Androgen Excess in PCOS Throughout the Life Cycle

Nowadays, androgen excess is considered to be the cornerstone to the pathogenesis of PCOS. Ovarian theca cells synthesize C19 androgens under the stimulus of luteinizing hormone, and androgens are then converted to estradiol by aromatase in granulosa cells.^[18] Increased androgen biosynthesis is a stable phenotype of PCOS theca cells in long-term culture, indicating that increased androgen secretion is a primary characteristic of these women.^[19] Considering that expression of p450c17α – the essential enzyme for the synthesis of dehydroepiandrosterone and androstendione – in primary and theca interstitial cells of the fetal primordial follicle is present at 3 months of fetal life in humans and increases through pregnancy,^[20] it is quite possible that androgen excess may be present during fetal life in affected women.

Adrenal hyperandrogenism is also frequent in patients with PCOS. However, the mechanisms leading to excessive androgen secretion by the adrenals remain elusive, possibly because ethical constraints preclude obtaining adrenal samples from patients with PCOS, as the adrenals are essential for life.

Molecular genetic studies targeting adrenal steroidogenesis failed to reveal mutations and polymorphisms in the genes encoding for the enzymes responsible for androgen synthesis.^[21–25] However, abnormalities in peripheral cortisol metabolism may stimulate adrenal androgen secretion secondarily to mild reduction in cortisol levels. In cortisone-reductase deficiency, impaired regeneration of active cortisol from inert cortisone by 11β-hydroxysteroid dehydrogenase (11β-HSD1; HSD11B1 gene) may result in increased cortisol clearance, compensatory activation of the hypothalamic–pituitary–adrenal axis and adrenocorticotropin-mediated adrenal hyperandrogenism.^[26] To act as an oxoreductase catalyzing the activation of glucocorticoids, 11β-HSD1 requires a high NADPH/NADP+ ratio in the endoplasmic reticulum, and this is provided by hexose-6-phosphate dehydrogenase (H6PDH; H6PD gene).^[27] Cortisone reductase deficiency is caused by mutations in either HSD11B1^[28] or H6PD.^[29] Prelimiary data suggest that polymorphisms in HSD11B1^[30] and H6PD^[31] influence adrenal hyperandrogenism and metabolic function in patients with PCOS.

Evidence Supporting Prenatal Androgen Excess in PCOS

The hypothesis of developmental programming in PCOS proposes that prenatal testosterone excess could program reproductive and metabolic dysfunctions during adulthood, as suggested by animal models in which prenatal exposure to androgen excess leads to biochemical and clinical features of PCOS after birth.^[32]

In a remarkable series of experiments in rhesus monkeys, Abbot and colleagues showed how prenatal administration of testosterone propionate recreates the PCOS phenotype in adulthood including hyperandrogenemia, increased secretion of androgens in response to recombinant human chorionic gonadotropin, oligo-ovulation and polyfollicular ovaries, and these abnormalities are accompanied by accumulation of visceral fat, insulin resistance and impaired insulin secretion, especially in animals exposed to androgens early during gestation.^[33]

Similar results were found in sheep and rodents, indicating that testosterone administration during pregnancy may program PCOS-like phenotypes in other species.^[34,35]

Familial clustering suggests an inherited basis for PCOS,^[7] and therefore affected female fetuses may inherit the genes related to PCOS from their parents and start producing an excessive amount of androgens in utero, programming their reproductive and metabolic function, as occurs in animal models of androgenization.

Obviously, experimental exposure to high levels of androgens during pregnancy has not been studied in humans because of ethical concerns. However, there are clinical disorders in which female fetuses develop in an androgenic environment including hyperandrogenic congenital adrenal hyperplasia and congenital adrenal virilizing tumors.^[36–38]

Girls with classic 21-hydroxylase deficiency are exposed to excessive androgen levels of adrenal origin during pregnancy and may present with a variable degree of virilization at birth, whereas girls with the less severe phenotype, nonclassic 21-hydroxylase deficiency, do not show any clinical signs of virilization at birth but present with a PCOS-like phenotype later in life.^[39] Prenatal programming by androgen excess may contribute to insulin resistance^[40] and a predominantly abdominal distribution of fat^[41] in these women. The fact that masculine-type behavior, including preference for masculine toys^[42] and homosexual/bisexual orientation,^[43] are relatively common in girls and women with 21-hydroxylase deficiency further supports exposure to excessive prenatal androgens at critical stages of brain development during pregnancy.

