Hyperandrogenism and

virilization

Assoc Prof Dr Hanifullah Khan

Amira, Atiqah, Sufia

Objectives

1. Androgen2. Virilization3. Causes and patophysiology4. Sign and symptoms5. Question

What are androgens?These are generally referred to

as male hormonesThey stimulate or control the

development and maintenance of male characteristics

They are also the precursors of estrogens

Relationships between hormones

AndrogensTestosterone, 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

Figure 1 Schematic overview of the generation of androgen precursors and their conversion towards active androgens in women.

Arlt W Eur J Endocrinol 2006;154:1-11

© 2006 Society of the European Journal of Endocrinology

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.

Ferrimen-Gallwey

Facial hair

Overview of androgenic effects

Acanthosis nigricans

Male esutheon Receding hair line

Hirsutism

Why do women have androgens?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

Virilization The development of exaggerated masculine characteristics, usually in women, often as a result of overproduction of androgensSo, if hyperandrogenism becomes extreme, virilization occurs

Symptoms of virilizationSymptoms 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)

CAUSES AND PATHOPHYSIOLOGY

HyperandrogenismExcess of androgens may be caused

by:◦primary gonadal disorders◦primary adrenal disorders◦ iatrogenic

In practice though, the causes are restricted to a few conditions:PCOSCushing’s syndromeCAHTumours

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

Developmental origin of PCOS (adapted from Abbott et al., 2002).

Hum. Reprod. Update 2008;14:293-307

© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Ovaries

Other features

Metabolic syndrome

Acanthosis nigricans

Rotterdam criteria 2003A 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

Primary adrenal disordersCushing’s diseaseCongenital adrenal hyperplasiaAdrenocortical neoplasms

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’sHypercortisolism

◦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 adrenal hyperplasiaDepends on the nature and severity of the enzymytic defect. Onset of clinical symptoms 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

ACTH

Cholesterol

Pregnolone

17 - hydroxypregnenolone

17 - hydroxyprogesterone

21

11 – deoxycortisol

CortisolGlucocorticoid

s

Progesterone

21

Aldosterone

Corticosterone

11 - deoxycortisone

Mineralocorticoids

Testosterone

Androstenedione

Dehydroxypiandrosterone

Sex steroids

Adrenal cortex (bilateral hyperplasia)

Congenital adrenal

hyperplasia

Adrenocortical neoplasmsAdrenocortical 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 tissues.

Tumours

Androgen secreting tumoursMay 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

Document androgen

excess

2Other

causes of androgen excess/ irregular

periods to be ruled

out

3Look for

metabolic abnormalit

iesEg

Glucose/ Lipids

Lab Testosterone and Dehydroepiandrosterone

sulphate (DHEAS)◦ DHEAS hyperandrogenemia of adrenal origin

Serum prolactinthyroid stimulating hormone (TSH)Serum 17 hydroxyprogesterone (17-OHP) test

–if suspect CAHLH and FSH ( suggestive of PCOS if ratio >2)Lipid profileOGTT

◦ Relying on a fasting glucose level alone is inadequate as it is a poor predictor of impaired glucose tolerance or diabetes

TVS

Therapy

CASE SCENARIO

A 22 year old nulligravid women presents to her gynaecologist because of irregular widely spread menses

History

1. What question would like to ask the patient?

Examination

1. Firstly, what systems would you like to assess

2. Secondly, what are the specific signs would you like to elicit?

Further cluesMenarche 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

Manage wisely