HYPERANDROGENISM

HYPERANDROGENISM
• Any clinical or laboratory
evidence of androgen excess
in women
 Androgen
• Induce maleness
• Responsible in the fetus for
forming the male external
genitalia
• Absence of androgen or the
absence of testosterone
receptors results in a female
phenotype despite a 46 XY
karyotype.
• Also responsible for the
 Sources of Androgens in
Women
• Both the adrenals and the
ovaries secrete androgen, and
the pilosebaceous glands
metabolize secreted androgens
into more potent androgens.

– Ovarian androgen secretion

– Adrenal androgen secretion
Ovarian androgen secretion
Adrenal androgen secretion
 PERIPHERAL
COMPARTMENT
Androstenedione
and DHEA

Testosterone

2/3 = peripheral
1/3 = ovary conversion of
androstenedione to
testosterone
 Signs and Symptoms
• General
Appearance
–Muscular
male body
habitus (e.g.
Shoulder
girdle)
–Android
obesity
• Miscellaneous Changes
– Virilization
• characterized by temporal
balding, breast atrophy,
clitoral enlargement,
deepening of the voice, and
extreme hirsutism
– Deepening of voice
– Clitoromegaly
– Increased libido
clitoromegaly
• Menstrual Irregularity
–Amenorrhea
–Infertility
• Endocrine Changes
–HPN
–Hyperlipidemia
–Glucose Intolerance
• Skin Changes
– Hirsutism (Ferriman-Gallwey (F -G)
scoring system)
– Alopecia
• Vertex or crown hair loss
• Bitemporal hair loss may also
occur
– Acanthosis nigricans (HAIR-AN
syndrome)
– Oily skin
– Acne vulgaris
– Male sweat changes (malodorous
perspiration)
Alopecia
Acanthosis nigricans
 F – G scoring system
Body Area Evaluated Score
(Graded from 0 – 4*)
Upper lip
Chin
Upper abdomen
Lower abdomen
Thigh
Upper back
Lower back/ buttocks
*0 = no hirsutism; 4 = severe hirsutism
 Hyperandrogenic
Syndromes
• HAIR AN syndrome
• Polycystic Ovary Disease
(Stein – Leventhal Syndrome)
 Evaluation of
Hyperandrogenism
History
Onset Onset at menarche suggests
PCOS, idiopathic hirsutism or 21 –
hydroxylase deficiency. Onset
distinct from menarche suggests
Progression tumor.
Rapid progression of hirsutism or
other syptoms suggests tumor.

Physical Examination
Hirsutism and Acne PCOS or idiopathic hirsutism.
Virilization Ovarian or adrenal tumr,
hyperthecosis.
 Evaluation of
Hyperandrogenism
Laboratory Tests
Total and Free Testosterone Confirm hyperandrogenism, rule
out tumor.
17 – Hydroxyprogesterone Rule out mild 21 – hydroxylase
degiciency. Perform ACTH
stimulation test in patients of
Prolactin, TSH Askenazi Jewish
In all patients descent.
with oligo –
amenorrhea or dysfunctional
bleeding.
 Evaluation of
Hyperandrogenism
Imaging
Transvaginal Ultrasound Confirm polycystic ovaries, rule out
ovarian tumor.

Color – flow doppler – helpful adjunct

for tumor detection and localization.
CT of Adrenal Glands CT scan: Adrenal androgen –secreting
tumors usually can be detected.

MRI: Adrenal and some ovarian

tumors can be detected with MRI;
however, it is more useful for adrenal
lesions.

