Testosterone and immune-reproductive tradeoffs in healthy women

Although testosterone (T) has been characterized as universally immunosuppressive across species and sexes, recent ecoimmunology research suggests that T's immunomodulatory effects (enhancing/suppressing) depend on the organism's reproductive context. Very little is known about the immune effects of T in healthy females, and even less about how reproductive effort modulates the immune effects of T in humans. We investigated how the interaction between endogenous T and sexual activity predicted menstrual cycle-related changes in several measures of immunity: inflammation (indexed by interleukin-6, IL-6), adaptive immunity (indexed by immunoglobulin A, IgA), and functional immunity (indexed by bactericidal assay). Thirty-two healthy women (sexually abstinent, N = 17; sexually active with one male partner, N = 15) provided saliva samples at four points in the menstrual cycle: menses, follicular, ovulation, and luteal phases. Among sexually abstinent women, T was positively associated with IL-6 across the cycle; for sexually active women, however, T was positively associated with IL-6 in the luteal phase only, and negatively associated with IL-6 at ovulation. High T predicted higher IgA among women who reported infrequent intercourse, but lower IgA among women who reported very frequent intercourse. Finally, across groups, T was positively associated with greater bacterial killing at menses, but negatively associated in the luteal phase. Overall, rather than being universally immunosuppressive, T appeared to signal immunomodulation relevant to reproduction (e.g., lowering inflammation at ovulation, potentially preventing immune interference with conception). Our findings support the hypothesis that the immunomodulatory effects of endogenous T in healthy females depend on sexual and reproductive context.     

Physical activity of adult female rhesus monkeys (Macaca mulatta) across the menstrual cycle

Physical activity is an important physiological variable impacting on a number of systems in the body. In rodents and several species of domestic animals, levels of physical activity have been reported to vary across the estrous cycle; however, it is unclear whether such changes in activity occur in women and other primates across the menstrual cycle. To determine whether significant changes in activity occur over the menstrual cycle, we continuously measured physical activity in seven adult female rhesus monkeys by accelerometry over the course of one menstrual cycle. Monkeys were checked daily for menses, and daily blood samples were collected for measurement of reproductive hormones. All monkeys displayed ovulatory menstrual cycles, ranging from 23 to 31 days in length. There was a significant increase in estradiol from the early follicular phase to the day of ovulation (F(1.005,5.023) = 40.060, P = 0.001). However, there was no significant change in physical activity across the menstrual cycle (F(2,12) = 0.225, P = 0.802), with activity levels being similar in the early follicular phase, on the day of the preovulatory rise in estradiol and during the midluteal phase. Moreover, the physical activity of these monkeys was not outside the range of physical activity that we measured in 15 ovariectomized monkeys. We conclude that, in primates, physical activity does not change across the menstrual cycle and is not influenced by physiological changes in circulating estradiol. This finding will allow investigators to record physical activity in female primates without the concern of controlling for the phase of the menstrual cycle.     

Sialic acid and neuraminidase activity in the frog oviduct: comparative biochemical investigation in the different tracts during the reproductive cycle

1. A biochemical study was carried out on the protein-bound and lipid-bound sialic acid, and neuraminidase activity in the different tracts of the oviduct of the frog Rana esculenta during the reproductive cycle. 2. Plasma sexual steroids were also investigated by RIA. 3. Fluctuations in neuraminidase activity are related to that of glycoprotein sialic acid and plasma estradiol. Glycolipid sialic acid does not have a close relationship either with neuraminidase or plasma estradiol. 4. Very high plasma concentration of progesterone before ovulation and, on the contrary, its drop after ovulation were observed. 5. The results are discussed and hypotheses advanced to explain fluctuations of the studied parameters during the reproductive cycle.     

