Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder that implies various severe consequences to female health, including alarming rates of infertility. Although its exact etiology remains elusive, it is known to feature several hormonal disturbances, including hyperandrogenemia, insulin resistance (IR), and hyperinsulinemia. Insulin appears to disrupt all components of the hypothalamus-hypophysis-ovary axis, and ovarian tissue insulin resistance results in impaired metabolic signaling but intact mitogenic and steroidogenic activity, favoring hyperandrogenemia, which appears to be the main culprit of the clinical picture in PCOS. In turn, androgens may lead back to IR by increasing levels of free fatty acids and modifying muscle tissue composition and functionality, perpetuating this IR-hyperinsulinemia-hyperandrogenemia cycle. Nonobese women with PCOS showcase several differential features, with unique biochemical and hormonal profiles. Nevertheless, lean and obese patients have chronic inflammation mediating the long term cardiometabolic complications and comorbidities observed in women with PCOS, including dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Given these severe implications, it is important to thoroughly understand the pathophysiologic interconnections underlying PCOS, in order to provide superior therapeutic strategies and warrant improved quality of life to women with this syndrome.
2. DR ALKA MUKHERJEE
MBBS DGO FICOG FICMCH PGDCR PGDMLS MA(PSY)
Director & Consultant At Mukherjee Multispecialty
Hospital
MMC ACCREDITATED SPEAKER
MMC OBSERVER MMC MAO – 01017 / 2016
Present Position
Director of Mukherjee Multispecialty Hospital
Hon.Secretary INTERNATIONAL COUNCIL FOR HUMAN
RIGHTS
Hon.Secretary NARCHI NAGPUR CHAPTER (2018-2020)
Hon.Secretary AMWN (2018-2021)
Hon.Secretary ISOPARB (2019-2021)
Organizing secretary AMWICON – 2019
Life member, IMA, NOGS, NARCHI, AMWN &
Menopause Society, India, Indian medico-legal &
ethics association(IMLEA), ISOPARB, HUMAN RIGHTS
Founder Member of South Rapid Action Group,
Nagpur.
On Board of Super Specialty, GMC, IGGMC, AIIMS
Nagpur, NKPSIMS, ESIS and Treasury, Nagpur for “
WOMEN SEXUAL HARASSMENT COMMITTEE.”
mukherjeehospital@yahoo.com
www.mukherjeehospital.com
https://www.facebook.com/
Mukherjee Multispeciality
https://www.instagram.com/
Achievement
Winner of NOGS GOLD MEDAL – 2017-18
Winner of BEST COUPLE AWARD in Social
Work - 2014
VIDARBHA RATNA PURASKAR - 2019
Past Position
Vice President of NOGS(2016-2017)
Organizing joint secretary ENDO-GYN
Vice President IMA Nagpur (2017-2018)
Organizing joint secretary ENDO-GYN 2019
3.
4.
5.
6.
7. Practice Essentials
• Women with polycystic ovarian syndrome (PCOS) have
abnormalities in the metabolism of androgens and estrogen and
in the control of androgen production - abnormal function of
the hypothalamic-pituitary-ovarian (HPO) axis.
8. Insulin Resistance, Hyperinsulinemia, and
Hyperandrogenemia: A Vicious Cycle
• Insulin and Dysregulation of Hypothalamus-Hypophysis-Ovary and
Adrenal Signaling - Insulin may play a part in the development of the
typical increased amplitude and frequency of GnRH and LH pulse
secretion seen in PCOS.
• Insulin and Sex Hormone Binding Globulin - Elevated insulin
concentrations have been associated with lower levels of SHBG, leading
to enhanced bioavailability of androgens
• Insulin Signaling in Ovarian Tissue and Selective Insulin Resistance -
Pleiotropy is a distinguishing feature of insulin signaling, being involved
in a wide catalogue of physiologic and pathophysiologic roles through
distinct, yet interconnected, second-messenger pathways
• cAMP-Dependent Activation of PKA - Insulin appears to act in synergy
with LH to elevate intracellular concentration of cAMP, which activates
StAR, potentiating steroidogenic activity.
