1. Dr. ASMAA A. AL SANJARY

2. The student at the end of this lecture should be able to : Differentiate the hirsutism from virilisim. Determine the severity by using ferriman gallway score. Understand the sources of androgen in the body. Classify the causes of hirsutism. Analyze history and edxamination to predict the cause of hirsutism. Outline the investigations required for diagnosis. Describe the treatment of hirsutism case.

3. Hirsutism : increase in terminal hair on the face,chest,back and inner thighs in a women and the development of male escutcheon on the pubic hair(diamond, female is triangular). It may be accompanied by anovulatory amenorrhoea, dysfunctional uterine bleeding,or infertility. Virilism : is development of hirsutism in addition to male features such as: Deepining of the voice, frontal balding,increased muscule mass, clitoromegaly, increased libido and may features of defeminisation, such as decreased breast size and loss of vaginal lubrication.

4. Hisutism and virilism are both a clinical manifestation of androgen excess. The defect is either: -Increase androgen production. -increase androgen transport. -increase target organ response. The most common abnormality is increased androgen production which may arise from a functional or neoplastic process.

5. Pathophysiology: the main source of androgen in women are the adrenal, ovary and peripheral transformation in the liver and skin Androgen is synthesized from clolesterol together with estrogen,progesterone. The stimulus for ovarian androgen production is pituitary LH,for the adrenal is pituitary ACTH.

6. The most commonly studied androgen which have biological significance are : -Testosterone. -Androstendione -Dehydroepiandrosterone DHEA. -DHEAS. preandrogen Half of testosterone and androsteindione is produced by the ovary and other half from the adrenal. DHEA,DHEAS are mainly produced by the adrenal. 99% of androgen are protein bound (inactive) 1% is free (active).

7. All preandrogen are converted in the liver to testosterone,which is the main androgen. In the peripheral tissue testosterone is converted to dihydrotestosterone (greater potency). The pilosebaceous unit in the skin is sensitive to androgen stimulation,so they are the principal clinical sign of excess androgen production.

8. Causes of hirsutism: Disorder of adrenal origin: -cogenital or adult onset adrenal hyperplasia. -androgen-producing tumors Disorder of ovarian origin: 1-polycystic ovary syndrome 2-androgen producing tumor arrenoblastoma Granulosa-theca cell tumor lutoma of pregnancy 3-hyperthecosis 4-chronic anovulation associated with: hypothalamic amenorrhea emotional disorders thyroid disorder

9. Disorder of pituitary origin: -cushing’s syndrome -acromegaly Intersex problem: -male pseudohermaphroditism -Gonadal dysgenesis(turner’s syndrome)with androgen manifestation.

10. Drug induced: without virilization:phenytoin,diazoxide,ACTH,coticosteroids. With potential virilization:progesterone,anabolic agent,androgen therapy. Corticosteroid and androgen reduce SHBG so increase the free testosterone. Intrinsic factors: -genetic :racial, familial. -Physiologic :premature pubarche,precocious puberty,puberty,pregnancy and menopause. -Idiopathic.

11. Congenital adrenal hyperplasia: 21 hydroxylase deficiency : -first most common. - result in accumulation of 17-hydroxyprogesterone (normally not more than 200ng/dl ). -autosomal recessive -newborn present with ambiguous genitalia life threatening salt-wasting. -adolescent onset of severe hirsutism and virilism with menstrual irregularities. 11 B-hydroxylase deficiency result in accumulation of DHEA

12. Cushing’s syndrome: is the second major adrenal disease leading to excess cortisol and there is excess production of androgen as intermediate product. It’s due to pituitary adenoma, ectopic ACTH production or adrenal tumor. It’s characterised by : Truncal obesity. Moon like facies. Hypertention Impaired glucose tolerance Muscle wasting Osteoporosis Abdominal striae and easy bruisability. Acne with hirsutism Irregular menstrual cycle

13. Ovarian neoplasm: -androgen secreting ovarian tumors are extremely uncommon (functional tumor) or other like cystadenoma or krukenberg’s tumor (non functional) will stimulate proiferation in adjecent ovarian stroma result in increase androgen production. -Arrenoblastoma or sertoli-leydig cell tumor usually give rise to a palpable mass.

14. Evaluation of patient with PCOS: History : onset: sudden(neoplastic),gradual(PCOS) symptoms of hirsutism and virilism menstrual history:regular(ideopathic) drug history family history Examination: Distribution of hair: ( modified Ferriman and Gallway score )severity and follow up Body habitus and female contour Breast examination for atrophic changes Features of PCOS or cushing syndrome Pelvic examination to exclude ovarian tumor

15. Diagnostic evaluation: Laboratory evaluation: -free testosterone(androgen excess) level >200ng/dl suggest an adrenal neoplasm -17 hydroxyprogesterone (CAH)and DHEAS(adrenal cause) -LH:FSH ratio >3 indicate PCOS -If normal testosterone 5 alpha reductase for peripheral conversion -pelvic ultrasound (ovarian tumor,PCOS) -CT scan or MRI (adrenal and ovarian tumor) -Dexamethasone suppression test if cushing syndrome is suspected(1mg,8:00am cortiol level should be less than 5 microg/dl) if positive high dose test should be performed. -

16. Treatment : -treatment of the serious underlying cause as ovarian and adrenal tumors,hypophysectomy for cushing syndrome, corticosteroid for virilizing adrenal hyperplasia. -The largest group are of PCOS or idiopathic. -In idiopathic hirsutism medical treatment is used only after failure of cosmotic treatment. -In PCOS or when there is associated problem of infertility or menstrual cycle irregularities treat by induction of ovulation if the pregnancy is desired.

17. - Treatment require long time 6-9 month to notice the benefit Treatment require long time 6-9 month to notice the benefit so COCP is used together with other cosmotic treatment till the response is established. -Once the terminal hair is established treatment of the disease state will not remove the total excess hair growth but will slow the rate of growth. Cosmotic treament are: Temporary: Bleaching,shaving,chemical and wax depilators. Perminant: electrolysis,laser.

18. Medical treatment : Hormonal suppression: combined oral contraceptive pills: -decrease ovarian and adrenal production of steroids(androgen). -progesterone suppress LH reduce ovarian androgen synthesis. -Estrogen increase hepatic production of SHBG reduce free testosterone. -estrogen decrease the conversion of testosterone t DHT in the skin by inhibiting the 5 alpha reductase.

19. IMedroxyprogesterone. GnRH analgs Glucocorticoids: It’s used in a small dose of 0.25 mg to reduce the adrenal and ovarian androgen it’s side effect are adrenal suppression and osteoporosis when used on long term.

20. : antiandrogen: cyproterone acetate: is synthetic progesterone acts by inhibiting androgen binding to the cytoplasmic receptors. It cause irregular bleeding so it should be combined with ethinyl estradiol. High Dose treatment( 100mg) for first 10 days of each cycle combined with ethinylestradiol for 21 days, treatment required for 24- 36 months. dianette is 30microgram ethinyl estradiol with 2mg cyproterone acetate

21. spironolactone : is adiuretic,it inhibit androgen biosynthesis and have antiandrgen action in target cell. Dose is 25-100 mg daily both CPA and spironolactoe reguire contraception because the risk of feminization in male fetuses if pregnancy occur Other antiandrogen like flutamide,not used because their side effect(liver toxicity) with action similar to spironolactone.

22. Steroidogenic enzyme inhibitor : Ketoconazole :it can reduce androgen when given in a low dose of 200 mg/day. 5 alpha reductase inhibitor: Finasteride:7.5 mg /day also femenise male fetuses so it’s used with COCP(contraception ).