 Referred to as androgen excess

› Hyperandrogenemia
› Skin manifestations
 Acne
 Hisutism
 Alopecia
 Virilization (rare)
 Pilosebaceous Unit
› Abnormalities of the sebaceous component
 Acne
› Abnormalities of the pilary component
 Hirsutism
 Alopecia
 HIRSUTISM  VIRILIZATION
› Testosterone › Testosterone ≥2ng/mL
<1.5ng/mL › Rapid onset
› Gradual onset › Temporal balding,
› Mild: upper lip & chin clitoral hypertrophy,
› Severe: cheeks, chest, decreased breast
abdomen, thighs, size, dryness of the
lower back, vagina, increased
intergluteal area muscle mass
› Normal ovulatory › Almost always
menstrual cycles, amenorrheic
oligomenorrhea, or
amenorrhea
 FERRIMAN & GALLWEY SCORING
 Androgen sources of production
› Glandular sources
 Ovaries
 Adrenal glands
› Peripheral compartment (modulates
androgens produced by the ovarie and
adrenals
 Extrasplanchnic
 Nonglandular
 Ovaries
› Testosterone (0.1mg/day)
› Androstenedione (1-2mg/day)
› DHEA (<1mg/day)
 Adrenal glands
› Dehydroepiandrosterone sulfate (6-
24mg/day)
› Androstenedione (1mg/day)
 85% of testosterone is tightly bound to
sex hormonebinding globulin
 10-15% is loosely bound to albumin
 1-2% is free testosterone

