INDIA

PCOS
TUTORIALS
A Post Graduate
Certificate Course in
PCOS Management

Module 6
PCOS and Long-Term
Health Consequences

Brought to you by The PCOS Society (India)

 INDIA

Course Directors

Dr. Duru Shah Dr. Madhuri Patil

Founder President Chair, Scientific Committee
The PCOS Society, India. The PCOS Society, India.

Guest Editors

Dr. Nikhil Bhagwat Dr. Ganapathi B.

Associate Professor, MD, DM (Endo.),
Department of Endocrinology, DNB (Endo.), MNAMS,
BYL Nair Ch. Hospital & Prof. of Endocrinology,
TN Medical College, Mumbai; Dept. of Endocrinology,
Consultant Endocrinologist, St. John's Medical College &
Breach Candy Hospital, Hospital, Bangalore.
HN Reliance Foundation Hospital & Past Vice President – KRSSDI;
Wockhardt Hospitals, Mumbai. Past Vice President - Endocrine Society of India;
Past Secretary - Endocrine Society of India.
 Module VI
PCOS and Long-Term Health Consequences

1
Table of Contents
1. Module Overview 3

2. Learning Objectives 3

3. Pre-Test 4

4. Introduction 6

5. Neoplastic Consequences of PCOS 8

6. Metabolic Consequences of PCOS 19

7. Cardiometabolic Consequences of PCOS 26

8. Other Consequences of PCOS 30

9. Management of Long-Term Health Consequences of PCOS 34

10. Conclusion 37

11. Key Points 37

12. Suggested Readings 39

2
Module Overview
• Polycystic ovary syndrome (PCOS) is a common disorder and in the previous
modules we have seen how it can affect the adolescents and the younger
women.
• Cosmetic issues related to PCOS have been discussed in module 3.
• Association of PCOS with chronic anovulatory infertility has been discussed in
module 4.
• Complications associated with pregnancy in women with PCOS have been
discussed in module 5.
• The effects of PCOS last for a lifetime and long-term consequences of this
syndrome will be briefly discussed in this module.
• Many women with PCOS are obese and tend to have a higher prevalence of
impaired glucose tolerance (IGT), type II diabetes (T2DM) and sleep apnoea
than observed in the general population. Evidence of an adverse cardiovascular
risk profile, characteristic of the cardiometabolic syndrome characterised by
higher association with hypertension, dyslipidaemia, visceral obesity, insulin
resistance and hyperinsulinaemia among women with PCOS is noted. Oligo- or
amenorrhoea in women with PCOS predisposes them to a higher risk of
endometrial hyperplasia and subsequent carcinoma.
• Most often, it is the gynaecologists who diagnose PCOS and it is, therefore,
important that there is a good understanding of these long-term implications of
the diagnosis to ensure a holistic approach to this disorder.
• This module will provide information, based on clinical evidence, regarding
these long-term health consequences of PCOS.
Reference:
1. RCOG. Long-term Consequences of Polycystic Ovary Syndrome. Green-top Guideline No.
33, 2014. Available at: [Link]
guidelines/gtg_33.pdf

Learning Objectives
At the completion of this module, the participant is expected to:
• Be aware of the various known long-term consequences associated with PCOS.
• Be competent to provide the information regarding these consequences to their
patients.
• Provide health education to the patients to defer these long-term consequences
of PCOS.
• Educate and arrange for the screening and monitoring of conditions such as
postmenopausal bleeding, blood glucose levels, blood pressure, lipids, heart
diseases, sleep apnoea, liver function tests and other associated conditions.
• Understand the management and be able to make a timely decision for the
referral to the concerned experts for various long-term consequences of PCOS.

3
 PCOS and Long-Term Health Consequences

PRE-TEST
State whether the following statements are True or False.

1. Endometrial hyperplasia is seen more often in women with PCOS.

a) True

b) False

2. Breast cancer is more common among women with PCOS.

a) True

b) False

3. Risk reduction of long-term consequences of PCOS is possible with

lifestyle changes.

a) True

b) False

4. Cardiovascular risk factors such as obesity, dyslipidaemia, diabetes and

hypertension are seen more frequently among women with PCOS.

a) True

b) False

5. Metformin decreases the risk of endometrial hyperplasia and hence

endometrial cancer.

a) True

b) False

6. Women with PCOS carry the same risk as general population for
diabetes.

a) True

b) False

7. Obese women with PCOS are at a greater risk of metabolic syndrome.

a) True

b) False

4
8. Letrozole increases the risk of breast cancer.

a) True

b) False

9. Kidney and colon cancers have been found to have lower frequency
among women with PCOS.

a) True

b) False

10. Haepatomegaly is the only way to screen for non-alcoholic fatty liver
disease.

a) True

b) False

Answers: 1. True; 2. False; 3. True; 4. True; 5. True; 6. False; 7. False; 8. False; 9. False; 10. False

5
 Introduction
PCOS is one of the most common endocrinopathies diagnosed in premenopausal
women but it can continue to influence even the postmenopausal health of the
women. PCOS has been redefined as a reproductive and metabolic disorder after
the recognition of the important role of insulin resistance in the pathophysiology of
the syndrome.1

Long-term health consequences associated with PCOS

• Neoplastic
• Metabolic consequences
• Dyslipidaemia and vascular dysfunction
• Mental health disorders

• As mentioned above, PCOS has been related with significant adverse

sequelae that affect overall long-term health and well-being.2
• These long-term morbidities of PCOS are grouped into:
o Neoplastic (primarily endometrial adenocarcinoma and other cancers)
o Metabolic consequences (IGT, T2DM, metabolic syndrome, and
non-alcoholic fatty liver disease [NAFLD])
o Dyslipidaemia and vascular dysfunction (including hypertension,
i n c re a s e d i n c i d e n c e s o f c e re b ro v a s c u l a r a c c i d e n t s a n d
thromboembolism on oral contraceptives)
o Mental health disorders (including greater incidences of depression,
anxiety disturbances and psychosexual dysfunction)3

Prevalence of Long-Term Consequences in Women with PCOS

• High prevalence of endometrial and some boderline serous subtypes of ovarian
cancer, kidney, colon and brain cancers are seen among women with PCOS.

Metabolic risk factors Prevalence among PCOS women

Impaired glucose tolerance 20– 35%
T2DM in young women with PCOS 2–8% (seems related to body weight
and ethnic group)
T2DM among women with PCOS 10–16%
>40 years age and/or postmenopausal
T2DM: Type 2 diabetes mellitus

• High prevalence of risk factors accociated with vascular dysfunction e.g., obesity,
IGT, diabetes, hypertension, mood disorders and metabolic syndrome are seen
among women with PCOS
• High prevalence of depression and anxiety are seen among women with PCOS.

6
In women with PCOS, the prevalence of uterine pathology extending up to
neoplasia, metabolic disequilibrium resulting in insulin resistance, T2DM and
cardiovascular risk factors is significantly high.2
Higher prevalence of neoplasia
• A stronger association between PCOS and endometrial cancer particularly
when restricted to type I (endometrioid) cancer has been noted.
• Evidence supports a link between PCOS and the borderline serous subtype
of ovarian cancers, resulting in higher prevalence of the latter among women
with PCOS.
• The current evidence points towards no increase/decrease in the risk of
breast cancer among women with PCOS.
• A higher prevalence than expected of kidney, colon, and brain cancers has
been seen among women with PCOS, as reported by the Danish study.4
High prevalence of metabolic syndrome and cardiovascular risk factors
• Young women with PCOS have been associated with higher prevalence of
T2DM and cardiovascular diseases (CVD).
• The prevalence of IGT ranges between 20 and 35% in patients while the
prevalence of T2DM ranges between 2 and 8% and seems related to body
weight and ethnic group.
• Moving from the young fertile age to the 40s and the menopause the
prevalence of T2DM continues to increase compared to the general female
population and may reach to 10–16 % of women with PCOS.5
• Adolescents and reproductive age women with PCOS have an increased
prevalence of cardiovascular risk factors. These include obesity, IGT,
diabetes, hypertension, mood disorders and metabolic syndrome. There is
sufficient evidence to confirm the presence of subclinical atherosclerosis in
women with PCOS compared to age-matched controls.
• Further studies are needed to assess the prevalence of non-fatal and fatal
cardiac events in women with well-defined PCOS.6
High prevalence of mental health disorders
• High prevalence of depression and anxiety are seen among women with
PCOS.7
References:
1. Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J
Gastroenterol. 2014;20(26):8351–8363.