9. • Serine Phosphorylation Theory - This unifying proposal for
hyperinsulinemia-hyperandrogenemia in PCOS stems from observations
of Dunaif et al., who ascertained a significant decrease in tyrosine-kinase
activity, accompanied by considerably higher serine-kinase activity, in
fibroblasts of women with PCOS. This differential behavior resulted in
attenuated metabolic effects of insulin with normal mitogenesis
• Inositolphosphoglycan Signaling - this pathway stands apart from
previous mechanisms as it appears to be independent of all insulin
signaling-related molecules except INSR itself
10.
11.
12.
13. • History
• The family history of
patients with polycystic
ovarian syndrome (PCOS)
may include the following:
• Menstrual disorders
• Adrenal enzyme
deficiencies
• Hirsutism
• Infertility
• Obesity and metabolic
syndrome
• Diabetes
• Menstrual history -
chronic anovulation. (The
patient usually has a
history of menstrual
disturbance dating back
to menarche.)
• oligomenorrhea
• secondary amenorrhea
(an absence of
menstruation for 6
months).
• Dysfunctional uterine
bleeding and infertility
14. HYPERANDROGENISM
• Excess terminal body hair in a male distribution pattern. Hair on the
upper lip, on the chin, around the nipples, and along the linea alba of the
lower abdomen, acne and/or male-pattern hair loss (androgenic
alopecia).
• Clitoromegaly, increased muscle mass, voice deepening - extreme form
of PCOS (hyperthecosis). Rule out androgen-producing tumors,
exogenous androgen administration, or virilizing congenital adrenal
hyperplasia.
• Premature adrenarche - a precursor to PCOS.
• Hirsutism and obesity pre-menarchal adolescent girls with PCOS.
15. Sebaceous glands are also androgen-dependent structures, with
sebocytes being highly sensitive to androgen signaling, which is
exacerbated in PCOS, leading to the development of acne and
seborrhea
Androgens stimulate sebocyte proliferation—especially in the mid-
back, forehead, and chin—and secretion of sebum, a mixture of
lipids including glycerides, squalene, free fatty acids (FFA), and
cholesterol
Local bacteria further complicate the process by secreting lypolytic
enzymes which break down triglycerides produced in the sebocyte.
The resulting FFA that are released into sebaceous ducts by
apocrine glands are responsible for the characteristic odor observed
in these patients
Acne and Seborrhea
16. Androgenic alopecia is a disorder in which hair is miniaturized, due to
an increased telogen : anagen ratio—with telogen hair being at mitotical
rest and anagen hair being mitotically active—and associated to genetic
susceptibility related to increased 5-reductase activity in the hair follicle.
This increased enzymatic activity would favor the local conversion of
testosterone into DHT, a more powerful androgen
67% of the women with alopecia areata have PCOS and elevated levels
of testosterone and androstenedione.
The balding pattern is dominated by the frontal and parietal scalp
zones, leaving the occipital area with great hair density, as opposed to
thinner and scarcer hair in the crown area.
Androgenic Alopecia
17. Nails are also subject to possible alterations in PCOS, in the
form of onycholysis—separation of the nail plate from the
nail bed due to disruption of the onychocorneal band and
onychorrhexis, splitting of nails in lengthway bridges.
The association of these nail conditions with excess
androgen is not fully understood, but their presence has
been observed to be exacerbated when coexisting with
hypothyroidism or dysglycemia
Onycholysis and Onychorrhexis
19. PCOS OBESITY AND
METABOLIC SYNDROME
• . Prothrombotic state
characterized by elevated
plasminogen activator inhibitor-
1 (PAI-1) and fibrinogen levels.
