Polycystic Ovarian Syndrome & fertility

Dr sundar narayananM.D, DIP LAP, DIP ART, DIP US

INTRODUCTION

• The polycystic ovary syndrome is the most common metabolic abnormality in young women today of reproductive age.

• Most common cause of infertility in women

• Studies of PCOS in India reported a prevalence of 3.7% to 22.5%, upto 36% prevalence in adolescents

Etiology • A large number of genomic variants has been

associated with PCOS and many of these associations have not been replicated in different populations.

• It is believed that the picture is of a multigenic etiology in which non-genetic factors such as diet and exercise have strong influence on the development of the disorder

PCOSSyndrome characterized by• Oligoammenorhoea / amenorrhoeaLaboratory criteria of

• Hyperandrogenemia• Hyperinsulinemia

• Polycystic ovaries on USG

Diagnostic criteria

• Classic syndrome originally described by Stein and Levanthal (1935)

• Hyperandrogenism• Menstrual irregularity• Polycystic ovaries• Central adiposity

• Few of these original features are now considered consistent findings in PCOS

NATIONAL INSTITUTES OF HEALTH AND CHILD HEALTH AND HUMAN DEVELOPMENT(1990)

• Chronic anovulation• Hyperandrogenemia• Clinical signs of hyperandrogenism• Exclusion of other androgenic disorders

ROTTERDAM CRITERIA (2003)• 2 out of 3

• Polycystic ovaries (>12 peripheral follicles or increased ovarian volume >10cm3)

• Oligo- or anovulation• Clinical and/or biochemical signs of

hyperandrogenism• And exclusion of other etiologies such as

hypothyroidism, hyperprolactinemia, congenital adrenal hyperplasia, cushing syndrome, androgen secreting tumors

AE-PCOS SOCIETY 2006• Hyperandrogenism-hirsutism and/ or

hyperandrogenemia• And• Ovarian dysfunction-oligo-anovulation and/

or polycystic ovaries• Exclusion of other androgen excess or

related disorders

pathogenesis

Pituitary –ovarian –Adrenal Inter action

Abnormal Pituitary Function—Altered Negative Feedback Loop• Increased GnRH from hypothalamus• Excessive LH secretion relative to FSH

by pituitary gland• Ineffective suppression of the LH pulse

frequency by estradiol and progesterone

• LH stimulated excessive androgen production • Intraovarian androgen excess results in

excessive growth of small ovarian follicles• Inhibition of follicular maturation • Thecal and stromal hyperplasia

Pathogenesis: Hyperandrogenism• Reduced sex-hormone-binding globulin

(SHBG) more free testosterone• Insulin insensitivity• Lipid abnormalities• Abdominal obesity• Symptoms of androgen excess

HYPERANDROGENISM

• 50-90% patients have elevated serum androgen levels

• Causes hirsutism, acne, male pattern balding, alopecia

• Deepening voice, clitoromegaly

Insulin resistance in PCOS:

• Insulin resistance in PCOS is independent of obesity• Increased risk for impaired glucose tolerance and

type 2 DM in PCOS women • Obese women with PCOS tend to be more insulin

resistant than normal-weight counterparts. • 30-40% prevalence of glucose intolerance• 7-10% prevalence of type 2 DM in PCOS women• Insulin resistance worsens over time

ETIOLOGY OF INSULIN RESISTANCE

• Unknown largely.• Genetic link• Mutation of the insulin receptor gene in the

peripheral target tissues• Reduced tyrosine auto phosphorylation of the

insulin receptor.

Pathogenesis: Insulin resistance• Excess insulin production and insulin

resistance• Favors anovulation, reduced SHBG, IGF-1 BP

and androgen excess • Metabolic syndrome• Abdominal obesity

IR influencing Hypothalamic-Pituitary-Ovary Axis

Reference: Understanding polycystic ovary syndrome [Internet]. Available at: http://www.bpac.org.nz/BPJ/2008/April/polycystic.aspx. Accessed on May 06,2016.

