Background On Polycystic Ovarian Syndrome Among Adolacents

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2.1. Adrenal and Gonadal Maturation in Adolescence

Circulating levels of androgens are similar in male and female children prior to adrenarche. The pubertal changes in androgens in females plotted as a function of Tanner pubic hair stage are demonstrated in Fig. 2 (6). As can be seen, plasma levels of DHEA achieve adult levels at an earlier stage of development than do those of testosterone. The changes in circulating levels of A4 are intermediate. The pattern of increase in DHEAS levels (not shown) is similar to those of DHEA. A similar discordance in the chronological evolution of DHEA/DHEAS compared to that of testosterone also occurs during adolescence in both girls and boys. The striking increases in plasma levels of DHEA and DHEAS in children coincide with the appearance of the zona reticularis in the adrenal and its progressive broadening during adolescence (7).

The absence of 3P-HSD in the zona reticularis, coupled with the presence of CYP17, cytochrome b5, and DHEA sulfotransferase in this zone (1,4,5,8,9), is permissive to the increasing production of DHEA and DHEAS during adrenarche. The immunohistochemical evidence for functional changes in the capacity for adrenal androgen production during development is consistent with enzymatic changes, as noted by Schiebinger et al. (10), who observed a fourfold increase in 17,20-lyase and 17a-hydroxylase activities but no alteration in 3P-HSD in the postpubertal adrenal compared to that of adolescents.

The mechanism for the growth and development of the zona reticularis during the transition from childhood to adulthood has yet to be determined. The increased production of adrenal androgens is not attributable to any increases in circulating levels of adrenocorticotropic hormone (ACTH) and is not accompanied by alterations in cortisol levels. Although the existence of an adrenal androgen-stimulating hormone has been postulated, no factor has yet been identified that satisfies the expectations for such a substance. It is likely that acute and chronic regulation of steroid secretion in the zona reticularis is dependent on pituitary ACTH, and the functional phenotype (downregulation of 3P-HSD, but enhanced expression of CYP17, cytochrome b5, and hydroxysteroid sulfotransferase) of these cells probably is influenced by other, as yet unidentified, factors. Alternatively, there is evidence for central nervous system and pituitary regulation of gonadal maturation during puberty, which is initially mediated by the occurrence of pulsatile luteinizing hormone (LH) secretion during sleep in late adolescence.

Although they are usually temporally linked, the onsets of adrenal and gonadal maturation are not functionally interdependent. For example, adrenarche occurs normally in girls with ovarian dysgenesis (e.g., Turner's syndrome), precocious adrenarche can occur without premature gonadarche, and gonadal development at puberty occurs normally in the presence of adrenal insufficiency (e.g., Addison's disease). It seems clear that nutritional status and hormones involved in growth regulation during childhood play important roles in modulating both ovarian and adrenal maturation. Factors involved in bone maturation may also be linked to adrenal androgens in the peripubertal period. Among similar-aged premenarcheal girls chosen for low or high dietary calcium intake, those with low dietary calcium had significantly reduced levels of DHEA and DHEAS compared to the high-calcium-intake group; however, no differences in testosterone or estradiol levels were noted between the two groups of girls (11).

Recently, the concept of intrauterine programming has been extended to include possible fetal influences on androgen production in the peripubertal period. For example, Ibanez et al. (12) found evidence for precocity, ovarian androgen excess, and hyperinsulinism among some girls who had experienced restricted fetal growth. Other investigators have also found evidence for differences in the androgenic milieu of low-birthweight infants during childhood and beyond. For example, Korhonen et al. (13) reported significantly increased levels of DHEAS and androstenedione at age 7 among previously growth-restricted infants compared to normal infants. Szathmari et al. (14) reported increased levels of DHEA, DHEAS, and A4 during young adulthood in formerly low-birthweight girls; no such effects were seen among formerly low-birthweight males, however. Future studies of these relationships are obviously required.

