Gonadal changes and blood sex steroids levels during natural sex inversion in the protogynous Mediterranean red porgy, Pagrus pagrus (Teleostei: Sparidae)

Changes in gonadal structure and serum levels of sex steroids were investigated during natural sex inversion from female to male in reared populations of the protogynous Mediterranean red porgy, Pagrus pagrus. Four developmental phases were identified by histological observation: female, early transitional (ETr), late transitional (LTr), and male phases. At female phase, a few nests of spermatogonia were observed at the posterior-ventral part of the gonad mainly in females out of the breeding season. At ETr phase, spermatogonial proliferation occurred while perinucleolar oocytes showed signs of degeneration. At LTr phase, seminiferous lobules were formed and spermatogonial proliferation expanded along the ovary which degenerated. All types of male germ cells could be found. At male phase, functional testis underwent active spermatogenesis while small ovarian remnants associated to fat tissue could be detected. Both 17beta-estradiol (E2) and estrone (E1) blood levels were significantly lower in fish at transitional and male phases in comparison to breeding females, while levels of 11-ketotestosterone (11-KT) and testosterone (T) gradually increased in the transitional and male phases. In conclusion, the protogynous P. pagrus possess a delimited type bisexual gonad with a medio-dorsal ovarian area and a latero-ventral testicular zone. Sex inversion starts mainly after the female breeding season with an active spermatogonial proliferation. The testis tissues develop while ovarian tissues regress to disappear completely in the functional male. This process is accompanied by a sharp decrease of estrogens levels and a progressive increase of androgens levels. The physiological significance of such endocrine changes is discussed.     

Action of sex steroid hormones on temperature-induced sex determination in the snapping turtle (Chelydra serpentina)

Administration of exogenous estradiol benzoate (EB) or an estrogen agonist, R2858, into eggs of snapping turtles caused all embryos incubated at male-producing temperatures to develop as females, whereas testosterone propionate (TP) caused 42% of the embryos to develop as females. Some of the embryos treated with EB, R2858, or TP also had hypertrophied oviducts. Neither dihydrotestosterone (DHT) nor cholesterol had any apparent effect on the sex determination of embryos incubated at male-producing temperatures. Injections of TP, DHT, the androgen agonist R1881, or cholesterol had no apparent effect on sex determination of embryos incubated at female-producing temperatures. Administration of estradiol antiserum or testosterone antiserum resulted in some individuals having undifferentiated or ambiguous gonads. Although both exogenous estrogens and androgens can induce embryonic gonads to develop as ovaries, the findings of this study indicate that estrogen is the female-inducing hormone and that androgens may feminize gonads via aromatization to estrogen. Furthermore, the results of the antisera injection suggest that endogenous steroid hormones may have a natural role in gonadal differentiation of reptiles with environmental sex determination.     

Diabetogenic role of insulin's counterregulatory hormones in the isletectomized, diabetic goby

In an experimental model of insulin-dependent diabetes mellitus (IDDM) in the teleost fish, the goby Gillichthys mirabilis, an isletectomy procedure completely removes the pancreatic endocrine tissue without affecting the exocrine acini or other essential tissues. Interestingly, isletectomized (Ix) gobies do not exhibit a significant hyperglycemia until 10-15 d after this procedure, suggesting a lack of initial diabetogenic actions of a pancreatic factor(s). Administering exogenous glucagon in otherwise nonsymptomatic 7-d Ix gobies, however, induces a hyperglycemic state comparable to that in severely diabetic rats or gobies (after 20 d post-Ix). The spontaneously arising hyperglycemia observed between 10 and 15d post-Ix, on the other hand, is significantly correlated with increasing serum cortisol concentrations, with both exhibiting sustained elevated levels (approx 23 mmol/L and >100 ng/mL, respectively) at 20- and 25-d post-Ix. Exogenous cortisol treatment also significantly induced hyperglycemia in nonsymptomatic, 7-d Ix gobies. By contrast, growth hormone (GH) had no detectable diabetogenic effect in 7-d Ix gobies. Serum levels of ammonia, the principal nitrogenous waste in this species, were not affected by glucagon treatment but were reduced slightly by GH treatment (30% reduction; p < 0.05). Cortisol treatment, on the other hand, increased ammonia levels twofold, suggesting that the glucocorticoid induces a negative nitrogen balance. These results indicate that the counterregulatory hormones--glucagon and cortisol--are effective diabetogenic factors in the Ix goby, capable of driving metabolic imbalance in this model of IDDM.     