Insulin Resistance: Associated Conditions

Insulin Resistance

Type 2 diabetes

Hypertension

Impaired Glucose tolerance

Obesity (central)

Polycystic ovary diseaseHyperuricemia

Acanthosis Nigricans

Decreased Fibrinolytic Activity

Dyslipidemia

Atherosclerosis

Clinical presentation

Reference: Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2014;6:1–3.

Clinical Presentation of Women with PCOS

Obesity

OBESITY AND INSULIN RESISTANCE• > 50 % patients with PCOS are obese• > 80% are hyperinsulinemic and have insulin

resistance• Hyperinsulinemia contributes to

hyperandrogenism & associated hirsutism and menstrual irregularities.

• Even 2/3 of lean PCOS (normal BMI) have excessive body fat and central adiposity

ASSOCIATED MEDICAL CONDITIONS

• Low HDL and high triglycerides• Sleep apnea• Nonalcoholic steatohepatitis• Metabolic syndrome—43% of PCOS patients (2

fold higher than age-matched population)• Elevated CRP and heart disease• Advanced atherosclerosis

MENSTRUAL DYSFUNCTION• Oligo or amenorrhea typically begins in the

peripubertal period• Reduction in ovulatory events leads to

deficient progesterone secretion• Chronic estrogen stimulation of the

endometrium with no progesterone results in intermittent breakthrough bleeding or DUB

• Increased risk for endometrial hyperplasia and/or endometrial CA

HIRSUTISM

Hair & sebaceous Follicle Response to Hyperandrogenism

Acne & baldness

Male Type Hair Growth

Ferriman Gallwey score Extent of terminal (coarse pigmented) hair growth at each of

the following 11 hormonally sensitive sites Upper lip Sideburn area Chin Jaw & Neck Upper back Lower back Chest Upper abdomen Lower abdomen Upper arms Thighs

Score of 6 or above used to define clinical hyperandrogenemia

Modified Ferriman Gallwey score9 areas• Score 1-4• 0-absence of terminal hair• 4-extensive terminal hair growth

>8 - hirsutism

Modified Ferriman Gallwey score

Acanthosis nigricans

Metabolic Syndrome• Personal or family history of DM• Obesity• Hyperinsulinemia• Hypertension• Atherogenic Dyslipidemia• Atherosclerosis• Hyperglycemia• The AACE have already included PCOS as an

important risk factor for diabetes and have recommended screening for DM by age 30 in all patients with PCOS.

Laboratory investigations

Hyperandrogenism

Laboratory features Elevated total testosterone

Most values in PCOS <150 ng/dl (if >200 ng/dl, consider ovarian or adrenal tumor)

Free testosterone assays not reliable yet Free androgen index > 4.5 (FAI= total testosterone x

100 /SHBG). Considered a better indicator

DHEA-S Most normal or slightly high in PCOS If >800 mcg/dl, consider adrenal tumor

LH/FSH ratio Levels vary over menstrual cycle, released in

pulsatile fashion, affected by OCPs LH/FSH ratio >2 has little diagnostic sensitivity

and need not be documented

Hyperinsulinemia• Fasting glucose level of 110-125 mg/dL

• Glucose level of 140-199 mg/dL after75 gm glucose challenge test

• Stimulated testing with OGTT may be more sensitive than fasting measurements

•  Fasting glucose/insulin ratio (G/I) . A ratio < 4.5 has in general been shown to be > 90% sensitive

ATP III Clinical Identification of the Metabolic Syndrome• Waist circumference:

• Women>88 cm (>35 in)• Triglycerides >150 mg/dL• HDL cholesterol: 

• Women<50 mg/dL

• Blood pressure 130/ 85 mm Hg• Fasting glucose >100 mg/dL

Presence of any 2 of 5 criteria

DIFFERENTIAL DIAGNOSIS1. Hyperprolactinemia/ hypothyroidism

• Prominent menstrual dysfunction• mild hyperandrogenism

2. Congenital Adrenal Hyperplasia• morning serum 17-hydroxyprogesterone

concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis

3. Ovarian and adrenal tumors• serum testosterone concentrations are always

higher than 150 ng/dL• adrenal tumors: serum DHEA-S concentrations

higher than 800 mcg/dL• LOW serum LH concentrations

4. Cushing’s syndrome5. Drugs: danazol; OCPs with high

androgenicity

Polycystic Ovaries - USG

Criteria by ultrasound Increased ovarian area (>5.5 cm2)