2.2. Androgen Regulation in Adult Women

The adrenals and ovaries contribute variably to the circulating levels of androgens in adult women (15). Generally, it is thought that A4 is derived in roughly equal amounts from the ovary and the adrenal, while testosterone is derived approximately 25% from the adrenal, 25% from the ovary, and 50% from the peripheral conversion of A4. DHT is produced in peripheral tissues from testosterone and circulates at levels about one-third to one-half that of testosterone. DHEA and DHEAS are almost exclusively of adrenal origin. DHEA is secreted in a pulsatile manner and demonstrates a diurnal rhythm similar to that of cortisol in young women (16). Because of the low metabolic clearance rate (MCR) of DHEAS, however, there are only minor changes in its concentration throughout the day. Androstenedione and testosterone levels also exhibit a diurnal rhythm (15), although less variable than that of DHEA and cortisol.

In the ovary, androgens are synthesized in the theca cells, which have this synthetic capacity by virtue of their expression of CYP17 and cytochrome b5; follicular granulosa cells do not have such factors (1) and therefore are dependant on the theca cell as a source of substrate for estrogen formation. There are no substantial changes in the circulating levels of DHEA, DHEAS, or A4 throughout the ovarian cycle. On the other hand, Abraham (17) described the occurrence of a slight mid-cycle peak of testosterone and also noted higher levels of this androgen in the luteal phase than during the early to midfollicular phase of the menstrual cycle. Such findings have generally been observed in other subsequent studies of ovulatory women. The concentrations of A4 and testosterone are higher in ovarian vein blood than in the periphery and are usually highest in blood draining a mature ovarian follicle or functional corpus luteum (Fig. 3) (18). The slight increase in the circulating levels of testosterone and A4 during the luteal phase are probably a result of the fact that CYP17 and cytochrome b5 also are expressed in the theca-luteal cells of the ovary (1).

Fig. 3. Steroid concentrations in peripheral and ovarian venous plasma of premenopausal women. The concentrations of androstenedione (A4), testosterone, estrone, and estradiol in peripheral blood, blood draining the ovary having either a dominant follicle and/or an active corpus luteum, and in blood draining the contralateral ovary are shown for women having gynecological surgery. CL, corpus luteum. (Data from ref. 18.)

Fig. 3. Steroid concentrations in peripheral and ovarian venous plasma of premenopausal women. The concentrations of androstenedione (A4), testosterone, estrone, and estradiol in peripheral blood, blood draining the ovary having either a dominant follicle and/or an active corpus luteum, and in blood draining the contralateral ovary are shown for women having gynecological surgery. CL, corpus luteum. (Data from ref. 18.)

Ovarian suppression in adult women because of the ingestion of oral contraceptive steroids is often accompanied by reductions in circulating levels of androgens, including those who are treated with low-estrogen preparations (19,20) . Such observations have also been made among women who were treated with high levels of estrogens (21,22). While the mechanism for oral-contraceptive-induced reductions in ovarian androgens seems clear, the mechanisms for the reductions in DHEAS levels noted in each of the above studies are not readily apparent. Androgen levels are strikingly decreased among women with hypopituitarism, particularly among those displaying combined hy-poadrenalism and hypogonadism (23). Among both reproductive and postmenopausal aged women with hypopituitarism, those treated with estrogen replacement therapy had androgen levels that were similar to those not treated.