Seasonal changes in sex and adrenal steroid hormones of gopher tortoises (Gopherus polyphemus)

We sampled a population of gopher tortoises (Gopherus polyphemus) from May to October 1997 to determine seasonal cycles of steroid hormones (testosterone, T; 17beta-estradiol, E; and progesterone, P) and related them to observations of mating behavior. In males, plasma T levels peaked in July and August and remained elevated through October. This coincides with the reported time of peak mating and spermatogenesis, indicating that males display an associated pattern of reproduction. In females, E levels were high in September and October. Plasma T levels in females were elevated in May, decreased to basal levels in June and July, and rose again in August and September. Elevated E and T levels correspond to the reported time of peak vitellogenic activity, indicating that females also display an associated cycle. Plasma P in females remained basal throughout the active season, suggesting that ovulation occurs in late winter. We also determined levels of corticosterone (B) to assess the influence of capture stress on tortoises and correlated B levels with tortoise activity patterns and sex steroid levels. We found no seasonal variation in levels of B in males or females. Plasma B levels were not correlated with levels of T or E, but were positively correlated with female P levels. Further, we found no relationship between plasma B levels in males and mean distance moved, mean number of burrows used, or mean home range size. However, there was a significant negative correlation between plasma B levels and male body size. In females, there was no relationship between B levels and mean distance moved, but B levels were significantly negatively correlated with the number of burrows females occupied. Lastly, there was no relationship between levels of B and the number of minutes required to obtain blood from an animal. However, B levels increased with the length of time that a tortoise spent in a trap, suggesting that trapped tortoises do exhibit capture stress.     

Gender disparity in COVID-19: Role of sex steroid hormones

The emerging pandemic of COVID-19 caused by the novel pathogenic human coronavirus SARS-CoV-2 has caused significant morbidity and mortality across the globe, prompting the scientific world to search for preventive measures to interrupt the disease process. Demographic data indicates gender-based differences in COVID-19 morbidity with better outcome amongst females. Disparity in sex-dependent morbidity and mortality in COVID-19 patients may be attributed to difference in levels of sex steroid hormones-androgens and estrogens. Evidence suggests that apart from the regulation of viral host factors, immunomodulatory and cardioprotective roles exerted by estrogen and progesterone may provide protection to females against COVID-19. Exploring the underlying mechanisms and beneficial effects of these hormones as an adjuvant to existing therapy may be a step towards improving the outcomes. This article aims to review studies demonstrating the role of sex steroidal hormones in modulating SARS-CoV-2 host factors and summarize plausible biological reasons for sex-based differences seen in COVID-19 mortality.     

Effect of steroid hormones on the process of natural sex reversal in the rice-field eel, Monopterus albus (Zuiew)

Monopterus albus is a sex-reversing hermaphrodite that changes from functional female, through an intersexual stage, to the functional male phase during its life cycle. Since previous findings indicated that steroid hormones may play some part in the process of sex reversal of Monopterus, an investigation on the role of sex steroid hormones was made using hormone administration together with biopsy study.Various androgens, including methyltestosterone, testosterone and 11-ketotestosterone, at different dosages failed to bring about precocious sex reversal in the female and no significant changes in the ovaries were observable after treatment. Methyltestosterone also failed to enhance the development of testicular lobules in the intersex animals. On the other hand, oestrogens injected into the intersex and male fish caused suppression of spermatogenesis and destruction of testicular lobules, but failed to cause the fish to change in the female direction.By the use of cyanoketone, an inhibitor of steroidogenesis, and the administration of methyltestosterone, it was demonstrated that androgens failed to bring about sex reversal even in the absence of endogenous oestrogens. Hence the failure of androgens to stimulate the development of male germ cells in the female phase is probably not due to any inhibitory effects by endogenous oestrogens. It is therefore concluded that sex steroids do not appear to play any primary role in the triggering of natural sex reversal of this protogynous fish.     

