PCOS is the most common endocrinopathyin women and is the most common causeof androgen excess, affecting about 5% ofreproductive aged women. Althoughandrogen excess in women has beenrecognized since the time of Hippocratesand had been described in associationwith diabetes in the nineteenth century
PCOS was first identified by Stein and Leventhal in 1935 so that it can alsobe known as Stein – Leventhal Syndrome.
Most common cause of infertility in women Classic syndrome originally described by Stein and LevanthalHyperandrogenism Menstrual irregularity Polycystic ovaries Central adiposity Syndrome, not a disease—multiple potential etiologies with variable clinicalexpression
Pathophysiology of Polycystic Ovary Syndrome PCOS is a complex, heterogeneous disorder. It is likely genetic, environmental factors contribute to its pathophysiology, and that no single gene mutation will be found that is both necessary and sufficient to cause PCOS. The familial clustering that occurs in PCOS is consistent with a genetic susceptibility.
About 50% of sisters of PCOS probands have hyperandrogenemia with or withoutanovulation, which suggests an autosomaldominant inheritance for a factorpredisposing to ovarian hyperandrogenism
The etiology of anovulation in PCOS is often explained by high intraovarian androgen levels which induce atresia and prevent the emergence of a dominant follicle
The ovarian hyperandrogenism is a result ofincreased activity throughout the thecal cellsteroid production pathwayThe ovarian hyperandrogenism of PCOS isgonadotropin dependent, and gonadotropinsuppression with sex steroid or GnRHa results innormal androgen levels . It has been reportedthat 75% of women with clinical evidence ofPCOS have an elevated LH level and 94% havean increased LH/FSH ratio . These gonadotropinsecretory abnormalities have been thought toplay an important role in the development of theovarian hyperandrogenism characteristic ofPCOS
GnRH hypothalamus LH pituitary Androgens block X inhibitory effect of progesterone ovaryandrogens
US 25% of normal ovulating women would have polycystic-appearing ovariesOvaries will have a typical appearance of enlarged subcapsular small follicles(<10 mm )The ovarian volume in women with PCOS is >10 cm3 &the normal range is 4.7 -5.2 cm3
Anatomic Features of the Polycystic OvaryTube Uterus Polycystic Cystic Ovaries Follicles
The association between increased insulin resistance & PCO is well recognized. Acanthosis nigricans in hyperandrogenic women is dependent upon the presence & severity of hyperinsulinemia. There are several mechanisms for the state of insulin resistance: peripheral target tissue resistance, decrease hepatic clearance or increased pancreatic sensitivity.
Acanthosis Nigricans• Velvety plaqueson nape of neck and intertriginous areas• Epidermal hyperkeratosis• Associated with insulinresistance
Insulin resistance leads to compensatory hyperinsulinemia to the target tissues of insulin action, that become resistant to insulin, the ovaries remain responsive to insulin throughout the interaction with its own receptors. Excess insulin participate in increased ovarian androgen syntheses (androsteindione & testosterone)
Hyperinsulinemia leads to inhibition of hepatic syntheses of SHBG & inhibition of hepatic production of IGF-1 binding protein. In vitro studies indicate that both insulin & IGF-1 directly inhibit SHBG secretion by human hepatoma cells.
o Menstrual abnormalities 80%o Infertility ―anovulation‖o Hirsutism 60%, acne 70%, alopleciao Increased risk of atherosclerosis & cardiovascular events.o Increased risk of diabetes mellitus in patients with hyperinsulinemia.
o Increased risk of endomentreal cancer & ? Breast cancero Hyperlipidemia with its impact on atherosclerotic changes.o Hypertension observed later in lifeo Obesity 40% with health risks including saphenous varicosities, hemorrhoids, hernias & osteoarthritis.o Several mental health problems, depression, anxiety..etc
Major criteria Minor criteria Anovulation Polycystic ovaries on Oligominorrhea ultrasound Hyperandrogenemia Elevated LH:FSH Severe hirsutism Acne Insulin resistance Mild hirsutism Obesity
Rotterdam Criteria (2 out of 3) Menstrual irregularity due to anovulation oligo- •ovulationEvidence of clinical or biochemical •hyperandrogenismPolycystic ovaries by US •presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increasedovarian volume
The differential diagnosis of hirsutism & oligomenorrha includes: - congenital adrenal hyperplasia - cushing syndrome - hyperthecosis ovarii - benign & malignant androgen secreting tumors or ovaries. • - Hyperprolactinemia Prominent menstrual dysfunction • Little hyperandrogenism . • - Drugs: danazol; OCPs with •androgenicity
o History & physical examinationo CD3: LH:FSH, E2, testosterone, androstendione, SHBG, 17-OHp, DHEAS, prolactin, TSH, T3, T4 & fasting insulin level.o FBS, total cholesterol, LDL & HDL.o Pelvic ultrasound scan for the ovarian features of PCOo Specific imaging procedures to exclude adrenal tumors if presentation is rapid.
Treatment of Polycystic Ovary Syndrome As PCOS is found in a large proportion of the femalepopulation, treatment is only required for the patientssymptoms.1- AmenorrhoeaEither induce ovulation which will result in regularmenstruation (see below), or protect the endometriumagainst the effects of unopposed oestrogen stimulation by:• using the oral contraceptive pill which will result inregular menses• giving progestogens three or four times per year to induceendometrial shedding.
