Androgens Testosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, and androstenediol The ovaries produce 50% of circulating testosterone, 50% of the androstenedione and 20% of DHEA. The adrenal glands produce all the DHEAS and 80% of the DHEA. The adrenals also secrete 50% of androstenedione and 25% of circulating testosterone. Adrenal androgens increase in response to ACTH stimulation LH stimulates theca cells of the ovaries to secrete androgens
Effect of androgens Fat deposition (small breast) Androgens inhibit the ability of some fat cells to store lipids Muscle mass (heavy mascular mass) Androgens promote the enlargement of skeletal muscle cells Brain Enhanced libido.
Effects of androgens on skin Pilosebaceous unit (PSU) Androgens cause excess sebum secretion. Lesions of the PSU are called acne. Hair androgens promote the conversion of vellus hairs to coarser terminal hair. excess growth of terminal hair in a male pattern is called hirsutism. Follicles shrink causing a receding hair line
Hirsutism Excessive male pattern hair growth (face, back, chest, abdomen and inner thighs) Graded with the Ferriman and Gallwey scoring system Hirsutism of rapid onset and growth (over a few months) should raise the concern of an androgen secreting tumour or intersex state Please note that the appearance of hair on the upper lip or mild hirsutism does not necessarily constitute hyperandrogenism, and ethnic origin should be taken into consideration.
Male esutheon Receding hair lineAcanthosis nigricans Hirsutism
Why do women haveandrogens? Androgens have important functions in women ◦ Essential in the production of E2 (in ovary & adipose tissue) ◦ Responsible for dev. & maint. of axillary & pubic hair ◦ Important for libido
VirilizationThe development of exaggerated masculinecharacteristics, usually in women, often as a result ofoverproduction of androgensSo, if hyperandrogenism becomesextreme, virilization occurs
Symptoms of virilization Symptoms of virilization include ◦ excess facial and body hair (hirsutism), ◦ baldness ◦ acne ◦ deepening of the voice ◦ increased muscularity ◦ an increased sex drive. In women, ◦ the uterus shrinks ◦ the clitoris enlarges (clitoromegaly) ◦ the breasts become smaller ◦ normal menstruation stops (amenorrhea)
Hyperandrogenism Excess of androgens may be caused by: ◦ primary gonadal disorders ◦ primary adrenal disorders ◦ iatrogenic In practice though, the causes are restricted to a few conditions: PCOS Cushing’s syndrome CAH Tumours
PCOS ◦ A primary gonadal disorder Characterized by multiple small cysts within the ovary and by excess androgen production from the ovaries ◦ Increase in LH and androgen secretion ◦ Low aromatase levels (due to FSH levels) therefore androgens can’t be converted to estrogens in peripheral tissue Excess androgens converted to testosterone in peripheral tissue
Features of PCOS• Symptoms- • Oligomenorrhoea/ammenorhea • Excessive hair • Infertility • May present with metabolic symptoms• Sign- • Hirsutism • Acne • Acanthosis nigricans (increased velvety skin pigmentation ex at the axilla) • Obesity• Ix – • Clinical/biochemical signs of hyperandrogenism (hirsutism) • Polyystic ovaires by ultrasound
Rotterdam criteria 2003 A meeting in Rotterdam crafted compromise criteria ◦ Any two features from Irregular cycles Hyperandrogenism Ultrasound demonstration of polycystic ovaries ◦ (Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81:19) Importantly, the Rotterdam criteria allows for ◦ the previously excluded ovulatory women with features of PCOS ◦ as well as for women with irregular cycles and polycystic ovaries, but without any evidence of androgen excess
Cushing’s disease ◦ Primary hypothalamic-pituitary disease ◦ Oversecretion of ACTH from pituitary ◦ Presence of adenoma or areas of corticotroph cell hyperplasia in the anterior pituitary ◦ Lead to cortical hyperplasia ◦ Causes hypercortisolism, hyperandrogenism
Signs of Cushing’s Hypercortisolism ◦ central obesity, hyperhidrosis ◦ buffalo hump, moon face, striae Hyperandrogenism ◦ hirsutism, male pattern baldness, acne, deepening of the voice, muscularity, and an sex drive ◦ uterus shrinks, (clitoromegaly), the breasts become smaller, and normal menstruation stops (amenorrhea)
Congenital adrenalhyperplasiaDepends on the nature and severity ofthe enzymytic defect. Onset of clinicalsymptoms can occur in the• Perinatal period• Later childhood• Adulthood (less common)
Congenital adrenal hyperplasia◦ Autosomal recessive deficiency of an enzyme in the cortisol synthetic pathways.◦ Cortisol secretion is reduced and feedback leads to increased ACTH secretion to maintain adequate cortisol leading to adrenal hyperplasia.◦ Diversion of the steroid precursors into the androgenic steroid pathways occurs. Thus, 17- hydroxyprogesterone, androstenedione and testosterone levels are increased, leading to virilization.
