PCOS - Excemed

PCOS: infertility management
and pregnancy outcome
Dr Sesh K Sunkara MD, MRCOG
Royal Marsden Hospital, London
Kings Healthcare Partners (Guy’s & St Thomas NHS Foundation
Trust), London, UK
PCOS: the hidden epidemic

Most common female endocrine disorder


Prevalence based on definition
20 % using the Rotterdam criteria (Yildiz et al., Hum Reprod
2012)

75% of women with anovulatory infertility (Adams et al.,
BMJ 1986; Hull. Clin Endocrinol 1987)

Increased incidence of PCOS with obesity

BMI correlates with hyperinsulineamia, menstrual
irregularity and infertility (Balen & Anderson Hum Fertil 2007;
Franks et al., Hum Reprod Update 2008)
Manifestations of PCOS

Immediate




Menstrual irregularities
Hirsutism
Infertility
Long term



Pregnancy complications
Insulin resistance (IR) syndrome: type 2 diabetes and
cardiovascular diseases
Cancer risk
Fertility management
Obesity
Insulin
resistance

Understanding the intrinsic link between obesity,
insulin resistance (IR) and PCOS is fundamental to
the management

Treatment of PCOS symptoms should be centred
taking into account desire for fertility

PCOS
Hormonal treatment options for menstrual problems and
hirsutism could be counterproductive
Lifestyle interventions

Life style interventions: 1st line management in
women with PCOS and obesity (ESHRE/ ASRM consensus, Hum
Reprod 2008; Fertil Steril 2008)
PCOS and obesity
 Significantly higher prevalence of overweight and obesity in women with PCOS (Lim
et al., Hum Reprod Update 2012)
 ↑ BMI worsens negative reproductive effects of PCOS (Lim et al., Obes Rev 2012)
Weight loss: fertility outcome



24 women with PCOS and mean weight 91.5 (± 14.7)
kg
6-7 month low calorie diet (1000 kcal/ day)
13 women lost > 5% weight



9 women showed an improvement in reproductive
function
5 conceived, others had more regular menstrual cycles
vs
Only 1 among 8 women with < 5% weight loss had
improvement in reproductive function
(Kiddy et al., Clin Endocrinol 1992)
Weight loss: fertility outcome






18 women with BMI ≥ 30 kg/m2 and previous
clomiphene citrate resistance
Group treatment format with dietary changes and
regular exercise for 6 months
13 women completed the treatment
Significant weight loss in women who completed
treatment (6.3 ± 4.2 kg)
12 of 13 women in the treatment group ovulated in
6 months and 10 conceived after 12 months
None of the 5 drop outs ovulated nor conceived
(Clark et al., Hum Reprod 1995)
Clomiphene citrate





Synthetic anti-oestrogen
1st line drug for ovulation induction (OI)
Affects hypothalamic activity by occupying the
oestrogenic receptors
Hypothalamus and pituitary falsely interpret this as
low oestrogen levels
Triggers a negative feedback mechanism leading to
secretion of GnRH and FSH that effect ovarian
stimulation
Clomiphene citrate
(Brown et al., Cochrane Database Syst Rev 2009)
Clomiphene citrate

75 - 80% ovulation (Homburg Hum Reprod 2005; Messinis Hum
Reprod 2005)

22% conception rate/ cycle in women ovulating
(Hammond et al., Obstet Gynecol 1983; Kousta et al., Hum Reprod Update
1997; Eijkemans et al., Hum Reprod 2005)

Cumulative live birth rate of 50 – 60% after 6 cycles
(Kousta et al., 1997)


15% remain anovulatory following CC - CC resistant
PCOS (Hammond et al., Obstet Gynecol 1983)
50% of women ovulating with CC fail to conceive (Raj
et al., Obstet Gynecol 1997)
Clomiphene citrate
(Kousta et al., Hum Reprod Update 1997)
• Treatment should be limited to 6 ovulatory cycles (NICE 2013)
Insulin sensitising agents

Insulin resistance, hyperandrogenism and obesity
have a significant impact on reproductive
performance in women with PCOS

Metformin (a biguanide) is an insulin sensitising
agent that lowers insulin levels

It is assumed that a decrease in serum insulin levels
and hyperandrogenism improves reproductive
outcomes in women with PCOS
Metformin
Metformin in women with PCOS: live birth
(Tang et al., Cochrane Database Syst Rev 2012)
Metformin
Metformin versus CC in women with PCOS: live birth
(Tang et al., Cochrane Database Syst Rev 2012)
Metformin
Metformin + CC versus CC in women with PCOS: live birth
(Tang et al., Cochrane Database Syst Rev 2012)
Aromatase inhibitors





Proposed as an alternative to clomiphene citrate
Inhibit enzyme aromatase thus decreasing
aromatization of androgens to oestrogens
Decrease in oestrogens levels releases the pituitary
from the negative feedback effect
Resultant increase in pituitary FSH
Letrozole, anastrazole associated with good
pregnancy rates and lower multiple pregnancy rates
(Casper and Mitwally, JCEM 2006)

Discontinued because of teratogenic concerns
Gonadotrophins


2nd line ovulation induction in CC resistant PCOS
Risks




Multiple follicle recruitment
Multiple pregnancy
OHSS
Prevention of risks by using