• . An increased prevalence of
coronary artery calcification and
thickened carotid intima media
•43% prevalence of metabolic syndrome -
abdominal obesity (waist circumference
>35 in),
•Dyslipidemia (triglyceride level >150
mg/dl, high-density lipoprotein cholesterol
[HDL-C] level < 50 mg/dl),
•Elevated blood pressure,
•A proinflammatory state characterized by
an elevated c-reactive protein level, and
20. • Obesity As an IR-Independent Pathophysiologic Factor in PCOS -
Menstrual irregularities and anovulation appear to be more prevalent
and severe in obese women with PCOS than in their nonobese
counterparts, and weight loss of at least 5% tends to be associated with
improvement of these conditions
• Obesogenic Dietary Patterns and Hyperandrogenemia
• Effects of Obesity on Steroid Hormone Physiology and Metabolism
• The Role of Leptin in PCOS with Obesity
• Leptin, known as the prototypical adipokine, is a 167 amino acid peptide
secreted primarily from white adipose tissue, although it is present at
several other sites, including the ovary
21. Polycystic Ovary Syndrome in Non-obese
Women
• A primary alteration in β cell function as a pathophysiological component
independent of weight - this intrinsic disruption in β cell function may be linked
to in utero exposure to elevated androgen levels (fetal stimulation resulted in
altered expression of genes associated with β cell function and mass as well as
altered insulin secretion response in vitro and altered β cell quantity).
• Increased endogenous opioid signaling by virtue of elevated levels
of β endorphins in peripheral circulation.
• Nonobese individuals also show greater lh/fsh ratios, which seem to play a
major role in this subset of subjects
• Endogenous opioids - play an important role
• Lean women with PCOS have been found to display diminished sensitivity to
catecholamine-mediated lipolysis in SAT resulting in preservation of this tissue.
Because leptin is primarily secreted from SAT this may partially explain
hyperleptinemia found in normal-weight women with PCOS
• Adrenal steroidogenesis – more with lean PCOS
• Oxidative stress and low-grade inflammation
22. PCOS & DIABETES MELLITUS
• Approximately 10% of women with PCOS have type 2
diabetes mellitus, and 30-40% of women with PCOS
have impaired glucose tolerance by 40 years of age.
• ACOG recommends screening for type 2 diabetes and
impaired glucose tolerance in women with PCOS by
obtaining a fasting glucose level and then a 2-hour
glucose level after a 75-g glucose load.
23. PCOS & SLEEP APNEA
• Many women with PCOS have obstructive sleep apnea
syndrome (OSAS), which is an independent risk factor for
cardiovascular disease. Ask these patients and/or their
partners about excessive daytime somnolence; individuals
with obstructive sleep apnea experience apnea/hypopnea
episodes during sleep.
• Patients may also be screened for OSAS in the clinic using
such tools as the Epworth sleepiness score.
24. PHYSICAL EXAMINATION IN PCOS
• Blood pressure
• Patients with signs and symptoms of
metabolic syndrome may have elevated
blood pressure, with a systolic blood
pressure of 130 mm Hg or higher and a
diastolic blood pressure of 85 mm Hg or
higher.
• Enlarged ovaries
• Enlarged ovaries may not always be
present. Evaluate for an ovarian mass.
25.
26. DIAGNOSTIC CONSIDERATIONS
• Adolescent polycystic
ovarian syndrome (PCOS),
hyperandrogenemia is
essential for the diagnosis
Although obesity itself is not
considered part of the
differential diagnosis, obesity
is associated with insulin
resistance or any condition
that is associated with severe
insulin resistance - may
clinically manifest in the
same way as PCOS. Obesity
may unmask features of
PCOS in women who are
genetically predisposed to
this syndrome.
28. APPROACH CONSIDERATIONS
Biochemical and/or imaging
studies - Exclude all other
disorders that can result in
menstrual irregularity and
hyperandrogenism,
A karyotype usually excludes
mosaic Turner syndrome as a
cause of the primary
amenorrhea.
RCOG recommends thyroid
function tests, serum prolactin
levels, and a free androgen
index (defined as total
testosterone divided by sex
hormone binding globulin
[SHBG] × 100, to give a
calculated free testosterone
level). [5]
Infertility workup
Samples for laboratory studies
should be drawn early in the
morning, with the patient in a
fasting state; in women with
regular menses, samples
should be taken between days
5 and 9 of the menstrual
cycle.
A serum human chorionic
gonadotropin (hCG) level/ UPT
29. SCREENING LABORATORY STUDIES
• Serum 17-hydroxyprogesterone levels - late-onset congenital adrenal hyperplasia
due to 21-hydroxylase deficiency
• 24-hour urine sample for free cortisol and creatinine - women with pcos should
be screened for cushing syndrome or acromegaly
• An overnight dexamethasone suppression test is also useful for screening for
cushing syndrome.
