The document discusses hyperandrogenism and virilization. It begins by defining androgens and their effects on male characteristics. It then discusses the relationships between hormones and the sources of androgens. Several conditions are covered that can cause hyperandrogenism and virilization including polycystic ovary syndrome (PCOS), Cushing's syndrome, congenital adrenal hyperplasia, and androgen-secreting tumors. The signs, symptoms, causes, and pathophysiology of each condition are described. Laboratory tests and ultrasound are discussed for evaluating patients. Lastly, a case scenario is presented of a woman with irregular periods and potential diagnosis of PCOS is discussed.
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
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
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.
13. Male esutheon Receding hair line
Acanthosis nigricans 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)
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
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
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 Congenital
ACT
adrenal
H
Adrenal cortex (bilateral
hyperplasia
hyperplasia)
Cholesterol
Pregnolon
e
Progesteron
e 17 - hydroxypregnenolone Dehydroxypiandrosteron
21
e
11 -
17 - Androstenedion
deoxycortisone
hydroxyprogesterone e
21
Corticosterone
11 – deoxycortisol
Aldosteron Testosterone
e
Mineralocorticoids
Cortisol Sex
steroids
Glucocorticoids
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
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.
36.
37. The goals of lab testing
1 2 3
Other causes
of androgen Look for
Document excess/ metabolic
androgen irregular abnormalities
excess periods to be Eg Glucose/
ruled out 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
41. A 22 year old nulligravid women presents to her
gynaecologist because of irregular widely spread
menses
CASE SCENARIO
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