7
2. Wild RA. Long-term health consequences of PCOS. Human Reproduction Update.
2002;8(3): 231–241.
3. Zore T, Joshi NV, Lizneva D, et al. Polycystic Ovarian syndrome: long-term health consequences.
Semin Reprod Med 2017; 35(03): 271–281.
4. Gottschau M, Kjaer S, Jensen A, et al. Risk of cancer among women with polycystic ovary
syndrome: a Danish cohort study. Gynecol Oncol. 2015;136:99–103.
5. Carmina E. Polycystic ovary syndrome: metabolic consequences and long-term management.
Scand J Clin Lab Invest Suppl. 2014;244:23–6.
6. Dokras A. Cardiovascular disease risk in women with PCOS. Steroids. 2013;78(8):773–6.
7. Blay SL, Aguiar JVA and Passos IVC. Polycystic ovary syndrome and mental disorders: a
systematic review and explorator y meta-analysis. Neuropsychiatr Dis Treat.
2016;12:2895–2903.

Neoplastic Consequences of PCOS

Neoplasia and PCOS

PCOS

Endometrial– Ovarian (borderline

Colon cancer Kidney cancer Brain cancer
type 1 (endometrioid) serous subtype)

PCOS: Polycystic ovary syndrome

• The altered metabolic and hormonal environment among women with PCOS
may increase their risk for certain cancers:
o Endometrial cancer have higher occurrence among women with PCOS.
o Ovarian cancers have potentially increased risk among women with
PCOS.
o Breast cancer has no consistent association with PCOS risk.
o Other cancers, e.g., kidney, colon, and brain cancers have increased
frequency among women with PCOS.1, 2

8
 PCOS and Endometrial Cancer
Secretory Prevalence • 2.7% increased risk in women with
PCOS
Functionalis • 9% lifetime risk of developing an
Risk factors endometrial cancer in women with PCOS

endometrial hyperplasia
Proliferative • Oestrogen

Factors inducing
Pathogenesis • Anovulation leads to prolonged exposure
• Nulliparous to unopposed oestrogen
Functionalis • Diabetes
• Ovulation induction drugs and synthetic
• Hypertension progestins act on secretory endometrium
• Obesity
Surveillance • TVS for examining endometrial thickness
• PCOS
• Endometrial biopsy
Basalis Basalis • Tamoxifen
Myo Management • Surgeries include total abdominal
Myo hystrectomy with bilateral salpingo-
oophorectomy+pelvic and para-aortic
Since endometrial hyperplasia is a precursor to cancer, all
lymph node dissection
risk-factors of endometrial cancer are related to
endometrial hyperplasia. • Chemotherapy
• Radiotherapy
• If patient desires fertility, medical
treatment is an option.

PCOS: Polycystic ovary syndrome; TVS: Transvaginal ultrasound screening

• Endometrial hyperplasia, the precancerous stage of endometrial cancer, has

demonstrated a strong association with PCOS.
• Multiple studies reported that women with PCOS were at a higher risk for
endometrial cancer; however, several of these studies did not take into
account the body mass index (BMI), a strong and well-established risk factor
for endometrial cancer.3,4
• Endometrial tumours display a variety of histologic features but the majority
of cases are adenocarcinomas (>95%) and can be classified into two main
subtypes, endometrioid (type I) and non-endometrioid (type II).
• A stronger association between PCOS and endometrial cancer is observed
when limited to type I (endometrioid) cancer.1
Prevalence
• Women with PCOS display nearly three times increased risk of developing
endometrial cancer.
• Caucasian women with PCOS have 9% higher lifetime risk of developing
endometrial cancer.4
Pathogenesis
• The main cause of increased malignancy risk is prolonged exposure of the
endometrium to unopposed oestrogen that results from anovulation.

9
• Additionally, secretory endometrium of some women with PCOS undergoing
ovulation induction or receiving exogenous progestin exhibits progesterone
resistance accompanied by dysregulation of gene expression controlling
steroid action and cell proliferation.
Surveillance and prevention
• Endometrial surveillance includes transvaginal ultrasound and/or
endometrial biopsy to assess thickened endometrium, prolonged
amenorrhoea, unopposed oestrogen exposure or abnormal vaginal
bleeding.5
Management
• One- fourth of the patients are diagnosed in fertile age.
• Primary progesterone therapy, sometimes combined with local surgical
excision, has been used as conservative treatment in early well
differentiated tumours.
• Using hormonal therapy ± hysteroscopic resection, a mean of 72% complete
response was reported, with a 23% relapse rate.
• Endometrial hyperplasia is the premalignant stage for endometrial cancer
which needs to be treated actively.6

Therapeutic Options for Endometrial Hyperplasia

Current therapies Future targets
Progestin therapy Surgical modalities Other therapy • Oestrogen receptor
• MPA • Thermal balloon ablation • GnRH therapy • Hydroxy-steroid dehyrogenase
• Megestrol acetate • Laser therapy • Metformin • Wnt signalling
• Levonorgestrel • Hysterectomy • Genistein • Pro-inhibitory cytokines
• Norethindrone acetate • Resectoscopic surgery • Danazol • Growth factors
• Aromatase

MPA: Medroxyprogesterone acetate; GnRH: Gonadotropin-releasing hormone; Wnt: Wingless-int

• It is prudent to refer these patients to specialists early in the course of

disease.
• For endometrial cancers, the management is preferably carried out by team
of experts including onco-surgeons, oncologists, onco-pathologists and
radiologists.

10
• Briefly, the management of endometrial cancers includes:
o Surgery
– TAH+BSO (total abdominal hysterectomy with bilateral salpingo-
ophorectomy), pelvic and para-aortic lymph node dissection (LND) or
sampling.
– For high-grade cancers such as papillary serous carcinoma, clear cell
carcinoma, or carcinosarcoma; omentectomy and peritoneum
sampling is added to the above mentioned surgery.
– For advanced stages (entire visible tumour is removed/debulked along
with extended surgery) radical hysterectomy, LND or sampling,
omentectomy and peritoneum sampling is carried out.
o Radiotherapy
– Vaginal brachytherapy + pelvic radiation
– Frail patients who cannot withstand surgery are only treated with
radiation.
o Chemotherapy
– Carboplatin+taxol, cisplatin, doxorubicin with other agents
– For high-grade cancers such as uterine carcinosarcoma along with the
above mentioned drugs ifosfamide may also be added in
chemotherapy.
o Hormone therapy
– Progestins and tamoxifen is used, while aromatase inhibitor are being
explored.
o Fertility preservation
– Medroxyprogesterone acetate is given orally 400–800 mg/day in three
divided doses as an initial treatment for 3 months.
– Megestrol acetate is given orally 160 mg daily and is a preferred
treatment as associated with a better remission probability and a
slower progression rate.
– Instead of progesterone tablets one can also use a progesterone
intrauterine device (IUD).
– After 3 months, if regression occurs assisted reproductive treatment
(ART) is performed.
– If no regression occurs additional MPA or megestrol is given.
– Twenty-eight percent of complete responders subsequently
conceived with or without ART.
– Prevalence ratios are 32% to 100% in patients attempting to conceive.

11
 – In case, surgery cannot be avoided due to advanced disease the option
for fertility preservation is to stimulate the patient preferably using
mild forms of stimulation in an antagonist cycle along with aromatase
inhibitors to keep the oestradiol levels low. Depending on whether the
women have a partner or not one could either freeze the oocytes or
embryos.
– After opinion with oncologist and pathologist, treatment with
progestins in form of pill, injection or IUD can be carried out until
childbearing is complete, followed by TAH+ BSO and LND/ sampling
as soon as childbearing is completed. This is not a routine procedure
and increases the risk of cancer progression.

