PCOS

Polycystic Ovarian Syndrome

Prof. M.C. Banal.

Founder Principal & Controller;

Jhalawar Medical College and Hospital , Jhalawar.

Ex Principal& Controller ;

Mahatma Gandhi Medical College And Hospital,

Sitapura, Jaipur.

Dr, Khusboo Saxena. PG (st) NIMS Medical College

Jaipur.

INTRODUCTION

• Most common cause of infertility in women

• Classic syndrome originally described by Stein and Levanthal

• Hyperandrogenism• Menstrual irregularity• Polycystic ovaries• Central adiposity

• Syndrome, not a disease—multiple potential etiologies with variable clinical expression

History

• Originally described by Stein and Leventhal in 1935, first known as the “Stein-Leventhal syndrome”

• 7 women with amenorrhea, hirsutism, and obesity, found to have a polycystic appearance to their ovaries.

PCOS

Syndrome characterized by

• Oligoammenorhoea / amenorrhoea

Laboratory criteria of

• Hyperandrogenemia

• Hyperinsulinemia

Diagnostic criteria based on the modified consensus of National Institutes of Health and Child Health and

Human Development.

• Major

– Chronic anovulation

– Hyperandrogenemia

– Clinical signs of hyperandrogenism

– Other etiologies excluded

• Minor

–   Insulin resistance

– Perimenarchal onset of hirsutism and obesity

– Elevated LH : FSH ratio

– Intermittent anovulation associated with hyperandrogenemia (free testosterone, DHEAS).

Rotterdam criteria

•2 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

Pituitary –ovarian –Adrenal Inter action

PATHOGENESIS

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

pituitary gland• LH stimulates ovarian thecal cells-- androgen

production • Ineffective suppression of the LH pulse

frequency by estradiol and progesterone• Androgen excess increases LH by blocking the

hypothalamic inhibitory feedback of progesterone

Abnormal steroidogenenesis

• Intraovarian androgen excess results in excessive growth of small ovarian follicles

• Follicular maturation is inhibited

• Excess androgen causes thecal and stromal hyperplasia

HYPERANDROGENISM

• Hirsutism, acne, male pattern balding, alopecia

• 50-90% patients have elevated serum androgen levels

• Free testosterone levels most sensitive

• Rare: increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm)

Pathogenesis: Hyperandrogenism

• Symptoms of androgen excess

• Reduced sex-hormone-binding globulin (SHBG) more free testosterone

• Insulin insensitivity

• Lipid abnormalities

• Abdominal obesity

Origin and sequelae of abnormal neuroendocrine function in PCOS

PCOS Women

Persistent rapid LH dysfunction (1LH pulse/hour)Persistent rapid LH dysfunction (1LH pulse/hour)

↑ ↑ LH & LH : FSH ratioLH & LH : FSH ratio ↓ ↓ FSHFSH

↑ ↑ ovarian androgensovarian androgens Impaired follicular developmentImpaired follicular development

Impaired hypothalamicImpaired hypothalamicProgesterone sensitivityProgesterone sensitivity

Impaired Progesterone Impaired Progesterone productionproduction

Source : Blank SK et al Hum Reprod updare 2006 Jul - AugSource : Blank SK et al Hum Reprod updare 2006 Jul - Aug

Insulin resistance in PCOS:

• Insulin resistance in PCOS is independent of obesity– Obese women with PCOS tend to be more insulin resistant

than normal-weight counterparts.– Obesity is an independent risk factor for glucose intolerance

or DM in PCOS

• 3-fold increased incidence of metabolic syndrome in PCOS, vs general population, independent of obesity.

• Insulin resistance ≠ glucose intolerance– Many insulin resistant PCOS pts have normal glucose

tolerance– 30-40% prevalence of glucose intolerance in PCOS women– 7-10% prevalence of type 2 DM in PCOS women– Insulin resistance worsens over time– Increased risk for impaired glucose tolerance and type 2 DM

ETIOLOGY OF INSULIN RESISTTANCE

• Unknown largely.