Radionucleide studies:
Iodonorcholesterol (NP-59) can light
up steroid – secreting areas of the
adrenal gland or ovary and, if
available, is helpful to differentiate
and locate a tumor hen other
Cause of Hyperandrogenism in
Reproductive aged women can be
divided into Five Categories:
1. Polycystic Ovary Syndrome (PCOS)
2. Idiopathic Hirsutism
3. Adrenal or Ovarian Steroidogenic
Enzyme Deficiencies
4. Ovarian and Adrenal Androgen
Secreting Hormone
5. Other Endocrine Disorders
a. Hyperprolactinemia with or
without pituitary Adenoma
b. Cushing Syndrome
c. Acromegaly
 Polycystic Ovary
Syndrome (PCOS)
• most
common
cause of
hirsutism
and most
common
endocrinopa
thy on
reproductive
Pathophysiology:
• Complex, heterogenous disorder
• It is likely genetic, environmental
factors and that no single gene
mutation will be found that is
both necessary and sufficient to
cause PCOS
• The familial clustering that
occurs in PCOS is consistent with
genetic susceptibility
• Autosomal dominant inheritance
• CYP 11 gene – encodes
cholesterol side-
chain cleavage
enzyme
• PCOS ovaries are defined on
ultrasound by 10 or more 2-8 mm
follicles and an increased,
echodense stromal area
• Elevated levels of total or free
testosterone, which do not
suppress normally with
• About one half of PCOS subjects
have increased adrenal
androgen production as defined
by increased ketosteroid
response to ACTH, with the
adrenal being the primary source
of androgen excess in those with
adrenal hyperandrogenism
• LH hypersecretion (90%)
• Women with PCOS are
hyperinsulimic and insulin
 Ovarian hyperthecosis
• Rare variant of PCOS
• Present in both pre and post
menopausal women
• (+) virilization, ↑ testosterone
levels (>200 ng/dl), lower levels
of LH than classic PCOS
• They are obese and have an
extreme insulin resistance.
 Idiopathic Hirsutism
• Excess
terminal hair
production in
androgen-
dependent
areas in the
of regular
ovulation and
normal
androgen
Pathophysiology:
• Secondary to increased 5
alpha-reductase activity in
the skin or its appendages
• Alterations in androgen
metabolism
• Increased sensitivity of
androgen receptors
 Adrenal or Ovarian
Steroidogenic Enzyme
Deficiencies

• Uncommon to very rare

 Ovarian and Adrenal
Androgen Secreting
Tumors

• Rare causes
Androgen secreting ovarian
tumors:

• Sertoli-leydig cell tumors

• Leydig cell tumors
• Lipoid or lipid cell tumors
• Granulose-theca cell tumors
• Adrenal adenoma and
carcinoma
- may present with
virilization and
hyperandrogenemia
• Women with androgen
secreting tumors have abrupt
onset of symptoms distinct
from menarche and a more
rapid progression of
symptoms compared to
PCOS.
Signs of
virilization
are
common:

• Clitoromegal
y
• Frontal
balding
• Deepening
of the voice
• Testosterone
levels are
usually
greater than
 Other Endocrine
Disorders
• Hyperprolactinemia with or
without pituitary adenoma
 Other Endocrine
Disorders
• Cushing’s
syndrome –
can be ruled
out by a
normal 24
hour urinary
cortisol or
normal
overnight
dexamethason
 Other Endocrine
Disorders
• Acromegaly
-
Somatomedi
n C level
(IGF-I) and/or
growth
hormone
suppression
test should
be done.
 Laboratory
• Serum Testosterone (N = 20 – 80
ng/dl)
– Measure on 2 separate occasions
– Level < 200: Hyperandrogenic Chronic
Anovulation
– Level > 200: Assess for virilizing tumor
 Laboratory
• Serum 17a – Hydroxyprogesterone
(N = < 2 ng/dl)
– Test > 4 ng/ ml suggests Congenital
Adrenal Hyperplasia
– Check Adrenocorticotropic stimulation
test
 Laboratory
• Dehydroprogesterone Sulfate (N =
250 – 300 ng/dl)
– DHEAS < 700 ng/ dl: Hyperandrogenic
Chronic Anovulation
– DHEAS > 700 ng/ dl: Adrenal tumor
secreting androgens
 Laboratory
• Other laboratories to consider
– Dexamethasone Suppression Test (AM
Serum Cortisol)
• Assess for Cushing’s Syndrome
– Leutinizing Hormone and Follicle
Stimulating Hormone
• Assess for ovarian tumors
– Lipid Profile
• Lipids elevated in hyperandrogenism
 DIAGNOSIS
• Testosterone level is greater than
200 ng/ dl; DHEAS level is normal.

– Possible Diagnosis: Rule out ovarian

neoplasm
– Workup
• CT scan of adrenals
• Pelvic ultrasound
• Ovarian and adrenal venous sampling
 DIAGNOSIS
• Testosterone level is variable; DHEAS
level is greater than 7 microgram/dl.

– Possible Diagnosis
• Possible adrenal tumor
• Possible Cushing Syndrome
– Workup
• Adrenal CT scan
• Dexamethasone suppression test
 DIAGNOSIS
• Testosterone level is greater than 70
ng/ dl; DHEAS level is elevated but less
than 7 microgram/dl.