Fertility Preservation in Endometrial Carcinoma

Candidate for P4 Not a candidate

Stage 1, Grade 1–2 for P4

P4 for 3 months followed by D & C with

or without hysteroscopy Surgery can be delayed Surgery cannot
for 2–6 weeks be delayed

NED Persistence of
atypical cells Surgical staging +
hysterectomy
OI
IVF: AI + FSH
Ovaries BSO
Attempt pregnancy preserved
Oocyte Embryo
cryopreservation cryopreservation Ovarian tissue
cryopreservation
Gestational carrier

NED: No evidence of disease; BSO: Bilateral salpingo-ophorectomy; OI: Ovulation induction; P4: Progesterone;
IVF: In vitro fertilisation; D: Dilation; C: Curettage; FSH: Follicle-stimulating hormone; AI: Artificial insemination

o Recurrent endometrial cancer

– Spots can be treated by local surgery/radiation and hormone therapy.
Extensive cases are treated as stage 4, chemotherapy may be
necessary for widespread recurrences.7

PCOS and Ovarian Cancer

Prevalence Increased risk of borderline serous ovarian cancers
Pathogenesis PCOS has been hypothesised to increase ovarian cancer risk
through increased androgen exposure
Risk reduction Use of oral contraceptive pills reduces the risk
Reduction is directly proportional to the duration of use

12
There were confusing reports regarding the association of ovarian cancer and
PCOS, but as it is well known, there are several histological types of ovarian
cancer. Hence, only after the study of PCOS and particular histological types
were pursued the picture became clearer.
Prevalence
• Olsen, et al. and North East Cerebrovascular Consortium (NECC) study
reported an association between PCOS and the borderline serous subtype
(odd ratio [OR]=2.5; 95% confidence interval [CI]=1.0–6.1) and noted this
association was strongest among women with a BMI ≥ 25
(OR=3.0; 95% CI= 1.2–7.5).8
Pathogenesis
• PCOS has been hypothesised to increase ovarian cancer risk through
increased androgen exposure.1
Risk amelioration
• There is strong data to suggest that oral contraceptive use is protective
against ovarian cancer and increases with the duration of therapy.
• The mechanism of this protection may be through suppression of
gonadotropin secretion rather than the prevention of "incessant ovulation".
Surveillance
• Almost 30% of patients with borderline ovarian tumours (BOTs) are
asymptomatic; approximately 50%–60% of patients complain about
nonspecific symptoms (abdominal pain or abdominal distension) and
10% complain of bleeding abnormalities.9
• Most BOTs are detected by ultrasound.
• In line with the low performance of cancer antigen 125 (Ca125), the risk of
malignancy index (RMI), developed by Jacobs et al. in 1990, did not perform
well for patients with BOTs.10

Serous Borderline Ovarian Tumor

13
Management
• These tumours are commonly found in reproductive age group. The
therapeutic decisions that need to be considered are regarding fertility-
sparing surgery, treatment of infertility or premature hormonal deprivation,
intra- and postoperative morbidity, and adjuvant chemotherapeutic
treatment.
• Fertility preserving surgery
o Conservative surgery for sparing fertility (i.e., involving the preservation
of the uterus and at least part of one ovary, with comprehensive surgical
staging) for borderline tumours of the ovary in all stages.11
o Conservative approach is a standard management in early stage, which
may increases the risk of recurrence without affecting the survival.
o Spontaneous fertility rate is about 60% after conservative surgery.
o The available data suggest that the rate of recurrence is higher after
conservative surgery (10% to 20% vs. approximately 5% for radical
surgery).12
o For women with advanced disease- frozen embryo and uterus can be
preserved before bilateral oophorectomy.
o Cystectomy can be considered in serous borderline ovarian tumours,
however must be weighed against the risk of high recurrence rate of 31%.
o Removal of the preserved ovary after patients complete their fertility
plans depends on several factors such as histologic subtype, Federation
of Gynaecology and Obstetrics (FIGO) stage of disease, type of
conservative surgery, and the patient's own will.

Fertility Preservation in Ovarian Cancer

Borderline ovarian tumours Epithelial ovarian tumours Germ cell tumours
Conservative surgery in stage IA Stage IA, IC grade 1 and possibly Sensitive to chemotherapy
Intra surgery oocyte and ovarian grade 2 tumours of mucinous, Majority will resume normal
tissue cryopreservation endometrioid or serous types menstrual function following their
suitable for fertility sparing surgery chemotherapy
Post surgery COS with IVM or IVF
Oophorectomy with If oophorectomy required
cryopreservation of ovarian tissue cryopreservation of ovarian tissue
from contralateral ovary and IVM and IVM from aspirated follicles
from aspirated follicles of the contralateral ovary
Oophorectomy with preservation of
controloteral ovary followed by
IVM or IVF

Must monitor contralateral ovary by USG and tumour markers regularly

Risk of re-implanting cancer cells with OT transplant
Once fertility complete→ oophorectomy
COS: Controlled ovarian stimulation; IVM: In vitro maturation; IVF: In vitro fertilization; USG: Ultrasound;
OT: Ovulation tracking

14
• Intraoperative diagnosis and staging
o BSO in combination with hysterectomy is recommended.
o Lymphadenectomy is not indicated because the recurrence and survival
rates for patients with positive or negative lymph nodes were similar.9
• Adjuvant treatment (chemotherapy, radiotherapy, hormone therapy, and
targeted therapy)
o More studies are required to establish the safety and effectiveness of all
the adjuvant therapies mentioned above.
• Fertility
o Spontaneous conception is reported after conservative surgery in 50% of
patients without any deterioration in the survival rate.13
o For patients who fail to conceive spontaneously, in vitro fertilisation (IVF)
must be considered by the multidisciplinary team comprising of
specialist from reproductive medicine, gynaecologists, oncologists, and
others.
• Hormone replacement therapy (HRT)
o HRT is carried out to prevent CVD, osteoporosis and improve quality of life
(QoL). It is an important issue, as many patients with BOTs are relatively
young women. HRT should be offered to these patients.
• Follow-up
o Regular and intensive follow-up of the patients is essential for the early
detection of recurrence in the form of borderline or invasive disease.
o This must be conducted for a longer period of time than for patients with
ovarian cancer.
o Studies have reported cases in which relapse and death occurred after
more than 10–15 years. 10,13,14

Other Cancers
Associated with PCOS Not associated with PCOS
Kidney cancer Breast cancer
Colon cancer Vaginal cancer
Brain cancer Vulvar cancer
Cervical cancer/Uterine leiomyosarcoma

15
Cancers associated with PCOS
• Higher prevalence of kidney, colon, and brain cancers was observed among
women with PCOS compared to expected rates in the general Danish
population.1
Cancers not associated with PCOS
• The association between PCOS and breast cancer has been complex as
infertility resulting from anovulatory dysfunction decreases breast cancer
risk.15 While, obesity which is a common occurrence with PCOS, increases
the breast cancer risk among postmenopausal women.
• Several studies including the Danish registry and the Iowa Women’s Health
Study reported no elevation in risk for women with PCOS. 3,2,16
• There are insufficient data to evaluate any association between PCOS and
vaginal, vulvar and cervical cancer or uterine leiomyosarcoma.5

PCOS Medication That May Influence Cancer Risk

Oral contraceptive pills Metformin Ovulation induction agents
• Decrease risk of: • Lab studies • Clomiphene
o Ovarian cancer support its o Non significant increase in
anti-cancer endometrial cancer, thyroid
o Endometrial cancer properties cancer
• Small short-term increase in:
o Significant increase in
o Breast cancer risk melanoma
• Letrozole
o Decrease in breast cancer risk

Combined oral contraceptives pills

• Combined oral contraceptives are associated with decreased risk of
ovarian17and endometrial cancers.18
• The protective effect of oral contraceptives on ovarian cancer risk is likely
explained by a decreased lifetime number of potentially damaging
ovulations, while the protective effect in endometrial cancer may be the
result of reducing exposure to unopposed oestrogen which limits the cell
proliferation that is stimulated by oestrogens.
• In contrast, oral contraceptives may result in a very small short-term increase
in breast cancer risk, while 10 years after cessation of use the risk among
women who had used oral contraceptives was similar to those who had not
used oral contraceptives.1

16
Metformin
• Evidence has suggested that metformin use may be protective against
various forms of cancer.
• This is supported by laboratory studies that demonstrate metformin’s
anti-cancer activities.19
• However, fewer studies have examined the impact of metformin on the
incidence of endometrial, breast, and ovarian cancer.1

Mechanism of Action of Metformin’s Anti-cancer Activity

Insulin Insulin

Insulin Insulin
Metformin
Tumour cells

OCTs?

