Circulating Sex Steroid Concentrations Research Articles

Sex hormones, their receptors and bone health

Sex steroids regulate skeletal maturation and preservation in both men and women, as already recognized in the 1940s by Albright and Reifenstein. The impact of gonadal insufficiency on skeletal integrity has been widely recognized in adult men and women ever since. In the context of their skeletal actions, androgens and estrogens are no longer considered as just male and female hormones, respectively. Androgens can be converted into estrogens within the gonads and peripheral tissues and both are present in men and women, albeit in different concentrations. In the late 1980s, sex steroid receptors were discovered in bone cells. However, the understanding of sex steroid receptor activation and translation into biological skeletal actions is still incomplete. Due to the complex metabolism, sex steroids may have not only endocrine but also paracrine and/or autocrine actions. Also, circulating sex steroid concentrations do not necessarily reflect their biological activity due to strong binding to sex hormone binding globulin (SHBG). Finally, sex steroid signaling may include genomic and non-genomic effects in bone and non-bone cells. This review will focus on our current understanding of gonadal steroid metabolism, receptor activation, and their most relevant cellular and biological actions on bone.

Responses of Shortfin Eel (Anguilla Australis) Exposed In Situ to Pulp and Paper Effluent

The responses of shortfin eel (Anguilla australis) to discharges from two pulp and paper mills, municipal wastewater, and a geothermal power plant wastewater were examined. Eels were caged at 3 sites along the Tarawera River, North Island, New Zealand, to explore effects of a 3-wk exposure down a contamination gradient (Ref → D1 → D2). Most of the observed effects were seen in eels caged at the furthest downstream site (D2), below all the discharge areas. General hematology in eels was unaffected, as measures did not differ markedly at the two downstream sites compared with the reference site. At D2, eels were significantly lighter per unit length (reduced condition factor), although liver and spleen size (LSI and SSI) were unaffected. Significantly elevated circulating sex steroid concentrations (testosterone and estradiol) were measured in D2 eels and increasing sex steroid levels at both sites downstream of the reference site were observed. Significant ethoxyresorufin O-deethylase (EROD) activity induction was seen in D2 eels and bile chemistry showed significant accumulation of pyrene and retene equivalents. However, significantly greater concentrations of total resin acids were found in the bile of eels from the intermediate site (D1), between the two pulp and paper mills. The higher polycyclic aromatic hydrocarbon (PAH) equivalents found in the bile of D2 eels suggest that resin acid neutrals, particularly retene, are responsible for some of the effects observed in eels at the furthest downstream exposure site. Levels of pulp and paper mill extractives in sediment, including the PAH retene, support this conclusion.

Effects of social status and moderate alcohol consumption on mammary gland and endometrium of surgically postmenopausal monkeys.

To evaluate the effects of social subordination stress and chronic moderate alcohol consumption on indices of breast and endometrial cancer risk. Forty-six adult, ovariectomized, cynomolgus monkeys (Macaca fascicularis) were trained to voluntarily drink a placebo or a two-drink/day equivalent of ethanol (0.5 g/kg), 5 days a week for 26 months, the latter resulting in average blood alcohol levels of 42 mg/100 mL. Indices of cell proliferation and sex steroid receptor abundance were measured. Compared with dominants, socially subordinate females had increased cell proliferation and proportions of glandular (P < 0.02) and epithelial tissue (P = 0.009) and less stroma (P < 0.02) in endometrium, and increased tissue thickness in breast (P < 0.05). There was no evidence of increased risk of breast or endometrial cancer with chronic moderate alcohol consumption, as indicated by markers of cell proliferation and sex steroid receptor abundance. Chronic moderate alcohol consumption did not effect circulating sex steroid concentrations (all P > 0.10). The adipocyte hormones leptin and adiponectin were correlated with indices of cell proliferation and sex steroid receptor abundance. These observations suggest that social status was more important than chronic moderate alcohol consumption in endometrial and breast biology of surgically postmenopausal females. Endogenous sex steroid metabolism was not significantly affected by chronic moderate alcohol exposure consistent with the lack of estrogen-like effects on breast and endometrium. Social subordination stress was associated with initial cellular changes that may increase endometrial cancer risk. Ovariectomized cynomolgus monkeys may be a useful model for the study of effects of social factors and obesity on breast and endometrial cancer risk.

