POLYCYSTIC OVARIAN SYNDROME - DR. TEJAL VAIDYA

PREVALENCE - Polycystic ovarian syndrome (PCOS) affects 4% to 9% of women of reproductive age.

It is the leading cause of infertility and 20 % anovulation in infertile women is due to PCOS.

DEFINITION - It is a heterogenous ,multisystem endocrinopathy in women of reproductive age group with ovarian expression of various metabolic disturbances and wide spectrum of clinical features like- obesity ,menstrual abnormalities and hyperandrogenism.

STEIN AND LEVENTHAL SYNDROMEIt was originally described by Stein and Leventhal (1935) as a syndrome manifested by amenorrhoea ,hirsuitism, and obesity associated with enlarged ovaries.

NICHD guidelines(1990)- 1) Clinical and /or biochemical signs of

hyperandrogenism 2) Oligo or chronic anovulation Exclusion of other etiologies of androgen excess and anovulatory infertility is necessary.

ESHRE/ASRM / ROTTERDAM REVISED (2003) CRITERIA (2 OUT OF 3) FROM BELOW MENTIONED LIST MUST BE PRESENT TO DIAGNOSE PCOS.

1. Oligo-ovulation and/or anovulation2. Clinical and/or biochemical signs of

hyperandrogenism.3. Polycystic ovaries

AES ( ANDROGEN EXCESS SOCIETY) GUIDELINES (2006)

Patient demonstrates both – 1) hirsutism and /or hyperandrogenism 2) oligo / anovulation and /or polycystic ovaries

ETIOLOGY Change in lifestyle, stress, diet

Familial occurrence

Environmental and Genetic factors- autosomal dominant inheritance. 50 % first degree relatives have pcos

Genetic causes are undetermined, but may include genes related to insulin secretion, insulin receptor function, ovarian steroidogenesis and paracrine regulators of ovarian functionHypothalamic –pituitary compartment abnormality

Androgen excess

Anovulation

Insulin Resistance (key role) – Insulin resistance with resultant hyperinsulinaemia initiates PCOS in 50 – 70 % cases. Mutation of insulin receptor gene in peripheral target tissues Autoantibodies Receptor defect Reduced tyrosine autophosphorylation of insulin receptor Tyrosine serine phosphorylation Post receptor insulin signaling defect Decreased hepatic clearance

Selective insulin resistance , skeletal muscles continue to remain resistant other tissues like hypothalamus ,ovary,adrenals remain sensitive compensatory hyperinsulinemia decreased levels of SHBG ADRENALS/OVARIES/HYPOTHALAMUS increased levels of GnRH

PATHOPHYSIOLOGY

TWO CELL TWO GONADOTROPIN THEORY

In the ovary, estradiol is formed from the conversion of testosterone into estradiol by the enzyme cytochrome P450 aromatase. This occurs in granulosa cells.

However, granulosa cells do not have the enzyme 17a-hydroxylase/lyase, and thus cannot convert progesterone into androgens.

CYP17 gene encoding 17-hydroxylase/C17-20-lyase activity crucial to androgen synthesis, is expressed exclusively in thecal cells.

The FSH receptor gene is expressed exclusively in granulosa cells, where FSH acts directly to induce cytoproliferation and differentiation via cyclic AMP/protein kinase-A mediated post-receptor signalling.

CHRONIC ANOVULATION high estrogen

positive feedback negative feedback on LH. on FSH.

inadequate LH surge stimulates maturation of follicles. no rupture of follicle. Polycystic ovaries.

HYPERANDROGENISM Hyperandrogenism in the ovarian microenvironment is a cardinal feature of PCOS. Types: 1) Ovarian 2) Adrenal

Ovarian: Increased LH

stimulates theca cells of follicle

androgens

Adrenal: Adrenal androgenism coexists with ovarian androgenism in PCOS. The causes of this adrenal androgen excess are due to..

1)Selective activation of the androgenic pathway 2) Estrogen induced stimulation of adrenal androgenesis.