• Mutation of the insulin receptor gene in the peripheral target tissues

• Reduced tyrosine auto phosphorylation of the insulin receptor.

Pathogenesis: Insulin resistance

• Favors anovulation, androgen excess, reduced SHBG

• Metabolic syndrome

• Abdominal obesity

HYPERINSULINEMIA

• Excess insulin production and insulin resistance

• Genetic link

Genetic Predisposition

Aging

Pregnancy

Drugs

Lifestyle

Insulin ResistanceInsulin Resistance

HyperinsulinemiaHyperinsulinemia

Altered Fat MetabolismAltered Fat Metabolism

Altered Steroid Hormone MetabolismAltered Steroid Hormone Metabolism

PCOS: Acne, hirsutism, hyperandrogenism infertility

PCOS: Acne, hirsutism, hyperandrogenism infertility

Adapted from Cristello F et al, Gynecological Endocrinology, 2005.

Android Obesity

Android Obesity

↑ Lipid Storage↑ Lipid Storage

Insulin Resistance: Associated Conditions

Insulin Resistance Insulin Resistance

Type 2 diabetesType 2 diabetes

Hypertension Hypertension

Impaired Glucose Impaired Glucose tolerancetolerance

Obesity (central)Obesity (central)

Polycystic ovary Polycystic ovary diseasediseaseHyperuricemiaHyperuricemia

Acanthosis Acanthosis Nigricans Nigricans

Decreased Decreased Fibrinolytic Fibrinolytic Activity Activity

DyslipidemiaDyslipidemia

AtherosclerosisAtherosclerosis

Elevated AndrogensElevated Androgens

PancreasPancreasPancreasPancreas

Insulin Receptor DysfunctionInsulin Receptor Dysfunction

HyperinsulinaemiaHyperinsulinaemia

LiverLiverLiverLiver

LHRHLHRH

HypothalamusHypothalamusHypothalamusHypothalamus

PituitaryPituitaryPituitaryPituitary

AdrenalAdrenalAdrenalAdrenal StromaStromaStromaStroma FollicleFollicleFollicleFollicle

LH LH FSHFSH

Elevated DHEASElevated DHEASReduced SHBGReduced SHBG

Free androgens Free androgens

Hyperinsulinaemia & Hyperandrogenaemia

Clinical Presentation of Women with PCOS

Adolescent Period

Reproductive Period

Menopausal

Menstrual IrregularityCosmetic concerns

Acne Hirsutism Hair Loss

Infertility Early Pregnancy loss During pregnancy

PIH GDM

Metabolic Syndrome Ca Endometrium

ObesityObesity

MENSTRUAL DYSFUNCTION

• Oligo or amenorrhea– Menstrual irregularity typically begins in the

peripubertal period– Delayed menarche

• Reduction in ovulatory events leads to deficient progesterone secretion

• Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding

• Increased risk for endometrial hyperplasia and/or endometrial CA

OBESITY

• Prevalence of obesity varies from 30-75%

• 2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity

• Obese patients can be hirsute and/or have menstrual irregularities without having PCOS

Apple Shape Pear Shape

OBESITY AND INSULIN RESISTANCE• ½ patients with PCOS are obese

• > 80% are hyperinsulinemic and have insulin resistance (independent of obesity)

• Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver

ASSOCIATED MEDICAL CONDITIONS

• Increased risk of developing Type 2 Diabetes and Gestational diabetes

• 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

Hair & sebaceous Follicle Response to Hyperandrogenism

HIRSUTISM

Hirshutism

Male Type Hair Growth on Abdomen-PCOS

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

the following 11 hormonally sensitive sitesUpper lipSideburn areaChin Jaw & NeckUpper backLower backUpper armsThighsChestUpper abdomenLower abdomen

Score of 6 or above used to define clinical hyperandrogenemia

Modified Ferriman Gallwey score

9 areas

• Score 1-4

• 0-absence of terminal hair

• 4-extensive terminal hair growth

>8 - hirsutism

Modified Ferriman Gallwey score

Ref : Hum Reprod 2004: 19Ref : 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 infertilityPCOS and infertility

