Polycystic ovarian syndrome

POLYCYSTIC OVARIAN SYNDROME

Presented by :

Hem nath subedi

3rd year resident

OBGYN

COMS-TH

Background • PCOS 5% to 10% of women worldwide. • This familial disorder appears to be inherited as a complex

genetic trait . • It is characterized by a combination of – Hyperandrogenism (either clinical or biochemical), – Chronic anovulation and– Polycystic ovaries.

• associated with

– Insulin resistance– Obesity.

1.Endocrine disorder, PCOS In: Berek and Novaks Gynecology, Fifteen Edition , New Delhi ,Wolter Kluwer,2012 pp1075 t0 1090

History

• In 1935, Irving F. Stein and Michael L. Leventhal first described a symptom complex associated with anovulation.

• Stein and Leventhal described 7 patients (4 of whom were obese) with amenorrhea; hirsutism; and enlarged, polycystic ovaries.

Reproductive endocrinology, polycystic ovary in speroff’sendocrinology in gynecology , 7 th edition ,walter wilkinsons pp


Diagnostic criteria1990 Criteria (both 1 and 2) NIH

1. Chronic anovulation and

2. Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies.

Revised 2003 criteria (2 out of 3)

1. Oligoovulation or anovulation

2. Clinical and/or biochemical signs of hyperandrogenism

3. Polycystic ovaries and exclusion of other etiologies (congenital adrenal

hyperplasia, androgen-secreting tumors, Cushing’s syndrome)

From Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop

Group. Revised 2003 consensus on diagnostic criteria and long-term health risksrelated to polycystic ovary syndrome. Fertil Steril 2004;81:19–25


• Other pathologies that can result in a POCS phenotype include – Adult onset adrenal hyperplasia– Adrenal or ovarian neoplasm– Cushing syndrome– Hypo- or hypergonadotropic disorders– Hyperprolactinemia– Thyroid disease

• Classically, the disorder is lifelong, characterized by abnormal menses from puberty with acne and hirsutism arising in the teens.


• It may arise in adulthood, concomitant with the emergence of obesity.1

• PCOS is accompanied by increasing hyperinsulinemia.1

• The sonographic criteria for PCO requires the presence of 12 or more follicles in either ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume (>10 mL).

• A single ovary meeting these criteria is sufficient to affix the PCO diagnosis.1



Pathology• Macroscopically, ovaries in women with PCOS

are two to five times the normal size.

• A cross-section of the surface of the ovary discloses a white, thickened cortex with multiple cysts that are typically less than a centimeter in diameter.

• Microscopically, the superficial cortex is fibrotic and hypocellular and may contain prominent blood vessels.1

• The characteristics of the ovary reflect this dysfunctional state

• The surface area is doubled, giving an average volume increase of 2.8 times.


• The same number of primordial follicles is present, but the number of growing and atretic follicles is doubled. Each ovary may contain 20 to100 cystic follicles.

• The thickness of the tunica (outermost layer) is increased by 50%.

• A one-third increase in cortical stromal thickness and a 5-fold increase in subcortical stroma are noted.

• The increased stroma is due both to hyperplasia of theca cells and to increased formation subsequent to the excessive follicular maturation and atresia.

• There are 4 times more ovarian hilus cell nests (hyperplasia).



Pathophysiology and laboratory finding

• The hyperandrogenism and anovulation that accompany PCOS may be caused by abnormalities in four endocrinologically active compartments: – (i) the ovaries– (ii) the adrenal glands– (iii) the periphery (fat)– (iv) the hypothalamus–pituitary compartment


• In patients with PCOS, the ovarian compartment is the most consistent contributor of androgens.

• Dysregulation of CYP17, This hormone relates to ovarian androgenic activity in PCOS in a number of ways.

– Total and free testosterone levels correlate directly with LH levels.

– The ovaries are more sensitive to gonadotropic stimulation, possibly as a result of CYP17 dysregulation.

– Gonadotropin-releasing hormone (GnRH) agonist effectively suppresses serum testosterone and androstenedione levels.

– Larger doses of a GnRH agonist are required for androgen suppression

• The peripheral compartment, defined as the skin and the adipose tissue, manifests its contribution to the development of PCOS in several ways.– Aromatase and 17β-hydroxysteroid dehydrogenase activities are

increased in fat cells.– The presence and activity of 5α-reductase in the skin largely

determines the presence or absence of hirsutism .

– With obesity the metabolism of estrogens is decreased.