• A serum insulin-like growth factor (igf) ̶ 1 level - acromegaly.
(Serum igf-1 is a sensitive and specific marker of growth hormone (gh) excess)
• Fasting serum prolactin concentration.
• FSH level should be checked to rule out primary ovarian failure.
30. • Ultrasonography
• CT scan and MRI
• If a tumor is suspected, obtain a computed
tomography (CT) scan or magnetic resonance
image (MRI) to visualize the adrenals and ovaries.
MRI is an excellent method for imaging the
ovaries and is a useful alternative in very obese
women in whom the ovaries might not be
visualized with transvaginal ultrasonography
(TVUS) and in those patients in whom TVUS is
inappropriate, such as adolescent girls.
31. APPROACH CONSIDERATIONS
• Certain lifestyle changes, such as diet and exercise – 1st line
• Pharmacologic treatments are reserved for anovulation, hirsutism, and
menstrual irregularities. Medications - oral contraceptives, metformin,
prednisone, leuprolide, clomiphene, and spironolactone.
• Mean platelet volume (MPV) is a marker associated with adverse
cardiovascular events, and women with newly diagnosed PCOS appear
to have significantly elevated MPV levels. Kabil Kucur et al reported that
use of ethinyl estradiol/cyproterone acetate or metformin for the
treatment of women with PCOS seemed to have similar beneficial effects
in reducing MPV.
• Consultation with an endocrinologist is necessary for performing an
adrenocorticotropic hormone (ACTH) stimulation test or for other causes
of menstrual irregularity such as thyroid disease or pituitary adenoma.
32. IN OCTOBER 2013, THE ENDOCRINE SOCIETY RELEASED PRACTICE
GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF PCOS.
Use the Rotterdam criteria for diagnosing PCOS (presence of 2 of the following: androgen
excess, ovulatory dysfunction, or polycystic ovaries).
In adolescents with PCOS,
hyperandrogenism is
central to the
presentation; hormonal
contraceptives and
metformin are treatment
options in this population.
Postmenopausal women
do not have a consistent
PCOS phenotype.
Exclude alternate
androgen-excess disorders
and risk factors for
cardiovascular disease,
diabetes, endometrial
cancer, mood disorders,
and obstructive sleep
apnea.
For menstrual
abnormalities and
hirsutism/acne, hormonal
contraceptives are first-line
treatment.
For infertility, clomiphene
is first-line treatment.
For metabolic/glycemic
abnormalities and for
improving menstrual
irregularities, metformin
is beneficial.
33. FIRST-LINE TREATMENT IN MANAGEMENT OF PCOS
LIFESTYLE
MODIFICAT
IONS
ACOG ,
SOGC
WEIGHT
LOSS
INCREASED
EXERCISE
Endocrine-metabolic
parameters markedly
improve after 4-12 weeks of
dietary restriction. Their sex
hormone–binding globulin
(SHBG) levels rise, and free
testosterone levels fall by 2-
fold. Serum insulin and
insulin-like growth factor-1
(IGF-1) levels also decrease.
In patients with PCOS who
are obese, weight loss is
associated with a reduction
of hirsutism and a return of
ovulatory cycles in 30% of
women, thereby improving
pregnancy rates, as well as
improving glucose tolerance
and lipid levels.
weight loss is associated with a
reduction of hirsutism and a
return of ovulatory cycles in
30% of women, thereby
improving pregnancy rates, as
well as improving glucose
tolerance and lipid levels.[15, 4]
A moderate amount of daily
exercise increases levels of IGF-
1 binding protein and decreases
levels of IGF-1 by 20%. Modest
weight loss of 2-5% of total
body weight can help restore
ovulatory menstrual periods in
obese patients with PCOS. A
decrease of 500-1000 calories
daily, along with 150 minutes of
exercise per week, can cause
ovulation.
34. DRUG TREATMENT
Aim- treatment of metabolic derangements, anovulation, hirsutism, and menstrual
irregularity.