– Diagnosis
• PCOS
• Possible adrenal tumor
• Possible Cushing Syndrome
– Workup
• NO further workup
• Rule out Cushing Syndrome
• Rule out CAH
 DIAGNOSIS
• Testosterone level is normal; DHEAS
level is normal.

– Possible Diagnosis
• End – organ Sensitivity
• Decreased SHBG
– Workup
• Free Testosterone
• 5 – alpha – androstanediol – glucuconide
TREATMENT of HIRSUTISM

Medical Therapy
 Treatment of Hirsutism
Aim:
• Suppress androgen production, block
androgen receptors or decrease the
conversion of testosterone to
dihydrotestosterone by inhibition of
the enzyme 5 alpha – reductase.
 Treatment of Hirsutism
• Oral Contraceptive Pills
– Commonly used to treat px with hirsutism
and other signs of androgen excess.
– inhibits pituitary secretion of LH ->
decreases ovarian androgen production
– progestins also deacrease adrenal DHAS
production -> via negative feedback loop
through the glucocorticoid receptor
– estrogen component – increases
production of SHBG -> decrease the
amount of free testosterone available.
 Treatment of Hirsutism
• NOTE: all formulations of low dose
(<35microgram ethinyl estradiol) OCP
available today, despite the touted
differences in their progestational
components, have low androgenic
potential and are probably equally
efficacious in treating acne and hirsutism.
• OCP are excellent choice for px with
abnormal cycles and acne but used alone
are not the most efficacious therapy for
hirsutism
 Treatment of Hirsutism
• Gonadotropin ReleasingHormone
Agonists
– Such as Leuprolide acetate
– Suppresses ovarian androgen
production by inhibiting pituitary
gonadotropin secretion.
– Result = decreased levels of circulating
testosterone and androstenedione with
no effect on adrenal androgens.
 Treatment of Hirsutism
• Glucocorticoids
– Hirsutism secondary to late – onset
congenital adrenal hyperplasia or
functional adrenal hyperandrogenism
may respond to tratment with low doses
of glucocorticoids, 5 mg of prednisolone
or 0.25 mg of dexamethasone every
other day.
 Treatment of Hirsutism
• Androgen Receptor Antagonists
– Cyproterone Acetate
• First androgen receptor antagonst used
clinically .
• Competitive inhibitor of testosterone and
dihydrotestosterone recepto binding
• Has progestational and weak glucocorticoid
properties.
 Treatment of Hirsutism
• Androgen Receptor Antagonists
– Spironolactone
• Competitive inhibitor of the aldosterone
receptor
• Usually utilized as a potassium sparing
diuretic.
• Soon, discovered to have antiandrogenic
properties in combi with OCP
• First line treatment of hirsutism
 Treatment of Hirsutism
• Androgen Receptor Antagonists
– Spironolactone
• MECHANISMS:
– Blockade of androgen receptors in the hair follicle
– Inhibits androgen biosynthesis through the
cytochrome p450 system and directly inhibits 5
alpha – reductaseactivity.
• Dosage: 200 mg/d for at least 3 – 6 months
• Efficacy alone: 75 – 95% using subjective
measures such as px satisfaction and F-G
score; objective decrease in hair shaft
diameter.
• S/E: irregular vaginal bleeding, polyuria,
fatigue
 Treatment of Hirsutism
• Androgen Receptor Antagonists
– Spironolactone
• IMPORTANT: use of spironolactone, as with
all antiandrogens = pregnancy can still
occur with the theoretical potential for
feminization of male fetuses.
• It also control AUB and possibly potentiate
the effect of spironolactone.
 Treatment of Hirsutism
• Androgen Receptor Antagonists
– Flutamide
• Nonsteroidal antiandrogen that appears to
work only at the androgen receptor.
• Dosage: 250 mg/d for 6 months
• Severe hyperandrogenism or alopecia may
respond better to flutamide.
• S/E: most are mild including dry skin and
increased appetite.
 Treatment of Hirsutism
• 5 alpha – reductase
– Finasteride
• Potent inhibitor of 5a – reductase
• Reduces the conversion of testosterone to
its active metabolite dihydrotestosterone.
• Initially used to treat benign prostatic
hypertrophy
• Recently a low dose (Propecia, 1 mg/ d) has
been approved in the treatment of male
pattern baldness.
• Well tolerated with minimal S/E at the
standard dose of 5 md/d
 Treatment of Hirsutism
• Insulin Sensitizing Agents
– Metformin
• decrease F – G score and objective hair
growth rate by about 15% in women with
PCOS.
• Overall S/E on hirsutism appears to be
modest.
• No studies of these agents compared to
standard OCP/andtiandrogen therapies.
TREATMENT of HIRSUTISM