– Whereas estradiol (E2) is at a follicular phase, estrone (E1) levels are increased as a result of peripheral aromatization of androstenedione.

– A chronic hyperestrogenic state, with reversal of the E1-to-E2 ratio, results and is unopposed by progesterone.1.Endocrine disorder, PCOS In: Berek and Novaks Gynecology, Fifteen Edition , New Delhi ,Wolter Kluwer,2012 pp1075 t0 1090

T h e hypothalamic–pituitary compartment participates in aspects to the development of PCOS.

– An increase in LH pulse frequency relative to those in the normal follicular phase is the result of increased GnRH pulse frequency.

– This increase in LH pulse frequency explains the frequent observation of an elevated LH and LH-to-FSH ratio.

– FSH is not increased with LH, likely because of the combination of increased gonadotropin pulse frequency.

• About 25% of patients with PCOS exhibit mildly elevated prolactin levels.


• Genetic studies of PCOS reported allele sharing in large PCOS patient populations and linkage studies focused on candidate genes most likely to be involved in the pathogenesis of PCOS. These genes can be grouped in four categories:

– (i) insulin resistance–related genes– (ii) genes that interfere with the biosynthesis and the action

of androgens– (iii) genes that encode inflammatory cytokines.– (iv) other candidate genes



Clinical consequences

1. Infertility.

2. Menstrual bleeding problems, ranging from amenorrhea to dysfunctional uterine bleeding.

3. Hirsutism, alopecia, and acne.

4. An increased risk of cardiovascular disease.

5. An increased risk of diabetes mellitus in patients with insulin resistance.

6. An increased risk of endometrial cancer and, perhaps, breast cancer.


Infertility.

• The most common cause of oligo-ovulation and anovulation among women presenting with infertility—is polycystic ovarian syndrome (PCOS)


Menstrual bleeding problems • The menstrual dysfunction in PCOS arises from anovulation

or oligo-ovulation.

• Ranges from amenorrhea to oligomenorrhea.

• Regular menses in the presence of anovulation in PCOS is uncommon.

• one report found that among hyperandrogenic women with regular menstrual cycles, the rate of anovulation is 21%


Hirsutism, alopecia, and acne.

• Hirsutism occurs in approximately 70% of patients with PCOS of USA patient.

• Only 10% to 20% of patients with PCOS in Japan .

• A likely explanation for this discrepancy is the genetically determined differences in skin 5α-reductase activity.

• Evaluation includes more than the assessment of the degree of hirsutism done by Ferriman-Gallwey hirsutism scoring system.

• When hirsutism is moderate (>9) or severe or if mild hirsutism is accompanied by features that suggest an underlying disorder, elevated androgen levels should be ruled out.


Insulin resistance

• Patients with PCOS frequently exhibit insulin resistance and hyperinsulinemia.

• Insulin resistance and hyperinsulinemia participate in the ovarian steroidogenic dysfunction of PCOS.

• The most common cause of insulin resistance and compensatory hyperinsulinemia is obesity.

• obesity has its frequent occurrence in PCOS, obesity alone does not explain this important association

• Multiple other testing or screening scheme were proposed to assess the presence of hyperinsulinemia and insulin resistance.

• In one, the fasting glucose-to-insulin ratio is determined, and values less

than 4.5 indicate insulin resistance.

• A peak insulin level of over 150 μIU/mL or a mean level of over 84 μIU/mL over the three blood draws of a 2-hour GTT as a criteria to diagnoses hyperinsulinemia.

• Insulin resistance indicating an increased risk of diabetes mellitus and cardiovascular disease.

• About one-third of obese PCOS patients have impaired glucose tolerance (IGT), and 7.5% to 10% have type 2 diabetes mellitus.



• Interventions• Two-Hour Glucose Tolerance Test Normal Glucose Ranges (World

Health Organization criteria, after 75-gm glucose load)– Fasting 64 to 128 mg/dL– One hour 120 to 170 mg/dL– Two hour 70 to 140 mg/dL

• Two-Hour Glucose Values for Impaired Glucose Tolerance and Type 2 Diabetes

• (World Health Organization criteria, after 75-gm glucose load)

Normal (2-hour) <140 mg/dL

Impaired (2-hour) = 140 to 199 mg/dL

Type 2 diabetes mellitus (2-hour) ≥200 mg/dL


Metabolic Syndrome

• In addition to addressing the increased risk for diabetes.

• insulin resistance or hyperinsulinemia as a cluster syndrome called metabolic syndrome or dysmetabolic syndrome X.