HISTOLOGICAL FEATURES• Thickening of tunica albugenia• Cysts are follicles at varying stages of

maturation and atresia.• Theca cell hypertrophy(STROMAL

HYPERTHECOSIS)• Increased collagenization of tunica• Increased cortical stroma thickness• Increased subcortical stroma

CLINICAL FEATURES 1) Clinical hyperandrogenism male type alopecia acne hirsutism 2) Clinical feature of insulin resistance acanthosis nigrans 3) Obesity4) Menstrual abnormalities- Oligomenorrhoea/ amenorrhoea/ DUB5) Infertility / first trimester abortions

SKIN MANIFESTATIONS –

Hirsutism: Appearance of hairs in androgen dependent sites in which hair

normally are not present in women. Target areas are midline facial, moustache, beard, chest and

intermammary hairs and on inner thighs. F-G SCORE FOR HIRSUTISM

Alopecia: Progressive non scarring patterned loss of scalp

terminal hairs.Acanthosis nigricans: Mucocutaneous eruptions characterised by hyperkeratosis, papillomatosis, and increased pigmentation. Sites are axillae, nape of the neck, under breasts and flexures. Acanthosis nigricans is a reliable marker of insulin resistance in hirsute women. The HAIR-AN syndrome consists of hyperandrogenism, insulin resistance and acanthosis nigricans. acne: Sign of increase androgen activity.

CLINICAL D/D- 1. HYPOTHYROIDISM- dry skin, cold

intolerance,goiter, increased fatigue 2. HYPERPROLACTINAEMIA – galactorrhoea 3. VIRILIZATION – ovarian tumours , adrenal

tumours 4. CUSHING’S SYNDROME- hypertention ,

buffalo hump, pad of fat in the nape of neck, purple striae ,plethoric face

DIFFERENTIAL DIAGNOSIS AND SCREENING TESTS

Diagnosis Laboratory testPregnancy Pregnancy testHypothyroidism TSHHyperprolactinemia ProlactinLate-onset CAH 17-hydroxyprogesteronea

Ovarian tumor Total testosteroneb

Hyperthecosis Total testosteroneAdrenal tumor DHEA-Sb

Cushingís syndrome 24-hour urine free cortisol

Differential diagnoses and screening tests.

ON EXAMINATION Obesity- waist over hip ratio > 0.72 is abnormalBody mass index between 25-30 is overweight and above 30 is obesity Hirsutism, acne is looked for Acanthosis nigra over nape, axilla, below the breast , thigh is looked forBlood pressure is raised in most casesPelvic findings are normal , pelvic pain may be present in few cases, it is not common to palpate enlarged ovaries .

INVESTIGATIONS 1) Blood glucose levels – 2 hrs After 75 g oral glucose•Normal - <140 mg/dl•Impaired – 140-199 mg/dl•Diabetes - > 200 mg/dl OGTT IMPAIRED 2 hour glucose tolerance test: glucose levels. fasting 64 – 128 mg/dl 1 hr 120 – 170 mg/dl 2 hr 70 – 140 mg/dl

Diagnostic criteria for the insulin resistance syndrome in women.

Any three or more of the following: Waist circumference >88 cm Triglycerides ≥ 150 mg/dL HDL-cholesterol <50 mg/dL Blood pressure ≥130/85 mmhg Fasting glucose ≥110 mg/dL

2) Serum FSH and LH – LH increases , FSH level decreases LH : FSH = 2:1

3) TOTAL TESTOSTERONE - A total testosterone is likely to be more reliable than a free testosterone. Most testosterone values in PCOS will be ≤150 ng/dL (≤5.2 nmol/L).Testosterone values of ≥200 ng/dL (≥6.9 nmol/L) warrant consideration of an ovarian or adrenal tumor.

4) DIHYDROEPIANDROSTERONE –SULPHATE - DHEA-S values may be normal or slightly elevated in PCOS.DHEA-S values ≥800 µg/dL (21.7 µmol/L) warrant consideration of an adrenal tumor.