Non – Medical Therapy

 TREATMENT of HIRSUTISM
• Shaving
– fast, simple and inexpensive means of
temporary hair removal.
– Hair quickly regrows at a normal rate.
– Some studies (mice) revealed that
shaving may actually induce hair to
change from telogen to the anagen or
growth phase.
 TREATMENT of HIRSUTISM
• Epilation
– Includes plucking and waxing
– Involves removal of the hair from the
bulb.
– Does not change the rate of hair growth
but repeated plucking may lead to a
delay in the return of anagen and
thinner hair secondary to permanent
matrix damage.
– Acceptable means of removal.
– Only temporary, lasts 2 – 3 weeks longer
associated with pain and infammation at
 TREATMENT of HIRSUTISM
• Depilatories
– Painless method that generally last
longer than shaving without bristly
regrowth of hair
– Act by breaking the sulfide bonds in hair
causing it to break off at or just beneath
the surface of the skin
– S/E: irritative dermatitis (m/c)
 TREATMENT of HIRSUTISM
• Electrolysis
– Permanent method of hair removal that
utilizes electrical current to destroy the
hair follicle.
– Slow technique that may take months of
repeated therapy.
– S/E: pain during and shortly after the
treatment, scarring, pigmentation
changes and local infection.
 TREATMENT of HIRSUTISM
• Lasers
– Destroy hair follicle.
– Implies that a spcific target is utilized
that can absorb light at a specific
wavelength.
– M/C chromophore that lasers are
targeted against is melanin = high
concentration in the hair follicle but not
the surrounding dermis.
 TREATMENT of HIRSUTISM
• Photodynamic therapy
– Utilizes light and a chemical
photosensitizer to permanently destroy the
hair follicle.
– Best studied: topical use of ALA
– ALA = induce the synthesis of a potent
photosensitizer, photoporphyrin IX in the
hair follicle, when activated by red light will
cause cell membrane damage by the
formation of oxygen free radicals
– ADV: ability to quickly treat larger areas,
however, still in the developmental stage.
 TREATMENT of INSULIN
RESISTANCE AND OTHER
METABOLIC ABNORMALITIES
Weight Loss
 TREATMENT of
ANOVULATION
Anovulation is the primary cause of
infertility in about 20% of couples, and
PCOS is estimated to be the cause of
70% of anovulatory fertility
 TREATMENT of
ANOVULATION
• Clomiphene citrate
– Still the first line of therapy for ovulation
induction in women with PCOS
– Satandard dosage: 50 mg/d for 5 days
beginning on cycle day 3 – 5 following
spontaneous or progestin – induced
bleeding.
– If serum progesterone in the mid luteal
phase is less than 10 ng/ml, the dose
can be increased by 50 mg/d in
subsequent cylcles to a dose of 150
mg/d.
 TREATMENT of
ANOVULATION
• Metformin
– Dosage: 150 – 1700 mg/d = significantly
increases rates of spontaneous
ovulation and clomiphene – induced
ovulation.
 TREATMENT of
ANOVULATION
• Cortecosteroids
– Short course of Dexamethasone
• 0.5 – 2 mg daily with clomiphene citrate.
• Reduces adrenal androgen production
thereby reducing peripherally produced
estrogens and estrogen negative feedback
on FSH secretion
• Or reduced adrenal androgens may also
result in decreased peripheral conversion of
DHEAS and androstenedone to testosterone
and thereby reduce follicular atresia.
SURGICAL OVULATION
INDUCTION
Final option in treating
Clomiphene citrate resistant
PCOS
 SURGICAL OVULATION
INDUCTION
• Bilateral Ovarian Wedge Resection
– Primary therapy to induce ovulation in
PCOS for many years.
– About 80% of patients treated ovulated
at some point after therapy and about
55% achieved pregnancy.
 SURGICAL OVULATION
INDUCTION
• Laparoscopic methods to surgically
induce ovulation in women with PCOS.
– Electrocautery or laser is used to produce
multiple burns in the ovarian capsule, or
ovarian tissue may be excised by scissors.
– All result in similar rates of ovulation and
pregnancy.
– ADV: result in long term ovulation without
any other therapy.
– Miscarriage and multiple pregnancy rates
are low, but similar to those seen with low-
dose gonadotropin therapy.