HIRSUTISM

Cutaneous Signs of AndrgenizationDr. Muhammad Saleem GhauriMBBS; MCPSSenior Consultant DermatologistSocial Security Hospital Faisalabad

A Recent ArticleSkin Often a 'Window' Into Underlying Endocrine DisordersTwo separate studies have provided new insights into cutaneous manifestations of common endocrine disorderswww.medscape.com/viewarticle/856696

First StudyHirsutism and the skin pigmentation disorder acanthosis nigricans, especially if located in the axillae, are the most reliable cutaneous markers of the polycystic ovary syndrome (PCOS) in womenTimothy Schmidt, MD, PhD, University of California, San Francisco

Second StudyPostadolescent males with acne are more likely to have insulin resistanceMohit Nagpal, MD, Postgraduate Institute of Medical Education and Research,Chandigarh, India

Both studies were published online December 23, 2015 in JAMA Dermatology.

The accompaying editorial

The two studies "highlight the important role that the dermatologist plays in identifying and characterizing patients with common skin disorders who may be at risk for metabolic and androgen mediated disease.

Published online December 23, 2015 in JAMA Dermatology

Androgens / AndrogenizationAndrogens: Male Sex Hormones (Steroids) produced by Testes (or Ovaries to a lesser extent) and Adrenal Cortex

Androgenization: Clinical evidence of / excessive production of Adrenal or Gonadal androgens

Androgen Biosynthesis in womenAdrenals and ovariesOvarian Source: Testosterone and the androgen precursor androstenedione Adrenal Source: PreandrogensDehydroepiandrosterone (DHEA), DHEA Sulfate, and Androstenedione. Peripheral conversion in the skin and liver to testosterone.Testosterone Dihydrotestosterone (by 5--reductase) Receptor molecules are necessary. Testosterone bound to carrier molecules (SHBG) in the plasma at a 99% level, and it is the unbound free testosterone that is active, the levels of free testosterone correlate with clinical evidence of androgen excess.

Hypothalamus-Pituitary-Adrenal/Ovarian Axis

Pathogenesis of AndrognizationExcessive secretion of androgens from either the ovary or the adrenal glandThe excessive secretion may be from functional excesses or, rarely, from neoplastic processesOvarian causes Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome)A variety of ovarian tumors, both benign and malignantAdrenal CauseCAHNon-classical Adrenal Hyperplasia (Adult-onset)Adrenal Tumors

ANDROGEN-DEPENDENT SYNDROMESPolycystic Ovarian Syndrome (PCOS)

Adrenal adenomas, carcinoma or hyperplasia, Leydig cell tumors in men and arrhenoblastomas in women.

Congenital Adrenogenital Syndrome (CAH) or late onset Adrenal Hyperplasia (Non-Classical CAH)

Cutaneous & other signs of Excess Androgens in women Acne, Hirsutism, Female Pattern Hair Loss, SeborrheaEnlargement of the clitoris, and decreased breast size.Hyperpigmentation of the skin, areolae, genitalia, palmar creases, and buccal mucosa in some patients.Acanthosis nigricans is common in PCOS. A deepening voice, increased muscle mass, galactorrhea, and irregular or absent periods are other signs of androgen excess in women.

HirsutismAn excess of terminal hair growth in women in a pattern more typical of menAndrogen-dependent growth areas affected Upper lip, cheeks, chin, central chest, breasts, lower abdomen, and groin.This altered growth pattern of the hair may be associated with other signs of virilizationFemale Pattern Hair Loss, masculine habitus, deepening of voice, clitoral hypertrophy, and amenorrhea.Acne is an additional sign of hyperandrogenism.

Hirsutism

Hirsutism

Ethnic Variation

Women of Southwest Asian, Eastern European and Southern European heritage commonly have facial, abdominal, and thigh hair; whereas Asian and Indian women generally have little terminal hair growth in these areas.

Acne / Hidradenitis Suppurativa

Seborrhoea Capitis

Female Pattern Hair Loss (FPHL)

Polycystic Ovary Sundrome (PCOS)PCOS is defined by:Anovulation (fewer than nine periods a year or periods longer than 40 days apart)Clinical evidence of hyperandrogenism. Ovarian cysts and laboratory and imaging studies are not required to establish the diagnosis. The pathogenesis of PCOS may relate to insulin resistance with resultant elevated insulin levels leading to ovarian overproduction of androgens.Prevalence rates of PCOS for black and white women in the US are 8.0% and 4.8%, respectively.

