Parental hormone levels and mammalian sex ratios at birth

I have previously suggested that parental levels of several hormones (gonadotrophin, oestrogen, testosterone) at the time of conception affect the sex of mammalian offspring (James, 1986, J. theor. Biol. 118, 427). In this note it is suggested that progesterone also has such an effect. Clutton-Brock & Iason (1986, Q. Rev. Biol. 61, 339) concluded that variation of sex ratio had been reasonably well established with a number of variables in a number of non-human mammalian species. In this note, discussion centres on the adequacy of my hypothesis to accommodate these and other data. The evidence now is strong that hormonal variation is associated with variation of sex ratio at birth in some mammalian species: in a few species (e.g. man and the vole) there is a strong presumption that the relationship is causal. However the same sort of cause apparently affects the sex ratio in opposite directions in different species: so it may be speculated that the same hormone has opposite effects on sex ratio in different species.     

Maternal Gestational Cortisol and Testosterone Are Associated with Trade-Offs in Offspring Sex and Number in a Free-Living Rodent (Urocitellus richardsonii)

The adaptive manipulation of offspring sex and number has been of considerable interest to ecologists and evolutionary biologists. The physiological mechanisms that translate maternal condition and environmental cues into adaptive responses in offspring sex and number, however, remain obscure. In mammals, research into the mechanisms responsible for adaptive sex allocation has focused on two major endocrine axes: the hypothalamic pituitary adrenal (HPA) axis and glucocorticoids, and the hypothalamic pituitary gonadal (HPG) axis and sex steroids, particularly testosterone. While stress-induced activation of the HPA axis provides an intuitive model for sex ratio and litter size adjustment, plasma glucocorticoids exist in both bound and free fractions, and may be acting indirectly, for example by affecting plasma glucose levels. Furthermore, in female mammals, activation of the HPA axis stimulates the secretion of adrenal testosterone in addition to glucocorticoids (GCs). To begin to untangle these physiological mechanisms influencing offspring sex and number, we simultaneously examined fecal glucocorticoid metabolites, free and bound plasma cortisol, free testosterone, and plasma glucose concentration during both gestation and lactation in a free-living rodent (Urocitellus richardsonii). We also collected data on offspring sex and litter size from focal females and from a larger study population. Consistent with previous work in this population, we found evidence for a trade-off between offspring sex and number, as well as positive and negative correlations between glucocorticoids and sex ratio and litter size, respectively, during gestation (but not lactation). We also observed a negative relationship between testosterone and litter size during gestation (but not lactation), but no effect of glucose on either sex ratio or litter size. Our findings highlight the importance of binding proteins, cross-talk between endocrine systems, and temporal windows in the regulation of trade-offs in offspring sex and number.     

The effects of sex hormones on immune function: a meta‐analysis

The effects of sex hormones on immune function have received much attention, especially following the proposal of the immunocompetence handicap hypothesis. Many studies, both experimental and correlational, have been conducted to test the relationship between immune function and the sex hormones testosterone in males and oestrogen in females. However, the results are mixed. We conducted four cross‐species meta‐analyses to investigate the relationship between sex hormones and immune function: (i) the effect of testosterone manipulation on immune function in males, (ii) the correlation between circulating testosterone level and immune function in males, (iii) the effect of oestrogen manipulation on immune function in females, and (iv) the correlation between circulating oestrogen level and immune function in females. The results from the experimental studies showed that testosterone had a medium‐sized immunosuppressive effect on immune function. The effect of oestrogen, on the other hand, depended on the immune measure used. Oestrogen suppressed cell‐mediated immune function while reducing parasite loads. The overall correlation (meta‐analytic relationship) between circulating sex hormone level and immune function was not statistically significant for either testosterone or oestrogen despite the power of meta‐analysis. These results suggest that correlational studies have limited value for testing the effects of sex hormones on immune function. We found little evidence of publication bias in the four data sets using indirect tests. There was a weak and positive relationship between year of publication and effect size for experimental studies of testosterone that became non‐significant after we controlled for castration and immune measure, suggesting that the temporal trend was due to changes in these moderators over time. Graphical analyses suggest that the temporal trend was due to an increased use of cytokine measures across time. We found substantial heterogeneity in effect sizes, except in correlational studies of testosterone, even after we accounted for the relevant random and fixed factors. In conclusion, our results provide good evidence that testosterone suppresses immune function and that the effect of oestrogen varies depending on the immune measure used.     