2.3. Pregnancy/Fetal Development

In pregnancy, circulating levels of testosterone, A4, and DHT are all increased relative to the levels found in nonpregnant women (24-26). The mechanisms for increased levels of testosterone, A4, and DHT are varied. Increased circulating levels of testosterone and A4 are evident as early as a few days after ovulation in a conception cycle, whereas there are no early changes in DHEAS, suggesting that only ovarian androgen production is augmented in early pregnancy (27). Late in gestation, the increase in testosterone and DHT levels is the result of substantial increases in sex-hormone-binding globulin (SHBG) and a resultant decrease in the MCRs of these androgens. On the other hand, the production rates for DHEA and DHEAS are increased in late pregnancy. Nevertheless, circulating levels of DHEAS at term are 50% or less than those in nonpregnant women. The reduction in circulating levels of DHEAS is progressive during gestation and is considered to result largely from ever-increasing rates of uptake and utilization in the placenta for estrogen formation (28). Shortly after delivery, circulating androgen levels in women return to levels seen in the nonpregnant state. Among infants delivered at or near term, umbilical cord concentrations of A4 and testosterone are significantly lower than maternal levels, and there are no differences in maternal or umbilical cord blood concentrations related to the gender of the infant. Between 10 and 20 weeks gestation, however, testosterone levels in the fetal compartment are strikingly higher in pregnancies carrying a male fetus than are those with a female fetus; this difference arises from fetal testicular responses to the high levels of gonadotropins produced at this time (29).

Interestingly, the maternal concentrations of DHEAS, A4, and testosterone have recently been shown to decrease with increasing maternal age in women in late gestation (30). The cause and physiological significance of this observation is unclear at present. Racial differences have also been recently reported with respect to the endocrine milieu of pregnancy: African American women had significantly increased levels of total, free, and bioavailable testosterone compared to Caucasian women in both the first and third trimesters of pregnancy (31). These increases could be related to greater levels of SHBG among African American women, particularly at term. Further studies of the effects of race and ethnicity on the endocrine milieu of pregnancy seem warranted, particularly in view of the widely recognized disparities in pregnancy outcomes among the races.

2.4. Perimenopause

Johnston and colleagues (32) evaluated cross-sectional differences in the endocrine milieu of women transitioning into the menopause. Significant correlations between bone mass and concentrations of estrogens and testosterone were seen, and the investigators concluded that vertebral bone loss might begin before menses cease. Other investigators (33) have also noted in cross-sectional studies a significant positive correlation between circulating levels of free testosterone, DHEAS, and bone mass in postmenopausal women. In this instance, there were differences noted in the relationship according to bone type (cortical vs trabecular).

Endocrine differences as a function of menopausal transitional status are also of interest. Serum estradiol levels are strikingly reduced among women in late perimenopause (with menstrual irregularity and a follicle-stimulating hormone [FSH] > 40 mlU/mL), compared to women in the early perimenopause (FSH < 40 mlU/mL with minimal menstrual irregularity) (32) (Fig. 4). Alternatively, serum levels of testosterone were indistinguishable between women in these groups. A further clear decline in serum estradiol levels was noted in menopausal women having no menses during the prior year compared to perimenopausal women; testosterone levels were only slightly lower compared to those in women in early perimenopause. Among women 12-55 months postmenopause, serum testosterone levels were similar to those of women just entering menopause. The reductions in circulating estradiol levels were attributable to striking reductions in rates of production; the stability of testosterone levels was associated with a fairly consistent production rate among all the groups of women studied. In no instance was there evidence for alterations in MCR of steroids among these women; therefore, circulating levels of androgens and estrogens in the perimenopause and perhaps for long periods thereafter reflect glandular secretion and peripheral conversion from precursors.

As part of a 7-year longitudinal surveillance of women undergoing menopause, Rannevik and colleagues (34) reported detailed analyses of hormonal parameters during the 6 months prior to cessation of menses and the first 6 months of postmenopause. None of these subjects were using hormone replacement therapy. Whereas FSH and LH levels increased 78% and 57% during this time period, respectively, estradiol levels declined 67%. They also noted slight reductions in the serum levels of A4 (16%) and testosterone (18%) that were, nevertheless, statistically significant during this interval of striking change in the functions of the hypothalamic-pituitary-ovarian axis. The serum levels of testosterone and A4 were fairly stable for the 3 years prior to menopause, with a tendency to decline progressively thereafter. Alternatively, serum levels of DHEA and DHEAS generally tended to decline progressively over the entire 7-year period of study. These results are compatible with the view that DHEA and DHEAS are primarily of adrenal origin and that age-associated declines are more related to age per se than abrupt changes in ovarian function during the perimenopausal period.

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