulin resistance. Based on recent data available, the routine use of this drug, alone, in ovulation induction is not recommended.
2010 Published by Elsevier Masson SAS.

Keywords: Infertility; Polycystic ovary syndrome; Clomifene citrate; Gonadotrophin; Ovarian drilling; Assisted reproduction techniques; Metformin

Polycystic ovary syndrome is a frequent pathology, which Consensus Conference (2003), two of these criteria suffice to
presents as a complex genetic disease, associating a strong famil- characterize the syndrome.
ial link, and a modulating role of the environment, in particular The treatment of infertility associates lifestyle measures, and
of body weight excess. Excess body weight is associated with the use of drugs to induce ovulation [13]. In this endeav-
variable degree of insulin resistance, which influences androgen our, clomifene citrate (CC) should be used as the first line of
secretion and the clinical phenotype. It is generally accepted that treatment, followed eventually by low dose gonadotrophin stim-
510% of all women are attained. ulation, as a second line. In rare cases, in case of failure of the
This enigmatic syndrome associates dysovulation with CC treatment, ovarian drilling i.e. laparoscopic ovarian surgery
oligomenorrhea, hyperandrogenism, and multifollicular devel- (LOS), and finally assisted reproduction techniques can be used,
opment on ovary US scans. According to the Rotterdam if needed.
Overall, ovulation induction (representing the CC
gonadotrophin paradigm) is highly effective with a cumulative
E-mail address: philippe.bouchard@sat.ap-hop-paris.fr. singleton live birth rate of 72%.

0003-4266/$ see front matter 2010 Published by Elsevier Masson SAS.


doi:10.1016/j.ando.2010.03.006
226 P. Bouchard / Annales dEndocrinologie 71 (2010) 225227

The use of insulin sensitizers i.e. metformin in PCOS should of human chorionic gonadotrophin (hCG) in mid-cycle improves
be restricted to women with glucose intolerance and/or insulin the chances of conception.
resistance. Based on recent data available, the routine use of this Approximately, 7580% of patients with PCOS will ovulate
drug, alone, in ovulation induction is not recommended. after CC [6]. Although there appears to be discrepancy between
Insufficient evidence is currently available to recommend the ovulation and pregnancy rates, a conception rate of up to 22%
clinical use of aromatase inhibitors for routine ovulation induc- per cycle is widely accepted in those ovulating on CC. A max-
tion. These products are still not approved by drug agencies. imum of six cycles is generally proposed, with a cumulative
It is noteworthy that once pregnant, women with PCOS are pregnancy rate of 5060%. A normal body weight remains the
exposed to a high risk of miscarriage, although the mechanisms main prognosis criterion for success.
of these pregnancy interruptions remain poorly understood
and may reflect abnormal oocyte development. In addition, 4. Gonadotrophin therapy (FSH)
complications of pregnancy such as preeclampsia and gesta-
tional diabetes can be observed, and women should be carefully In case of anovulation with CC, treatment with gonadotrophin
informed of these risks and of the need of a strict surveillance should be used [6,13]. The data available support the use
of their pregnancy. of low dose regimens starting with 50 IU per day. In order
to avoid ovarian hyperstimulation, and multiple pregnancies,
1. Lifestyles measures cycle cancellation is advised when more than three follicles
of 16 mm or larger were observed. It would seem prudent to
The treatment of obesity is always mandatory in case of PCOS withhold hCG administration in the presence of more than two
with excess weight [46]. Treatment associates behavioural follicles > 16 mm or more than one follicle > 16 mm and two
counselling, lifestyle therapy (diet and exercise), pharmacolog- additional follicles > 14 mm, in order to minimize the risk of
ical treatment, and eventually bariatric surgery. A reduction of multiple pregnancies in women with PCOS under the age of 38
5% of body weight is generally recommended. Although we lack without any other infertility factors.
proofs of its efficacy in terms of live birth rate, there is a general Low-dose regimens result in a monofollicular ovulation rate
agreement that weight reduction is of paramount importance of 70%, a pregnancy rate of 20% and a multiple live birth rate
to improve ovulation rate, efficacy of drugs used in ovulation of 5.7%. The major complication of ovulation induction is the
induction, and to reduce the pregnancy complications linked to occurrence of a 10% multiple pregnancy rate unless a strict low
obesity. dose regimen is used.

2. Insulin sensitizers 5. Laparoscopic ovarian surgery (LOS)

Glitazones are very potent insulin sensitizers; however they Surgical approaches to ovulation induction have developed
cannot be used in women seeking pregnancy because of potential from the traditional wedge resection [4,6,13,14]. Multiple ovar-
adverse effects since PPAR, the nuclear receptors to which they ian puncture performed either by diathermy or by laser is known
bind plays a crucial role during development. as ovarian drilling.
Metformin use in PCOS should be restricted to women with The main indication for LOS is CC resistance in women with
glucose intolerance. However, in terms of induction of ovula- anovulatory PCOS. As few as four punctures have been shown
tion, although many studies have been performed, results remain to be effective. LOS can achieve monofollicular ovulation with
uncertain, and women should not be treated by metformin alone no risk of OHSS or multiple pregnancies.
for more than a few months [611]. Randomized controlled trials Intensive monitoring of follicular development is not required
have been unable to demonstrate a uniform efficacy of met- after LOS.
formine in ovulation induction and improvement of pregnancy LOS is an alternative to gonadotrophin therapy for CC-
rate. Further, the risk of spontaneous abortion is not improved resistant anovulatory PCOS.
by metformin use [12]. Another potential advantage is the lack of need for US surveil-
lance unless additional treatment (CC or FSH) is associated.
3. Clomifene citrate
6. Assisted reproduction techniques: IVF
CC use is the first line of ovulation induction therapy [6].
The starting dose of CC should be 50 mg/day, for five or six In principle, anovulation is not an indication for IVF. Clearly,
days, starting on Day 2 of the cycle, following a spontaneous the logical therapy for women with PCOS is induction of
or progestin-induced withdrawal bleeding. The recommended ovulation, especially by CC administration, and in case of fail-
maximum dose is 100150 mg/day, as there is no clear evidence ure by using exogenous gonadotrophin therapy. As discussed
of efficacy at higher doses. It is prudent to monitor the first cycle before, the major complication of ovulation induction is the
with ovary US scan in order to allow adjustment of the dose in occurrence of a 10% multiple pregnancy rate after the use of
subsequent cycles. A pretreatment ultrasound is also needed. gonadotrophin therapy. For this reason, use of gonadotrophins
Finally progesterone measurements to demonstrate ovulation may be questioned. If IVF is proposed, the cycle cancellation
are also recommended. There is no evidence that administration rate is significantly increased in patients with PCOS (12.8 versus
P. Bouchard / Annales dEndocrinologie 71 (2010) 225227 227

4.1%; OR 0.5, 95% CI 0.21.0) [6,15]. Duration of stimulation [5] Otta CF, Wior M, Iraci GS, Kaplan R, Torres D, Gaido MI, et al. Clin-
is significantly longer in patients with PCOS (1.2 days, 95% CI ical, metabolic, and endocrine parameters in response to metformin and
0.91.5), even when the daily dose of FSH is similar to that of lifestyle intervention in women with polycystic ovary syndrome: A ran-
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