PCOS- Is obesity a concern

Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility
Centre, Kolkata
• Managing Committee Member, Bengal Obstetric & Gynaecological
Society (BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology Committee,
BOGS- 2019-20
• Member, Endocrinology Committee, FOGSI
• Convener, Spectrum MRCOG Course, Kolkata
• Winner, Prof Geoffrey Chamberlain Award, RCOG World
Congress, London, 2019
PCOS- Is OBESITY a Concern?

Good things
come to
those who
wait
but
bad things
come to

Men and women each have risk factors that can contribute to infertility,
which may be genetic or environmental or lifestyle related.
Obesity
one of the most well known risk factors for infertility
J Women’s Health Care 2015, 4:6

Understanding obesity and its impact on
female reproductive function is important
because future generations, namely, the
children of obese women, ultimately will
be affected.

Obesity & PCOS
• Obesity leading to insulin resistance is one of the
major root cause for PCOS leading to infertility.
• PCOS affects 2-26% women of during
reproductive years.
• Obesity associated PCOS results in Type 2
Diabetes in long term.
• Obesity which occurs in 30-75% of women with
PCOS increases the magnitude of hormonal and
metabolic dysfunction in these women.

Decrease sex hormone
Binding globulin
Increase in insulin
Like growth factor 1
Thecal cell hyperplasia
In ovary
Increase in androgen activity
Increase in LH
Hyperinsulenemia
Insulin Resistance
Excess Body Fat
Anovulation
BMJ 1998;317(7154):329

PCOS even without obesity
• Insulin resistance is present in around 65–80%
of women with PCOS, independent of obesity,
and is further exacerbated by excess weight.
• Insulin resistance has been shown to worsen
reproductive and metabolic features, type II
diabetes and CVD risk in PCOS.
• The highest incidence of metabolic abnormalities
is seen in women with marked
hyperandrogenism and anovulation.
• PCOS is classified as a nonmodifiable risk
factor for type II diabetes

PCOS with Obesity
• Anovulation
• Menstrual irregularities
• Insulin Resistance, IGT, Type II DM
• Metabolic Syndrome
• Cardiovascular Events
• Obstructive Sleep Apnoea (OSA)
• Non-alcoholic fatty liver (NAFD)
• Endometrial Cancer
• Pregnancy Complications

Obesity → PCOS?
• Fasting → ↑Ghrelin and Adiponectin → ↓GnRH Pulse
generator
• Teleologically, this mechanism helps conserve energy
during times of famine, while encouraging reproduction
when food is more readily available.
• High caloric intake→ ↑leptin→ ↓neuropeptide Y (NPY) →
↑proopiomelanocortin (POMC) → ↑hypothalamic GnRH
pulse generator → ↑ gonadotropin levels, mainly LH.
• Both insulin and leptin also act peripherally on the ovaries,
where leptin potentiates insulin-induced theca cell
proliferation and intra-ovarian androgen production.
• leading to PCO/PCOS phenotypes.

Khairy M, Rajkhowa M. Effect of obesity on assisted reproductive treatment
outcomes and its management: A literature review. The Obstetrician &
Gynaecologist 2017;19:47–54.
• A minority of morbidly obese patients have
mutations in the leptin or leptin receptor
genes leading to a complete lack of response to
leptin with phenotypic features of obesity
and hypogonadotrophic hypogonadism.

Obesity and Female Sexual
Dysfunction
• Low Libido
• Difficult Arousal
• Difficult to reach orgasm
• Early orgasm

Women with metabolic syndrome had a significantly
lower Female Sexual Functioning Index (FSFI) score,
compared with the control group.

PCOS, Obesity, Sexual Dysfunction

Impact of Obesity on Fertility
Obesity in women has been shown to increase time to
conception.
The relative risk of anovulatory infertility is 2.7 (95% CI,
2.0-3.7) in women with BMI≥ 32 kg/m2at age 18, while in
ovulatory but subfertile woman the chance of
spontaneous conception decreases by 5% for each unit
increase in the BMI.
J Hum Reprod Sci. 2010 May-Aug; 3(2): 62–67.

