Hyperandrogenism & chronic anovulation and exclude secondary causes such as
neoplasm, hyperprolactinemia, and adult-onset congenital adrenal hyperplasia.
1. Pathology
Macroscopically, white thickened cortex with multiple cysts that are typically less
than 1cm in diameter.
Microscopically,
Superficial cortex is fibrotic & hypocellular and may contain prominent blood
vessels
Increased number of follicles with luteinized interna.
Stroma : luteinized stromal cells.
2. Pathophysiology & Lab. findings
Dysregulation of the cytochrome P-450c17, the androgen-forming enzyme in both
the adrenals and the ovaries, may be the central pathogenetic mechanism underlying
hyperandrogenism in PCOS
Peripheral compartment : skin, adipose tissue
The presence of 5-a-reductase in the skin largely determines the presence or
absence of hirsuitism
Aromatase and 17-b-HSD activities are increased in fat cells and peripheral
aromatization is increased with body weight.
The metabolism of estrogens, by way of reduced 2-hydroxylation and
17-a-oxidation, is decreased.
Whereas E2 is at a follicular phase level in PCOS patients, E1 levels are
increased as a result of peripheral aromatization of androstenedione
Chronic hyperestrogenic state results with reversal of the E1:E2 ratio.
Hypothalamic - pituitary compartment
GnRH pulse frequency --> LH pulse frequency ↑
LH pulse frequency --> LH↑,LH/FSH ratio ↑
FSH : not increased with LH (because of the synergistic negative feedback of
chronically elevated estrogen levels and normal follicular inhibin.)
Elevated prolactin level : abnormal estrogen feedback to the pituitary gland.
3. Insulin Resistance
Most common cause of insulin resistance & compensatory hyperinsulinemia
: obesity
Acanthosis nigricans
Marker for insulin resistance in hirsute women
Thickened, pigmented, velvety skin lesion -- vulva, axilla, nape of the neck, below
the breast, inner thigh
USG -- Ovarian size is increased. Bilaterally increased number of microcysts
measuring 0.5 ~ 0.8 cm with generally more than five microcysts in each ovary
5. Long-term risks
Coronary artery disease.
Persistently elevated estrogen levels, uninterrupted by progesterone --> increased the
risk of endometrial cancer.
Pituitary ACTH-secreting adenomas or Cushing's disease are the most common cause
of Cushing's syndrome.
Ectopic ACTH syndrome is most often caused by malignant tumors
ex) Small-cell carcinoma of the lung, bronchial & thymic carcinoma, Carcinoid tumor
of the pancreas, medullary carcinoma of the thyroid
The hallmark of ACTH-dependent forms of Cushing's syndrome
; presence of normal or high plasma ACTH concentrations with increased cortisol
levels.
; adrenal glands -- hyperplastic bilaterally
The most common cause of ACTH-independent Cushing's syndrome is exogenous or
iatrogenic (superphysiologic therapy with cortical steroids) or factitious (self-induced)
Figure 25.2
Table 25.4
2. Treatment of Cushing syndrome : surgical removal of a neoplasm
3. Treatment of Ectopic ACTH/CRH-producing neoplasm
a. Surgical therapy : Trans-spheroidal resection
b. Radiation therapy ; high-voltage external pituitary radiation
In the ACTH stimulation test, plasma levels of 17-HP are checked 1 hour following
intravenous administration of a bolus of 0.25mg ACTH 1-24
17-HP levels after ACTH stimulation in adult-onset adrenal hyperplasia are
generally > 1000 ng/dl.
2. Clinical Presentation
PCOS (39%)
Hirsuitism alone without amenorrhea (39%)
Cryptic(22%) -- Hyperandrogenism but no hyperandrogenic symptom
3. Genetics
21-hydroxylase gene is located on the short arm of chromosome 6 in the midst of
the HLA region
21-hydroxylase gene is now termed CYP 21,
Its homologue is the pseudogene cyp21p
The CYP21 gene & the CYP21p pseudogene alternate with two genes called C4b &
C4a, both of which code for the fourth component(C4) of serum complement
4. 11-β hydroxylase def.
11-deoxycortisol levels are higher than 25ng/ml 60min. after ACTH 1-24 stimulation
Classic pattern
a. Diagnosed at a younger age.
b. Virilization, hypertension with related cardiomyopathy
c. Retinopathy.