If a patient has been anovulatory for morethan a year, an endometrial biopsy isrecommended before instituting therapy. Theoral contraceptive pill (OCP) is an excellentchoice, as it both inhibits endometrialproliferation and reduces ovarian androgenproduction, thus ameliorating theconsequences of hyperandrogenismInsulin-sensitizing drugs may also decreasethe risk of endometrial cancer in PCOS bylowering insulin levels and increasing thefrequency of ovulation
Combination estrogen-progestin pill first line when fertility is not desiredDecrease in LH secretion and decrease in •androgen productionIncrease in hepatic production of sex-hormone •binding globulinDecreased bioavailablity of testosterone •Decreased adrenal androgen secretion •Regular withdrawal bleeds •Prevention of endometrial hyperplasia •
2-ObesityWeight reduction has many benefits for the patient butusually proves very difficult. Once considerably overweight,patients become less active and their basal metabolic rate(BMR) is reduced, thus they require less calories tomaintain their body weight. The resulting frustration for themcan mean they become very disheartened with attempts tolose weight - a full explanation before commencing a weightloss programme may avert this problem
The aim of medical therapy is to suppressandrogen production, block androgenreceptors or decrease the conversion oftestosterone to dihydrotestosterone byinhibition of the enzyme 5a-reductase
Oral Contraceptive Pills - OCPs have commonlybeen used to treat patients with hirsutism andother signs of androgen excess. Theprogestational component of the OCP inhibitspituitary secretion of LH, which in turn decreasesovarian androgen production. Progestins alsodecrease adrenal DHAS production, possibly via anegative feedback loop through the glucocorticoidreceptor . In addition, the estrogen component oforal contraceptive pills increases production ofSHBG thus decreasing the amount of freetestosterone available . All formulations of lowdose (≤ 0.35mg ethinyl estradiol) oralcontraceptive pills available today,
Androgen Receptor Antagonists – cyproterone acetate was the first androgenreceptor antagonist to be used clinically and isstill widely used in Europe . It is a competitiveinhibitor of testosterone anddihydrotestosterone receptor binding and alsohas progestational and weak glucocorticoidproperties . It is an effective and well-toleratedtreatment for hirsutism.
Spironolactone is a competitive inhibitor of thealdosterone receptor and was initially utilized as apotassium sparing diuretic. It was soon discoveredto have antiandrogenic properties, and when usedtogether with the OCP, it is the first line treatmentfor hirsutism in the United States. Its antiandrogeniceffects come from several mechanisms, the mostimportant of which is the blockade of androgenreceptors in the hair follicle . In additionspironolactone also inhibits androgen biosynthesisthrough the cytochrome p450 system and directlyinhibits 5a-reductase activity. Treatment withspironolactone should begin at a dose of 200 mg/dfor at least 3-6 months
Treatment with spironolactone is generallyvery well tolerated with the most commonside effects being irregular vaginal bleeding,polyuria and fatigue . It is important toremember that with spironolactone, as withall antiandrogens, pregnancy can still occurwith the theoretical potential for feminizationof male fetuses. For that reason the OCP isoften used in conjunction withspironolactone. Not only will it protectagainst pregnancy, but also control abnormaluterine bleeding and possibly potentiate theeffect of spironolactone .
Flutamide is a nonsteroidal antiandrogen that appears to work only at the androgen receptor. Flutamide 250 mg/d for six months is effective intreating hirsutism most common side effects of flutamide are mild andinclude dry skin and increased appetite. However,the potential exists for a rare but severe drug-induced hepatitis which limits the usefulness of thismedication . Because of this potentially severe sideeffect, it is generally recommended that flutamide beutilized after other therapies have failed and that livertransaminases are monitored appropriately.
5a-reductase Inhibitors - Finasteride is apotent inhibitor of 5a-reductase and thusreduces the conversion of testosterone toits active metabolite dihydrotestosteroneFinasteride is well tolerated with minimalside effects at the standard dose of 5mg/day. Insulin Sensitizing Agents *Metformin has been shown to decrease theFerriman-Gallwey score and objective hairgrowth rate by about 15% in women withPCOS *troglitazone * Eflornithine HCL
Gonadotropin Releasing Hormone Agonists -Administration of a long-acting gonadotropinGnRHa such as leuprolide acetatesuppresses ovarian androgen production byinhibiting pituitary gonadotropin secretion.This results in decreased levels of circulatingtestosterone and androstenedione with noeffect on adrenal androgens
Epilation - Epilation includes plucking and waxingand involves removal of the hair from the bulb. Itdoes not change the rate or duration of hairgrowth but repeated plucking may lead to adelay in the return to anagen and thinner hairsecondary to permanent matrix damage .Epilation is an acceptable means of hairremoval. Again it is only temporary although itmay last 2-3 weeks longer than shaving.However, it is costly and may be associated withpain and inflammation at the site.
Treatment of Anovulation Anovulation is the primary cause of infertility in about 20% of couples, and PCOS isestimated to be the cause of 70% ofanovulatory fertility . There are manytherapies for the induction of ovulation inPCOS patients. The general paradigm is tobegin with the easiest to manage therapies,and if these do not result in ovulation orpregnancy in a reasonable period of time, tomove on to more elaborate therapies.
Clomiphene Citrate Clomiphene citrate is still the first line of therapy for ovulation induction in womenwith PCOS , although the argument hasbeen made that metformin is preferable .The standard clomiphene regimen is 50 mg/day for 5 days beginning on cycle day 3-5following spontaneous or progestin-inducedbleeding. If serum progesterone in the midluteal phase is less than 10 ng/mL, the dosecan be increased by 50 mg a day insubsequent cycles to a dose of 150 mg/day.
Metformin Metformin in doses of 1500-1700 mg/day significantly increases rates of spontaneousovulation .
Diarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfortCaused 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 restrictionCimetidine causes increased metformin levels •
Gonadotropins Options for women unresponsive to standard or modified clomiphene citratestimulation therapies or to metformin aloneinclude stimulation with gonadotropins orsurgically induced ovulation
Ovarin wedge resection .is not done .1anymoreLaparoscopic electro coagulation or laser .2electro coagulation ovarian drilling.