Anterior pituitary Congenital ACT adrenal H Adrenal cortex (bilateral hyperplasia hyperplasia) Cholesterol Pregnolon e Progesteron e 17 - hydroxypregnenolone Dehydroxypiandrosteron 21 e11 - 17 - Androstenediondeoxycortisone hydroxyprogesterone e 21 Corticosterone 11 – deoxycortisol Aldosteron Testosterone e Mineralocorticoids Cortisol Sex steroids Glucocorticoids
Adrenocortical neoplasms Adrenocortical neoplasms associated with symptoms of excess of androgen are more likely to be androgen secreting adrenal carcinomas than adenomas. It is also often assoc with hypercortisolism (mixed syndrome) The tumour secretes androgen thus increasing in circulation and converted to testosterone at the peripheral
Androgen secreting tumours May occur at any age. relatively rare. should be suspected when the onset of androgenic symptoms is sudden (i.e., generally <2 yr) and the pace of symptoms is rapid, and when they lead to virilization and masculinization. may be associated with other systemic symptoms including weight loss, anorexia, a feeling of abdominal bloating, back pain.
The goals of lab testing 1 2 3 Other causes of androgen Look forDocument excess/ metabolicandrogen irregular abnormalities excess periods to be Eg Glucose/ ruled out Lipids
Lab Testosterone and Dehydroepiandrosterone sulphate (DHEAS) ◦ DHEAS hyperandrogenemia of adrenal origin Serum prolactin thyroid stimulating hormone (TSH) Serum 17 hydroxyprogesterone (17-OHP) test –if suspect CAH LH and FSH ( suggestive of PCOS if ratio >2) Lipid profile OGTT ◦ Relying on a fasting glucose level alone is inadequate as it is a poor predictor of impaired glucose tolerance or diabetes
A 22 year old nulligravid women presents to hergynaecologist because of irregular widely spreadmensesCASE SCENARIO
History1. What question would like to ask the patient?
Examination1. Firstly, what systems would you like to assess2. Secondly, what are the specific signs would you like to elicit?
Further clues Menarche was at the age of 14, but she has rarely had regular cycles. For the past year she has had only three complete menses. Once going 6 months between period. She is 165cm and weighs 83kg. She is over weight, with acne and a few dark hairs on her upper lip and chin. She is sexually active and uses condom for contraception.3. What is the likely diagnosis
Summary of causes &diagnosis PCOS. ◦ At least two of the following three abnormalities were present: chronic anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound NCAH. ◦ Clinical hyperandrogenism + increased serum 17OHP or mildly increased serum 17OHP with an increased response to ACTH ( Androgen-secreting tumors. ◦ The finding of an androgen-secreting tumors (ovarian or adrenal) in women with very high serum androgen levels Idiopathic hirsutism. ◦ Normal serum androgen levels (T, free T, and DHEAS) in the presence of normal ovulatory cycles and normal ovaries on ultrasound. Idiopathic hyperandrogenism. ◦ Clinical hyperandrogenism, increased serum androgen levels in the presence of normal ovulatory cycles, and normal ovaries on ultrasound
References Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: toward a rational approach. In: Dunaif A, ESHRE/ASRM Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81:19-25. The Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41- 47. Azziz R, Carmina E, Dewailly D, et al. Androgen Excess Society. Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endo & Metab 2006; 91(11): 4237-4245. Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, Taylor K, Boots LR 2004 Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 89:453–462 E. Carmina, F. Rosato, A. Jannì, M. Rizzo, and R. A. Longo Relative Prevalence of Different Androgen Excess Disorders in 950 Women Referred because of Clinical Hyperandrogenism. JCEM 2006 91: 2-6; doi:10.1210/jc.2005-1457