Changes in Sleep Time and Sleep Quality across the Ovulatory Cycle as a Function of Fertility and Partner Attractiveness

Research suggests that near ovulation women tend to consume fewer calories and engage in more physical activity; they are judged to be more attractive, express greater preferences for masculine and symmetrical men, and experience increases in sexual desire for men other than their primary partners. Some of these cycle phase shifts are moderated by partner attractiveness and interpreted as strategic responses to women''s current reproductive context. The present study investigated changes in sleep across the ovulatory cycle, based on the hypothesis that changes in sleep may reflect ancestral strategic shifts of time and energy toward reproductive activities. Participants completed a 32-day daily diary in which they recorded their sleep time and quality for each day, yielding over 1,000 observations of sleep time and quality. Results indicated that, when the probability of conception was high, women partnered with less attractive men slept more, while women with more attractive partners slept less.     

Sporadic sexual behavior and menstrual cycle length in women

In an initial study of 248 university students prospective double-blind monitoring of sexual behavior and menses onsets showed that sporadic (less than regular weekly) sexual activity was associated with aberrant menstrual cycle lengths. This study examines the sample of sporadically active women for behavioral correlates of aberrant cycle lengths. It is shown that women reporting a high frequency of sexual activity (though in a sporadic pattern) showed a higher incidence of aberrant cycle lengths than women reporting a low frequency of sporadic coitus. Stable ongoing sexual behavior patterns appear to associate with a different endocrine background than less stable, sporadic sexual patterns.     

Women's estradiol predicts preference for facial cues of men's testosterone

A growing body of research has shown that women express stronger attraction to more masculine traits when they are tested near ovulation than when tested during other times in the menstrual cycle. Although these effects have been interpreted as increased preferences for markers of elevated testosterone during times in the cycle when conception is most likely, no previous studies have directly demonstrated that women express stronger attraction to higher testosterone men at different times in the cycle. In addition, little research has addressed which hormonal or other physiological mechanisms may regulate temporal shifts in women's attractiveness judgments. In this research, we demonstrate that women with higher estradiol concentrations exhibit stronger preferences for the faces of men with higher testosterone concentrations, and that women's testosterone preference and estradiol curves track one another across days of the cycle. The findings are the first direct demonstration in humans that hormone concentrations in one sex are associated with attraction to cues of hormonal status in the opposite sex. The results support a functional role for estradiol in calibrating women's mating psychology to indices of their current fertility, analogous to similar processes that have been documented in nonhuman species. A strong correlation between estradiol and testosterone preference specifically during the luteal phase further suggests that women's mate preferences may track their fertility between different cycles in addition to being calibrated to the timing of ovulation within individual cycles.     

Neural activation in the orbitofrontal cortex in response to male faces increases during the follicular phase

Women's sexual interest changes with hormonal fluctuations across the menstrual cycle. It is unclear how hormones modify women's sexual behavior and desire, but one possibility is that they alter women's positive appraisals of stimuli and thus their sexual interest. Using 3 T fMRI, we measured neural activation in women at two time points in their menstrual cycle (late follicular, luteal) while they evaluated photos of men presented as potential sexual partners. Participants were ten heterosexual women aged 23-28 none of who was using hormonal contraceptives or in a committed relationship. In an event-related design, the women were presented with as series of photos of male faces and asked questions to assess their degree of sexual interest in the men depicted. Results demonstrate an overall effect of menstrual cycle phase on neural activation. During their follicular versus luteal phase, women demonstrated increased activation in the right medial orbitofrontal cortex (OFC), suggesting increased positive appraisal. Activation in the OFC was positively correlated with women's estradiol to progesterone ratios. There were no areas that demonstrated increased activation during the luteal versus follicular phase. The observed increase in activation in the OFC during the follicular phase may reflect a hormonally mediated increase in appetitive motivation and may prime women towards increased sexual interest and behavior around ovulation.     