 Total Serum Testosterone

› Biologically active testosterone
 Serum Free Testosterone
 Idiopathic Hirsutism and PCOS are the
most common disorders causing
androgen excess ( over 90% of cases)
 PCOS is the most frequent disorder
 Manifested by signs of hirsutism and regular
menstrual cycles in conjunction with normal
circulatory levels of androgens
 Families of Mediterranean descent
 A.k.a. familial/constitutional hirsutism
 Due to increased 5α-reductase activity
 A disorder of the peripheral compartment
 Tx: antiandrogens that block peripheral
testosterone action or interfere with 5α-RA
 Amenorrhea, hirsutism, and obesity in
association with enlarged polycystic
ovaries
 Definition: women who are anovulatory
and have irregular periods as well as
hyperandrogenism, as determined by signs
such as hirsutism or elevated blood levels of
androgens, testosterone, or DHEAS. This
should be in the absence of enzymatic
disorders, Cushing’s syndrome, or tumors
 Diagnosis does not require UTZ findings
 Polycystic-appearing Ovaries (PAO) or
Polycystic Ovarian Morphology (PCOM)
› No signs and symptoms of PCOS but with
polycystic ovaries
› May be a risk factor for PCOS
 Thin women may also have PCOS
 All symptoms of PCOS are worse in women who are
overweight or obese
 Characteristic endocrinologic features:
› ↑ GnRH pulse amplitude or
› ↑ pituitary sensitivity to GnRH
› ↑ LH causing anovulation
› ↑ circulating androgens produced by ovaries and adrenal glands
› Normal or ↓ FSH
› ↑ biologically active (non-SHBP-bound) estradiol – due to
decrease in SHBG levels brought about by increased androgens
and obesity, with high insulin levels
› ↑ estrone due to increased peripheral (adipose) conversion of
androgen
 Total circulating estradiol is not increased
› ↑ prolactin
 Some degree of insulin resistance occurs in most women
with PCOS, even in those of normal weight
 Insulin and IGF-1 enhance ovarian androgen production
› by potentiating the stimulatory action of LH on ovarian
androstenedione and testosterone secretion
 The granulosa cells also produce IGF-1 and IGF-binding
proteins (IGFBP)
› may result in paracrine control and enhancement of LH
stimulation and production of androgens by the theca cells in
women with PCOS
 IGFBP are lower in PCOS  increased bioavailable IGF-1 
increased stimulation of theca cells in combination with
LH  increased androgen production
 Insulin resistance is primarily a peripheral insulin resistance,
manifest primarily in muscle and adipose and minimally at
the level of ovary or adrenal
 Fasting glucose levels are a poor
predictor of diabetes
 HbA1C is the most efficient means of
ruling out glucose intolerance or frank
diabete
 Acanthosis nigricans – 30% of
hyperandrogenic women
 HAIR-AN Syndrome
› Hyperandrogenism
› Insulin Resistance
› Acanthosis Nigricans
 ↑ insulin and IGF-1 enhances
development of AN
 Müllerian-inhibiting substance (MIS) or
anti-müllerian hormone (AMH)
› Glycoprotein produced by granulosa cells of
preantral follicule
› Significantly ↑ in women with PCOS
 Due to the larger number of preantral follicles
› Measure of ovarian reserve and ovarian
aging
› Decreases with age
 Obesity is one of the major factors leading
to increased CV mortality and the
development of metabolic syndrome
 Adult Treatment Panel III Criteria (3 of 5 of
the following)
› Waist circumference >88cm
› High-density lipoprotein <50mg/dL
› Triglycerides >150mg/dL
› Blood pressure >130/85mmHg
› Fasting blood sugar >110mg/dL
 Treatment
› Before ovulation induction: BMI < 28 kg/m2
› Ovulation induction:
 Metformin
 Clomiphene
 Letrozole
 Gonadotropins
 Pulsatile GnRH
 Ovarian diathermy or drilling
 Uncommon benign ovarian disorder
 Ovaries are bilaterally enlarged to approx
5-7 cm in diameter
 Histologically: nests of luteinized theca cells
within the stroma
 Thick capsule like PCOS but subcapsular
cysts are uncommon
 Initially: anovulation or amenorrhea &
hirsutism
 At the 4th decade of life: virilization
 Produce excess testosterone (hirsutism
and/or virilization)
› Benign and malignant cystadenomas
› Brenner’s tumors
› Krukenberg’s tumors
 Germ cell tumors which almost always
cause virilization
› Sertoli-Leydig cell tumors (reproductive years)
› Hilus cell tumors (menopausal years)
 Produce increased amounts of testosterone
and/or DHEAS
› Lipoid cell (adrenal rest) tumors
 Generate large amounts of the C19 steroids
normally produced in the adrenal gland
› DHEAS
› DHEA
› Androstenedione
 Does not secrete testosterone directly
 Testosterone is produced by extraglandular
conversion of DHEA and androstenedione
 DHEAS > 8μg/mL
 Testosterone > 1.5ng/mL
 Dx confirmed by CT Scan or MRI of adrenal
glands
 TREATMENT
› Sertoli-Leydig cell tumors – unilateral
salpingo-oophorectomy
› Hilus cell tumors – bilateral salpingo-
oophorectomy and total abdominal
hysterectomy
› Adrenal adenomas and carcinomas –
operative removal
› Stromal hyperthecosis – bilateral salpingo-
oophorectomy with total abdominal
hysterectomy
 Congenital Adrenal Hyperplasia (CAH)
› Inherited disorder
› Caused by an enzymatic defect (usu. 21-hydroxylase or less
often, 11β-hydroxylase)
› Decreased cortisol biosynthesis
› ACTH secretion increases
› Adrenal cortisol precursors produced proximal to the enzymatic
block accumulate
› Converted mainly to 17-hydroxyprogesterone and
androstenedione  testosterone
› Musculinization of female external genitalia
› dSevere form: most common cause of sexual ambiguity in the
newborn
 Attenuated (mild) block of 21-hydroxylase does not
produce physical signs associated with increased
androgen production until after puberty
 A.k.a. late-onset congenital adrenal
hyperplasia
 Most frequent autosomal genetic disorder
in humans
 Autosomal recessive at the CYP21B locus
and are linked to the HLA-B locus
 Usually associated with menstrual
irregularity
 Postpubertal onset of hirsutism and
oligomenorrhea or amenorrhea
 Hx of accelerated growth (6-8 y.o.)
 Measurement of basal (early morning)
serum 17-hydroxyprogesterone levels
› If > 8 ng/mL – LOHD
› If >2.5 to 3.3 ng/mL and < 8 ng/mL – ACTH
stimulation test should be performed
 0.25 mg of synthetic ACTH infused as a single
bolus
 After 1 hr, if > 10 ng/mL - LOHD
 Corticosteroid treatment is reserved for
patients wishing to conceive to restore
ovulatory function
› Hydrocortisone 15 to 20 mg
› Prednisone 5 to 7.5 mg
› Dexamethasone 0.5 to 0.75 mg
 OCPs more efficient and safer
 Excessive adrenal production of
glucocorticoids caused by increased
ACTH secretion (Cushing’s disease) or
 Adrenal tumors produces the signs and
symptoms of Cushing’s syndrome

