Androgens in Health and Disease.pdf - E Library

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small high-density atherogenic low-density lipoprotein (LDL) subclasses and hypertriglyceridemia.
Many women with PCOS have significant dyslipidemia. Studies have
shown that women with PCOS have lower high-density lipoprotein (HDL) and higher
triglyceride and LDL levels than age-, sex-, and weight-matched controls (23). This
elevation in LDL levels per se (as opposed to subclasses) is not one of the characteristic
findings of the insulin-resistance syndrome, but it contributes to increased cardiovascular
risk. Epidemiological studies have shown that hyperlipidemia, including hypertriglyceridemia
(especially in women) and elevated LDL/HDL ratios, are associated
with an increased risk of atherogenesis.
Hypertensive individuals are more likely to be hyperinsulinemic than controls who
are normotensive (21). Insulin resistance persists in these individuals despite successful
antihypertensive medication. However, hypertension has not been consistently
associated with PCOS, at least not in women of reproductive age (24,25). This is a
significant factor that prevents lumping all women with PCOS under the insulinresistance
syndrome. Long-term follow-up of women with PCOS may reveal an increased
incidence of hypertension compared to age- and weight-matched controls.
This may represent a later sequelae of prolonged insulin resistance. Recent studies
have documented other interim risk factors (e.g., increased carotid artery intimal thickness)
to suggest that these women have evidence of atherosclerotic disease at an earlier
and more advanced stage than appropriate control women (26). Confirmation of this
based on actual cardiovascular events such as stroke or myocardial infarction in women
with PCOS has not yet appeared.
NONCLASSICAL CONGENITAL ADRENAL HYPERPLASIA
The CYP21 (21-hydroxylase) gene is the most commonly mutated gene in humans,
as it is tightly linked to the human leukocyte antigen (HLA) locus on the short arm of
chromosome 6, a frequent site of genetic recombination. It is estimated to be present in
less than 1% of unselected hirsute women (27). CAH occurs with the highest frequency
in the US population among Native Americans in Alaska. Other populations with high
carrier status are Ashkenazi Jews (3.7%), Latinos (1.9%), Yugoslavs (1.6%), and Italians
(0.3%) (28). Because of the lack of 21-hydroxylation, 17-hydroxyprogesterone
accumulates. Because of the lack of cortisol synthesis, ACTH levels increase resulting
in overproduction and accumulation of cortisol precursors. These, in turn, can be shunted
to androgen biosynthetic pathways, which causes excessive production of androgens,
resulting in virilization. NC-CAH can be screened for with a fasting 17-OHP level in the
morning. A value less than 2 ng/mL is normal, and, recently, cutoffs as high as 4 ng/mL
have been proposed if obtained in the morning and during the follicular phase (29).
Values above the cutoff should be screened with an ACTH stimulation test. This is
performed in the early morning by giving 250 µg of Cortrosyn, a synthetic form of
ACTH, intravenously after baseline 17-OHP analysis and then obtaining a 1-h value.
Results are interpreted according to the nomogram of New et al. (30). In affected patients,
1-h values are generally > 10 ng/mL. Phenotype is largely the result of the amount of
functional enzymatic activity of the allelic variants, and those with NC-CAH have 10–
20% activity (31). About 70% will have oligomenorrhea, 80% hirsutism, and 40%
polycystic ovaries on ultrasound (32). Patients also appear to lack the insulin resistance
of PCOS. Treatment strategies focus primarily on suppression of adrenal function (see
the section Treatment of Androgen Excess).