Effects of Photoperiod Manipulation on Brook Trout Reproductive Development, Fecundity, and Circulating Sex Steroid Concentrations

The goal of this study was to determine the feasibility of conducting reproductive studies with brook trout Salvelinus fontinalis at times other than the normal fall-spawning period. The timing of sexual maturation, fecundity, and concentrations of serum sex steroids (17-β-estradiol, E2; and testosterone, T) in brook trout held under a normal photoperiod were compared with those in brook trout held under an altered photoperiod (initiated in early September). Fish held on a constant long photoperiod (18 h light: 6 h dark) did not reach sexual maturity during the normal fall-spawning time. When these fish were subsequently subjected to a 16-week accelerated photoperiod reduction from 18 h light/d to a day length of 8.5 h, the males and females matured in 8 and 13 weeks, respectively, and spawned successfully in April and May. Overall viability of embryos from this spring spawning was slightly lower than the average viability of control embryos from previous studies with fall-spawning fish in our laboratory; however, hatchability of viable embryos was similar for the spring-spawning fish and those from previous studies. Hormonal profiles of E2 and T were similar for both females and males in fall- and spring-spawning brook trout. These studies demonstrate that photoperiod alterations can be used to manipulate brook trout reproductive cycles for the purpose of conducting studies at times other than the fall.

Effect of Acute Stress on Plasma Concentrations of Sex and Stress Hormones in Juvenile Alligators Living in Control and Contaminated Lakes

Environmental contaminants can act as stressors, inducing elevated circulating concentrations of stress hormones such as corticosterone and corticod sol. Development in contaminated eggs has been reported to modify circulating sex steroid hormone concentrations in alligators (Alligator mississippiensis). We ex- amined plasma concentrations of testosterone (T), estradiol-17p (E2), and corticosterone (B) immediately upon and two hours after capture in male and female juvenile alligators living in either contaminated or relatively pristine lake systems. We observed that plasma T concentration was significantly depressed in males from the contaminated lake, whereas plasma E2 showed significant variation between sexes but not between lakes. Initial plasma B concentrations were similar between alligators from both lakes or either sex. Two hours of capture and restraint did not effect plasma T or E2 concentrations but was associated with a dramatic rise in plasma B concentrations. These data suggest that juvenile alligators exposed to contaminants in ovo are apparently unaffected in their rapid glucocorticoid response to acute stress.

Relation between circulating sex steroid concentrations and sexual behaviour during pregnancy and post partum in the domestic rabbit.

Sexual behaviour of 16 female and 12 male rabbits was studied during pregnancy and early post partum. The main behavioural events of the male (nuzzling and mounting) did not differ in the presence of receptive or non-receptive females. When introduced into the cage of the male, receptive and non-receptive females flattened to the floor or circled around. Sexual receptivity to males decreased in early pregnancy and increased to a maximum a few days around parturition; on Days 1 and 6 post partum, all experimental rabbits submitted to mating. Two groups of females were distinguished: one group submitting to mating whatever the stage of pregnancy, the second being receptive only during the few days before parturition or post partum. During pregnancy and early post partum there was no relation between the colour of the vulva and the female sexual behaviour. Does remained sexually receptive even when progesterone concentrations were high. Nevertheless, the number of receptive females was higher when progesterone concentrations decreased around parturition and the mean daily progesterone values were consistently higher in non-receptive than in receptive females. Oestrogen concentrations during pregnancy were very low and were not related to receptive behaviour.

Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women

The effect of estrogen and/or androgen replacement therapy on several aspects of cognitive functioning in surgically menopausal women was tested in a prospective, crossover design. Women who received either a combined estrogen-androgen preparation, estrogen alone, or androgen alone had scores on two tests of short-term memory, a test of long-term memory and a test of logical reasoning that were not different during the postoperative treatment phase compared to their preoperative performance. However, oophorectomized women who received placebo had lower scores on all four measures of cognitive functioning postoperatively, coincident with their significantly lower concentrations of plasma estradiol and testosterone. Patients who had a hysterectomy but whose ovaries were retained showed stability both in cognitive performance and in circulating sex steroid concentrations. These findings suggest that the drastic change in endocrine milieu following surgical menopause may have a direct, albeit modest, effect on aspects of cognitive functioning. Possible mechanisms of action of the sex hormones on cognitive functioning in women are discussed.

Endocrine impact of pure estradiol replacement in postmenopausal women: Alterations in anterior pituitary hormone release and circulating sex steroid hormone concentrations

Endocrine impact of pure estradiol replacement in postmenopausal women: Alterations in anterior pituitary hormone release and circulating sex steroid hormone concentrations

Dynamics of plasma gonadotropin and sex steroid release in polycystic ovarian disease after pituitary-ovarian inhibition with an analog of gonadotropin-releasing hormone.