Relative digit lengths and testosterone levels in Guinea baboons

A growing body of literature suggests that the ratio of the lengths of the second to fourth digits (2D:4D) on human hands is sexually dimorphic and associated with prenatal exposure to gonadal hormones, circulating serum testosterone, and a number of psychological and behavioral measures. Little research has investigated digit ratios in nonhuman species. In the present study, we investigated sex differences in digit ratios and their possible association with serum testosterone in a captive group of Guinea baboons (Papio papio). Contrary to the sex difference typically reported in humans, male baboons exhibited a substantially larger 2D:4D than did female baboons. Consistent with the human data, however, lower 2D:4D was associated with higher serum testosterone among the males. The present findings suggest that the relationship between digit ratios and male gonadal hormones may be phylogenetically well-conserved, although they also suggest possible species differences in the causal relationships between developmental mechanisms and sex-differentiated digit length patterns.     

Gonadal Steroid Hormone Receptors and Sex Differences in the Hypothalamo-Pituitary-Adrenal Axis

The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.     

The role of plasma-binding proteins in the cellular uptake of lipophilic vitamins and steroids.

Steroid hormones and many other lipophilic compounds are believed to enter cells solely by free diffusion through the plasma membrane. However, recent work using a megalin-deficient mouse model has identified a new endocytic pathway responsible for the delivery of steroids to renal and gonadal tissues. This review describes these new pathways for uptake of 25-hydroxy-vitamin-D3 and the gonadal sex-steroids (17beta-estradiol and testosterone) bound to vitamin D-binding protein and sex hormone-binding globulin respectively. Furthermore examples of other lipophilic molecules that enter cells by receptor-mediated pathways will be presented and the receptors responsible for their uptake described.     

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.     

Androgens and bone

Testosterone is the major gonadal sex steroid produced by the testes in men. Testosterone is also produced in smaller amounts by the ovaries in women. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These androgens collectively affect skeletal homeostasis throughout life in both men and women, particularly at puberty and during adult life. Because testosterone can be metabolized to estradiol by the aromatase enzyme, there has been controversy as to which gonadal sex steroid has the greater skeletal effect. The current evidence suggests that estradiol plays a greater role in maintenance of skeletal health than testosterone, but that androgens also have direct beneficial effects on bone. Supraphysiological levels of testosterone likely have similar effects on bone as lower levels via direct interaction with androgen receptors, as well as effects mediated by estrogen receptors after aromatization to estradiol. Whether high doses of synthetic, non-aromatizable androgens may, in fact, be detrimental to bone due to suppression of endogenous testosterone (and estrogen) levels is a potential concern that warrants further study.     

Effects of thyroidal, gonadal and adrenal hormones on tissue respiration of streaked frog, Rana limnocharis, at low temperature

In vivo and in vitro effects of thyroidal, gonadal and adrenal hormones were studied on the rate of liver and skeletal muscle respiration in both the sexes of R. limnocharis during active and inactive phases of the annual activity cycle. Triiodothyronine (L-T3) and thyroxine (L-T4) did not stimulate tissue (liver and muscle) respiration in any of the experiments irrespective of season, sex and temperature. Testosterone, estradiol and corticosterone stimulated O2 uptake significantly irrespective of season, sex and temperature. Adrenaline and nor-adrenaline also stimulated tissue respiration significantly during the winter month. Since the ambient temperature was low even during the active phase (max. temperature 21 degrees C), it seems that the frog might have developed tissue sensitivity for gonadal and adrenal hormones at low temperatures when thyroid hormones are calorigenically ineffective.     

Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women.