Effects of sex steroid hormones on pancreatic cancer in the rat

The incidence of spontaneous and induced neoplasms of the exocrine pancreas in rats is higher in males than in females. Castration, ovariectomy, and hormone replacement with estradiol and testosterone have been shown to influence the growth of carcinogen-induced preneoplastic foci in the azaserine-rat model of pancreatic carcinogenesis. Similar hormonal treatments have also influenced the growth of an azaserine-induced poorly differentiated acinar cell carcinoma that can be transplanted syngeneically in Lewis rats. The effect on growth of preneoplastic lesions and carcinomas is similar. The preneoplastic lesions and transplanted tumors grow faster in intact male rats than in castrated rats, and the growth of the lesions and tumors is inhibited by estrogen treatment. It appears that testosterone supports the growth of preneoplastic foci and carcinomas, whereas estrogen inhibits such growth. The mechanism is unknown and may be direct, or an indirect effect may be mediated through a peptide hormone. Tamoxifen treatment did not significantly influence the growth of the transplanted carcinomas in the rat model.     

Effect of urophysial homogenates on plasma ion levels in Gillichthys mirabilis (Teleostei: Gobiidae)

In seawater-acclimated Gillichthys mirabilis, 2 and 4 hr after receiving an intraperitoneal injection of Gillichthys urophysial homogenate (two urophyses per fish), plasma sodium, magnesium, and chloride levels were significantly greater than those observed following a saline injection. When sodium and magnesium levels were measured in injected urophysectomized fish, similar increases were noted. No differences were observed in plasma potassium or calcium or in hematocrit between fish receiving saline and those receiving the urophysial homogenate. No differences were observed between urophysectomized and sham-operated fish in plasma sodium, potassium, calcium, and magnesium or in hematocrit 1, 3, 7, or 14 days postoperatively. Transection of the spinal cord at the level of the seventh or eighth preterminal vertebra had no effect on plasma sodium, potassium, calcium, or magnesium compared with sham-operated fish 14 days postoperatively. These findings demonstrate an effect of urophysial factor(s) on osmotic and ionic regulatory mechanisms in a euryhaline marine teleost.     

Short term treatment with aromatase inhibitor induces sex change in the protogynous wrasse, Halichoeres trimaculatus

The purpose of this study was to specify the time when individuals are committed to female to male sex change in the protogynous wrasse, Halichoeres trimaculatus, induced by treatment with the nonsteroidal aromatase inhibitor (AI) Fadrozole. In this study, treatment with AI was carried out by providing adult females with a diet containing 500 μg AI/g food for 3 (AI-3), 5 (AI-5), and 10 days (AI-10). We examined the gonadal structure of the fishes histologically at the end of the AI treatment and 30 days after the start of the experiment. At the end of the AI treatment, all individuals in the AI-3 treated group had gonads with degeneration of yolky oocytes, indicating the onset of sex change. Most individuals in the AI-5 treated group had gonads with atretic vitellogenic oocytes, like those in AI-3 treated group, whereas most individuals in the AI-10 treated group had gonads with testicular tissue. At 30 days after the onset of the experiment, approximately 70% of the individuals in the AI-3 treated group had mature ovaries, whereas all fishes in AI-5 and AI-10 treated groups had mature testes, indicating sex change. Therefore, treatment with AI for only 5 days resulted in complete sex change. Our results also indicate that crucial events for testicular differentiation occur within 5 days from the start of AI treatment. Thus, we conclude that females are committed to change into males after 5 days of AI treatment.     