or volume (>11 ml) w/ presence of >12 follicles measuring 2-9 mm in diameter

Polycystic ovaries not specific for PCOS

> 20% normal women have incidental polycystic ovaries

Polycystic VS. Multicystic Ovaries• Polycystic ovaries

• Bilateral • At least 12 follicles• Follicular diameter

2 - 9 mm• Stroma increased

• Multicystic ovaries• Bilateral• Multiple cysts• Cyst diameter usually

> 10 mm• Stroma not increased

OVARIAN ABNORMALITIES• Thickened sclerotic

cortex• Multiple follicles in

peripheral location• 80% of women with

PCOS have classic cysts

PEARLY WHITE SMOOTH ENLARGED AND THICK WALLED OVARY ON LAPAROSCOPY

laparoscopy

Gross Appearance of Ovaries

• Polycystic ovaries are enlarged andhave a smooth thickened capsule that isAvascular• On cut section, subcapsular follicles in variousstages of atresia are seen in the peripheral partof the ovary• The most striking ovarian features of PCOS ishyperplasia of the theca stromal cells surrounding

arrested follicles

TREATMENT

ADOLESCENT PCOS• Immediate/Acute issues

• Hirsutism• obesity• Regulation of menses

• Long-term issues• Insulin resistance• Cardiovascular risk• Obstructive sleep apnea• Malignancy risk

Adolescent pcos - management

• Life style modification• Weight Reduction.• Diet management.• Hormone therapy

Diet and Exercise• In patients with PCOS who are obese, endocrine-

metabolic parameters markedly improve after 4-12 weeks of dietary restriction.

• Their SHBG levels rise and free testosterone levels fall by 2-fold.

• Serum insulin and IGF-1 levels also decrease.• Weight loss in patients with PCOS who are obese

is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women.

Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. Dec 3 2008;

Diet and Exercise• A moderate amount of daily exercise increases of levels

of IGF-1 binding protein and decreases IGF-1 levels by 20%.

• Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS.

• A daily 500-1000 calorie deficit with 150 minutes of exercise per week can cause ovulation.

• The AE-PCOS recommends lifestyle management as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications.

Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. Dec 3 2008;

Metformin• Metformin therapy is considered the initial

intervention in most women with PCOS, particularly in those who are overweight or obese.

• Metformin improves many metabolic abnormalities in PCOS and may improve menstrual cyclicity and the potential for pregnancy.

Metformin and hyperinsulinemia• This anti-diabetic drug improves insulin resistance and

decreases hyperinsulinemia in patients with PCOS.• Metformin also has a beneficial effect on metabolic

syndrome. • Decreases hepatic glucose production• Increases peripheral glucose uptake and utilization• Antilipolytic effect—reduces fatty acid concentrations

and reduces gluconeogenesis

Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. Oct 25 2003;327(7421):951-3. [Medline].

Metformin and Anovulation

• Patients have a high likelihood of having ovulatory cycles while taking metformin.

• will restore ovulation and menses in > 50% of patients

• In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation.

• N-acetylcysteine may also enhance the effect

METFORMIN DOSING• The usual starting dose is 500 mg given

orally twice a day.• Target—1500-1800 mg per day• Clinically significant responses not regularly

observed at doses less than 1000 mg per day• Sustained release formulations taken after

dinner have fewer side-effects.

Adverse effects• Diarrhea, nausea, vomiting, flatulence,

indigestion, abdominal discomfort• Caused by lactic acid in the bowel wall• Minimized by slow increase in dosage

• Lactic acidosis—rare• Avoid in CHF, renal insufficiency, sepsis• Discontinue for procedures using contrast (HSG)• Temporarily suspend for all surgical procedures

that involve fluid restriction

Oligomenorrhea• Combination estrogen-progestin pill first line

when fertility is not desired• Decrease in LH secretion and decrease in androgen

production• Increase in hepatic production of sex-hormone

binding globulin• Decreased bioavailablity of testosterone• Decreased adrenal androgen secretion• Regular withdrawal bleeds• Prevention of endometrial hyperplasia