Sex steroid hormones in both males and females have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Evidence also suggests a direct relationship between sex hormones and risk factors for cardiovascular disease. In the present review article, we will discuss recent studies that have examined the complex interrelationships between sex hormones, SHBG, obesity and risk factors for cardiovascular disease. Male obesity and excess abdominal adipose tissue accumulation is associated with reductions in gonadal androgen and low adrenal C19 steroid concentrations. Reduced C19 steroids are also related to an altered metabolic risk factor profile including glucose intolerance and an atherogenic dyslipidemic state. However, the concomitant visceral obese state appears as a major correlate in these associations. In women, menopause-induced estrogen deficiency and increased androgenicity are associated with increased abdominal obesity and with the concomitant alterations in the metabolic risk profile. The accelerated accretion of adipose tissue in the intra-abdominal region coincident with the onset of menopause may explain part of the increased risk of cardiovascular disease in postmenopausal women. In both men and women, plasma levels of sex hormone-binding globulin are strong correlates of obesity and risk factors for cardiovascular disease, and more importantly, the relationships between low SHBG and altered plasma lipid levels appear to be independent from the concomitant increased levels of visceral adipose tissue. SHBG concentration may, therefore, represent the most important and reliable marker of the sex hormone profile in the examination of the complex interrelation of sex steroid hormones, obesity, and cardiovascular disease risk.     

Age-dependent changes in the concentration of active sex steroids,precursors, metabolites,and regulatory agents in blood serum of male subjects

We measured blood concentration of active and non-active sex steroids, metabolites, and precursors and compared to changes in protein and peptide hormones controlling the reproductive axis (total 14 hormones and hormone-like substances) in male subjects aged 18 to 72 y.o. We found a significant decrease in serum concentration of precursors for active sex steroids (pregnenolone, progesterone, dehydroepiandrosterone, and DHEA-sulfate), free testosterone, androstenedione (non-active metabolite of testosterone) as well as 5α-dihydrotestone after the age of 35. However, the level of total testosterone and estradiol (another active testosterone metabolite) remained steady. The systems regulated production of active sex steroids resisted a higher load associated with age and caused the increase in luteinizing and follicle-stimulating hormones in hypophysis and activin in steroidogenic glands directly correlating with age; negative correlation for these hormones was confirmed with certain sex steroids explaining the negative feedback. Decrease in level of hypopheseal adrenocorticotropic hormone with age demonstrated a more substantial role for adrenal glands compared to that of testicles in reduction of blood concentration of active sex steroids. In general, despite the reduced activity of steroidogenic glands in 60-to 70-year old male subjects the level of testosterone and estradiol remained unchanged due to associated growth of level of luteinizing and follicle-stimulating hypopheseal hormones as well as activin in steroidogenic glands that stimulated biosynthesis of sex steroids. Also androgen effects were inhibited due to the reduced level of free (unbound) testosterone and 5α-dihydrotestone.     

Facial appearance is a cue to oestrogen levels in women

Although many accounts of facial attractiveness propose that femininity in women's faces indicates high levels of oestrogen, there is little empirical evidence in support of this assumption. Here, we used assays for urinary metabolites of oestrogen (oestrone-3-glucuronide, E1G) and progesterone (pregnanediol-3-glucuronide, P3G) to investigate the relationship between circulating gonadal hormones and ratings of the femininity, attractiveness and apparent health of women's faces. Positive correlations were observed between late follicular oestrogen and ratings of femininity, attractiveness and health. Positive correlations of luteal progesterone and health and attractiveness ratings were marginally significant. Ratings of facial attributions did not relate to hormone levels for women wearing make-up when photographed. There was no effect of sex of rater on the relationships between oestrogen and ratings of facial appearance. These findings demonstrate that female facial appearance holds detectable cues to reproductive health that are considered attractive by other people.     

Relation between the Adrenals and Thyroid and their Hormones and the Testicular cycle of a Subtropical Avian Species

In order to understand the hormonal interactions throughout the reproductive phases (non-breeding, progressive, breeding and regressive) of a sub-tropical avian species, the male common myna (Acriodotheres tristis), hormones like epinephrine (E), norepinephrine (NE), corticosterone, tri-iodothyronine (T 3), thyroxine (T 4) and testosterone (along with testicular sialic acid) were quantitated. Histometry and histology of the testis and adrenal glands were also performed. It became evident that a parallel relationship exists between the reproductive phases of the common myna and levels of the hormones E, NE, corticosterone, T 3, T 4 and testosterone. Considering the ambient climatological conditions, it is suggested that primarily daylength and secondarily humidity control the gonadal cycle of this species.     