Effect on the Oocytes
• Intracellular accumulation of FFAs in various tissues, including
ovarian tissues, leads to overproduction of ROS and
intracellular stress reactions, with associated damage and
dysfunction of the mitochondria and endoplasmic reticulum
leading to molecular defects of oocytes.
• Insulin acting via IGF1 (insulin like growth factor 1) enhances LH
mediated steroidogenesis in the theca cell and thus increases
ovarian androgens.
• Lower adiponectin and high leptin levels are associated with
increased circulating insulin which can cause hyperandrogenaemia
partly by inhibiting the hepatic SHBG (sex hormone binding
globulin) production.
• Hyperandrogenaemia results in granulosa cell apoptosis, while
peripheral conversion of androgens to estrogen in adipose tissue
inhibits gonadotrophin secretion.

Effect on the Endometrium
Analysis of implantation rates among recipient women in
different BMI categories following oocyte donor IVF
cycles using good quality embryos has shown a trend of
lower implantation rates in women in the higher
BMI group, suggesting an endometrial effect
Women with a BMI of >30 kg/m2 had significantly
higher numbers of endometrial polyps compared
with women with a BMI of <30 kg/m2
Onalan R, Onalan G, Tonguc E, Ozdener T, Dogan M, Mollamahmutoglu L.
Body mass index is an independent risk factor for the development of
endometrial polyps in patients undergoing in vitro fertilization. Fertil Steril
2009;91:1056–60.

Six thousand five hundred IVF-ICSI cycles were included and divided into
four groups:
lean (<20 kg/m2 ; n = 1,070; 16.5%); normal (20–24.9 kg/m2 ; n = 3,930;
60.5%); overweight (25–29.9 kg/m2 ; n = 1,081; 16.6%); and obese (≥30
kg/m2 ; n = 419; 6.4%).

Implantation, pregnancy, and live birth rates in IVF-ICSI cycles according to the
women’s BMI.
Fertility and Sterility Vol. 93, No. 2, January 15, 2010

Pregnancy outcome
Fertility and Sterility Vol. 93, No. 2, January 15, 2010

Egg or the Womb?
A recent systematic review reported on the outcome
of ART cycles in obese oocyte recipients with a
BMI of >30 kg/m2.This study has shown no
significant effect of obesity on the rates of clinical
pregnancy, implantation or miscarriage. This may
imply a predominant role of oocyte dysfunction
over endometrial receptivity in obese women.
Jungheim ES, Schon SB, Schulte MB, DeUgarte DA, Fowler
SA, Tuuli MG. IVF outcomes in obese donor oocyte
recepients: a systematic review and meta-analysis. Hum
Reprod 2013;28:2720–7

Recipients were divided in four BMI (kg/m2 ) groups: lean, with BMI ˂20 (n 92;
12.9%); normal, with BMI 20–24.9 (n 398; 55.9%); overweight, with BMI 25–
29.9 (n 172; 24.2%); and obese, with BMI≥30 (n 50; 7%).
Main Outcome Measure(s): Spontaneous abortion rates according to BMI.
(Fertil Steril 2003;79:1136–40.

(Fertil Steril 2003;79:1136–40.

Impact of Obesity on Fertility Treatment
Obese women tend to respond poorly to ovulation induction
using clomiphene citrate and pregnancy rates are lower in those
who do.
Ovulation induction

Impact of Obesity on ART

Khairy M, Rajkhowa M. Effect of obesity on assisted reproductive treatment
outcomes and its management: A literature review. The Obstetrician &
Gynaecologist 2017;19:47–54.
• women with BMI >30 kg/m2 have up to 68%
lower risk of having a live birth following their
first ART cycle compared with women with
BMI <30 kg/m2
• Furthermore, after adjusting for potential
confounders, it was found that having a BMI of
>25 kg/m2 significantly increased the risk of
miscarriage after both fresh and cryo-thawed
blastocyst transfer by 2 and 6 fold, respectively.