 Central obesity, dorsal neck fat pads,

abdominal striae, muscle wasting,
muscle weakness, hirsutism, menstrual
irregularity
 Overnight Dexamethasone Supression Test
› 1mg of dexamethasone ingested at 11PM
› Plasma cortisol is measured the following morning at 8AM
 If cortisol level > 5 μg/100mL – Cushing’s syndrome is
ruled out
 If cortisol level fails to supress to this degree –
diagnosis of Cushing’s syndrome is not established

 It is necessary to perform complete dexamethasone

depression test (Liddle’s test) or measure of urinary
free cortisol and plasma ACTH levels to determine
whether Cushing’s syndrome exists
 Creatinin level > 240μg (almost
diagnostic)
 May result from:
› Pituitary tumor producing ACTH (Cushing’s
disease)
› Ectopic tumor in the body
› Adrenal neoplasms
› Adrenal hyperplasia
 Assist in the diagnosis of
hyperandrogenism
 Assist in the diagnosis of
hyperandrogenism
› Total testosterone
› Free testosterone
› Free androgen index (more specific)
› Non-SHBG-bound testosterone (more
specific)
 Total testosterone
› More cost-effective to determine the
magnitude of elevated androgens
 Masculinizing ovarian or adrenal tumors (serum testosterone > 2
ng/mL)
› Bimanual pelvic exam
› Ultrasonography
› CT
› MRI
 Rapid progression of virilization and DHEAS > 8 μg/mL
› CT
› MRI
 Ovarian stromal hyperthecosis if with long history of gradually
increasing hirsutism and testosterone levels >1.5 ng/mL
 Menstrual irregularity is uncommon in women with idiopathic
hirsutism where testosterone and DHEAS are normal
 LOHD commonly have a family history of androgen excess and
dx is established by measurement of 17-hydroxyprogesterone
 Spironolactone and flutamide – most
frequently used agents
 Finasteride
 Cyproterone acetate (2mg) + ethinyl
estradiol
 Non-adrenergic progestogen
(desogestrel, norgestimate, drosperinon)
+ spironolactone (100-200mg) – first line
tx
 GnRH agonist with estrogen
 Alter lifestyle variables
 Exercise regimens
 Diet + Metformin 6-12 month therapy
 Reduce weight by 5-7% and insulin
resistance and improve metabolic
parameters
 Bariatric surgery
 Drosperinone and 17α-ethinylestradiol (EE2)
with flutamide and metformin – successful in
adolescents
 Because of the length of the hair growth
cycle, responses to treatment should not be
expected to occur within the first 3 months
of therapy
 Successful response should occur in approx
70% of women within 1 year of therapy
 Treatment should be continued for 4 years
then stopped to determine whether
hirsutism recurs
› If so, therapy can be reinitiated
 Electrolysis – remove remaining excess
hair
 Oral contraceptives
 GnRH agonist – expensive, reserved for
severe clinical manifestations
 Ketoconazole 200mg BID
 Spironolactone 50-200mg/day
 Finasteride 5mg/day
 Flutamide 250-500mg/day