The possibility of a maternal contribution to fetal androgen excess is unlikely because the physiological increase in sex hormone-binding globulin and especially placental aromatization typically protects the fetus from the potential virilizing effects of maternal androgens in cases where the mother is also affected by PCOS. Hence, androgen excess in the mother does not cause virilization of the fetus unless the levels of androgens are as high as levels observed after administration of exogenous virilizing drugs, Krukemberg tumors or placental aromatase deficiency.^[44]

For this hypothesis to be plausible, female fetuses from women with PCOS should inherit the defects leading to androgen excess more frequently than fetuses from women without hyperandrogenism and, as a group, female newborns from women with PCOS should have increased serum levels of androgens because the fetal ovary continues secreting steroid hormones a few weeks after birth.

Instead of obtaining blood samples directly from the newborns, in most, if not all, of the studies conducted to date addressing this question, blood was sampled from the umbilical cord, possibly explaining the controversial results observed. Fetal blood reaches the placenta via the two umbilical arteries in the villi whereas placental blood reaches the fetus through a single umbilical vein. Therefore, when aiming to study androgen concentrations in newborns by cordocentesis, blood should ideally be obtained from the umbilical artery as blood of the umbilical vein actually represents blood coming from the mother, although serum androgens appear to correlate between the umbilical arteries and veins.^[45,46]

However, studies aiming to measure androgen excess during pregnancy have not obtained blood samples from the umbilical artery. Barry et al. compared the levels of total testosterone in the umbilical vein of babies born to mothers with PCOS with those of babies born to mothers without androgen excess, and found that serum testosterone concentrations were higher in the former, and comparable to those of male newborns.^[47] On the contrary, no differences in serum androgen levels among newborns from women with and without PCOS have been found when using mixed umbilical cord blood, so there is no definite answer at present to the question of whether or not androgen excess is present during pregnancy in girls with PCOS.

Androgen Excess During Childhood, Adolescence & Adulthood

Although in most girls PCOS presents clinically after adolescence, premature pubarche (isolated growth of pubic hair in girls before 8 years of age) and premature adrenarche (premature pubarche with mildly increased adrenal androgen levels) are possibly the earliest clinical manifestations of PCOS in affected women. Almost half of the girls with premature pubarche/adrenarche develop PCOS after puberty.^[48] This association is especially important in girls born small for gestational age,^[49,50] suggesting that intrauterine growth restriction might program the metabolic function of these girls towards a thrifty phenotype characterized by early catch-up growth and development of visceral adiposity and insulin resistance.^[51]

Furthermore, these girls are prone to develop obesity and metabolic derangements in association with insulin resistance and hyperinsulinemia, increased IGF-1 levels and lower IGF-binding protein 1 concentrations, all of which may be present even before puberty.^[52–56]

Although these early findings may be considered as evidence supporting insulin resistance as the cause of androgen excess in women with PCOS, as stated previously, these girls may have been programmed towards abdominal adiposity and insulin resistance by androgen excess during fetal life.^[6,33]

The fact that PCOS and related disorders usually become apparent peripubertally may be related to the fact that the growth hormone/IGF-1 axis is especially active during this period. As occurs with insulin, IGF-1 stimulates the synthesis of androgens at the ovary and the adrenals^[57,58] and reduces sex hormone-binding globulin synthesis and secretion in human hepatoma cell lines,^[59] resulting in increased free testosterone levels. Of note, overtreatment with IGF-1 in women with insensitivity to growth hormone leads to androgen excess,^[60] further demonstrating the potent effects of this growth factor on androgen synthesis in vivo. Furthermore, the decline in the activity of the growth hormone/IGF-1 axis with age may be related to the well-known amelioration in androgen levels and hyperandrogenic symptoms found in certain patients with PCOS as they grow older.^[61]

Of note, several characteristics of normal adolescence in women, such as mild acne or menstrual irregularity soon after menarche, may resemble hyperandrogenic symptoms and might lead to an incorrect PCOS diagnosis. Therefore, the diagnosis of PCOS during adolescence should be especially strict to the extent that some authors recently proposed that a firm diagnosis of PCOS in this age range requires the presence of hyperandrogenemia, and not only hirsutism, in addition to chronic oligo-anovulation and polycystic ovarian morphology.^[62] In girls presenting with some but not all of these characteristics, a definite diagnosis of PCOS should be delayed to be sure that these features persist for a few years after puberty.^[62] It must be highlighted that the measurement of serum androgen levels during adolescence requires the use of appropriately accurate assays and that the normal ranges for such assays must be established from a carefully defined population of normal girls of the same age range.