The use of insulin-sensitizing drugs to improve insulin sensitivity is associated with a
reduction in circulating androgen levels, as well as improvement in both the
ovulation rate and glucose tolerance.
The Endocrine Society has published a clinical practice guideline on hirsutism
evaluation and treatment in premenopausal women.
ACOG notes that eflornithine in conjunction with laser treatment is superior to laser
therapy alone in treating hirsutism.
First-line medical therapy usually consists of an oral contraceptive to induce regular
menses. The contraceptive not only inhibits ovarian androgen production but
also increases sex hormone-binding globulin (SHBG) production
ACOG recommends use of combination low-dose hormonal contraceptive agents for
long-term management of menstrual dysfunction.
HIRSUTISM - an androgen-blocking agent
Pregnancy should be excluded before therapy with oral contraceptives or androgen-
blocking agents is started.
35. FIRST-LINE TREATMENT FOR OVULATION INDUCTION
Clomiphene citrate
Second-line strategies may be equally effective in infertile women with
clomiphene citrate–resistant PCOS.
A double-blind trial by Legro et al, letrozole is more effective than clomiphene in the
treatment of infertility in PCOS with equal birth rates for letrozole and
clomiphene
Combined metformin/letrozole and bilateral ovarian drilling are similarly effective as
second-line treatment in infertile women with clomiphene citrate–resistant PCOS
36. • Metformin - improves ovulation rates and pregnancy rates in PCOS
especially in obese women. Pretreatment with metformin - enhanced
efficacy of clomiphene for inducing ovulation.
• Combination of metformin and clomiphene in older women with visceral
obesity and clomiphene resistance
• N-acetylcysteine may enhance the effect of clomiphene citrate
• Morbidly obese women with PCOS should also be referred for pregnancy
risk
• metabolic surgery may be considered in morbidly obese women with
PCOS, because many features of this syndrome are reversible with
successful weight loss.
• In vitro fertilization is reserved for women with PCOS and unsuccessful
gonadotropin therapy or those with other indications for this procedure.
• A study by Chen et al found that among infertile women with PCOS, frozen-
embryo transfer was associated with a higher rate of live birth, a lower risk
of the ovarian hyperstimulation syndrome, and a higher risk of
preeclampsia after the first transfer than was fresh-embryo transfer.
37. METFORMIN
If the patient develops type 2 diabetes mellitus, consider
treatment with oral antihyperglycemic drugs, such as metformin.
Metformin can also be considered in other women with PCOS who
are insulin resistant and therefore at risk of developing
cardiovascular disease, even women without type 2 diabetes.
It can effectively reduce androgen levels, improve insulin
sensitivity, and facilitate weight loss in patients with PCOS as early
as adolescence.
One study concluded that the use of metformin throughout
pregnancy was associated with a 9-fold decrease in gestational
diabetes in women with PCOS.
In addition to having the potential to reduce gestational diabetes
in pregnant women with PCOS, metformin may also reduce the risk
of preeclampsia in this population.[64]
A long-term study suggested that metformin continued to improve
the metabolic profile of women with PCOS over a 36-month
treatment course, particularly improving circulating high-density
lipoprotein cholesterol (HDL-C), diastolic blood pressure, and body
mass index (BMI).
38. OTHER AGENTS
• For concomitant adrenal hyperandrogenism - low-dose
prednisone or dexamethasone
• Acne treatment - benzoyl peroxide, topical retinoids (retin-
a), and topical and oral antibiotics, systemic isotretinoin is
used for severe or refractory cases.
• Statins
• Sibutramine
39. Nonpharmacologic treatments of hirsutism - shaving and the use of chemical depilatories and/or
bleaching cream.
Plucking or waxing unwanted hair can result in folliculitis and ingrown hairs.
Long-term, more permanent measures for unwanted hairs include electrolysis and laser treatment.
Adjunctive eflornithine with laser treatment is superior to laser therapy alone in treating
hirsutism.
Eflornithine (Vaniqa) is a topical cream that can be used to slow hair growth. This agent works by
inhibiting ornithine decarboxylase, which is essential for the rapidly dividing cells of hair follicles.
Weight reduction decreases androgen production in women who are obese; therefore, losing
weight can slow hair growth.