Impact of Obesity in Pregnancy
NTD 1:1000
(BMI<30)
2 fold (BMI
>40)
Miscarriage 20% (BMI
<30)
25% (BMI
>30)
Macrosomia 7% (BMI 20-
30)
14% (BMI
>30)
Stilbirth 0.5% (BMI
<30)
1% (BMI >30)
• BMI >30- 3 times
more likely to develop
GDM
• BMI >35 – 2 fold risk
of pre-eclampsia

Management of Obesity-
Subfertility

Benefits of Weight Loss
5% weight loss results in improvement of endocrine parameters, such
as decrease in free testosterone, lower fasting insulin levels and
increased frequency of ovulation.
In addition, weight loss causes a significant reduction in central fat
deposits (11%) and serum luteinizing hormone levels with return of
normal menstrual cycles in four out of five women.

Life Style
Changes
• Diet
• Exercise
Pharmacologic
al Interventions
• CNS- Acting
Drugs
• Non-CNS-
Acting Drugs
Others
• Bariatric
Surgery
• Screening for
health problems
• Fertility
Enhancement

Lifestyle Intervention
• The main principle of dietary modification is a low caloric intake with
a recommended daily caloric intake of 600 kcal less than caloric
requirement to maintain a stable body weight.
• Very low-calorie diets (<800 kcal/day) should not be used routinely
and if used in cases of emergency, the diet should be nutritionally
complete and followed for a maximum of 12 weeks.
• Furthermore, activities should be of a type that can be incorporated into
the daily routine, such as brisk walking, cycling, gardening or
supervised exercise programmes.
• The weight-loss target should be set realistically at no more than 0.5–
1 kg/week and should be agreed individually with each woman.
• The importance of a multidisciplinary approach to lifestyle
interventions aimed at combating obesity has recently been re-
emphasised, as no single intervention seems to be effective for long-
term control.

Target of Weight Control
• SMART (Specific Measurable, Achievable, Realistic and Timely)
• A minimum of 150 min/week of moderate intensity physical
activity or 75 min/week of vigorous intensities or an equivalent
combination of both, including muscle strengthening activities on 2
non-consecutive days/week
• activity be performed in at least 10-minute bouts or around 1000
steps, aiming to achieve at least 30 minutes daily on most days.
• a minimum of 250 min/week of moderate intensity activities or
150 min/week of vigorous intensity or an equivalent combination of
both, and muscle strengthening activities involving major muscle
groups on 2 non-consecutive days/ week
• minimised sedentary, screen or sitting time.

Specific Dietary Advice
• Base your meals on starchy foods such as potatoes, bread, rice and
pasta, choosing wholegrain if possible. These foods are satisfying without
containing too many calories.
• Eat at least 5 portions of different fruit and vegetables every day rather
than foods that are higher in fat and calories. Potatoes do not count towards
your five-a-day target.
• Eat a low-fat diet and don’t increase the number of calories you eat.
Avoid drinks that are high in added sugars, other foods such as sweets,
cakes and biscuits that have a high fat or sugar content and fried food.
• Eat fibre-rich foods such as oats, beans, lentils, grains and seeds, as
well as wholegrain bread, brown rice and wholemeal pasta.
• Eat some protein every day; choose lean meat, and try to eat two
portions of fish a week. Lentils, beans and tofu are also a good source of
protein.
• Always take breakfast.