5) PROLACTIN - Mild hyperprolactinemia has been reported in 5% to 30% of patients with PCOS. Patients with prolactinomas may have polycystic ovaries on ultrasound

6) 17 – HYDROXYPROGESTERONE- A morning, fasting, unstimulated level of <200 ng/dL (<6 nmol/L) in the follicular phase reliably excludes late-onset 21-hydroxylase deficiency.

7) 24 HR URINE FREE CORTISOL - Mild elevations can be seen in PCOS with values ≥2 times the upper limit of normal more consistent with Cushing's syndrome.

8) Lipid profile Full fasting cholesterol panel Elevated total cholesterol Elevated LDL cholesterol Decreased HDL cholesterol Elevated triglycerides

9) PELVIC USG-( STRING OF PEARLS /NECKLACE)

The criteria for PCOS put forth by Adams et al. are the most often cited: the presence of ≥12 cysts measuring 2–9mm around a dense core of stroma or scattered within an increased amount of stroma.

 

10) LAPROSCOPY - “Oyster ovaries” - Thick sclerotic capsule is noted in chronic cases. No evidence of corpus luteum or stigma of ovulation are noted. - Both diagnostic and therapeutic value.

11) ENDOMETRIAL BIOPSY- Helpful to rule out endometrial hyperplasia in those with prolonged amenorrhea (more than 5 months).

MANAGEMENT OF PCOS Treatment depends on the patients goal. Some patients require hormonal contraception, whereas others desire ovulation induction.

But, in all cases in which there is significant ovulatory dysfunction, progestational interruption of unopposed estrogen effects on the endometrium is required.

Interruption of the steady state of hyperandrogenism and control of hirsutism usually can be accomplished simultaneously.

WEIGHT REDUCTION Initial recommendation.

It promotes health, reduces insulin,androgen levels,increase SHBG and may restore ovulation either used alone or in combination with ovulation induction agents.

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

UNMARRIED/ ADOLESCENT GIRLS WITH PCOS 1) LIFESTYLE MODIFICATIONS- •Weight reduction ,diet ,exercise 2) REGULATION OF MENSTRUATION - •Combined oral contraceptive pill – low dose /ultralow dose •Cyproterone acetate + EE 3) HYPERANDROGENISM- •Antiandrogens • cyproterone acetate 4)INSULIN RESISTANCE •Metformin

Combined ocps with aldosterone derivative – (drosperinone) It has antimineralocorticoid activity and mild antiandrogenic Yasmin,jasmine,yarina Drosperinone 3 mg and EE 30 microgm Myo-inositol derivatives

Decrease serum testosterone increases insulin sensitivity Improves ovulatory function

MARRIED WOMEN WITH INFERTILITY 1) Lifestyle modifications 2) Metformin 3) Clomiphene citrate 4) CC +dexamethasone 5) Metformin+ clomiphene citrate 6) FSH ,LH , GNRH analogues 7) low doses glucocorticoids benefit women with androgenic anovulation 8) Clomiphene resistant cases – laproscopic ovarian drilling

MARRIED BUT FAMILY COMPLETED 1) lifestyle modifications

2) menstrual regulation – ocp

3) hyperandrogenism / hirsutism perimenopausal woman Hyperandrogenism

HIRSUTISM 70 % Of women with pcos have hirsutism Combined Oral Contraceptive Pills The progestin component suppresses LH, resulting in diminished ovarian androgen production. The estrogen increases hepatic production of SHBG, resulting in decreased free testosterone concentration. Estrogen decreases conversion of testosterone to DHT in skin by inhibition of 5-alpha reductaseOC pill alone may be relatively ineffective ( less than 10% success rate) in the treatment of hirsutism in patients with PCOS. So management includes co administration of agent that impede androgen action

CYPROTERONE ACETATE –

Steroid derivative of 17 – hydroxyprogesterone Progestational, antigonadotrophic, antiandrogenic

activity

The mechanism of action:

1. Compititive inhibition of testosterone and DHT at the level of androgen receptors.

2. Induces hepatic enzymes and may increase the metabolic clearance rate of plasma androgens.

Administered in the reverse sequential regimen (cyproterone acetate 100 mg/day on days 5 to 15, and ethinyl estradiol 30 to 50 mg/day on cycle days 5 to 26). This cycle schedule allows regular menstrual bleeding, provides excellent contraception and is effective in treatment of even severe hirsutism and acne.