Redd I IRS-1 P13K

TSC1
TSC2 AKT
Complex I AMPK

Rag
RHEB
GTPase
Raptor
mTORC1
mTOR

ATP
SGK1

Protein translation and

Apoptosis 4E–BP1 S6
cell growth

OCTs: Organic cation transporters; Rag: Recombination activating gene; TSC: Tuberous sclerosis;
mTOR: Mammalian target of rapamycin; AMPK: AMP-activated protein kinase; BP: Binding proteins;
SGK: Serine/threonine-protein kinases; ATP: Adenosine triphosphate; IRS: Insulin receptor substrate;
P13K: Phosphatidylinositol 3-kinase; RHEB: Ras homolog enriched in brain
Redd: Regulated in development and DNA damage response

• Metformin exerts its anti-tumour effects by insulin-dependent and insulin-

independent mechanisms. Metformin can suppress cell growth by
inactivation of AKT-mTOR pathway and/or may act on both AMPK and
mitochondrial complex I, leading, respectively, to increase in apoptosis and
downregulation of protein translation and inhibition of cell growth.
Ovulation induction drugs
• Clomiphene
o Breast cancer is generally not associated with increased risk, but a
statistically non-significant increased risk was observed for those with
over 12 cycles.20

17
 o A non-significant increased risk was observed in ovarian cancer,
o A non-significant increased risk was observed in endometrial cancer.21
o A statistically significant increased risk of melanoma (hazard ratio
[HR]=2.0; 95% CI=1.2–3.2), a non-significant increased risk of thyroid
cancer (1.6; 95% CI=0.9–2.8), and non-significant increased risks of
colorectal or lung cancer was observed.22
• Letrozole
o Letrozole is currently used as an adjuvant treatment for hormone
receptor-positive postmenopausal breast cancer1,23 thus it could be
hypothesised that it would likely decrease hormonal related cancer risk.
References
1. Harris HR and Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast
cancer: a systematic review. Fertil Res Pract. 2016; 2:14.
2. Gottschau M, Kjaer S, Jensen A, et al. Risk of cancer among women with polycystic ovary
syndrome: a Danish cohort study. Gynecol Oncol. 2015;136:99–103.
3. Barry JA, Azizia MM and Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women
with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update.
2014;20:748–758.
4. Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and
polycystic ovary syndrome. Hum Reprod. 2012;27:1327–1331.
5. Dumesic DA and Lobo RA. Cancer risk and PCOS. Steroids. 2013;78(8):782–5.
6. Chandra V, Kim JJ, Benbrook DM, et al. Therapeutic options for management of endometrial
hyperplasia. J Gynecol Oncol. 2016;27(1): e8.
7. American Cancer Society, Treatment choices for endometrial cancer, by stage. Available on:
[Link] Last acessed on:
February 29, 2017.
8. Harris H, Titus L and Cramer D. Long and irregular menstrual cycles, polycystic ovary syndrome,
and ovarian cancer risk in a population-based case–control study. Int J Cancer.
2017;140(2):285–291.
9. du Bois A, Ewald-Riegler N, du Bois O, et al. Borderline tumors of the ovary: a systematic review.
2009;69:807–833.
10. Fischerova D, Zikan M, Dundr P, et al. Diagnosis, treatment, and follow-up of borderline ovarian
tumors. Oncologist. 2012;17(12):1515–1533.
11. Uzan C, Kane A, Rey A, et al. Outcomes after conservative treatment of advanced-stage serous
borderline tumors of the ovary. Ann Oncol. 2010;21:55–60.
12. Trillsch F, Mahner S, Ruetzel J, et al. Clinical management of borderline ovarian tumors. Expert
Rev Anticancer Ther. 2010;10:1115–1124.
13. Morice P. Borderline tumours of the ovary and fertility. Eur J Cancer. 2006;42:149–158.
14. Silva EG, Gershenson DM, Malpica A, et al. The recurrence and the overall survival rates of
ovarian serous borderline neoplasms with noninvasive implants is time dependent. Am J Surg
Pathol. 2006;30:1367–1371.
15. Terry K, Willett W, Rich-Edwards J, et al. A prospective study of infertility due to ovulatory
disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med.
2006;166:2484–2489.

18
16. Shen CC, Yang AC, Hung JH, et al. A nationwide population-based retrospective cohort study of
the risk of uterine, ovarian and breast cancer in women with polycystic ovary syndrome.
Oncologist. 2015;20:45–49.
17. La Vecchia C. Oral contraceptives and ovarian cancer: an update. Eur J Cancer Prev.
2006;15:117–124.
18. Cancer CGoESoE endometrial cancer and oral contraceptives: an individual participant meta-
analysis of 27276 women wiht endometrial cancer from 36 epidemiological studies. Lancet
Oncol. 2015;16:1061–1070.
19. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the
beginning. Cancer Discov. 2012;2:778–790.
20. Brinton LA, Scoccia B, Moghissi KS, et al. Long-term relationship of ovulation-stimulating drugs
to breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2014;23:584–593.
21. Brinton LA, Westhoff CL, Scoccia B, et al. Fertility drugs and endometrial cancer risk: results from
an extended follow-up of a large infertility cohort. Hum Reprod. 2013;28:2813–2821.
22. Brinton L, Moghissi K, Scoccia B, et al. Effects of fertility drugs on cancers other than breast and
gynaecologic malignancies. Fertil Steril. 2015;104:980–988.
23. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American society of clinical oncology clinical
practice guideline: update on adjuvant endocrine therapy for women with hormone
receptor–positive breast cancer. J Clan Oncol. 2010;28:3784–3796.

Metabolic Consequences of PCOS

Components of metabolic syndrome that overlap with PCOS

Impaired glucose Lipid problems Hypertension Non-alcoholic

tolerance fatty liver disease
Leads to following associated consequences

Type 2 diabetes Heart disease Dementia Cancer

PCOS and metabolic disorders

• Metabolic syndrome is a constellation of metabolic disorders which include
mainly abdominal obesity, insulin resistance, IGT, hypertension and
dyslipidaemia.
• These associated disorders directly increase the risk of T2DM, coronary heart
disease (CHD),CVD and endometrial cancer.

19
• Many patients with PCOS have features of metabolic syndrome such as
visceral obesity, hyperinsulinaemia and insulin resistance.
• These place patients with PCOS under high risk of developing CVD, T2DM
and gynaecological cancer, in particular, endometrial cancer.
• Metabolic syndrome is also increased in infertile women with PCOS.1

Prevalence of Metabolic Syndrome in Women with

PCOS based on ATP-III and WHO criteria.

50
Control women
PCOS by ATP–III criteria
40 PCOS by WHO criteria
Prevalence (%)

30

20

10

The prevalence of metabolic syndrome in PCOS was 3.4–6.6 times higher than in the matched control
population suggesting that PCOS per se results in a higher prevalence of metabolic syndrome

Prevalence of Different Elements of the Metabolic Syndrome in

Women with PCOS

70
Obesity
60 Increased waist circumference
Increased blood pressure
50 High fasting glucose
Altered glucose tolerance
Prevalence (%)

40 Reduced insulin sensitivity

High fasting insulin
30 Increased serum triglycerides
Low serum high-density
20
lipoprotein cholesterol

10

Prevalence of metabolic syndrome in women with PCOS

• Women with PCOS demonstrate the higher prevalence of being overweight
(BMI >25 kg/m2) and obese (BMI >30 kg/m2) as compared to women without
PCOS.

20
• Sixty-one percent of women with PCOS are obese and overweight.2
• The prevalence of metabolic syndrome in PCOS is strongly influenced by the
criteria used to diagnose metabolic syndrome as well as the criteria used to
diagnose PCOS.
• However, higher prevalence of metabolic syndrome is seen in women with
PCOS than in the general population in women of similar age.3
• Further, the prevalence of each cardiac risk factor is approximately double for
women with PCOS when compared with controls, while it is 1.5 times higher
in BMI-matched studies beginning in adolescence and it is found in every
decade.4
• Women with PCOS are twice as likely to suffer from hypertension when
compared to women without PCOS.5

Association of PCOS with Metabolic Syndrome and

Other Long-Term Consequences
Increased insulin demand
Oveweight/Obese/
Atherosclerosis Normal weight/Metabolically
Hyperinsulinaemia Vicious circle obese
Hypertension
Insulin resistance Hyperinsulinaemia T2DM

Renal damage
Glucose intolerance
Metabolic disturbances
CVD
Visceral fat↑

Hyperandrogenism↑SHBG↑Hyperinsulinaemia↑ Hormonal disturbances

↑
LH, IGF-I, and TNF-∝ TG↑
LH/FSH ratio↑ Free testosterone
LDL-C/HDL-C↑
PCOS Endometrial hyperplasia PA1-I↑
Inflammation↑
Endometrial cancer Cytokines (TNF-, IL6)↑
Oestrogen biosynthesis↑

T2DM: Type 2 diabetes mellitus; LDL-C: Low-density lipoprotein cholestrol;

HDL-C: High-density lipoprotein cholestrol; FSH: Follicle-stimulating hormone; LH: Luteinising hormone;
TNF: Tumour necrosis factor; IL: Interleukin; PAI-1: Plasminogen activator inhibitor-1;
PCOS: Polycystic ovary syndrome; CVD: Cardiovascular disease; SHBG: Sex hormone-binding globulin

• Key pathogenetic link – Excessive weight and larger abdominal

circumference are the key pathogenetic link between PCOS and metabolic
syndrome.