Effects of estradiol and FSH on leptin levels in women with suppressed pituitary

ABSTRACT: BACKGROUND: Female fertility depends on adequate nutrition and energy reserves, suggesting a correlation between the metabolic reserve and reproductive capacity. Leptin regulates body weight and energy homeostasis. The aim of this study was to investigate whether estradiol or FSH alone has a direct effect on the production of leptin. METHODS: A total of 64 patients submitted to controlled ovarian hyperstimulation with recombinant FSH for assisted reproduction and 20 patients using estradiol valerate for endometrial preparation for oocyte donation treatment were included in the study. All patients used GnRH analogues before starting treatment to achieve pituitary suppression. Blood samples for hormonal measurements were collected before starting and after completing the respective treatments. Data were analyzed statistically by the chi-square test, Student's t-test and Pearson's correlation test. RESULTS: We observed an elevation of serum leptin levels secondary to the increase in estradiol, in the absence of influence of any other ovarian or pituitary hormone. The rising rate of leptin levels was higher in women treated with recombinant FSH, which also had higher levels of estradiol, than in those treated with estradiol valerate. CONCLUSIONS: This study demonstrates a correlation between serum levels of estradiol and leptin, suggesting that estradiol is an important regulator of leptin production and that its effects can be amplified by its association with FSH.     

Species differences in the regulation of tyrosine hydroxylase in Cnemidophorus whiptail lizards

Evolution of behavioral phenotype involves changes in the underlying neural substrates. Cnemidophorus whiptail lizards enable the study of behavioral and neural evolution because ancestral species involved in producing unisexual, hybrid species still exist. Catecholaminergic systems modulate the expression of social behaviors in a number of vertebrates, including whiptails, and therefore we investigated how changes in catecholamine production correlated with evolutionary changes in behavioral phenotype by measuring the size and number of catecholamine producing (tyrosine hydroxylase-immunoreactive, or TH-ir) cells across the reproductive cycle in females from two related whiptail species. Cnemidophorusuniparens is a triploid, parthenogenetic species that arose from hybridization events involving the diploid, sexual species C. inornatus. Prior to ovulation, females from both species display femalelike receptive behaviors. However, after ovulation, only parthenogenetic individuals display malelike mounting behavior. In all nuclei measured, we found larger TH-ir cells in the parthenogen, a difference consistent with species differences in ploidy. In contrast, species differences in the number of TH-ir cells were nucleus specific. In the preoptic area and anterior hypothalamus, parthenogens had fewer TH-ir cells than females of the sexual species. Reproductive state only affected TH-ir cell number in the substantia nigra pars compacta (SNpc), and C. uniparens individuals had more TH-ir cells after ovulation than when previtellogenic. Thus, species differences over the reproductive cycle in the SNpc are correlated with species differences in behavior, and it appears that the process of speciation may have produced a novel neural and behavioral phenotype in the parthenogen.     

Low sexual desire in women: the role of reproductive hormones

The role of reproductive hormones in mediating sexual desire in healthy women is still unclear. Elucidation was sought in this study by comparing the hormonal milieu of two groups of subjects with markedly different levels of sexual desire. Seventeen women ages 27-39 who met DSM III-R criteria for severe, persistent, and generalized loss of desire (hypoactive sexual desire disorder, HSD), but had no other current psychological or medical problem, were compared to 13 healthy, sexually active women. All subjects and spouses were interviewed extensively to determine the women's sexual desire and responsiveness. Blood samples were drawn every 3 to 4 days for one menstrual cycle and were analyzed by RIA for testosterone, SHBG, estradiol, progesterone, prolactin, and luteinizing hormone. Results indicated that the HSD women's gonadal hormones fluctuated normally over the menstrual cycle, were within normal limits for each cycle phase, and were never significantly different from those of controls. Neither testosterone, non-SHBG bound testosterone, nor prolactin differentiated between the HSD women with the most and least severe HSD parameters (e.g., frequency of fantasy, masturbation, or female-initiated coitus), nor between women with lifelong and acquired HSD. The present findings did not provide evidence that reproductive hormones are important determinants of individual differences in the sexual desire of these eugonadal women.     