Hormone therapy for Adolescent Patients• Combined OCPs containing estrogen and

Progesterone given cyclically help in controlling menstrual problem , hirsutism and acne

• Periodic progesterone withdrawal• Medroxyprogesterone 10 mg/day x 7-10 days

• Anti androgens• Mechanical hair removal

Plucking/shaving/electrolysis/laser

Pharmacological Profile of natural progesterone and synthetic progestrogens Drug Progestrongi

c activityAnti androgenic activity

Antimineralocorticoid activity

Glucocorticoid activity

Progesterone(Natural) + ( + ) + -Drosperinone + + + -Cyproterone Acetate

+ + - ( + )

Desogestrel + - - -Dienogest + + - -Gestodene + - ( + ) -Levonorgestrel + - - -Norgestimate + - - -

+ Effct (+) negligible

- No effct

Long-Term Issues• Cardiovascular Risk

• Increased prevalence of HTN• Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL)• Predisposition to macrovascular disease and

thrombosis• Multidisciplinary management

Long-Term Issues• Obstructive Sleep Apnea

• 30-fold increased risk of OSA, not explained by obesity alone.

• Insulin resistance strongest predictor of OSA (not BMI, age, testosterone)

• Consider polysomnography if at risk

Long-Term Issues• Risk for malignancy

• 3 fold increased risk endometrial carcinoma in PCOS

• Increased risk of ovarian and breast cancer

• Warrants regular screening

MESSAGE TO THE YOUNG GIRLSYoung girls should be advised to adopt healthy life style in the form of balanced diet having locally available food articles like all cereals, pulses, green leafy vegetables, seasonal fruits, fish, jaggery and dairy products in appropriate amount.They should avoid soft drinks, chocolates and junk food.

They should be advised to play out door games and do regular physical exercises like cycling, skipping, jogging, swimming etc.

This will go long way to prepare a girl to let her develop as a perfect adolescent with minimal menstrual dysfunction..

Infertility in pcos

PCOS & INFERTILITY

Reference: Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome.Clin Epidemiol. 2014;6:1–3.

Approx. 85–90% of women with oligomenorrhea have PCOS

>80% of women having symptoms of androgen

excess present with PCOS

Hirsutism occurs in up to 70% of women with PCOS

Infertility is seen in 40% of women with PCOS

Spontaneous abortion is seen more frequently in PCOS with incidences

ranging from 42–73%

Approx. 90–95% of anovulatory women reporting to infertility clinics have PCOS

Approx. 15–30% of adult women having PCOS manifest acne

30–40% of women with amenorrhea will have PCOS

PCOS

Ref : Hum Reprod 2004: 19

Ovulation

Fertilization

Implantation

Fetal Viability

Healthy Live born

Poor Oocyte Quality

?Effects gestationalDiabetes and hypertension

Endometrial Abnormality

Effects Hyperinsulinemia

PCOS and infertility

Treatment modalities

• Lifestyle Modifications • Insulin Sensitizing Agents • Clomiphene Citrate • Gonadotrophins • Laparoscopic Ovarian Drilling • Ovulation Induction and IUI • IVF

Consensus on infertility treatment related to PCOS

FIRST LINECLOMIPHENE CITRATE

SECOND LINELOD/GONADOTROPINS

THIRD LINEIVF

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March 2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008

RESISTANCE

RESISTANCE

FAILURE

INFERTILITY TREATMENT• Clomid

• 50 mg from cycle days 2-6 for 3 months• Incremental 50 mg every 3 months up to 150 mg.• Most women with PCOS do not respond to normal

dose—20% ovulation rate!• Clomid: 80% will ovulate, 50% will conceive• Combined metformin+clomiphene better

conception rate compared to clomiphene alone• FSH injections

Letrozole• Release the pituitary/hypothalamic axis from

the estrogenic negative feedback, increase Gnt secretion, stimulate ovarian follicle development

• Locally in the ovary: increase the follicular sensitivity to FSH

• Letrozole associated with fewer birth defects than clomiphene but this is not statistically significant.