Side effects includes fatigue, weight gain, decreased libido, irregular bleeding, nausea and headaches.

SPIRONOLACTONE Aldosterone antagonist , also a potent antiandrogen Competitively binds to androgen receptor in hair follicle Suppression of testosterone biosynthesis by the decrease in the CYP450 enzymes.Inhibition of skin 5-alpha reductase activity Increase in androgen catabolism with increased peripheral conversion of testosterone to estrone.

dose- 50 to 100 mg twice daily.

The common side effects are menstrual irregularity, nausea ,vomiting

Other side effects are mastodynia, urticaria, scalp hair loss.

Periodic electrolyte and blood pressure monitoring

FLUTAMIDE It is a pure non steroidal antiandrogen, and is approved for the treatment of prostate cancer.

Mechanism of action is inhibition of nuclear binding of androgen in the target tissue.

When combined with OC pills there is a significant improvement in hirsutism and drop in androstenedione, DHT, LH and FSH levels. Dose- 250 mg / day

The side effects of this treatment includes fatigue, headache, nausea, dizziness, decreased libido, liver toxicity ,cholestatic jaundice ,hepatic necrosis ,vomiting

FINESTERIDE It is specific inhibitor of type 2 5-alpha reductase enzyme activity.

It causes improvement in hirsutism when given as 5 mg/day

KETOKONAZOLE An antifungal agent, inhibits the key steroidogenic cytochromes. (CY P 450)

When administered at low doses (200 – 400 mg/day) significantly reduces the levels of androstenedione, testosterone and calculated free testosterone.

Side effects- nausea ,vomiting, pruritis, hepatic dysfunction

METFORMIN Insulin sensitizers improve Hyperinsulinaemia and Hyperandrogenism ,hence Metformin is now the most widely used insulin sensitizer.Biguanide family Improves the sensitivity of peripheral tissues to insulin resulting in reduction of circulating levels .

METFORMINInhibits hepatic uptake and gluconeogenesis Increases the glucose uptake by peripheral tissues and reduce fatty acid oxidation . Supports ovarian function and return to normal ovulation. Inhibits human theca cell androgen synthesis . increases levels of SHBG . Used for induction of ovulation and also prevents ovarian Hyperstimulation

Side effects Gastrointestinal intolerance in 30% (nausea, abdominal pain and/or diarrhea)

Precautions Hold for 48 hours prior to and after surgery and/or administration of radiocontrast materials

Contraindications Creatinine ≥1.4 mg/dL (for women)Liver disease (or risk thereof: alcohol abuse/binge drinking)Other risks for lactic acidosis: pulmonary disease, congestive heart failure

Tab metformin 500 mg bd/tds dose

GNRH AGONISTS AND ANTAGONISTS Gnrh agonists- nafarelin/leuprorelin/busirelin Decreased LH AND FSH s/e- due to reduced levels of estrogen therefore, estrogen add back therapy should be started

Gnrh antagonists –cetrorelix,ganerelix Inhibits LH AND FSH Advantages over gnrh agonists- 1)no flare up due to no intrinsic activity 2)competitive receptor binding hence dose dependent action 3) resumes ovulatory function in 6 weeks of stoppage of drug

PREGNANCY COMPLICATIONS Gestational diabetesObesity Insulin resistanceBirth defects

Pregnancy-induced hypertensionWomen over 40Obese Insulin resistance

Premature delivery Miscarriage.

SEQUELAE Type 2 Diabetes mellitus (15%) Cardiovascular diseases Lipidaemias Hypertension Endometrial cancer Breast cancer Premature ovarian failure following surgery