Ovulatory shifts in human female ornamentation: near ovulation, women dress to impress

Humans differ from many other primates in the apparent absence of obvious advertisements of fertility within the ovulatory cycle. However, recent studies demonstrate increases in women's sexual motivation near ovulation, raising the question of whether human ovulation could be marked by observable changes in overt behavior. Using a sample of 30 partnered women photographed at high and low fertility cycle phases, we show that readily-observable behaviors - self-grooming and ornamentation through attractive choice of dress - increase during the fertile phase of the ovulatory cycle. At above-chance levels, 42 judges selected photographs of women in their fertile (59.5%) rather than luteal phase (40.5%) as "trying to look more attractive." Moreover, the closer women were to ovulation when photographed in the fertile window, the more frequently their fertile photograph was chosen. Although an emerging literature indicates a variety of changes in women across the cycle, the ornamentation effect is striking in both its magnitude and its status as an overt behavioral difference that can be easily observed by others. It may help explain the previously documented finding that men's mate retention efforts increase as their partners approach ovulation.     

The endocrinology of the menopauseProceedings of Xth International Congress on Hormonal Steroids, Quebec, Canada, 17–21 June 1998.

Menopause is defined as the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. Ovarian primordial follicle numbers decrease with increasing age up to about age 38 following which there is a much steeper decline in the last 12 or so years of reproductive life. At the time of the menopause itself, few follicles remain within the ovary. The recent availability of assays specific for the dimeric inhibins A and B has permitted clarification of the endocrine events leading up to and occurring around the time of final menses. Those women who show clear elevations in serum FSH above age 40, while continuing to cycle regularly have significantly lower inhibin B levels than those whose FSH levels remain in the range seen earlier in reproductive life. Early in the menopause transition, when cycle irregularity is first observed, the initial event is a decline in circulating inhibin B levels in the early follicular phase. In the late perimenopause, levels of estradiol and inhibin A also fall, inhibin B levels remain low and FSH is markedly elevated. The variability of hormone levels in women in their 40s, even in those who are continuing to cycle regularly makes FSH and estradiol unreliable markers of menopausal status. Serum androgen levels appear to fall with age rather than having any clear cut relationship to the menopause transition or menopause. The endocrine changes which occur during the menopausal transition and early postmenopausal period have clinical consequences in terms of symptoms and changes in bone mass.     

Reproductive synchronization in squirrel monkeys (Saimiri)

Groups of squirrel monkeys (Saimiri) that are exposed to certain seasonal environmental stimuli experience a yearly reproductive cycle with discrete mating and birth seasons. Seasonal rainfall or some rainfall induced seasonal changes (such as changes in vegetation or insect fauna) appear to be responsible for timing theSaimiri reproductive cycle. Animals of both sexes show significant physiological and behavioral changes during the yearly cycle. Whether the environmental timing factors affect both the males and the females equally, or affect only one sex directly and the other sex indirectly through social communication is not clear. Three mechanisms by which the reproductive activity of both males and females could be synchronized are presented, and data from a laboratory study and a field study relevant to each mechanism are presented. Several social interaction patterns frequently observed in the field study suggest that (1) male sexual activity may excite female sexual activity through male penile display and/or other stereotyped interactions and/or (2) female sexual activity may excite male sexual activity through pheromone and/or other communication channels.     

Lack of support for relation between woman's masculinity preference,estradiol level and mating context

It has been proposed that women's preferences for male facial sexual dimorphism are positively correlated with conception probability and differ between short- and long-term mating contexts. In this study, we tested this assumption by analyzing relationships between estradiol levels to the women's preferences of male faces that were manipulated to vary in masculinity. Estradiol was measured in daily saliva samples throughout the entire menstrual cycle collected by Polish women with regular menstrual cycles. In our analyses, we included the three most commonly used definitions of the fertile window in the literature. After computing the overall masculinity preference of each participant and measuring hormone levels, we found that i) the timing of ovulation varied greatly among women (between − 11 and − 17 days from the onset of the next menses, counting backwards), ii) there was no relationship between daily, measured during the day of the test (N = 83) or average for the cycle (N = 115) estradiol levels and masculinity preferences, iii) there were no differences in masculinity preferences between women in low- and high-conception probability phases of the cycle, and iv) there were no differences in masculinity preferences between short- and long-term mating contexts. Our results do not support the idea that women's preferences for a potential sexual partner's facial masculinity fluctuate throughout the cycle.     