21
• PCOS and obesity – Obesity has a bidirectional relationship with PCOS, as
women with PCOS are more inclined to weight gain and excessive weight
gain increases PCOS prevalence.6
• Obesity and metabolic syndrome – Visceral obesity correlates with greater
fasting insulin levels and greater insulin area under the curve.7,8
• Excess central adiposity echoes a worsened dyslipidaemic profile, with
higher triglyceride levels, increased levels of small dense low-density
lipoprotein (LDLs) particles and low high-density lipoprotein (HDL)
cholesterol levels, a lipid pattern similar to that seen in patients with T2DM.9

Obesity and PCOS

Hypothalamus
GnRH
Ghrelin (inappropriate ↑
Leptin
(increased appetite) increase) (decreased appetite)
Stomach Pituitary
↓ Leptin
(increased
Pancreas appetite)
LH↑ Fat cells
FSH Insulin resistance
Ovary (no change) Obesity
Hyperinsulinaemia

Adrenals

↑
Androgen excess

Hyperandrogenemia

PCOS

GnRH: Gonadotropin-releasing hormone; FSH: Follicle-stimulating hormone; LH: Luteinising hormone;

PCOS: Polycystic ovary syndrome

Dyslipidaemia
• Commonly represented by hypertriglyceridaemia and low HDL cholesterol
levels and small dense LDL cholesterol particles (also called atherogenic
lipoprotein phenotype), similar to that found in T2DM and typical for the
states of insulin resistance.10
• Increased LDL cholesterol in PCOS is less dependent on body weight and
may be partially related to the hyperandrogenism.11
• Hypertriglyceridaemia
o Insulin resistance has been postulated to play a key role in causing
hypertriglyceridaemia in PCOS.
o Obesity has been associated with high triglyceride levels.

22
. o Lean women with PCOS had normal triglyceride levels.
o Increased plasma triglyceride concentrations in obese women with PCOS
are likely due, at least in part, to hyperandrogenaemia and relative
progesterone deficiency.12

Insulin Resistance
• Several studies have pointed out that insulin resistance may be the key
that connects the various disorders that are seen among women with
PCOS as seen in the figure below:

Accelerated Type 2 diabetes

atherosclerosis
Hypertension

Dyslipidaemia Impaired glucose

Insulin tolerance
Resistance
Obesity
Coagulation/
(central)
Fibrinolytic defects

Acanthosis Polycystic ovary syndrome

nigricans Endothelial
dysfunction

Type 2 Diabetes
• Level A evidence has been attributed by ESHRE/ASRM statement of the
third PCOS Consensus Workshop Group, for PCOS is an independent risk
factor for the development of glucose intolerance which may extend variably
to T2DM. 4
• Obesity and overweight increase the risk of developing T2DM in PCOS
women.13
• PCOS is a significant risk factor for development of diabetes both in later life
and in young overweight or obese women with PCOS.4
• Presence of PCOS, elevated the risk of developing T2DM by four fold when
compared to their BMI matched controls, whiles the OR for IGT was 2.5.14
• The likelihood of developing T2DM significantly increased as BMI, fasting
glucose, and glucose area under the curve (AUC) at baseline increased and
significantly decreased as sex hormone-binding globulin (SHBG) levels at
follow-up increased.15

23
 PCOS and NAFLD
High prevalence of NAFLD is seen in:
• Obese individuals (90%)
Obesity
• Women with diabetes (70%)
• Women with premenopausal NAFLD
Insulin reistance/
had been diagnosed with PCOS by
Hyperinsulinaemia Central adiposity
Rotterdam criteria. (10 out of 14)

PCOS
Link between NAFLD and PCOS:
NAFLD
• Obesity
• Insulin resistance
• Hyperandrogenism

Tests to screen NAFLD:

Hypernadrogenism • Serum aminotransferase levels
• Haepatic steatosis by abdominal
ultrasound

PCOS: Polycystic ovary syndrome; NAFLD: Non-alcoholic fatty liver disease

• NAFLD is the most common cause of chronic liver disease.

• It extends from liver damage from fatty infiltration to end-stage liver disease,
in patients without significant alcohol consumption.
Prevalence
• Increased prevalence of NAFLD has been reported in patients with PCOS.
• Studies support high prevalence of NAFLD in obese individual reaching up to
90%.
• In morbidly obese individual and in people with diabetes up to 70%.
• Women with premenopausal NAFLD had been diagnosed with PCOS by
Rotterdam criteria. (10 out of 14).16
Pathophysiology
• Main factors related to NAFLD in PCOS are:
o Obesity, in particular central adiposity
o Insulin resistance
• Androgen excess is the main feature of PCOS and is interrelated to insulin
resistance, may be an additional contributing factor to the development of
NAFLD.
Surveillance
• PCOS patients, particularly obese patients with features of the metabolic
syndrome, should be submitted to screening for NAFLD comprising of :
o Assessment of serum aminotransferase levels
o Haepatic steatosis by abdominal ultrasound

24
Risk amelioration and management
• Lifestyle modifications including diet, weight loss and exercise are the initial
therapeutic interventions for PCOS patients with NAFLD.
• Metformin may be considered, when above measures fail, although currently
there is no medical therapy of proven benefit for NAFLD.17
• A trial of pioglitazone and vitamin E 800mg has been tried for the treatment of
nonalcoholic steatohaepatitis (NASH) in adults without diabetes with few
benefits.18
References
1. Tariq AA. Polycystic ovary syndrome and metabolic syndrome. Èes. Gynek. 2015; 80(4):279–289.
2. Lim SS, Davies MJ, Norman RJ, et al. Overweight, obesity and central obesity in women with
polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update.
2012;18(6):618–637.

3. Carmina E, Napoli N, Longo RA, et al. Metabolic syndrome in polycystic ovary syndrome (PCOS):
lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis
of PCOS. Eur J Endocrinol. 2006;154:141–145.
4. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic
ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus
Workshop Group. Fertil Steril. 2012;97(1):28–38.

5. Martins WP, Soares GM, Vieira CS, et al. Cardiovascular risk markers in polycystic ovary
syndrome in women with and without insulin resistance. Rev Bras Ginecol Obstet.
2009;31(3):111–116.

6. Teede HJ, Joham AE, Paul E, et al. Longitudinal weight gain in women identified with polycystic
ovary syndrome: results of an observational study in young women. Obesity.
2013;21(8):1526–1532.

7. Carmina E, Bucchieri S, Esposito A, et al. Abdominal fat quantity and distribution in women with
polycystic ovary syndrome and extent of its relation to insulin resistance. J Clin Endocrinol
Metab. 2007;92(7):2500–2505.

8. Cascella T, Palomba S, De Sio I, et al. Visceral fat is associated with cardiovascular risk in women
with polycystic ovary syndrome. Hum Reprod. 2008;23(1):153–159.

9. Palomba S, Santagni S, Falbo A, et al. Complications and challenges associated with polycystic
ovary syndrome: current perspectives. Int J Womens Health. 2015;7:745–763.

10. Bodmer M, Becker C, Meier C, et al. Use of metformin and the risk of ovarian cancer: A
case–control analysis. Gynecol Oncol. 2011;123:200–204.

11. Harris HR and Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast
cancer: a systematic review. Fertil Res Pract. 2016; 2:14.
12. Nitsche K and Ehrmann DA. Obstructive sleep apnea and metabolic dysfunction in polycystic
ovary syndrome. Best Pract Res Clin Endocrinol Metab. 2010; 24(5): 717–730.

13. Alberti KG, Zimmet P and Shaw J. International Diabetes Federation: a consensus on type 2
diabetes prevention. Diabet Med. 2007;24(5):451–463.

25
14. Moran LJ, Misso ML, Wild RA, et al. Impaired glucose tolerance, type 2 diabetes and metabolic
syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod
Update. 2010;16(4):347–363.

15. Gambineri A, Patton L, Altieri P, et al. Polycystic ovary syndrome is a risk factor for type 2
diabetes: results from a long-term prospective study. Diabetes. 2012;61(9):2369–2374.

16. Bedogni G, Miglioli L, Masutti F, et al. Prevalence of and risk factors for nonalcoholic fatty liver
disease: the dionysos nutrition and liver study. Hepatology. 2005;42:44–52.

17. Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J
Gastroenterol. 2014; 20(26): 8351–8363.

18. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic
steatohepatitis. N Engl J Med. 2010;362(18):1675–85.

