Hyperandrogenism and Polycystic Ovary Syndrome

Hyperandrogenism

Hyperandrogenism: It is characterised by an abnormally elevated serum concentration of androgen or physical findings consistent with androgen excess.

It is manifested clinically by: 

Hirsutism (Excessive growth of androgen dependant sexual hair or male distribution of hair in females). 
Hirsutism is associated with excess androgen production (either from ovaries or adrenals), so any cause which increases androgens causes hirsutism.

1. M/C cause of hirsutism in a young female is idiopathic
2. M/C pathological cause of hirsutism in young female – PCOS
3. M/C cause of rapid onset hirsutism in a young female: Testosterone producing tumor.

Virilization: It is characterized by more extensive androgen induced changes than hirsutism alone, like acne, increased oily skin, temporal balding, clitoromegaly, deepening of voice, development of male muscular pattern and body habitus with atrophy of breasts

Major Causes of Hyperandrogenism 

1. PCOS 
2. Late Onset Congenital Adrenal Hyperplasia (CAH) 
3. Tumors of ovary and adrenal gland 
4. Cushing’s syndrome 
5. Idiopathic or drug induced process 

Hyperprolactinemia can be associated with hyperandrogenism as it is likely that prolactin receptors are located on adrenal glands. When prolactin binds to these adrenal receptors, it stimulates the release of DHEAS.

Polycystic Ovary Syndrome (PCOS) Or Stein-leventhal syndrome

PCOS: It's the Most common cause of anovulation. Affects 4–6% of women. Chronic anovulation resulting in infertility, irregular bleeding, obesity, hirsutism, and enlarged ovaries.

Incidence is fast increasing due to change in lifestyle and stress. 20–25% of women with normal ovulation demonstrate ultrasound findings typical of polycystic ovaries.

PCOD patients typically have excess androgens (androstenedione), increased estrogen levels, increased LH levels, incre­ased GnRH levels, and decreased FSH levels (with a high LH/FSH ratio).

Ovaries are usually 2–5 times the normal size, graywhite with a smooth outer cortex, and studded with subcortical cysts. Multiple cysts (12 or more) of 2–9 mm size are located peripherally along the surface of the ovary

The cause of this syndrome is thought to be the abnormal secretion of gonadotropins by the pituitary.

• Increased secretion of LH stimulates the thecal cells to secrete excess amounts of androgens, which are converted to estrone by the peripheral aromatization of androgens by the adrenal gland. 
• Excess estrogens in turn increase the levels of gonadotropin-releasing hormone (GnRH) but decrease the levels of FSH. 
• The GnRH increases the levels of LH, which then stimulate the thecal cells of the ovary to secrete more androgens, and the hormonal cycle begins again.

Role of Insulin resistance in the development of PCOS

Insulin resistance is the hallmark in patho­physiology of PCOS. 

• Inc­re­ased insulin secretion stimulates increased ova­rian androgen production and inhibits serum hepa­tic SHBG production.
• Insulin resistance with resultant hyperinsulinaemia initiates PCOS in 50–70% cases.
• Insulin resistance also leads to hyperpigmented velvety patches of skin in nape of neck/ axilla/ below breast or thigh called as acanthosis nigricans and in future patients can develop diabetes.
  

HAIRAN Syndrome: Hyperandrogenism, Insulin resistance, Acanthosis nigricans

Clinical features of PCOS

Central obesity (BMI>30kg/m3), only 30% patients are obese in PCOS pts.

• Waist measurement is the— smallest circumference between rib cage and iliac crest.
• Hip measurement is the largest circumferemce between waist and thighs

2) Oligomenorrhoea (87%), amenorrhoea (26%) followed by prolonged or heavy periods. 
3) Infertility (20%) 
4) Pregnancy loss (20–30%) 
5) Hyperandrogenism: Hirsutism, Acne, Acanthosis nigricans

Short term consequences of PCOS: Hirsutism, Irregular cycles, Infertility

Long term consequences of PCOS/ Anovulation 

1. ↑ risk of cardiovascular disease
2. ↑ risk of diabetes (Type 2) 
3. ↑ risk of endometrial cancer
4. ↑ risk of breast Ca 
5. ↑ use of Ovarian Ca 
6. ↑ risk of depression & mood disorder
7. ↑ risk of metabolic X syndrome.
8. ↑ risk of sleep apnea syndrome
9. ↑ risk of non-alcoholic steatohepatitis

Metabolic X syndrome: Any 3 of following 5 should be present:

1. Abdominal obesity (waist circumference > 88 cm or 35 inches)
2. Triglyceride > 150 mg/dl 
3. HDL- cholesterol < 50 mg/ dl
4. BP > 130/85 mm of hg 
5. Fasting blood sugar of 110 – 126 mg/dl and 2 hour 140 – 199 mg/dl

Diagnostic Criteria Rotterdam criteria (2003):

Any two of the following three should be present to diagnose a patient with PCOD.