Antiandrogens, such as spironolactone, are effective for hirsutism. [84] Spironolactone (50-100 mg
twice daily) is an effective primary therapy for hirsutism.
Oral contraceptives containing cyproterone acetate
Ovulation induction with clomiphene citrate, metformin,
40. SURGICAL INTERVENTION
Aim - mainly at restoring ovulation. Ovarian wedge resection has fallen out of favor because of
postoperative adhesion formation and the successful introduction of ovulation-inducing
medications.
Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy,
have been used with the goal of creating focal areas of damage in the ovarian cortex and
stroma.
According to the Society of Obstetricians and Gynaecologists of Canada (SOGC), laparoscopic
ovarian drilling may be considered in women with clomiphene-resistant PCOS, especially in the
presence of other laparoscopic indications.
Potential complications must be considered as well. These include formation of adhesions and
ovarian atrophy. Multiple pregnancy rates are lower with ovarian drilling than with
gonadotropin treatment (1% vs 16%, respectively), but there are ongoing concerns about the
long-term effects of ovarian drilling on ovarian function. [93]
41. LONG-TERM MONITORING
PCOS - a disease with many long-term
complications. Patients need regular follow-up
with their physicians for early detection and
management of any untoward sequelae
associated with the syndrome
Women with PCOS who conceive are at
increased risk for gestational diabetes,
preeclampsia, cesarean delivery, and preterm
and postterm delivery.
In addition, their newborns are at increased risk
of being large for gestational age, but they are
not at increased risk of stillbirth or neonatal
death.
Participation in a peer support group may
alleviate distress and improve self-
management.
42. GUIDELINES SUMMARY
• In November 2015, the American Association of Clinical Endocrinologists (AACE),
American College of Endocrinology (ACE), and Androgen Excess and PCOS Society
(AES) released new guidelines in the evaluation and treatment of PCOS.
• The diagnostic criteria for PCOS should include two of the following three
criteria: chronic anovulation, hyperandrogenism (clinical/biologic), and polycystic
ovaries
• Obtain levels of serum 17-hydroxyprogesterone and AMH -diagnosis of PCOS.
• Free testosterone levels are more sensitive for determining androgen excess than
total T levels and should be obtained with equilibrium dialysis techniques
• Women with PCOS should also be evaluated and treated for reproductive
function, hirsutism, alopecia, and acne.
• Adolescent girls with PCOS remain a diagnostic and therapeutic challenge. First-
line monotherapy in this age group includes metformin monotherapy and/or
combination therapy with oral contraceptive agents and antiandrogen agents.
43. MEDICATION SUMMARY
• Drugs - metformin (off-label use), spironolactone, eflornithine (topical cream to
treat hirsutism), and oral contraceptives.
• Oral contraceptives containing a combination of estrogen and progestin –
increase sex hormone–binding globulin (SHBG) levels and thereby reduce the free
testosterone level.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are also
suppressed. This restores cyclic exposure of the endometrium to estrogen-
progestin, with the resumption of menstrual periods and decreased hirsutism.
However, the use of oral contraceptives may be associated with an increased risk of
thrombosis and metabolic abnormalities.
• An oral contraceptive containing ethinyl estradiol and a progestin with minimal
androgenic activity, such as norgestimate, norethindrone, or desogestrel, should
be selected. Ethinyl estradiol combined with drospirenone (Yasmin) has a
progestin that acts as an antiandrogen and thus may add antiandrogenic effects.
44. • Withdrawal bleeding can be induced with medroxyprogesterone
(Provera) given for 5-10 days before the start of oral contraceptive
therapy. Pregnancy must be ruled out before oral contraceptive
therapy is started.
• The indications, contraindications, and adverse effects of metformin
therapy should be carefully reviewed with the patient before such
therapy is begun. In addition, women starting metformin therapy
should be informed that such treatment may result in ovulatory
menstrual cycles and increase the probability of pregnancy. It is
worth noting that metformin has the potential to reduce
preeclampsia and gestational diabetes in pregnant women with
PCOS.
• Women taking spironolactone require reliable contraception. An
oral contraceptive is preferable, but if that form of contraception is
contraindicated, another type of contraception should be used.