Cardiometabolic Consequences of PCOS

Association between PCOS and cardiometabolic risk factors

Hypertrophic adipocytes and macrophages

IL-1
Hyperandrogenemia IL-6
TNF-a
FFA ↓
Adiponectin
Leptin Resistin
Visfastin hs-CRP
PCOS

Insulin
resistance
Muscle Liver

Endothelial
? dysfunction
Traditional CV
ET-1 Oxidative stress
risks factors:
• Dyslipidaemia AT II NO
• Hypertension ADMA PG-I2
• Smoking PAI-1
• T2DM vWF Procoagulopathy

Myocardial dysfunction Atherosclerosis

CVD
? Ventricular hypertrophy
Arterial stiffness

IL: Interleukin; vWF: von Willebrand factor; PAI-1: Plasminogen activator inhibitor-1; AT-II: Antithrombin-II;
ET-1: Endothelin-1; ADMA: Asymmetric dimethylarginine; MDA: Malondialdehyde; NO: Nitric oxide;
FFA: Free fatty acids; hsCRP: high sensitivity C-reactive protein; PCOS: Polycystic ovary syndrome;
T2DM: Type 2 diabetes mellitus; CVD: Cardiovascular disease

26
• Higher prevalence of classic risk factors for CVD such as hypertension,
dyslipidaemia, diabetes, and obesity and non classic risk factors such as
C-reactive protein (CRP), homocysteine, and tumour necrosis factor-a are
seen in women with PCOS.1
• PCOS at any age is characterised by greater odds for elevated CVD risk
markers and these elevated makers can occur without obesity but are
magnified with obesity.
• The cardiometabolic profile of women with PCOS appears to be dependent
on PCOS reproductive phenotypes.
• Women with hyperandrogaenic PCOS (classic NIH-criteria PCOS) have a
worse cardiometabolic profile and higher prevalence of CVD risk factors
compared with women with non-hyperandrogenic PCOS.2, 3
• More than 25% prevalence of metabolic syndrome is seen in women with
hyperandrogenic PCOS.3
• Though metabolic and reproductive phenotypes mirror, different phenotypes
of PCOS with same BMI were found to carry similar cardiometabolic risks.
Thus obesity exacerbates the occurrence of metabolic syndrome.4
• A Swedish study found that even in the absence of a real hypertensive state,
PCOS women presented a significantly higher daytime systolic blood
pressure, mean arterial values of blood pressure, and an increased pulse
rate, than healthy controls.
• This significant pre-hypertensive state remained even after adjusting for
BMI, body fat distribution, and insulin resistance. Among the cardiovascular
risk factors, T2DM represents one of the most important risk factor and PCOS
is considered a major risk factor for developing IGT and T2DM.5
• Several non classic CVD risk factors, related to a systemic inflammatory
state, such as CRP are reported at higher levels in women with PCOS.
• Plasma homocysteine levels are widely accepted as an independent CVD
risk factor which several studies have reported are elevated in women with
PCOS.6
• Other biochemical, inflammatory and thrombotic markers of cardiovascular
risk have been reported in excess in women with PCOS compared with
non-PCOS controls,7,8 such as tumour necrosis factor-a, interleukin-6 (IL-6),
IL-18, IL-17, factor VIIc, tissue plasminogen activator (t-PA), fibrinogen,
von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1),
thrombo-modulin, D-dimers, antithrombin-II (AT-II), Sp (Selectin),
endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), intercellular

27
26
 adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1
(sVCAM-1), serum advanced glycation end-products (AGEs), membrane
receptor for AGEs (RAGE), malondialdehyde (MDA), nitric oxide (NO), and
latency-associated peptides (LAPs).2
• Typical features of PCOS, such as increased waist/hip ratio, hirsutism, or
polycystic ovarian morphology (PCOM), are more commonly related to
coronary artery disease in women undergoing coronary angiography.
Surveillance for metabolic syndrome
• Women with PCOS who are obese or overweight are at higher risk of
developing metabolic syndrome. Hence it is recommended to screen these
women for metabolic syndrome.2
• CVD surveillance
o Invasive and non invasive tests may be applied to evaluate endothelial
function, carotid intima-media thickness (CIMT), and coronary artery
calcification (CAC) scores.9
o Endothelial dysfunction, an early sign of atherosclerosis, can be assessed
by examining artery’s flow-mediated dilatation and, in a recent meta-
analysis, this parameter, measured at brachial artery, was found to be
lower in women with PCOS compared to controls, even after controlling
for age, BMI, and smoking.10, 11
Risk amelioration
• The INTERHEART study found nine potentially modifiable risk factors which
accounted for over 94% of the population-attributable risk of a first
myocardial infarction in women.13
• The nine factors are:
o Smoking, hypertension, dyslipidaemia, diabetes, visceral obesity,
psychosocial factors, decreased consumption of fruits and vegetables,
regular consumption of alcohol, and regular physical activity.
• The majority of these occur in the PCOS woman. Hence it is necessary to take
these crucial steps for reducing the risk of development of metabolic
syndrome/ CVD / T2DM.
o Step- 1: Lifestyle modifications such as exercise and weight reduction,
regular consumption of fruits and veggies (3–5 servings/ day) should be
considered and smoking and alcohol intake should be avoided, to reduce
insulin resistance, dyslipidaemia,T2DM and CVD risk factors. 12

28
 o Step- 2: Metformin is an effective treatment for diabetes with favourable
effects on lipid abnormalities to reduce cardiovascular risk. Metformin
lowers triglycerides, increase HDL cholesterol, and favourably influences
serum insulin levels.13
References
1. Toulis KA, Goulis DG, Mintziori G, et al. Meta-analysis of cardiovascular disease risk markers in
women with polycystic ovary syndrome. Hum Reprod Update. 2011;17(6):741–760.
2. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic
ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus
Workshop Group. Fertil Steril. 2012;97(1):28–38.
3. Daan NM, Louwers YV, Koster MP, et al. Cardiovascular and metabolic profiles amongst different
polycystic ovary syndrome phenotypes: who is really at risk? Fertil Steril. 2014;102(5):1444–1451.
4. Moran LJ, Norman RJ, Teede HJ. Metabolic risk in PCOS: phenotype and adiposity impact.
trends. Endocrinol Metab. 2015;26(3):136–143.
5. Palomba S, Santagni S and Falbo A. Complications and challenges associated with polycystic
ovary syndrome: current perspectives. Int J Womens Health. 2015; 7: 745–763.
6. Schachter M, Raziel A, Friedler S, et al. Insulin resistance in patients with polycystic ovary
syndrome is associated with elevated plasma homocysteine. Hum Reprod. 2003;18(4):721–727.
7. Wiltgen D and Spritzer PM. Variation in metabolic and cardiovascular risk in women with
different polycystic ovary syndrome phenotypes. Fertil Steril. 2010;94(6):2493–2496.
8. Samy N, Hashim M, Sayed M, et al. Clinical significance of inflammatory markers in polycystic
ovary syndrome: their relationship to insulin resistance and body mass index. Dis Markers.
2009;26(4):163–170.
9. Carmina E, Napol N, Longo RA, et al. Metabolic syndrome in polycystic ovary syndrome (PCOS):
lower prevalence in southern Italy than in the USA and the influence of criteria for the diagnosis
of PCOS. Eur J Endocrinol. 2006;154141–145.
10. Dokras A. Cardiovascular disease risk in women with PCOS. Steroids. 2013;78(8):773–776.
11. Sprung VS, Atkinson G, Cuthbertson DJ, et al. Endothelial function measured using flow-
mediated dilation in polycystic ovary syndrome: a meta-analysis of the observational studies.
Clin Endocrinol. 2013;78(3):438–446.
12. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with
myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet.
2004;364(9438):937–952.
13. Janci MM, Smith RC, Odegard PS. Polycystic ovarian syndrome: metformin or thiazolidinediones
for cardiovascular risk reduction? Diabetes Spectrum. 2012;25(4): 229–237.

29
 Other Consequences of PCOS

Body image

Self esteem

Depression

Anxiety

• The challenges to feminine identity and body image due to obesity, acne and
excess hair, as well infertility and long-term health-related concerns
compromise the QoL and adversely impact on mood and psychological well-
being.1
• Women with PCOS carry higher risk of developing depression, anxiety, low
self-esteem, negative body image, and psychosexual dysfunction.2
• The other critical aspect of psychosocial impact in PCOS is the negative
impact of mood disturbance, poor self-esteem and reduced psychological
well-being on motivation and on the ability to implement and sustain
successful lifestyle changes that are critical in this condition.1, 3
• High prevalence of depression and anxiety is seen among women with
PCOS.4
• Women with PCOS with lower BMI tended to have slightly lower anxiety and
depression scores, suggesting that having a lower BMI reduces anxiety and
depression.
• Holistic management of PCOS warrants the need to look out and treat these
conditions during PCOS assessment and management.
• Experts from the field must be involved in the care plan.