PCOS & Metabolic SyndromeMetabolic Syndrome:

• Cluster of Cardiovascular risk factors related to Insulin Resistance:- Obesity- Hyperinsulinemia- Hypertension- Atherogenic Dyslipidemia- Atherosclerosis- Hyperglycemia

• Major Risk Factors:- Physical inactivity- Atherogenic diet- Adiposity / abdominal obesity

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 >110 mg/dL*

•New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome•Presence of any 2 of 5 criterias required

Gross Appearance of Ovaries

• Polycystic ovaries are enlarged and

have a smooth thickened capsule that is

avascular

• On cut section, subcapsular follicles in various

stages of atresia are seen in the peripheral part

of the ovary

• The most striking ovarian features of PCOS is

hyperplasia of the theca stromal cells surrounding arrested follicles

• Microscopically luteinizing theca cells are seen

DIAGNOSTIC CRITERIA

AND

CLINICAL MANIFESTATIONS

Diagnosis

1. 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

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

Diagnosis

2. Oligoovulation or anovulation Oligomenorrhea or amenorrhea Dysfunctional uterine bleeding Infertility

30-50% 1st trimester miscarriage rate

3-fold increased risk endometrial carcinoma

Diagnosis

3. Polycystic Ovaries 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

Ultrasonic Criteria of PCOUltrasonic Criteria of PCO

• At least one of the following – 12 or more follicles measuring 2–9 mm in diameter– increased ovarian volume (>10 cm3).

• If there is a follicle >10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume

• The presence of a single PCO is sufficient for diagnosis

• The distribution of follicles and a description of the stroma (volume & echogenicity) are not required for diagnosis

USG IMAGE OF PCOS

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 LAPROSCOPY

( PCOS)

INFERTILITY

• Intermittent ovulation or anovulation

• Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomiphene citrate

Diagnosis

4. Absence of other disorders to account for these symptoms.

Pregnancy pregnancy test Hypothyroidism TSH Hyperprolactinemia prolactin Late onset congenital adrenal hyperplasia 17-

hydroxyprogesterone (r/o if <200 ng/dl) Ovarian tumor total testosterone (esp if >200

ng/dl)– Adrenal tumor DHEA-S (esp if > 800 mcg/dl)– Cushing’s syndrome salivary cortisol, 24 hr

urine cortisol

Diagnosis5. Supportive of insulin resistance

“Syndrome XX”: 3 or more of the following criteria:• Waist circumference > 88 cm• Triglycerides > 150 mg/dl• HDL <50 mg/dl• BP > 130/85• Fasting glucose >110 mg/dl

ACOG and ADA suggest screening all women w/ PCOS for glucose intolerance, type 2 DM.

Oral glucose tolerance test more sensitive than fasting glucose.

Personal or family history of DM Acanthosis nigricans

Acanthosis Nigrans

Acne & Hirsutism

DIFFERENTIAL DIAGNOSIS

1. Hyperprolactinemia– Prominent menstrual dysfunction

– Little hyperandrogenism

2. Congenital Adrenal Hyperplasia– morning serum 17-hydroxyprogesterone

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

– confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL

Androgens Level---

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 syndrome

5. Drugs: danazol; OCPs with high androgenicity

TESTING

• Serum HCG

• Serum prolactin

• Thyroid panel

• FSH: r/o ovarian failure

• Serum luteinizing hormone (LH)—elevated

• Serum estradiol—normal

• Serum estrone—elevated

TESTING• Fasting glucose: elevated -->110mg / dl

• 2 hour OGTT: elevated ---140-199mg/dl

• Ratio of fasting glucose(mmol/L) To fasting insulin (mu/ L ) -- < 4.5 .

• Fasting insulin: elevated

• Free testosterone: elevated

• DHEA-S: normal

• 17-hydroxyprogesterone: normal

• Pelvic US

• Lipids

TREATMENT

Women with PCOD (adolescent / unmarried)

1.The Report with---

• Menstrual problem.

• Acne .

• Obesity.