CNS Acting Drugs
• appetite suppressants -sibutramine
• cannabinoid receptor antagonists-
rimonabant
• have been withdrawn from the market in the
UK due to concerns over cardiovascular
effects (hypertension, palpitation) for the
former class and neuro-psychiatric effects
including depression and suicidal risks of
the latter class

Orlistat
NON CNS ACTING (Locally acting)
Orlistat is a class of drug called lipase inhibitors
Decrease Dietary Fat Absorption - (GI Tract)
One of the Greatest Discoveries of Drugs
For Obesity Management
ORLISTAT

• Orlistat induces a small weight reduction and
improves biochemical hyperandrogenaemia

Orlistat before ART
• The recommended dose is 120 mg taken immediately before,
during, or up to 1 hour after each meal (maximum 120 mg
TDS).
• Common side effects include flatulence, oily leakage from the
rectum with steatorrhoea and fecal urgency.
• Prolonged administration can lead to malabsorption, and vitamin
deficiency syndromes.
• Orlistat should, therefore, be used for longer than 12 weeks only
if weight loss exceeds 5% of the initial bodyweight and after
counselling patients about the potential risks and benefits.
Khairy M, Rajkhowa M. Effect of obesity on assisted reproductive
treatment outcomes and its management: A literature review. The
Obstetrician & Gynaecologist 2017;19:47–54.

Metformin
• Although a body of evidence has accumulated demonstrating the safety of these
drugs, there is currently no evidence that the use of insulin-sensitising
agents confers any long-term benefit.
• Metformin has been shown to have beneficial short-term effects on insulin
resistance and other cardiovascular risk markers in women with PCOS
without type II diabetes.
• There is evidence that metformin may modestly reduce androgen levels by
around 11% in women with PCOS compared to placebo and modest
reductions in body weight have been reported by some, but not all, studies.
• Women with a BMI of >37 kg/m2 may not respond well to the standard
dose of metformin therapy.
• lifestyle intervention was superior to metformin in improving
cardiometabolic risk factors and progression to type II diabetes
• Metformin can be considered in women with PCOS who are already
undergoing lifestyle treatment and do not have improvement in impaired
glucose tolerance and in those women with impaired glucose tolerance

Morley LC, Tang TMH, Balen AH on behalf of the Royal College of
Obstetricians and Gynaecologists. Metformin Therapy for the Management
of Infertility in Women with Polycystic Ovary Syndrome. Scientific
Impact Paper No. 13. BJOG 2017;124:e306–e313.
• For treatment of women who are anovulatory and
infertile with PCOS, metformin alone was
significantly less effective than clomifene citrate
alone and the addition of metformin to clomifene
citrate produced no significant benefit.
• Subgroup analysis of women with a BMI greater than
35 kg/m2 and in those with clomifene resistance did,
however, suggest a potential benefit from the
combined use of metformin with clomifene citrate.
• Furthermore, a significant decrease in the incidence
of severe OHSS was observed despite the higher
pregnancy rate in the metformin arm of the study.

Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus
Workshop Group. Consensus on infertility treatment related to
polycystic ovary syndrome. Hum Reprod 2008; 23:462–77.
• Metformin does not increase the chance of having a
livebirth. Furthermore, despite evidence of a reduction
in development of diabetes in a high risk non-PCOS
population the long-term use of metformin in
reducing the risk of developing metabolic syndrome
is questionable.
• should be restricted to those patients with glucose
intolerance or type 2 diabetes rather than those with
just insulin resistance. Therefore, on current
evidence metformin is not a first line treatment of
choice in the management of PCOS.

ESHRE 2018
• Metformin can be added in obese PCOS
women in whom life style interventions proved
ineffective in normalizing the reproductive
functions

Statins
• Lipid-lowering treatment is not
recommended routinely and should only be
prescribed by a specialist.
• There is emerging evidence that statins
improve hyperandrogenaemia and the
metabolic profile in women with PCOS.

Ovulation Induction
• Clomiphene vs Letrozole?
Letrozole
1. Monofollicular development
2. Lowers risk of OHSS and multiples
3. Lowers estrogen production
4. First line of choice (ACOG, ESHRE)

• Women with a BMI 30 kg/m2 or greater wishing to
become pregnant should be advised to take 5 mg folic
acid supplementation daily, starting at least 1 month
before conception and continuing during the first
trimester of pregnancy.
• Obese women are at high risk of vitamin D deficiency.
However, although vitamin D supplementation may
ensure that women are vitamin D replete, the
evidence on whether routine vitamin D should be given
to improve maternal and offspring outcomes remains
uncertain.