30
4
 PCOS and Eating Disorders
PCOS is associated with higher prevalence of eating disorders

Anorexia nervosa Bulimia nervosa Binge eating disorder

In patients with binge eating

disorder
Diagnosed with 50%
depression
Struggling with eating
44%
habit management

Diagnosed with 24%

bipolar disorder

Eating disorders is associated with higher number of deaths than any other mental disorder

Prevalence among women with PCOS

• Prevalence of clinical and subclinical eating disorders particularly bulimia
nervosa is increased among women with PCOS compared to healthy women.
• High prevalence of eating disorders is seen among women with PCOS:
o Clinical bulimia nervosa: 5.3%,
o Subclinical anorexia nervosa: 1.1%
o Subclinical bulimia nervosa: 10.5%
o Subclinical bulimia nervosa as detected in the hyperandrogeic group:
1.6%5
• PCOS women with anxiety and depression had higher odds of developing an
eating disorder.6
Consequences
• Disordered eating attitudes and behaviours are associated with decreased
QoL in women with PCOS.
• Eating disorders can have significant negative influence on the outcome of
the treatment of PCOS.
• Eating disorders are associated with higher number of deaths than any other
mental disorder.
Surveillance
• It is necessary to screen women with PCOS for eating disorders especially
those with co-existing anxiety or depressive symptoms.

31
• Eating disorder examination questionnaire (EDEQ) may be employed for
screening.
Management
• Psychological treatment of eating disorders among women with PCOS is
crucial.6

OSA and PCOS

• OSA occurs in 50% of women with PCOS
• Women with PCOS have 30% higher risk of developing OSA

OSA and PCOS have bidirectional relationship

OSA PCOS

• PCOS women with OSA have higher predisposition for development of T2DM and CVD than PCOS women without OSA
• OSA has a modulating effect upon triglyceride metabolism

OSA: Obstructive sleep apnoea; PCOS: Polycystic ovary syndrome; T2DM: Type 2 diabetes mellitus;
CVD: Cardiovascular disease

• Obstructive sleep apnoea (OSA) and excessive daytime sleepiness (EDS) are
strongly associated with insulin resistance.
• BMI-independent OSA risk has been noted in the PCOS population.7
• Neither the degree of androgen elevation nor BMI fully account for the
presence or severity of OSA in PCOS.
Prevalence
• PCOS patients were 30 times more likely to suffer from sleep disordered
breathing (SDB) than the controls [OR = 30.6, 95% CI (7.2–139.4)].
• OSA is found in 50% of women with PCOS.8
Pathophysiology
• Bi-directional relationship exists between OSA and PCOS as shown in the
figure above.
• Overweight and (visceral) obesity are exceptionally common in women with
PCOS and contribute to the increased risk of OSA in this population.
• IGT and T2DM are present at an early age and in a disproportionate number
of women with PCOS.
• The presence and severity of OSA may directly impact the mechanism of IGT
in women with PCOS.

32
 Disrupted Sleep Pattern – A Cause of Metabolic
Disorder in Women with PCOS
Lifestyle
Depression
Stress
Sleep–disordered
breathing Diabetic
Circadian symptoms
amplitude↓

Sleep ↓

Leptin↓
Ghrelin↑ Melatonin↓
Orexin↑ Sympathovagal Adipo– Cortisol↑
TSH↓ IL–6; Il–1 GH↑
balance↑ nectin↓ TNF–∝

Appetite↑ EE↓ Insulin resistance↑

Obesity Diabetes

IL: Interleukin; TSH: Thyroid-stimulating hormone; TNF: Tumour necrosis factor; GH: Growth hormone;
EE: Ethinyloestradiol; OSA: Obstructive sleep apnoea

Consequences
• PCOS women with OSA may have a much greater predisposition for
development of diabetes and CVD than PCOS women without OSA.
• Further, there is the potential that OSA has a modulating effect upon
triglyceride metabolism.
Surveillance
• There is a significant increase in risk for OSA in PCOS. When present, OSA
largely remains under-diagnosed and untreated.
• Patients need to be referred to sleep medicine for screening and
management.
Management
• Treatment of OSA with continuous positive airway pressure (CPAP) in PCOS
results in significant reductions in 24 hr secretory cortisol and
norepinephrine profiles as well as improved insulin sensitivity.9
References
1. Teede H, Deeks A, and Moran L. Polycystic ovary syndrome: a complex condition with
psychological, reproductive and metabolic manifestations that impacts on health across the
lifespan. BMC Med. 2010;8:41.
2. Deeks A, Gibson-Helm M, Teede H. Anxiety and depression in polycystic ovary syndrome
(PCOS): a comprehensive investigation. Fertil Steril. 2010;93:2421–2423.

33
3. Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a
position statement of the androgen excess and polycystic ovary syndrome society. Fertil Steril.
2009;92:1966–1982.
4. Harris HR and Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast
cancer: a systematic review. Fertil Res Pract. 2016; 2:14.
5. Bernadett M, and Szemán-N A . Prevalence of eating disorders among women with polycystic
ovary syndrome. Europe PMC. 2016;31(2):136–145.
6. Cooney LL, Saini S, Smith ME, et al. Increased risk of eating disorders in women with polycystic
ovary syndrome. Fertility and Sterility. 2016;106(3): e260–e26.
7. Dondik Y, Ehlers KA, Gentry A, et al. Assessing patient and physician compliance with
recommended sleep apnea screening in PCOS patients. Fertility and Sterility. 2016;106(3):e259.
8. Vgontzas AN, Legro RS, Bixler EO, et al. Polycystic ovary syndrome is associated with
obstructive sleep apnea and daytime sleepiness: role of insulin resistance. the journal of clinical
endocrinology & metabolism. 2001;86(2):517–520.
9. Nitsche K and Ehrmann DA. Obstructive sleep apnea and metabolic dysfunction in polycystic
ovary syndrome. Best Pract Res Clin Endocrinol Metab. 2010;24(5):717–730.

Management of Long-Term Health Consequences of PCOS

CVD risk assessment at any age-

Determine BMI and waist Categorise the PCOS-related BP, complete lipid profile, waist
circumference at every visit CVD risk as: “at risk”/ “high risk” circumference, BMI, glucose profile,
smoking, family history of CVD

USG / endometrial biopsy if Lifestyle change, including

Assess for depression, anxiety,
symptoms of abnormal uterine hypocaloric diet and
and QoL bleeding are present physical exercise,

TZDs are alternative therapy

Metformin for obese PCOS women
in insulin-resistant, obese PCOS
for risk reduction and for lean
patients who are intolerant or
women with insulin sensitivity
refractory to metformin

BMI: Body mass index; BP: Blood pressure; QoL: Quality of life; USG: Ultrasound; TZD: Thiazolidinedione;
CVD: Cardiovascular disease

• The long-term risks observed in women with PCOS are vary based on
different phenotypes and are negatively influenced by obesity and lifestyle
factors. It is recommended that BMI and waist circumference should be
determined at every visit, considering the presence of abdominal obesity in
women with a waist circumference of at least 80 cm.1
• Categorise the PCOS-related CVD risk as:
o “At risk” for PCOS women with any following risk factors: obesity,
cigarette smoking, hypertension, dyslipidaemia, subclinical vascular
disease, IGT, and/or family history of premature CVD (<55 years of age in
male relative, <65 years of age in female relative).

34
 o “At high risk” for PCOS women with metabolic syndrome and/or T2DM
and/or overt vascular or renal disease.
• CVD risk assessment at any age, for blood pressure, complete lipid profile
(including total, LDL, HDL, non-HDL cholesterol, and triglycerides), waist
circumference, BMI, glucose profile, cigarette smoking, and a family history
of early CVD.
• Because cardiovascular risk increases with age and it can be exacerbated by
obesity and worsened by environmental insults, periodic reassessment for
CVD risk is suggested but there is no agreement how often the CVD risk
assessment should be repeated.
• PCOS patients must be assessed also for depression, anxiety, and QoL.
• There is no agreement on the optimal method, whether ultrasound or
endometrial biopsy and timing of screening for endometrial cancer. In line
with American Cancer Society Guidelines, the decision to assess for the
presence of endometrial cancer should be based essentially on the presence
of abnormal uterine bleeding or spotting. Other relevant decision factors are
amenorrhoea length, women’s age, and the ultrasound appearance of
endometrium.2
• Lifestyle change, including hypocaloric diet and physical exercise, is
considered a cornerstone of the management of women with PCOS
presenting with obesity, particularly the abdominal phenotype; so it is
generally recommended as a first-line approach for obese PCOS women. A
5%–10% weight loss is considered clinically significant and able to reduce
IGT and metabolic syndrome prevalence in general population.3
• From a pharmacological standpoint, considering the metabolic and hormonal
relevance of insulin resistance and associated compensatory
hyperinsulinaemia, common features of the PCOS women, the treatment
choices have been expanded to insulin-sensitising agents, in particular,
metformin.4
• Moreover, metformin is not of benefit in improving weight loss, insulin
sensitivity, or lipid profiles; hence a long-term prophylactic treatment with
metformin is unlikely to prevent progression to diabetes. In line with these
considerations, the main5 societies agree to considered metformin for
prevention of diabetes in women with PCOS and IGT when lifestyle
modification is not successful and/or as an adjuvant to general lifestyle
modifications that remains the first-line therapy for PCOS women at
increased metabolic risk.6