• Hersutism.

2. Their treatment—

*Modification in life style .

* Weight Reduction.

* Diet management.

* Hormone therapy

Management

– Immediate/Acute issues– Hirsutism

– Regulation of menses

– Fertility issues

– Long-term issues– Insulin resistance

– Cardiovascular risk

– Obstructive sleep apnea

– Malignancy risk

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 Androgen Excess and Polycystic Ovary Syndrome Society 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• This anti-diabetic drug improves insulin resistance and decreases

hyperinsulinemia in patients with PCOS.

• Metformin also has a small but beneficial effect on metabolic syndrome. Ascertain that kidney and liver function are normal and that the patient does not have advanced congestive heart failure before starting metformin.

• The usual starting dose is 500 mg given orally twice a day.

• Inform patients that they have a high likelihood of having ovulatory cycles while taking metformin.

• The US Food and Drug Administration has not approved metformin for this indication; therefore, this use is off label

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– will restore ovulation and menses in > 50%

of patients– Treat with cyclic progestin to reduce

endometrial hyperplasia if regular menses not attained

• 10 mg for 7 to 10 days every two to four months

METFORMIN

• Decreases hepatic glucose production

• Reduces need for insulin secretion

• Improves insulin sensitivity (increases peripheral glucose uptake and utilization)

• Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis

Metformin and Anovulation

• Evidence suggests that metformin frequently—but not universally—improves ovulation rates in women with PCOS.

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

• Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-course metformin remains uncertain.

• N-acetylcysteine may also enhance the effect of clomiphene.

METFORMIN DOSING

• Target—1500-2550 mg per day

• Clinically significant responses not regularly observed at doses less than 1000 mg per day

• Extended release formulations—fewer side-effects. Entire dose should be given with dinner

Guidelines: Metformin

• Consideration of metformin therapy as 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.

• Of note, metformin has not been approved by the US Food and Drug Administration for use in PCOS, although abundant medical literature supports its efficacy.

SIDE 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 (withhold X 48 hours)

– Temporarily suspend for all surgical procedures that involve fluid restriction

– Cimetidine causes increased metformin levels

Hormone therapy for Adolescent Patients• Combined OCPs containing ---estrogen and Progesterone given

cyclically help in controlling menstrual problem , hirsutism, acne, and extra weight.

• Estrogen salt used is- --- Ethinylestradiol in the dose 0f 20/ 30 ug / day.

• Progeserones used are of many types and they have variable effect on Acne, weight , hirsutism, and menstrual with drawl bleeding also and have variable adverse side effect; to be considered when prescribing OCPs.

Pharmacological Profile of natural progesterone and other synthetic progestrogens Drug Progestrongic

activityAnti androgenic activity

Antimenraocorticoid activity

Glucocorticoid activity

Progestrone( Nat Ural + ( + ) + -

Drosperinone + + + -

Cyproteron Acetate

+ + - ( + )

Desogestrel + - - -

Dienogest + + - -

Gestodene + - ( + ) -

Levonorgestrel + - - -

Norgestimate + - - -

+ Effct (+) negligible - No effct

Advantages of Drospirenone over other Progesterogens 1. Counter acts water retension due to its anti mineralocorticoid activity.

2. 78% patient loose weight or remained same ( 105 lost >1kg , 24% lost < 1kg , 44% wt did not change.

3. Nearly half of Patients having skin Problem as acne / Hirsuitism or both report improvement ( 74%). It is due to its antiandrogenic activity.