• The more dysmetabolic syndrome X criteria are present, the higher the level of insulin resistance and its downstream consequences.

• Abnormal lipoproteins are common in PCOS.

• Obesity occurs in more than 50% of patients with PCOS.

• The body fat is usually deposited centrally (android obesity) and a higher waist-to-hip ratio.


Metabolic Syndrome Diagnostic Criteria

• Female waist >35 inches• Triglycerides >150 mg/dL• HDL <50 mg/dL• Blood pressure >130/85 mmHg• Fasting glucose: 110–126 mg/dL• Two-hour glucose (75 gm OGTT): 140–

199 mg/dL• Risk factors for the dysmetabolic syndrome

include


Acanthosis nigricans

• Acanthosis nigricans is a reliable marker of insulin resistance in hirsute women.

• This thickened, pigmented, velvety skin lesion is most often found in the vulva and may be present on the axilla, over the nape of the neck, below the breast, and on the inner thigh .

• The HAIR-AN syndrome consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN).

Cancer

• In chronic anovulatory patients with PCOS, persistently elevated estrogen levels.

• Uninterrupted by progesterone.

• Increase the risk of endometrial carcinoma.

• These endometrial cancers are usually well differentiated, stage I lesions with a cure rate of more than 90%.

• The risk of ovarian cancer is increased two- to threefold in women with PCOS1.Endocrine disorder, PCOS In: Berek and

Novaks Gynecology, Fifteen Edition , New Delhi ,Wolter Kluwer,2012 pp1075 t0 1090


Depression and Mood Disorders

• The clinical features of PCOS, such as infertility, acne, hirsutism, and obesity, promote psychological morbidity.

• Women with PCOS face challenges to their feminine identity that can lead to loss of self-esteem, anxiety, poor body image, and depression.


Hyperandrogenic women be evaluated with the following laboratory tests to exclude specific

causes and problems:

• Thyroid-stimulating hormone (TSH).• Prolactin.• Lipid and lipoprotein profile.• Screen for Cushing's Disease if appropriate.• Consider endometrial biopsy.

Mangement of pcos• Conservative

– Weight loss– Life style modification

• Medical– Hyperandrogenism

• OCPS• MPA• Gnrh agonist• Glucocorticoids• Ketokonazole• Spironolactone• Cyproterone acetate• Fenasteride

– Insulin resistance• METFORMIN

Management….

– Anovulation• CLOMIPHENE CITRATE• GONADOTROPINS• SURGICAL METHOD

– WEDGE RESECTION – LAPAROSCOPIC OVARIAN SURGERY(LOS)


Treatment of hyperandrogenism and PCOS

Weight Reduction • Weight reduction is the initial recommendation for patients with

accompanying obesity

• it promotes health, reduces insulin, SHBG, and androgen levels, and may restore ovulation either alone or combined with ovulation-induction agents .

• Weight loss of as little as 5% to 7% over a 6- month period can reduce the bioavailable or calculated free testosterone level significantly and restore ovulation and fertility in more than 75% of women.

Oral Contraceptives• Combination oral contraceptives (OCs) decrease adrenal

and ovarian androgen production and reduce hair growth in nearly two-thirds of hirsute patients .

• The progestin component suppresses LH, resulting in diminished ovarian androgen production.

• The estrogen component increases hepatic production of SHBG, resulting in decreased free testosterone concentration.

• Estrogens decrease conversion of testosterone to DHT in the skin by inhibition of 5α-reductase.

1.Endocrine disorder, PCOS In: Berek and Novaks Gynecology, Fifteen Edition , New

Delhi ,Wolter Kluwer,2012 pp1075 t0 1090


Medroxyprogesterone Acetate

• Oral or intramuscular administration of medroxyprogesterone acetate (MPA) successfully treats hirsutism.

• It directly affects the hypothalamic–pituitary axis by decreasing GnRH production and the release of gonadotropins, thereby reducing testosterone and,estrogen production by the ovary.

• Despite a decrease in SHBG, total and free androgen levels are decreased significantly.


Gonadotropin-Releasing Hormone Agonists

• Administration of GnRH agonists may allow the differentiation of androgen produced by adrenal sources from that of ovarian sources .

• Treatment with leuprolide acetate given intramuscularly every 28 days decreases hirsutism and hair diameter in both idiopathic hirsutism and hirsutism secondary to PCOS.

• Ovarian androgen levels are significantly and selectively suppressed.