To assess the dynamics of the suppression and recovery of plasma gonadotropins and sex steroids during and after inhibition of pituitary-ovarian function by a long-acting agonist GnRH-analog (GnRH-A), eight patients with polycystic ovarian disease were treated with 12 micrograms/kg X day GnRH-A for 56 consecutive days. In response to GnRH-A, these patients had a sharp and pronounced decline of their initially elevated immunoreactive LH and bioactive LH (bioLH) levels. Plasma immunoreactive FSH levels declined more rapidly than did bioLH, but the FSH decline was less sustained. Plasma testosterone, androstenedione, and estrone (E1) levels also declined during GnRH-A administration. The pattern of plasma androgen decrease resembled that of bioLH. There was a positive correlation between bioLH and the two androgens (r = 0.85; P less than 0.05, by Spearman's rank correlation, for both hormones). Cessation of GnRH-A administration was followed by prompt progressive increases in gonadotropin and androgen concentrations to pretreatment values. FSH recovered faster than bioLH. BioLH plasma concentrations reached pretreatment values by day 28. The recovery of plasma androstenedione and testosterone levels correlated positively with that of bioLH. Although plasma E1 levels were higher during the recovery period than during treatment, they never reached the concentrations found during the basal period, whereas estradiol concentrations were slightly but not significantly higher than those in the basal period. As a consequence, the E1 to estradiol ratio, very high in the basal period, approximated unity during recovery. These data indicate that hyperandrogenism in polycystic ovarian disease is gonadotropin dependent and accompanied by a relative abundance of LH bioactivity basally and during GnRH-A administration. Thus, the relative increase in bioLH secretion appears to be independent of the rate of gonadotropin secretion and the circulating sex steroid concentrations.

Endocrine impact of pure estradiol replacement in postmenopausal women: Alterations in anterior pituitary hormone release and circulating sex steroid hormone concentrations

Thirteen healthy postmenopausal volunteers were studied under basal conditions and at intervals (days 1, 5, 10, and 30) after intravaginal placement of a polysiloxane ring impregnated with 400 mg of estradiol. Mean serum estradiol concentrations rose 26-fold with a twofold increase in serum estrone concentrations. Serum Δ4-androstenedione, dehydroepiandrosterone sulfate, and total testosterone did not change, but absolute and percent free testosterone concentrations declined significantly by day 5. Concurrently, serum concentrations of immunoactive follicle-stimulating hormone declined progressively, while serum luteinizing hormone and free α-subunit concentrations exhibited a biphasic pattern of suppression. Serum levels of prolactin increased monophasically and those of growth hormone, somatomedin C, and thyroid-stimulating hormone did not change.

Effects of tamoxifen, medroxyprogesterone acetate, and their combination on human endometrial estrogen and progestin receptor concentrations, 17β-hydroxysteroid dehydrogenase activity, and serum hormone concentrations

Short-term and long-term progestin exposures elicit secretory and atrophic changes, respectively, in the human endometrium. To understand the mechanisms for these diverse effects of progestins, we administered medroxyprogesterone acetate (100 mg daily orally) alone or together with the antiestrogen tamoxifen (20 mg daily) for 3 weeks (from the third through twenty-third day of the cycle) to healthy, normally cycling women. Medroxyprogesterone acetate administration led to atrophic changes in the endometrium and reduced the activity of endometrial 17β-hydroxysteroid dehydrogenase on the twenty-third day of the cycle below the values measured on the same day of the preceding control cycle. These changes were accompanied by decreased cytosol estrogen and progestin receptor concentrations, while the respective nuclear receptor levels remained unchanged. Since the diminished cytosol progestin receptor content could be the primary reason for the aforementioned results, the 3-week progestin treatment was supplemented with the antiestrogen tamoxifen, also known to be a partial estrogen agonist. This combination elicited, however, endometrial atrophy and an even more pronounced reduction in the 17β-hydroxysteroid dehydrogenase activity, although it increased cytosol progestin and nuclear estrogen receptor concentrations. Tamoxifen alone did not alter endometrial receptor concentrations or 17β-hydroxysteroid dehydrogenase activity. However, tamoxifen markedly increased circulating sex steroid concentrations, which changes were abolished by a concomitant medroxyprogesterone acetate administration. It thus appears that the initial and stimulatory effect of progestins on the endometrial function is relatively short-lived and that the later depressive actions of these steroids are achieved as soon as 3 weeks. Therapeutic implications of these findings are discussed.