4. women having Premenstrual symptoms also have significant relief. Source—Gynaecology -2002 Vol 7 No 1: 23-26

Management:

Control of hirsutism Medical (need a trial of 6-12 months before deemed

ineffective)– Decrease testosterone production (predominantly from ovary)

» OCPs (improvement scores 33%) -Increase SHBG» Lifestyle modification/weight loss» Metformin (improvement scores 10-13%)» Glucocorticoids? -Theory: ACTH stimulates adrenal androgen synthesis. So,

suppress ACTH via glucocorticoids. -Study by Vanky, et al- dexamethasone 0.25 mg/day vs placebo

—reduction in testosterone, androstenedione, DHEA-S by 25-50%. No significant change in BMI, glucose, insulin, lipids

-problematic

Management:

Control of hirsutism (cont’d)• Decrease testosterone action

– Antiandrogens

» Spironolactone (start 50 mg bid 100 mg bid)

-Reduction in hirsutism 45%

-Preferred use w/ OCPs, 75% response

» Drospirenone (analogue of spironolactone, approved in Yasmin)

» 5α-reductase inhibitors (ex. Finasteride)

– Lifestyle modification/weight loss

– Metformin

Management:

Control of hirsutism • Mechanical

– Plucking/shaving/electrolysis/laser

– Vaniqa cream (eflornithine hydrochloride 13.9%)

» Mechanism: slows growth of hair by inhibiting L-ornithine decarboxylase (enzyme involved in hair growth)

» 58% demonstrated some improvement in hair growth vs 32% with placebo

» Hair growth rates return to normal 8 wks off therapy

» Not covered by most insurance policies

Hirsutism

• Mechanical hair removal

• Vaniqa (eflornithine hydrochloride)

• OCPs with minimal androgenicity

• OCP plus antiandrogen (spironolactone)

• Spironolactone, 50-200 mg per day

• Flutamide– Potential hepatic dysfunction

Hirsutism

• Spironolactone:

– Antiandrogens, such as spironolactone, are effective for hirsutism.

– Spironolactone 50-100 mg twice daily is an effective primary therapy for hirsutism.

– Because of the potential teratogenic effects of spironolactone, patients require an effective form of contraception (eg, an oral contraceptive).

– Adverse effects of spironolactone include GI discomfort, and irregular menstrual bleeding (which can be managed by adding an oral contraceptive).

Management:

• Regulation of menses• Oral contraceptives

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

every 3 months (approx 4 menses annually)

• Lifestyle modification/weight loss

• Metformin- ie., hitting the “root cause”– 500-1000 mg bid, 6 month trial reasonable for

improvement of menses

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

Management:

• Fertility issues– Lifestyle modification/weight loss

• Loss of >5% body wt, calorie-restricted diet, and exercise associated with improvement in spontaneous pregnancy rates (7.5-15% improvement)

– Clomiphene citrate– Most women with PCOS do not respond to normal dose—

20% ovulation rate!

Management

• Fertility issues (cont’d)– Metformin

– OR 3.88 in achieving fertility (compared to placebo), 4.4 (for metformin+clomiphene compared to clomiphene alone)

– Improved outcomes with in vitro fertilization (reduced risk of ovarian hyperstimulation when treated with FSH)

– Reduction in 1st trimester spontaneous abortions

– Thiazolidinediones• Early studies w/ rosiglitazone prior to

conception 30% improvement in fertility rates.

TREATMENT—no fertility desired

• Monophasic antiandrogenic OCP– ON 1/35 (norethindrone)– Orthocyclen (norgestimate)– Desogen or Orthocept (desogestrel)– Yasmin

INFERTILITY TREATMENT

• Metformin– 500 mg daily– Increase by 500 mg each week until:

• Normal menses

• Reached max dose

• Side-effects

• Clomid– 50 mg days 3-7 for 3 months– 100 mg days 3-7 for 3 months

Infertility

• Weight loss—reduction in serum testosterone concentration and resumption of ovulation

• Clomid: 80% will ovulate, 50% will conceive• Metformin: when added to clomid, improves

ovulatory rates • FSH injections• Laparoscopic surgery: wedge resections,

laparoscopic ovarian laser electrocautery• IVF

Clomid Challenge Test

• Day 3 FSH and estradiol levels

• 100 mg of Clomid on cycle days 5-9

• Day 10 FSH levels

• The test is abnormal if either the day 3 or day 10 FSH values are elevated (greater than 10) or if the day 3 estradiol is greater than 80

Surgical Management• Aimed mainly at restoring ovulation.

