Larger doses of a GnRH agonist are required for androgen suppression than for endogenous gonadotropin-induced estrogen suppression (47).
The increased testosterone levels in patients with PCOS are considered ovarian in origin. The serum total testosterone levels are usually no more than twice the upper normal range (20 to 80 ng/dL). However, in ovarian hyperthecosis, values may reach 200 ng/dL or more (48). The adrenal compartment plays a role in the development of PCOS. Although the hyperfunctioning CYP17 androgen-forming enzyme coexists in both the ovaries and the adrenal glands, DHEAS is increased in only about 50% of patients with PCOS (49,50). The hyperresponsiveness of DHEAS to stimulation with ACTH, the onset of symptoms around puberty, and the observation of 17,20-lyase activation (one of the two CYP17 enzymes) are key events in adrenarche that led to the hypothesis that PCOS arises as an exaggeration of adrenarche (48).
The peripheral compartment, defined as the skin and the adipose tissue, manifests its contribution to the development of PCOS in several ways.
1.
The presence and activity of 5α-reductase in the skin largely determines the presence or absence of hirsutism (22,23).
2.
Aromatase and 17β-hydroxysteroid dehydrogenase activities are increased in fat cells and peripheral aromatization is increased with increased body weight (51,52).
Figure 31.5 Pathophysiological characteristics of the polycystic ovary syndrome (PCOS). Insulin resistance results in a compensatory hyperinsulinemia, which stimulates ovarian androgen production in an ovary genetically predisposed to PCOS. Arrest of follicular development (red “X”) and anovulation could be caused by the abnormal secretion of gonadotropins such as follicle-stimulating hormone (FSH) or luteinizing hormone (LH) (perhaps induced by hyperinsulinemia), intraovarian androgen excess, direct effects of insulin, or a combination of these factors. Insulin resistance, in concert with genetic factors, may also lead to hyperglycemia and an adverse profile of cardiovascular risk factors. (From Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005;353:2578–2588, with permission.) 3.
With obesity the metabolism of estrogens, by way of reduced 2-hydroxylation and 17α-oxidation, is decreased and metabolism via estrogen active 16-hydroxyestrogens (estriol) is increased (53).
4.
Whereas estradiol (E2) is at a follicular phase level in patients with PCOS, estrone (E1) levels are increased as a result of peripheral aromatization of androstenedione (54).
5.
A chronic hyperestrogenic state, with reversal of the E1-to-E2 ratio, results and is unopposed by progesterone.
The hypothalamic–pituitary compartment participates in aspects critical to the development of PCOS.
1.
An increase in LH pulse frequency relative to those in the normal follicular phase is the result of increased GnRH pulse frequency (55).
2.
This increase in LH pulse frequency explains the frequent observation of an elevated LH and LH-to-FSH ratio.
3.
FSH is not increased with LH, likely because of the combination of increased gonadotropin pulse frequency and the synergistic negative feedback of chronically elevated estrogen levels and normal follicular inhibin.
4.