Polycystic Ovarian Syndrome (PCOS)Association of biochemical or clinical androgenism with chronic anovulation without specific underlying disease of the adrenal or pituitary glandsMost medically significant hirsutism is related to PCOSMenstrual irregularities, signs of androgen excess, obesity, insulin resistance, elevated serum luteinizing hormone (LH) levels, and increased risk of type 2 diabetes, cardiovascular events, and endometrial cancer

PCOSRotterdam Criteria: Two of the following three manifestations must be present: Irregular or absent ovulationClinical Evidence / Elevated levels of androgenic hormonesEnlarged ovaries containing at least 12 follicles each.A study of 873 patients of Hirsutism: PCOS -- 82%Elevated androgen levels with normal ovulation 6.75%.Idiopathic hirsutism -- 4.7%

Acanthosis Nigricans

Congenital Adrenogenital Syndrome / CAHAn inherited defect in any of the five enzymatic steps required to convert cholesterol to cortisolInadequate amounts of cortisol stimulates the pituitary to secrete excessive ACTH, which stimulates excess androgen productionIn boys, precocious puberty In girls, masculinization with the prominent cutaneous signs of excess androgen production.

Congenital Adrenal HyperplasiaAdrenogenital syndrome or Congenital Adrenal Hyperplasia (CAH): Autosomal-dominant disorder Deficiencies of the following enzymes: 21-hydroxylase (most common form, 95%), 11--hydroxylase, or 3--hydroxy steroid dehydrogenase. Onset is generally in childhood, with ambiguous genitalia, precocious growth, and virilism. Nonclassic (adult-onset) CAH may present with hirsutism.

Role of 21-Hydroxylase in Adrenal Steroidogenesis Pathway

Clinical Forms of CAH

Adrenogenital syndrome

Adrenal & Ovarian TumorsAdrenal tumors, such as adrenal adenomas and carcinomas.Ovarian Tumors:Unilateral benign microadenomasArrhenoblastomasLeydig cell tumors, hilar cell tumorsGranular/theca cell tumorsLuteomas are rare causes of hirsutism. In tumor-associated hirsutism, the onset is usually rapid, occurs with other signs of virilization, and begins between the ages of 20 and 40.

Pituitary & Prolactin related CausesCushing's disease, Acromegaly, and Prolactin-secreting adenomas. Prolactin-secreting Microadenomas have a 20% incidence of hirsutism and acne.Prolactin elevations may be seen in patients with PCOS.Other conditions in which prolactin levels may be elevated and that may lead to hirsutism include hypothyroidism, phenothiazine intake, and hepatorenal failure.

Other CausesExogenous intake of androgens. End-organ hypersensitivity may be a mechanism in patients with a normal evaluation with Hirsutism & FPHL Drugs such as minoxidil, diazoxide, corticosteroids, and phenytoin, which have been reported to cause hirsutism, generally cause hypertrichosis a generalized increase in hair that is not limited to the androgen-sensitive areas.

Evaluation

History:Onset and ProgressionVirilization, Menstrual and Pregnancy historyFamily / Racial background

Physical examination:Cushing's disease, hypothyroidism, or acromegaly. Distribution of muscle mass and body fatClitoral dimensions, voice depth, and galactorrhea.

ImagingPelvic Ultrasound: Helpful in PCOS

X-Ray skull: Pituitary fossa at times

CT Scan / MRI: May be required in case of Ovarian / Adrenal / Pituitary Tumors.

Lab EvaluationNeed is controversial.Of value only when it affects managementNo mandatory hormonal testing for stable hirsutism in patients who have no signs of virilizationPCOS does not require laboratory confirmationPCOS: Serum lipids and testing for glucose intolerance Suggestive Neoplasm: Total Testosterone levelSuggestive Adrenal Cause: DHEAS level Cushings Disease: 24-h urine cortisol Hypothyroidism: TSH levelAcromegaly: Growth hormone and Somatomedin C levels 17 Hydroxy Progesterone, ACTH stimulation, Prolactin level limited value

TreatmentSpironolactone Cyproterone acetate 2mg plus Ethinyl estradiol 35g2nd and 3rd generation Oral ContraceptivesFlutamide: 125mg to 500mg per day, HepatotoxicFinasteride: 2.5mg to 5mg per day Topical Eflornithine Insulin sensitizers (metformin) in PCOSProgestogen Drosperinone provide good cycle control in PCOS, with an improvement in acne but not in other manifestationsGonadotropin-releasing hormone agonists such as Leuprolide and NafarelinAlone and in various combinations

TreatmentContraception: Avoid the risk of Feminization of male foetus Hirsutism: Mechanical, Chemical or LASER / IPL epilationAcne: Topical &/or Systemic antibiotics (Tetracyclines, Macrolide), Benzoyl Peroxide, Topical Tretinoin / Isotretinoin, oral Isotretinoin in various combinationsSeborrhea Capitis: Antifungal shampoos, lotionsFPHL: Minoxidil 2% lotion BD or 5% Gel OD

Thank You!