5. 3-β hydroxysteroid dehydrogenase def.
6. Treatment of adult-onset adrenal hyperplasia
Dexamethasone - evening administration is more effective with a dosage of
0.25 - 0.5mg.
F. Androgen-secreting Ovarian & Adrenal Tumors
In prepubertal girls, virilizing tumors may cause signs of heterosexual precocious
puberty in addition to hirsuitism, acne, and virilization
Markedly elevated testosterone level (2.5times the upper normal range or over
200ug/dl) : typical of an ovarian tumor
DHEAS level > 8ug/ml --> typical of an adrenal tumor
Evaluation ; Vaginal & abdominal ultrasound, CT scanning. MRI, Selective venous
catheterization, nuclear medicine scanning of the abdomen and pelvis after injection
with Np-59
G. Androgen-Producing Ovarian Neoplasm
1. Granulosa cell tumor
Associated with estrogen production
Most common functioning tumors in children & lead to isosexual precocious
2. Thecoma
Rarely malignant, rarely bilateral
3. Sclerosing stromal tumor ; 30 yrs old↓
4. Sertoli-leydig cell tumor
Most common virilizing tumors in women of reproductive age.
5. Pure sertoli cell tumor
6. Gynandroblastoma
7. Sex cord tumors with annular tubulesSCTAT)
Associated with Peutz-Jeghers syndrome (GI polyposis, mucocutaneous melanin
pigmentation)
SCTAT with P-J SD ; bilateral, benign
SCTAT without P-j SD : unilateral ,malignant
H. Stromal hyperplasia & Stromal HyperThecosis
1. Stromal hyperplasia
Nonneoplastic proliferation of ovarian stromal cells.
Oral or vag. Bromocriptine, pergolide, cabergoline, methergoline, CV205-502
Repeat MRI at 6^12 months after prolactin levels are normal.
: Normal prolactin levels and resumption of menses should not be considered
proof of tumor response to treatment.
Discontinuation of bromocriptine therapy after 2 to 3 yrs - because some
adenomas undergo hemorrhagic necrosis & cease to function
Further MRI ; only to evaluate new symptoms.
Macroadenoma
Symptoms ; severe headache, visual change, Diabetes Insipidus, blindness
Follow Up ; after prolactin level has reached normal range, MRI within 6 months,
then yearly for several years, (prolactin ; 6 months)
Medical treatment
Bromocriptine : best initial & long-term treatment option.
1/2 : 50% reduction in size. after 6months of Tx.
1/4 : 33% reduction
Tumor regrowth occurs in over 60% after discontinuation
∴ long-term treatment is the rule
Surgical treatment
Indication Unresponsive to bromocriptine
Persistent visual field loss
Recurrence of hyperprolactinemia & tumor growth - not uncommon
Recurrent hyperprolactinemia - periodic MRI scan
4. Use of Estrogen in Hyperprolactinemia
In rodent, rapid prolactinoma occurs with high dose estrogen
In human, estrogen administration : no evidence of growth of pituitary adenoma
or progression of idiopathic hyperprolactinemia to adenoma
5. Pituitary adenoma in Pregnancy
Microadenoma : rarely create complication during pregnancy
Monitoring : serial gross visual field exam, fundoscopic exam, if symptom (+), MRI
* prolactin level : no value.
Macroadenoma : monitoring as microadenoma with monthly Goldman perimetry visual
field testing.
Bromocriptine : to resolve symptom & visual field deficiency temporarily to allow
completion of pregnancy before definitive therapy
Breast feeding : is not contraindication in the presence of prolactinoma.
III. Thyroid disorder.
10 times more common in women than men
1% of females : overt hypothyroidsm.
A. Thyroids Hormones
Iodide : actively transported into the thyroid follicular cell
--> Thyroid peroxide TPO) oxidizes iodide near the cell-colloid surface &
incorporates it into tyrosyl residues within the thyroglobulin molecule
--> result in the formation of monoiodotyrosine (MIT) & diiodotyrosine (DIT)
--> Triiodothyronine (T3) & Thyroxine (T4) formed by secondary coupling of MIT & DIT catalyzed by TPO