35
• Thiazolidinediones may be considered as an alternative therapy in insulin-
resistant, obese PCOS patients who are intolerant or refractory to metformin,
or in PCOS women with severe insulin resistance due to genetic disorder. At
present, in overweight/obese PCOS women, we advice lifestyle changes
(consisting of Mediterranean diet and physical activity) as preliminary
approach, at any age, with the aim of weight loss. We suggest the
association with metformin in obese/overweight PCOS patients, when
lifestyle program alone is not enough to obtain metabolic improvements and
we proposed metformin use in lean PCOS patients with impaired insulin
sensitivity.7
References
1. Rosenzweig JL, Ferrannini E, Grundy SM, et al. Primary prevention of cardiovascular disease
and type 2 diabetes in patients at metabolic risk: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab. 2008;93(10):3671–3689.
2. Smith RA, von Eschenbach AC, Wender R, et al. ACS Prostate Cancer Advisory Committee. ACS
Colorectal Cancer Advisory Committee. ACS Endometrial Cancer Advisory Committee
American Cancer Society guidelines for the early detection of cancer: update of early detection
guidelines for prostate, colorectal, and endometrial cancers. Also: update 2001–testing for early
lung cancer detection. CA Cancer J Clin. 2001;51(1):38–75.
3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J
Med. 2002;346(6):393–403.
4. Palomba S, Falbo A, Zullo F, et al. Evidence-based and potential benefits of metformin in the
polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30(1):1–50.
5. Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone,
pioglitazone, D-chiroinositol) for women with polycystic ovary syndrome, oligo amenorrhoea
and subfertility. Cochrane Database Syst Rev. 2012(5):CD003053.
6. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary
syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab.
2013;98(12):4565–4592.
7. Palomba S, Santagni S and Falbo A, et al. Complications and challenges associated with
polycystic ovary syndrome: current perspectives. Int J Womens Health. 2015; 7: 745–763.

36
 Conclusion

• PCOS is associated with serious long-term heath consequences.

• The prevalence of certain neoplastic, cardiometabolic and mental health
conditions is higher in women with PCOS when compared against those
without PCOS.
• Obesity and insulin resistance are the major pathologic factors that lead
to all these consequences.
• It is important to screen the patients with PCOS for identifying early
signs and promptly treating these serious health conditions.
• Lifestyle modification particularly associated with weight loss is the
first step to curtail the risk of endometrial cancer, cardiometabolic
syndrome and mental disorders.
• Pharmacological treatment may be necessary when lifestyle measures
are unable to meet the expectations of risk reduction.
• Several studies support the benefits of the use of metformin.
• Involvement of respective experts is necessary for the care of patients
with long-term health consequence of PCOS.

Key points
Key recommendations for clinical assessment and
treatment of long-term PCOS complications

Clinical assessment Therapeutic approaches

Metabolic risk Screening for IGT and T2DM Lifestyle change programmes
with 75 g OGTT in PCOS (hypocaloric diet and
women with: physical exercise) represent
• Age >40 years the first-line approach for
treating obese PCOS women
• BMI >30
Metformin use for prevention
• Classic phenotype
of diabetes in PCOS women
• Presence of acanthosis with IGT when lifestyle
nigricans modification is not successful
• Personal and/or family and/or as an adjuvant to
history of T2DM general lifestyle
BMI and waist circumference modifications
at every visit:
• Waist circumference >80 cm

37
 Key points (Table cont...)

Clinical assessment Therapeutic approaches

• Abdominal obesity Thiazolidinediones as
Periodic reassessment with alternative therapy in insulin-
OGTT resistant, obese PCOS
patients who are intolerant or
refractory to metformin, or
with severe insulin
resistance due to genetic
disorder

Cardiovascular risk CVD risk assessment at any Lifestyle modification:

age with: • Diet
• Blood pressure • Physical exercise
• Lipid profile • Smoking cessation
• Waist circumference Metformin use for prevention
• BMI of T2DM in PCOS women
• Glucose profile with IGT when lifestyle
modification is not successful
• Cigarette smoking
and/or as an adjuvant to
• Family history of early CVD
general lifestyle
• Evaluation for depression, modifications
anxiety, and quality-of-life
Statins to lower LDL-C levels
Categorise PCOS patients as
Antihypertensive drugs
“at risk” for CVD if present:
• Obesity
• Hypertension
• Dyslipidaemia
• Cigarette smoking
• Subclinical vascular
disease
• IGT
• Family history of premature
CVD
Categorise PCOS patients as
“at high risk” for CVD if
present:
• Metabolic syndrome

38
 Key points (Table cont...)

Clinical assessment Therapeutic approaches

• T2DM
• Vascular and/or renal
disease
Periodic clinical
reassessment
Cardiovascular risk In presence of amenorrhea or Periodic progestogen
abnormal uterine bleeding, withdrawal (at least four
assessment for the presence episodes per year) should be
of endometrial cancer with indicated in anovulatory
ultrasound and/or PCOS women
endometrial biopsy

CVD: Cardiovascular disease; OGTT: Oral glucose tolerance test; PCOS: Polycystic ovary syndrome; LDL-C:
Low-density lipoprotein cholesterol; BMI: Body mass index; T2DM: Type-2 diabetes mellitus; IGT: Impaired
glucose tolerance

Reference
1. Palomba S, Santagni S and Falbo A. Complications and challenges associated with polycystic
ovary syndrome: current perspectives. Int J Womens Health. 2015;7:745–763.

Suggested Readings

1. Harris HR and Terry KL. Polycystic ovary syndrome and risk of endometrial,
ovarian, and breast cancer: a systematic review. Fertil Res Pract. 2016;2:14.
2. Gottschau M, Kjaer S, Jensen A, et al. Risk of cancer among women with
polycystic ovary syndrome: a Danish cohort study. Gynecol Oncol.
2015;136:99–103.
3. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects
of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-
Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012; 97(1):28–38.
4. Palomba S, Santagni S and Falbo A. Complications and challenges associated
with polycystic ovary syndrome: current perspectives. Int J Womens Health.
2015;7:745–763.

39
Notes

40
 PCOS and Long-Term Health Consequences
POST-TEST
1. PCOS has been associated with:
a) Endometrial cancers
b) Orthopaedic cancers
c) Lung cancers
d) All of the above
2. Adolescents and reproductive age women with PCOS have an increased
prevalence of cardiovascular risk factors. Is this truth or myth?
a) Truth
b) Myth
3. Which of the following is not associated with PCOS ?
a) Depression
b) Anxiety
c) Both a and b
d) Schizophrenia
4. Which are the different modes of treating endometrial cancer? Select the
most appropriate answer.
a) Surgery only
b) Surgery and radio therapy
c) Surgery, radio and chemo therapy
d) Surgery, hormonal, radio and chemo therapy
5. For patients with conservative surgery for borderline ovarian serous
tumours , which of the following is true?
a) Most of them turn infertile
b) Spontaneous conception occurs in less than 20% patients
c) Spontaneous conception occurs in nearly 50% patients
d) All of the above are untrue
6. Clomiphene citrate increases the risk of ...................... and endometrial
cancer.
a) Ovarian cancer
b) Breast cancer
c) Colorectal cancer
d) Melanoma
7. Metabolic syndrome leads to increase in all, except:
a) Triglycerides
b) HDL
c) LDL
d) V-LDL
8. Which of the following is associated with PCOS?
a) Obstructive sleep apnoea
b) NAFLD
c) Coronary heart disease
d) All of the above
e) None of the above
9. All patients with PCOS must have endometrial biopsy at every visit to
screen for endometrial cancer.
a) True
b) False
10. How much weight loss is considered clinically significant and able to
reduce IGT and metabolic syndrome prevalence?
a) ≥
50%
b) 30–40 %
c) 20–25%
d) 5–10%

Answers: 1. a; 2. a; 3. d; 4. d; 5. c; 6. d; 7. b; 8. d; 9. b; 10. d
This initiative is supported by an unrestricted educational grant from
Developed by:
For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only.