The role of androgens in the pathophysiology of PCOS in adults has been described in detail elsewhere.^[6,8] In addition to causing the cutaneous manifestations of the syndrome, including hirsutism, acne and alopecia, intra-ovarian androgen excess leads to anovulation and polycystic ovarian morphology and possibly contributes to abdominal adiposity and insulin resistance,^[6] metabolic disturbances, increased cardiovascular risk markers^[63] and subclinical cardiovascular disease such as increased carotid intima-media thickness.^[64]

As a syndrome, PCOS is quite heterogeneous, and there may be a continuous spectrum with regards to the relative contribution of androgen excess and contributing factors such as abdominal adiposity and insulin resistance.^[6] In one extreme of the spectrum, some women have severe enough androgen excess to result in the PCOS phenotype without the need of any other triggering factor (Figure 2). In the other extreme of the spectrum, a very mild androgen excess in some women results in the PCOS phenotype only when a triggering factor, such as severe abdominal adiposity, is present (Figure 2). However, it must be highlighted that all women with PCOS share a primary defect in androgen secretion, because even massive obesity may not lead to PCOS if such a defect is not present.^[65] Therefore, targeting androgen excess for the long-term management of PCOS may prove useful not only for hyperandrogenic symptoms,^[66,67] but also for the amelioration of reproductive, metabolic and cardiovascular disturbances^[67–72] associated with the disorder.

Figure 2.

Enlarge

Polycystic Ovary Syndrome as the Result of the Interaction of a Primary Abnormality in Androgen Synthesis, Manifesting as Androgen Excess, with Environmental Factors Such as Abdominal Adiposity, Obesity and Insulin Resistance. In one extreme (†), in some patients, the disorder is severe enough to result in polycystic ovary syndrome even in the absence of triggering environmental factors. In the other extreme (‡), a very mild defect in androgen secretion is amplified by the coexistence of abdominal adiposity, obesity and/or insulin resistance. Between the two extremes, there is a spectrum in the severity of the primary defect in androgen secretion, explaining the heterogeneity of polycystic ovary syndrome patients with regards to the presence of obesity and metabolic comorbidities. However, patients share a primary defect in androgen secretion.
Reproduced from[6], with permission. © Elsevier (2007).

Androgen Excess After Menopause in PCOS

Menopause involves major hormonal changes including stable or slightly raised androgen levels and a fall in circulating E2 accompanied by an increase in gonadotropin levels.^[73] Both the ovaries and the adrenals contribute to the androgen milieu in healthy women after menopause. The postmenopausal ovary is hormonally active and is responsible for almost half of circulating testosterone and approximately 30% of androstendione, with the remaining steroids originating from the adrenals and from peripheral conversion of androgen precursors in adipose tissue.^[74,75] The major adrenal androgen, dehydroepiandrosterone sulfate, declines with age with no obvious relationship to menopause.

In healthy women, serum total testosterone concentrations remain unchanged^[73,76] or show a small decline after menopause,^[77] but while sex hormone-binding globulin concentrations decrease, free testosterone levels increase after menopause.^[73]

As stated above, PCOS features may ameliorate with age, with some patients presenting with regular cycles and spontaneous amelioration of hirsutism as they grow older. Furthermore, free and total testosterone levels in 42–47-year-old patients with PCOS are reduced by half compared with 20–42-year-old women with PCOS,^[61] further supporting the concept that an amelioration of hyperandrogenism may occur before menopause in PCOS.

However, postmenopausal women with PCOS still have increased serum total and free testosterone, androstendione, dehydroepiandrosterone sulfate, progesterone and 17-hydroxyprogesterone concentrations, compared with postmenopausal control women,^[78] suggesting that the negative consequences of androgen excess on metabolic and cardiovascular comorbidities may persist after menopause.