• Glucocorticoids

– Dexamethasone may be used to treat patients with PCOS who have either adrenal or mixed adrenal and ovarian hyperandrogenism.

– Doses of dexamethasone as low as 0.25 mg nightly or every other night are used initially to suppress DHEAS concentrations to less than 400 μg/dL.

• Ketoconazole– Ketoconazole inhibits the key steroidogenic cytochromes. – Administered at a low dose (200 mg per day), it can

significantly reduce the levels of androstenedione, testosterone, and calculated free testosterone.


Spironolactone• specific antagonist of aldosterone, which competitively binds to the

aldosterone receptors in the distal tubular region of the kidney.

– Competitive inhibition of DHT at the intracellular receptor level. – Suppression of testosterone biosynthesis by a decrease in the CYP

enzymes. – Increase in androgen catabolism (with increased peripheral

conversion of testosterone to estrone).– Inhibition of skin 5α-reductase activity.

• The most common dose is 50 to 100 mg twice daily.


Cyproterone Acetate• Cyproterone acetate is a synthetic progestin derived from 17-OHP,

which has potent antiandrogenic properties.

• The primary mechanism of cyproterone acetate is competitive inhibition of testosterone and DHT at the level of the androgen receptor

• Administered in a reverse sequential regimen cyproterone acetate 100 mg per day on days 5 to 15, and ethinyl estradiol 30 to 50 mg per day on cycle days 5 to 26.

• This cyclic schedule allows regular menstrual bleeding, provides excellent contraception.


• Flutamide• Flutamide, a pure nonsteroidal antiandrogen, is approved for

treatment of advanced prostate cancer.

• Its mechanism of action is inhibition of nuclear binding of androgens in target tissues.

• Although it has a weaker affinity to the androgen receptor than spironolactone or cyproterone acetate, larger doses (250 mg given two or three times daily) may compensate for the reduced potency.


Finasteride• Finasteride is a specific inhibitor of type 2 5α-reductase

enzyme activity.

• In a study in which finasteride (5 mg daily) was compared with spironolactone (100 mg daily), both drugs resulted in similar significant improvement in hirsutism, despite differing effects on androgen levels .

• Most of the improvement in hirsutism with finasteride occurred after 6 months of therapy with 7.5 mg of finasteride daily.


Insulin Sensitizers

• Because hyperinsulinemia appears to play a role in PCOS-associated anovulation.

• Treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities.

Metformin (Glucophage) is an oral biguanide antihyperglycemic drug used extensively for non–insulin-dependent diabetes.


• Metformin is pregnancy category B drug with no known human teratogenic effect.

• It lowers blood glucose mainly by inhibiting hepatic glucoseproduction and by enhancing peripheral glucose uptake.

• Metformin enhances insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal.

• Although the literature is conflicting, larger studies have suggested that the live birth rate with metformin alone (7.2%) .

• Lower than that achieved with clomiphene, and the combination does not confer additional benefit over clomiphene alone.


INFERTILITY DUE TO PCOS

• Ovulation Induction in Women with Polycystic Ovarian Syndrome

• The goal of ovulation induction refers to the therapeutic restoration of the release of one egg per cycle in a woman who either has not been ovulating regularly or has not been ovulating at all.


Clomiphene Citrate

• Clomiphene citrate is a weak synthetic estrogen that mimics the activity of an estrogen antagonist when given at typical pharmacologic doses for the induction of ovulation.

• It is cleared through the liver and excreted into the stool, with 85% clearance in 6 days.

• A functional hypothalamic–pituitary–ovarian axis is usually required for appropriate clomiphene citrate action.


Clomiphene Citrate Outcomes• Over the course of 6 months, clomiphene is associated with 49% ovulation,

23.9% pregnancy, and 22.5% live birth rates in women with anovulatory infertility.

• Multiple gestation rates with clomiphene citrate are approximately 8%, most of which are twins.

• Treatment should be limited to 6 ovulatory cycles or 12 total cycles.

• The drug is supplied in 50 mg tablets; the usual starting dose is 50 mg per day.

• Side effects of clomiphene citrate include vasomotor flushes, mood swings, breast tenderness, pelvic discomfort, and nausea.


Tamoxifen• Tamoxifen is an oral antiestrogen similar in structure to clomiphene

that is commonly used as an adjuvant therapy for breast cancer.• Used off-label to induce ovulation.• Ovulation and pregnancy rates are similar with tamoxifen and

clomiphene.