Influx of testosterone-binding globulin (TeBG) and TeBG-bound sex steroid hormones into rat testis and prostate

The availability of testosterone and estradiol to Sertoli and prostate cells is dependent upon 1) the permeability properties of the blood-tubular barrier (BTB) of the testis or prostate cell membrane, and 2) sex steroid binding to plasma proteins, such as albumin or testosterone-binding globulin (TeBG). Sex steroid influx into these tissues was studied after in vivo arterial bolus injections of [3H]testosterone or [3H]estradiol in anesthetized rats. Both testosterone and estradiol were readily cleared across the BTB or prostate cell membrane in the absence of plasma proteins and in the presence of human pregnancy serum, in which testosterone or estradiol are 80-95% distributed to TeBG. The extravascular extraction of [3H]TeBG across the BTB or prostate plasma membrane [73 +/- 2% (+/- SE) and 92 +/- 9%, respectively] was significantly greater than extraction of [3H]albumin or other plasma space markers and indicative of a rapid first pass clearance of TeBG by Sertoli or prostate cells. In summary, these studies indicate that 1) testosterone and estradiol are readily cleared by Sertoli and prostate cells; 2) albumin- and TeBG-bound sex steroids represent the major circulating pool of bioavailable hormone for testis or prostate; and 3) the TeBG-sex steroid complex may be nearly completely available for influx through the BTB or prostate plasma membrane.     

A case of adrenal tumor producing renin, aldosterone, and sex steroid hormones

A 27-year-old woman with an adrenal tumor that produced renin and aldosterone, associated with hypertension and adrenogenital syndrome, is described. Severe hypertension, cardiomegaly, a low serum potassium level, clinical symptoms of adrenogenital syndrome, and a left upper abdominal tumor also were found. Endocrinological studies showed that plasma and urinary levels of sex steroid hormones such as dehydroepiandrosterone, androsterone, and testosterone were markedly increased. Plasma renin activity, plasma angiotensin II, and plasma aldosterone levels also were increased markedly, although deoxycorticosterone levels remained within the normal range. The possibility of renovascular hypertension was excluded by angiography of the renal artery and by venous sampling of plasma renin activity. Abnormal elevations in plasma aldosterone levels persisted despite normalization of plasma angiotensin II by converting enzyme inhibitor administration. It was suspected that this patient had an adrenal tumor producing renin as well as sex steroids and aldosterone. Microscopy of the resected tumor revealed that the tumor was composed mostly of cells with large nuclei and light cytoplasm. The tumor contained dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, aldosterone, and renin. Immunohistochemical study showed that some of the tumor cells produced renin. Biopsy of the left renal tissue showed evident atrophy of the juxtaglomerular cells and pronounced arteriosclerosis. After resection of the tumor, all blood and urinary levels of the abnormally increased hormones returned to a normal range and an apparent fall of blood pressure was noted. To our knowledge, this is the first report of a renin and aldosterone-producing adrenal tumor associated with hypertension and adrenogenital syndrome.     

Relationship of sex steroid hormones with bone mineral density (BMD) in a nationally representative sample of men

Objective Sex steroid hormones influence bone mineral density (BMD) in women, but are less well‐studied in men. We evaluated the association of serum total and free sex steroid hormones and SHBG with osteopaenia in a nationally representative sample of men aged 20–90 years. Design BMD and sex steroid hormones were measured among participants in NHANES III, a cross‐sectional study of the US population. Population A total of 1185 adult men in morning examination session of Phase I of NHANES III (1988–91). Measurements Relation of oestradiol (E₂), testosterone, and SHBG concentrations with BMD. Osteopaenia was defined as 1–2·5   SD below the mean for white men aged 20–29 years. Results Men in the lowest quartile of free E₂ had 70% increased odds (OR = 1·69, 95% CI 0·95–2·98) of osteopaenia compared with men in the highest quartile. Men in the lowest quartile of free testosterone had nearly four times the odds of osteopaenia than those in the highest quartile (OR = 3·82, 95% CI 1·87–7·78). Lower concentrations of SHBG appeared protective against osteopaenia (P‐trend = 0·01). Neither total testosterone nor total E₂ was associated with BMD, although men with clinically low E₂ (< 20 ng/l) had lower BMD (0·930 g/cm², 95% CI 0·88–0·98) than men with normal‐range E₂ (1·024 g/cm², 95% CI 1·01–1·04; P = 0·004). Findings for free E₂ were most pronounced among elderly men, while the findings for free testosterone were most pronounced among younger men. Conclusions In this nationally representative study, men with lower free E₂, lower free testosterone, and higher SHBG concentrations in circulation were more likely to have low BMD.