1. Ovulatory dysfunction such as oligomenorrhea or amenorrhea 
2. Clinical (hirsutism/acne/alopecia) or biochemical evidence of hyperandrogenism i.e. S. testosterone between 70-150 ng/dl (levels > 200 indicate testosterone secreting ovarian tumor not PCOS)
3. Polycystic ovarian morphology on USG scan defined as presence of 12 or more cysts (2-9mm) in size in any one ovary or both ovaries with enlarged ovaries (>10ml) and other criterias being excluded (like cushing disease, adrenal hyperplasia)

Note: In contrast signs of virilization such as increased muscle mass, deepening of the voice and clitoromegaly are not typical of PCOS. Virilization reflects much higher andorgen levels and should prompt investigation for an androgen producing tumor of ovary or the adrenal gland.

Management of PCOS

Depends on the complain of the patient Complaint

Obesity: Lifestyle management targeting weight loss (BMI ≥ 25 kg/m²) and prevention of weight gain (BMI < 25 kg/m²) should include both reduced dietary energy (caloric) intake and exercise and should be first line therapy for all women with PCOS

• Weight loss of more than 5% of previous weight alone is beneficial in mild hirsutism 
• It restores the hormonal milieu 
• It increases secretion of sex hormone binding globulin from liver thereby reducing testosterone level. 
• Reduces insulin level

Smoking cessation (lowers E2 levels and raises DHEA and androgen levels)

Irregular periods: To maintain regular menstruation cycle – Oral combined pills 
– OCP’s and cyproterone acetate 
– OCP’s and spironolactone (spironolactone inhibit 5 alpha reductase so less DHT formation) 
– Ketoconazole (200 mg daily of ketoconazole reduces testosterone secretion)

Insulin resistance: Metformin (Can be used in pregnancy also)

Hirsutism/acne: OCP’s with cyproterone acetate

1. Elevated Testoterone (Ovary source): Combined contraceptives (COCs containing drospirenone or desogestral or cyproterone acetate dianette)
2. Normal testoterone and DHEA-S 3aAG ↑ (idiopathic): Antiandrogens like cyproterone, spironolactone, Flutamide
3. DHEA-S ↑, Normal testoterone: Dexamethasone (0.5 mg) at bedtime reduces androgen production – used in some infertile women with clomiphene if DHEA-S > 5 ng/mL.
4. Acne can be managed by 1% clindamycin lotion or 2% erythromycin gel if pustules form. For severe acne, isotretinoin is used (MUST be avoided in pregnancy) – Takes 3-6 months to show the effect effect on hirsutism 

Infertility: In PCOD—the basic cause of infertility is anovulation. It is easily reversible and treatable using ovulation inducing drugs 

1. First advise weight loss (In 5–10% cases-weight loss will cause resumption of ovulation)
2. 1st line drugs-SERM’S: Clomiphene citrate–DOC for ovulation induction in PCOS patients/ Tamoxifen-given to patients who cannot tolerate clomiphene. 
3. 2nd line agents- Gonadotropins: LH/FSH injection
4. Insulin Sensitizers: Metformin should be combined with clomiphene citrate to improve fertility outcomes rather than persisting with further treatment with clomiphene citrate alone in women with PCOS who are clomiphene citrate resistant, anovulatory and infertile with no other infertility factors.
5. Metformin could be used alone to improve ovulation rate and pregnancy rates in women with PCOS who are anovulatory, have a BMI < 30kg/m² and are infertile with no other infertility factors.
6.  3rd line agents-GnRH agonist: Luprolide, Guserelin given in pulsatile manner, Nafarelin

Surgery for PCOS

It is reserved for cases not responding to medical therapy Laparoscopic Ovarian Drilling (LOD) or Laparoscopic Electrocoagulation of Ovarian Surface (LEOS) 

1. Monopolar current or Laser is passed within the ovary to destroy the ovarian theca when very high doses of gonadotropins are required for ovulation.
2. Advantages: no risk of Ovarian hyperstimulation syndrome and multiple pregnancy
3. Disadvantages: if excessive ovarian tissue is damaged, it can lead to premature ovarian failure.