Aromatase Inhibitors• These drugs include letrozole and anastrazole.

• The off-label use of letrozole for ovulation induction in clomiphene-resistant patients was first reported in 2001

Gonadotropin Therapy• Anovulatory PCOS patients who fail to ovulate or conceive with oral

agents should be considered for ovulation induction with exogenous gonadotropin injections

• Typical protocols monitor at baseline, 4 to 5 days after treatment initiation, then every 1 to 3 days until follicular maturation (expected follicle growth is 1 to 2 mm daily after achieving 10 mm diameter)

• Given the goal of promoting growth of a single mature follicle, low initial gonadotropin doses of 37.5 to 75 IU per day are generally recommended

• Increases in doses by 50% of the previous dose after 7 days if no follicle greater than 10 mm is observed




Contraindications to Gonadotropins for the Treatment of Infertility in Women

1. Primary ovarian failure with elevated follicle-stimulating hormone levels

2. Uncontrolled thyroid and adrenal dysfunction

3. An organic intracranial lesion such as a pituitary tumor

4. Undiagnosed abnormal uterine bleeding

5. Ovarian cysts or enlargement not caused by polycystic ovary syndrome

6. Prior hypersensitivity to the particular gonadotropin

7. Sex hormone–dependent tumors of the reproductive tract and accessory organs

8. Pregnancy

Risks of Exogenous Gonadotropin Treatment

• Multiple Pregnancy– Twin births have risen by more than 50% and births of triplet and

higher order multiple pregnancies have more than quadrupled since 1980.

– When compared to other anovulatory patients, PCOS patients using gonadotropins are at higher risk for multiple gestations (36%),

• Ovarian Hyperstimulation Syndrome– Ovarian hyperstimulation syndrome is an iatrogenic

complication of ovulation induction with exogenous gonadotropins.

– ovarian hyperstimulation syndrome (4.6%).• cycle cancellation (10%) because of their high numbers

of baseline antral follicles.1.Endocrine disorder, PCOS In: Berek and Novaks Gynecology, Fifteen Edition , New Delhi ,Wolter Kluwer,2012 pp1075 t0 10902.Reproductive endocrinology, polycystic ovary in speroff’sendocrinology in gynecology , 7 th edition ,walter wilkinsons .

Ovarian Wedge Resection• Bilateral ovarian wedge resection is associated with only a transient

reduction in androstenedione levels and a prolonged minimal decrease in plasma testosterone .

• In patients with hirsutism and PCOS who had wedge resection, hair growth was reduced by approximately 16% .

• Although Stein and Leventhal’s original report cited a pregnancy rate of 85% following wedge resection and maintenance of ovulatory cycles.

• subsequent reports show lower pregnancy rates and a concerning incidence of periovarian adhesions Instances of premature ovarian failure and infertility were reported.



Laparoscopic Electrocautery• Laparoscopic ovarian electrocautery is

used as an alternative to wedge resection in patients with severe PCOS whose condition is resistant to clomiphene citrate.

• In a recent series, ovarian drilling was achieved laparoscopically with an insulated electrocautery needle, using 100-W cutting current to assist entry and 40-W coagulating current to treat each microcyst over 2 seconds (8-mm needle in ovary)

1.Endocrine disorder, PCOS In: Berek and Novaks Gynecology, Fifteen Edition , New Delhi ,Wolter Kluwer,2012 pp1075 t0 10902.Jeffcoats gynecology

Recent advances• LOS is used for ovulation induction in women

with PCOS after Clomiphene citrate failure.• Evidence from RCT and metanalysis indicate

that LOS is as effective as gonadotrophins for ovulation induction and has the advantage of avoiding complication such as multiple pregnancies and OHSS.

• Four punctures per ovary at 30w for 5seconds per puncture using a monopolar diathermy needle seems to be optimum amount of energy required for LOS.

Laparoscopic ovarian surgery for polycystic ovarian sydrome in recent advances in obstetrics and gynecoogy 24 th volume, churchill livingstone, pp241.


• About 2/3rd of women ovulate after LOS and 50% conceive within 12months

• About one third of the patients continue to benefit from LOD for many years.

• Postoperative adhesion formation can be minimized by avoiding thermal injury to the ovarian surface and by ample irrigation.

• Women with BMI ≥ 35kg/m2 , testersterone ≥ 4.5 nmol/l, FAI15 and or infertility for >3year are resistant to LOS

THANK YOU

Take home message

Health & Medicine

Polycystic ovarian syndrome