Relation between the Adrenals and Thyroid and their Hormones and the Testicular cycle of a Subtropical Avian Species

In order to understand the hormonal interactions throughout the reproductive phases (non-breeding, progressive, breeding and regressive) of a sub-tropical avian species, the male common myna ( Acriodotheres tristis ), hormones like epinephrine (E), norepinephrine (NE), corticosterone, tri-iodothyronine (T 3 ), thyroxine (T 4 ) and testosterone (along with testicular sialic acid) were quantitated. Histometry and histology of the testis and adrenal glands were also performed. It became evident that a parallel relationship exists between the reproductive phases of the common myna and levels of the hormones E, NE, corticosterone, T 3 , T 4 and testosterone. Considering the ambient climatological conditions, it is suggested that primarily daylength and secondarily humidity control the gonadal cycle of this species.     

Testicular hormones modulate circadian rhythms of the diurnal rodent, Octodon degus

Sex differences have been identified in a variety of circadian rhythms, including free-running rhythms, light-induced phase shifts, sleep patterns, hormonal fluctuations, and rates of reentrainment. In the precocial, diurnal rodent Octodon degus, sex differences have been found in length of free-running rhythm (tau), phase response curves, rates of reentrainment, and in the use of social cues to facilitate reentrainment. Although gonadal hormones primarily organize circadian rhythms during early development, adult gonadal hormones have activational properties on various aspects of circadian rhythms in a number of species examined. Gonadectomy of adult female O. degus did not influence tau, phase angle of entrainment, or activity patterns in previous experiments. The present experiment examined the role of gonadal hormones in adult male degus' circadian wheel-running rhythms. We predicted that male gonadal hormones would have an activational effect on some aspects of circadian rhythms, particularly those in which we see sex differences. Phase angles of entrainment, tau, length of the active period (alpha), maximum and mean activity levels, and activity amplitude were examined for intact and castrated males housed in LD 12:12. Responses to light pulses while housed in constant darkness (DD) were also compared. Castration had no significant effect on tau or light-induced phase shifts. However, castration significantly increased phase angle of entrainment and decreased activity levels. The data indicate that adult gonadal steroids are not responsible for the sex differences in endogenous circadian mechanisms of O. degus (tau, PRC), although they influence activity level and phase angle of entrainment. This is most likely due to masking properties of testosterone, similar to the activity-increasing effects of estrogen during estrus in O. degus females.     

A Trivers-Willard Effect in Contemporary Humans: Male-Biased Sex Ratios among Billionaires

Background

Natural selection should favour the ability of mothers to adjust the sex ratio of offspring in relation to the offspring''s potential reproductive success. In polygynous species, mothers in good condition would be advantaged by giving birth to more sons. While studies on mammals in general provide support for the hypothesis, studies on humans provide particularly inconsistent results, possibly because the assumptions of the model do not apply.

Methodology/Principal Findings

Here, we take a subset of humans in very good condition: the Forbe''s billionaire list. First, we test if the assumptions of the model apply, and show that mothers leave more grandchildren through their sons than through their daughters. We then show that billionaires have 60% sons, which is significantly different from the general population, consistent with our hypothesis. However, women who themselves are billionaires have fewer sons than women having children with billionaires, suggesting that maternal testosterone does not explain the observed variation. Furthermore, paternal masculinity as indexed by achievement, could not explain the variation, since there was no variation in sex ratio between self-made or inherited billionaires.

Conclusions/Significance

Humans in the highest economic bracket leave more grandchildren through sons than through daughters. Therefore, adaptive variation in sex ratios is expected, and human mothers in the highest economic bracket do give birth to more sons, suggesting similar sex ratio manipulation as seen in other mammals.     