• Ovarian wedge resection: This procedure has fallen out of favor because of postoperative adhesion formation and the introduction of ovulation-inducing medications.

• Laparoscopic surgery: 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.

– Potential complications include formation of adhesions and ovarian atrophy.

– Multiple pregnancy rates are lower with ovarian drilling than with gonadotrophin treatment (1% versus 16%), but there are ongoing concerns about the long-term effects on ovarian function.28

LAPROSCOPIC DRILLING OF OVARY (IN PCOD)

Management:Long-Term Issues• Insulin resistance

– Metformin• Function

– Lowers hepatic glucose production by reducing gluconeogenesis

– Increases peripheral glucose uptake by skeletal muscle and adipose tissue

– Reduces intestinal glucose absorption

• Outcomes– Estimated 31% reduction in development of type II DM

over mean period 3 years

– Taken during pregnancy, reduction in gestational diabetes and major fetal complications

Management:Long-Term Issues• Insulin resistance

– Thiazolidinediones• Function

– Selective ligands of the nuclear transcription PPARγ, expressed in adipose tissue, pancreatic beta cells, vascular endothelium, macrophages, HPO axis.

– “fatty acid steal” hypothesis» Promote fatty acid uptake and storage in adipose

tissue, sparing other tissues (muscle, liver) from harmful metabolic effects of free fatty acids (high levels in PCOS)

– Increased expression of adiponectin (adipocytokine with an insulin sensitivity effect)

– Decreased expression of 11β-hydroxysteroid dehydrogenase type 1 (enzyme converts inactive cortisone to active cortisol)

• Outcomes

Management:Long-Term Issues

• Cardiovascular Risk

– Increased prevalence of HTN

– Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL)

– Predisposition to macrovascular disease and thrombosis

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

Management:Long-Term Issues

• Risk for malignancy– 3 fold increased risk endometrial

carcinoma in PCOS– Increased risk of ovarian and breast

cancer– Warrants regular screening, low threshold

for endometrial biopsy

Other issuesRole of epilepsy?

– Increased incidence of reproductive disorders in patients with epilepsy

– Pts on valproic acid may have higher levels of insulin, testosterone, and TG

New things on the horizon…

• Somatostatin analogs– Function

• Blunts LH response to GnRH• Decreases GH secretion by pituitary• Inhibits pancreatic insulin release

– Outcomes: limited studies• 7 d administration octreotide in PCOS women

decreased fasting and glucose-stimulated insulin levels• Reduced LH, androgen, IGF-1 levels• Short half-life (80-110 min) requiring multiple injections• Extended release octreotide (octreotide-LAR)- inject IM

Q28 days- results in improvement in GH, insulin, IGF-1, hirsutism

• Not approved yet

RCOG

Guidelines

(May 2003)

Evidence based guidelines for reduction of long-term PCOS consequences

Guidelines (RCOG, May 2003)• Patients presenting with PCOS particularly if they are

obese, should be offered measurement of fasting blood glucose and urine analysis for glycosuria. Abnormal results should be investigated by a glucose tolerance test.

• Such patients are at increased risk of developing type II

diabetes

• Women who have been diagnosed as having PCOS before pregnancy (eg those requiring ovulation induction for conception) should be screened for gestational diabetes in early pregnancy, with referral to a specialized obstetric diabetic service if abnormalities are detected

Guidelines (RCOG, May 2003)

• Measurement of fasting cholesterol, lipids and triglycerides should be offered to patients with PCOS, since early detection of abnormal levels might encourage improvement in diet and exercise.

• Olig- and amenorrhoeic women with PCOS may develop endometrial hyperplasia and later carcinoma. It is good practice to recommend treatment with progestogens to induce withdrawal bleed at least every 3-4 months.

• 4-

Guidelines (RCOG, May 2003)• A body of evidence has accumulated demonstrating

safety and in some studies efficacy of insulin-sensitizing agents in the management of short-term complications of PCOS, particularly anovulation.

• Long-term use of these agents for avoidance of metabolic complications of PCOS can not as yet be recommended .