Tulandi T. Fertil Steril 85:1761, 2006

GonadotrophinsChronic low-dose regimen• Starting dose: 37.5 IU • Duration of starting dose:14 d • The weekly dose increment of 37.5 IU till

ovulation followed by IUI.Overall ovulation induction (CC/ CC+ GN/chronic low dose regimen) with IUI results in singleton live birth with marked reduction of OHSS

Adjuvants

Surgical Management

• Should be used only as a method of induction of ovulation not for treatment of PCOS symptoms.

• Laparoscopic drilling using electrocautery or laser is universally accepted procedure now, aimed with the goal of creating focal areas of damage in the ovarian cortex and stroma.

• LOD is usually effective in 50% of women and additional ovulation induction may be required.

• Potential complications include formation of adhesions & long-term effects of tissue damage on ovarian function.

Surgical induction of ovulationWedge resection

by LTLOD

Publications 18 11

Patients 1766 729

Ovulation 74.6 84.2

Pregnancy 58.8 55.7

Adhesions Moderate to severe

Minimal to mild

From Urman and Yakin JRM 2006

IVF• Failure to conceive on Gonodotrophin therapy

alone/ IUI after 6 ovulatory cycles (Araki, 2011) • Associated male factor or tubal factor infertility • Failure of wt reduction, antiestrogen therapy or

LOD in long standing infertility & advanced age, Gnt may be omitted and replaced by ovarian stimulation and IVF (Eijkemans et al., 2005)

• High response to FSH despite low dose to prevent OHSS and to eliminate the chances of multiple pregnancy

Challenges of treating infertility with IVF in the PCOS patient• Propensity for an exaggerated ovarian response• Difficulties in titrating gonadotropin dose• Increased risk of cycle cancellation• Increased incidence of early and late OHSS• Increased risk of spontaneous pregnancy loss

PreIVF considerations• Weight loss in overweight women• Metformin• LOD• All these above measures increase IVF

outcome and reduces incidence of OHSS.

Cycle management in the PCOS patient• Antagonist protocol preferred• Careful titration of the gonadotropin dose• Measures to prevent OHSS

• GnRHa for triggering final oocyte maturation• Single Blast transfer • Cryopreservation of all embryos (segmentation of IVF)• Cabergoline

Conclusions• PCOS patient is the most difficult to treat

with IVF• Cycle cancellation rates and risk of OHSS are

higher• Fine tailoring of ovarian stimulation is

necessary to avoid complications• Treating physicians should be well aware of

the difficulties and remedies/solutions

Recommendations

ACOG 2009

The following recommendations and conclusions are based on good and consistent scientific evidence (Level A):

• An increase in exercise combined with dietary change has consistently been shown to reduce diabetes risk comparable to or better than medication.

• Improving insulin sensitivity with insulin-sensitizing agents is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance.

• The recommended first-line treatment for ovulation induction remains the antiestrogen clomiphene citrate.

The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B):

• Women with a diagnosis of polycystic ovary syndrome (PCOS) should be screened for impaired glucose tolerance with a fasting glucose level followed by a 2-hour glucose level after a 75-g glucose load.

• Women with PCOS should be screened for cardiovascular risk by determination of BMI, fasting lipid and lipoprotein levels, and metabolic syndrome risk factors.

• There may be an increase in pregnancy rates by adding clomiphene to metformin, particularly in obese women with PCOS.

• If clomiphene citrate use fails to result in pregnancy, the recommended second-line intervention is either exogenous gonadotropins or laparoscopic ovarian surgery.

The following recommendations and conclusions are based primarily on consensus and expert opinion (Level C):

• Combination low-dose hormonal contraceptives are most frequently used for long-term management though no evidence favors the same.

• A chronic low-dose step up gonadotropin regimen is still recommended in women with PCOS though better protocols are available now a days.

• There is no clear primary treatment for hirsutism in PCOS though anti androgens and or laser may be helpful.

Conclusions• The comprehensive management of PCOS

requires:• A patient-centered approach• Significant time dedicated to thorough education and

counseling• Prudent use of referrals and local resources to tackle

metabolic syndrome.• Remaining up-to-date on newest advances in the

literature.• Improvement in health of the PCOS woman in pregnancy

could help “prevent” disease in the next generation

Thank you