hyperandrogenism-161029180748.pdf

1. Hyperandrogenis
m and virilization
Assoc Prof Dr Hanifullah
Khan
Amira, Atiqah, Sufia

2. Objectives
1. Androgen
2. Virilization
3. Causes and patophysiology
4. Sign and symptoms
5. Question

3. What are androgens?
 These are generally referred to as
male hormones
 They stimulate or control the
development and maintenance of
male characteristics
 They are also the precursors of
estrogens

4. Relationships between
hormones

5. 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

6. 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

7. 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.

8. 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

9. 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.

10. Ferrimen-Gallwey

11. Facial hair

12. Overview of
androgenic effects

13. Acanthosis nigricans
Male esutheon Receding hair line
Hirsutism

14. 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

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

16. 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)

17. CAUSES AND
PATHOPHYSIOLOGY

18. 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

19. 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

20. 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

21. 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

22. Ovaries

23. Other features

24. Metabolic syndrome

25. Acanthosis nigricans

26. 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

27. Primary adrenal disorders
 Cushing’s disease
 Congenital adrenal hyperplasia
 Adrenocortical neoplasms

28. 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

29. 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)

30. Congenital adrenal
hyperplasia
Depends on the nature and severity of
the enzymytic defect. Onset of clinical
symptoms can occur in the
• Perinatal period
• Later childhood
• Adulthood (less common)

31. 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.

32. Anterior pituitary
ACT
H
Cholesterol
Pregnolon
e
17 - hydroxypregnenolone
17 -
hydroxyprogesterone
21
11 – deoxycortisol
Cortisol
Glucocorticoids
Progesteron
e
21
Aldosteron
e
Corticosterone
11 -
deoxycortisone
Mineralocorticoids
Testosterone
Androstenedion
e
Dehydroxypiandrosteron
e
Sex
steroids
Adrenal cortex (bilateral
hyperplasia)
Congenital
adrenal
hyperplasia

33. 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

34. Tumours

35. 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.

37. The goals of lab testing
1
Document
androgen
excess
2
Other causes
of androgen
excess/
irregular
periods to be
ruled out
3
Look for
metabolic
abnormalities
Eg Glucose/
Lipids

38. 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

39. TVS

40. Therapy

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

42. History
1. What question would like to ask the
patient?

43. Examination
1. Firstly, what systems would you like
to assess
2. Secondly, what are the specific signs
would you like to elicit?

44. 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

45. 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

46. 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

47. Manage wisely