Bariatric Surgery
• BMI ≥ 40 kg/m2
• BMI 35-40 kg/m2 with other comorbidities, where
nonsurgical management has proven unsuccessful
• National Institute for Health and Care Excellence (NICE).
Obesity: Guidance on the prevention of overweight and
obesity in adults and children. NICE clinical guideline 43.
Manchester; NICE: 2006 [https://www.nice.org.uk/
guidance/cg43/resources/guidance-obesity-pdf]. Accessed
2015 Jul 27.

• 25% of women presenting for bariatric
surgery suffered from infertility.
• With regard to assisted conception, four out of
five IVF treatments following bariatric
surgery resulted in live term births (80%)
• improvement in the number of oocytes
retrieved in obese women after bariatric
surgery.

IVF after Bariatric Surgery
• A possible increased risk of OHSS, which can lead to ascites
and significant morbidity.
• Furthermore, laxity of skin with depleted adipose tissue can
limit the bioavailability of subcutaneous administration of
the gonadotrophin hormones required for the treatment.
• Other factors limiting IVF accessibility, such as maternal age,
need to be borne in mind when considering appropriate
treatment for obesity, especially in the light of
recommendations that women wait for at least a year after
surgery before attempting to become pregnant.

Screening for Diabetes
• Women presenting with PCOS
1. who are overweight (BMI ≥ 25 kg/m2; Asian >23 kg/m2)
2. who are not overweight (BMI <25 kg/m2), but who have additional risk
factors such as advanced age (>40 years), personal history of GDM or
family history of type II diabetes,
should have a 2-hour post 75 g OGTT performed.
• In women with impaired fasting glucose (fasting plasma glucose level 6.1-
6.9 mmol/l) or impaired glucose tolerance (plasma glucose 7.8 mmol/l- 11
mmol/l after a 2-hour OGTT), an OGTT should be performed annually.
• Fasting blood glucose level alone has been shown to be inaccurate and
results in underdiagnosis of type II diabetes in PCOS.
• it would be reasonable to carry out HbA1c measurements where women
are unwilling to have oral glucose tolerance tests or where the resources are
not readily available.

Cardiovascular Risk
• All women with PCOS should be assessed for CVD
risk by assessing individual CVD risk factors
(obesity, lack of physical activity, cigarette smoking,
family history of type II diabetes, dyslipidaemia,
hypertension, impaired glucose tolerance, type II
diabetes) at the time of initial diagnosis
• At the time of initial diagnosis, women with PCOS
should be assessed for obesity with BMI and waist
circumference.
• BP should be checked at the time of initial diagnosis
and during oral contraceptive therapy.

Tiredness
• Women diagnosed with PCOS should be asked
(or their partners asked) about snoring and
daytime fatigue/somnolence
• The prevalence of obstructive sleep apnoea is
increased in obese women with PCOS. Androgen
levels and insulin resistance are positively
associated with OSA in PCOS.
• Continuous positive airway pressure (CPAP)
therapy improves insulin sensitivity in affected
women.

Ethics?
NICE Guideline-
women seeking fertility treatment should have a
BMI of <35 kg/m2.
In addition, when clinical circumstances permit,
treatment of younger women should be delayed
until a BMI of <30 kg/m2 is achieved.
ESHRE- it is not unethical for fertility specialists
to insist on serious efforts to achieve weight loss
before treatment can be considered.

Lumsden MA, Hor K. Impact of obesity on the health of women in midlife. The
Obstetrician & Gynaecologist 2015;17:201–8.

Conclusion
• Obesity- affects fertility
• Obesity- reduces the success rate of fertility
treatment
• No single intervention is effective
• Combined intervention is needed
• No evidence that weight reduction is
difficult in PCOS than other women

PCOS- Is obesity a concern

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