Low dose step regimen (Hamilton-Fairley et al., Hum Reprod
1991)

Low dose step down regimen (Fauser et al., Ballieres Clin Obstet
Gynaecol 1993)

Adherence to strict cycle cancellation criteria
Gonadotrophins
hMG versus uFSH in women with PCOS: pregnancy rate
(Nugent et al., Cochrane Database Syst Rev 2009)
Gonadotrophins
uFSH versus rFSH in women with PCOS: pregnancy rate
(Bayram et al., Cochrane Database Syst Rev 2010)
Laparoscopic ovarian drilling


Alternative to gonadotrophins in CC resistant PCOS
Advantage: no risk of



Risks



Multiple pregnancy
OHSS
Related to surgery
Peri-ovarian adhesions, especially when excessive damage
to ovary
Suggested technique to obtain optimal outcome
whilst minimising risks: 4 seconds, 4 points, 40 W
(Armar et al., Fertil Steril 1990)
Laparoscopic ovarian drilling
LOD vs Gonadotrophin for CC resistant PCOS: live birth
(Farquhar et al., Cochrane Database Syst Rev 2012)
CC resistant PCOS: Metformin + CC
IVF treatment




Final treatment option for PCOS
Presence of other associated factors
Should be tailored to avoid OHSS
Consideration should be given to




COS regimen
Gonadotrophin dose; lower stimulation dose
Single embryo transfer in a fresh cycle
Cycle segmentation
Agonists vs antagonists in PCOS
Ongoing pregnancy rate
(Al-Inany et al., Cochrane Database Syst Rev 2011)
Agonists vs antagonists in PCOS
Ovarian hyperstimulation syndrome:
- 0.10 (- 0.07; - 0.14)
(Al-Inany et al., Hum Reprod Update 2011)
GnRH agonist vs hCG trigger
Ovarian hyperstimulation syndrome:
(Youssef et al., Cochrane Database Syst Rev 2011)
GnRH agonist vs hCG trigger
Live birth rate:
Fresh autologous cycles
Donor cycles
All cycles
Youssef et al., Cochrane Database Syst Rev. 2011
GnRH agonist trigger


Need for an intensified luteal support with GnRH
agonist trigger
Suggested regimens for luteal support


Dual trigger (hCG+GnRH a) (Shapiro et al., 2011)
Low dose hCG supplementation (Humaidan et al., 2006; 2009;
2010)

Intensive luteal oestradiol and progesterone
supplementation (Babayof et al., 2006; Orvieto et al., 2006;
Engmann et al., 2008; Griffin et al., 2012)


rec-LH supplementation (Papanikolaou et al., 2011)
Luteal GnRH agonist administration (Pirard et al., 2006)
GnRH agonist trigger with intense luteal support
Clinical pregnancy rate:
Sunkara et al., Unpublished
GnRH agonist trigger with intense luteal support
Ongoing pregnancy rate:
Sunkara et al., Unpublished
PCOS and pregnancy complications

Pregnancy complications attributed to PCOS




Early pregnancy loss, miscarriage
Gestational diabetes mellitus (GDM)
Pregnancy induced hypertensive disorders (PIH/
PET)
Small for gestational age (SGA) babies
PCOS and miscarriage

Suggested reasons for higher miscarriage in PCOS

Hypersecretion of LH (Homburg et al., BMJ 1988, Regan et al.,
Lancet 1990)


Higher prevalence of obesity
Hperinsulinaemia leading to higher levels of
plasminogen activator inhibitor – 1 (PAI – 1) (Glueck
et al., Metab 1999)

Endometrial dysfuntion (Jakubowicz et al., JCEM 2001,
Diamantis-Kandarakis et al., JCEM 2005)
PCOS and miscarriage
What we know

Higher risk of miscarriage in women who are
overweight or obese (Wang et al., Obes Res 2002)
What we do not know

Is it the obesity or PCOS per se that causes the
increased risk of miscarriage
PCOS and miscarriage
Wang et at., Hum Reprod 2001




1018 women undergoing IVF treatment
37% had PCOS
Miscarriage rate 25% in women with PCOS vs 18% in
non-PCOS group (p < 0.01)
 HOWEVER
No significant difference in miscarriage rate after
adjusting for obesity and treatment type
PCOS and GDM
Kjerulff et al., AJOG 2011
PCOS and PIH
OR 3.67; 95% CI: 1.98–6.81
Boosma et al., Hum Reprod Update 2006
PCOS and PET
OR 3.47; 95% CI: 1.95–6.17
Boosma et al., Hum Reprod Update 2006
PCOS and preterm delivery
OR 1.75; 95% CI: 1.16–2.62
Boosma et al., Hum Reprod Update 2006
Conclusions: infertility management





Logical management
Lifestyle interventions; weight loss
1st line OI
 Clomiphene citrate
2nd line OI
 Clomiphene citrate with metformin
 Gonadotrophin
 Ovarian drilling
IVF: GnRH antagonist regimen, GnRH agonist trigger
Conclusions: pregnancy management


Preconception advice
 Optimisation of weight with dietary modification
and exercise
Surveillance in pregnancy:
 Screening for GDM before 20 weeks gestation –
RCOG guideline (OGTT)
 Observe for hypertensive disorders in pregnancy ?
 Observe for foetal risks ?
Thank you