• No clear consensus has yet emerged concerned regular screening of women with PCOS for later development of diabetes and dyslipidemia but obese women with a strong family history of cardiac disease or diabetes should be assessed regularly.

• 6-

Guidelines (RCOG, May 2003)

• Young women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated with their condition.

• They should be advised regarding weight and exercise.

AACE POSITION STATEMENT2005

Guidelines-2005

• Well-defined published data indicate a high risk for development of T2DM and CVD in women with PCOS.

• In view of the lack of protective effect of female sex on CVD risk in patients with diabetes, the associated risks of CVD are magnified in women with diabetes who have PCOS.

• Clearly, this situation means that PCOS is a general health disorder of young women, with potential for reversal of some of the associated risk with early diagnosis and treatment.

Guidelines-2005

• Lifestyle modification with weight loss and exercise, avoidance of tobacco, correction of lipid abnormalities, and use of metformin may be of value.

• Metformin therapy not only reduces hyperinsulinism and improves steroidogenic dysfunction but also is helpful in achieving better regularity of menses and fertility potential.

 • Thiazolidinediones have also been shown to decrease

androgen levels, improve ovulation, and reduce progression to overt T2DM in patients with PCOS and IGT.

Guidelines-2005

• Early recognition of the syndrome.

• Lifestyle modification, with emphasis on the need for controlled eating patterns and regular aerobic exercise.

• Encouragement should be offered by an empathic physician, who will monitor the patient carefully during the course of treatment.

• Measurement of glucose (and possibly insulin levels). An oral glucose challenge may be considered, particularly in obese women with PCOS and those with a family history of T2DM.

Guidelines: Lipids and BP

• Detection and treatment of lipid abnormalities, with dietary measures first and then use of appropriate medications, such as a statin, fibrate, niacin, or ezetimibe (or some combination of these agents), as necessary.

• Careful attention to and treatment of blood pressure abnormalities.

• Measurement of atherogenic markers (C-reactive protein [CRP], fibrinogen, and possibly homocysteine).

Guidelines: OC and Anti-Androgen

• The use of a nonandrogenic oral contraceptive agent and an antiandrogen such as spironolactone for the skin manifestations of PCOS.

• The presence of hair thinning requires the maximal dose of spironolactone in conjunction with an oral contraceptive agent.

• Ancillary use of electrolysis and laser therapy may also be helpful.

Guidelines: TZD

• The use of these agents to improve hyperandrogenism and ovulation is considered only investigational at this time.

• Thiazolidinediones are category C drugs; their use is contraindicated during pregnancy.

RECOMMENDATIONS

ACOG 2009

Grades of Recommendations

• A- Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)

• B- Requires the availability of well controlled clinical studies but no randomized clinical trials on the topic of recommendations (Evidence levels IIa, IIb, III)

• C- Requires evidence obtained from expert committee reports or opinions and/ or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV)

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 addition of eflornithine to laser treatment is superior in the treatment of hirsutism than laser alone.

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 type 2 diabetes and 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 body mass index (BMI), fasting lipid and lipoprotein levels, and metabolic syndrome risk factors.

• Reduction in body weight has been associated with improved pregnancy rates and decreased hirsutism, as well as improvements in glucose tolerance and lipid levels.

• 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 and are recommended as the primary treatment of menstrual disorders.

• Women in groups at higher risk for nonclassical congenital adrenal hyperplasia and a suspected diagnosis of PCOS should be screened to assess the 17- hydroxyprogesterone value.

• A low-dose regimen is recommended when using gonadotropins in women with PCOS.

• There is no clear primary treatment for hirsutism in PCOS.

Doctor’s MESSAGE TO THE YOUNG GIRLS

During early school age , at the time of health education girls should be advised to adopt healthy life style in the form of balanced diet having locally available food articles like all cereals, pulses, beans, green leafy vegetables, seasonal fruits , jaggery and dairy products in appropriate amount.

Monotonous diet should be avoided as it will cause nutritional deficiencies.

Under the effect of advertisement in TV and print media , they should avoid to become crazy to soft cold drinks, chocolates and junk food.

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

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