Postmenopausal sex hormones in relation to body fat distribution

Being overweight or obese increases the risk of postmenopausal breast cancer. A potential reason may be the frequently observed positive association of BMI with endogenous sex hormones and its negative association with sex hormone-binding globulin (SHBG). The purpose of this study was to investigate whether a woman's body fat distribution shows a BMI-independent association with these breast cancer-related biomarkers. Performing cross-sectional analyses among 1,180 postmenopausal women, we assessed whether associations of surrogates for an abdominal (waist circumference; waist-to-hip ratio, WHR) and gluteofemoral (hip circumference) fat distribution with estrone, total and free estradiol, androstenedione, total and free testosterone, and SHBG changed after adjustment for, or stratification by, BMI. All anthropometric measures were positively associated with estrogens and free testosterone, and negatively with SHBG. After adjustment for BMI, associations of free estradiol, free testosterone, and SHBG with both waist circumference and WHR remained significant, but all initially significant associations with hip circumference were abolished. In stratified analyses, waist circumference and WHR correlated with free estradiol, free testosterone, and SHBG in women with a BMI < 30 kg/m(2) but not in women with a BMI ≥ 30 kg/m(2). The latter suggests that in obese women, a possibly unique effect of abdominal fat on these biomarkers may be masked by the already large amount of overall body fat. On the whole, our results indicate that waist circumference and WHR, but not hip circumference, are associated with SHBG and SHBG-related sex hormones (free estradiol and free testosterone) independently of BMI.     

A levels of endogenous gonadal hormones and their relationship with selected coronary artery disease risk factors among young women post myocardial infarction

In recent decades a significant raise in the incidence of myocardial infarction among young women has been recorded. It is presumed that, apart from the classical risk factors, other reasons exist for premature atherosclerosis in young women, related to the homeostasis of gonadal hormones. The aim of the study was to analyze the levels of gonadal hormones (estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone, testosterone and dehydroepiandrosterone) measured in the luteal phase, in 65 normally menstruating women post myocardial infarction (MI) and to investigate a possible relationship between the hormone profile and selected coronary artery disease (CAD) risk factors. The levels of gonadal hormones: estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone, testosterone and dehydroepiandrosterone were measured in the luteal phase. All examined women had normal mean levels of gonadal hormones. In the post MI patients leading a sedentary life style, a significantly lower mean progesterone concentration was observed (16.29 ± 9.11 versus 29.43 ± 21.14 nmol/l, p < 0.05) and significantly higher mean testosterone concentration (2.34 ± 0.98 versus 1.76 ± 1.09 nmol/l, p < 0.05) when compared to patients from the same group, but leading a more active life. In obese post MI women (BMI ≥ 30 kg/m(2)) a lower mean concentration of progesterone was detected (18.02 ± 8.12 versus 26.16 ± 14.72 nmol/l, p < 0.05), than in slimmer patients from the same group. In post MI women with a positive family history for CAD, a significantly higher mean concentration of testosterone was detected (2.31 ± 1.22 versus 1.67 ± 0.74 nmol/l, p < 0.05) than in patients with no family history. The results suggest a correlation between levels of gonadal hormones and classical CAD risk factors.     

Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal

Background  

Hormones are critical for early gonadal development in nonmammalian vertebrates, and oestrogen is required for normal ovarian development. In contrast, mammals determine sex by the presence or absence of the SRY gene, and hormones are not thought to play a role in early gonadal development. Despite an XY sex-determining system in marsupial mammals, exposure to oestrogen can override SRY and induce ovarian development of XY gonads if administered early enough. Here we assess the effect of exogenous oestrogen on the molecular pathways of mammalian gonadal development.     

Interrelationship between adrenal cortex and genital apparatus of the male rat]

Interactions between gonadal hormones and adrenocortical function have been studied in the male rat. After injection (im) of testosterone, the accessory reproductive organs are more stimulated in the castrated rats than in the castrated adrenalectomized rats. Gonadectomy increases lipids, cholesterol and corticosterone in adrenal glands and plasma corticosterone levels. Testosterone reverses these effects.