Effect of short term passive immunization of the cyclic ewe against estradiol-17β

Three groups of 4 ewes were passively immunised against estradiol 17β during days 2 through 7, 10 through 17 and 15 through 20 of the estrous cycle respectively. The effects of the neutralisation of estradiol 17β at these specific times, on corpus luteum function, plasma concentrations of luteinising hormone (LH), estrus, and ovulation were observed.Passive immunisation at any phase of the oestrous cycle did not appear to effect the appearance of large ovarian follicles (5–15 mm diameter) at the next time of expected estrus, or the lifespan of the corpus luteum of that cycle. Treatment from day 15 to 20 of the cycle appeared to inhibit estral activity, ovulation and the preovulatory LH surge. Treatment from day 10 to 17 was less disruptive although some extension of the length of the estrous cycle was indicated, and treatment from day 2 to 7 produced little interference with cyclic reproductive activity.     

Effect of moderate physical activity on plasma leptin concentration in humans

In subjects who maintain a constant body mass, the increased energy expenditure induced by exercise must be compensated by a similar increase in energy intake. Since leptin has been shown to decrease food intake in animals, it can be expected that physical exercise would increase energy intake by lowering plasma leptin concentrations. This effect may be secondary either to exercise-induced negative energy balance or to other effects of exercise. To delineate the effects of moderate physical activity on plasma leptin concentrations, 11 healthy lean subjects (4 men, 7 women) were studied on three occasions over 3 days; in study 1 they consumed an isoenergetic diet (1.3 times resting energy expenditure) over 3 days with no physical activity; in study 2 the subjects received the same diet as in study 1, but they exercised twice daily during the 3 days (cycling at 60 W for 30 min); in study 3 the subjects exercised twice daily during the 3 days, and their energy intake was increased by 18% to cover the extra energy expenditure induced by the physical activity. Fasting plasma leptin concentration (measured on the morning of day 4) was unaltered by exercise [8.64 (SEM 2.22) 7.17 (SEM 1.66), 7.33 (SEM 1.72) 1 microg x l(-1) in studies 1, 2 and 3, respectively]. It was concluded that a moderate physical activity performed over a 3-day period does not alter plasma leptin concentrations, even when energy balance is slightly negative. This argues against a direct effect of physical exercise on plasma leptin concentrations, when body composition is unaltered.     

Loss of estrus in human evolution: Too many answers,too few questions

Models addressing the importance of “loss of estrus” in human evolution assume that, as part of a general trend among higher primates, endogenous hormonal fluctuations have less influence on human female sexuality than cognitive and socioenvironmental factors. The diversity of reproductive patterns among primate species is not satisfactorily explained as the outcome of evolutionary trends along dimensions such as brain enlargement, behavioral flexibility, or relative independence of behavior from physiology. Rather, the role of hormones and other factors must be viewed in the context of species' life history and ecological constraints. Human studies on the relationship between the menstrual cycle and sexual behavior have been limited to Western women in industrialized societies, which may not reveal evolved behavioral-physiological patterns. Furthermore, available studies have yielded inconsistent results. No single pattern emerges that can be said to characterize the human female, and no conclusion can be reached regarding the relationship between cyclic hormonal fluctuations and sexual behavior and, thus, whether human ovulation is concealed. Future studies are needed that are methodologically improved and systematically document the interaction among ecological, subsistence, social, and physiological variables.     

Plasma leptin in female athletes: relationship with body fat, reproductive, nutritional, and endocrine factors.

The relationship of leptin to thyroid and sex hormones, insulin, energy intake, exercise energy expenditure, and reproductive function was assessed in 39 female athletes. They comprised elite athletes who were either amenorrheic (EAA; n = 5) or cyclic (ECA; n = 8) and recreationally active women who were either cyclic (RCA; n = 13) or taking oral contraceptives (ROC; n = 13). Leptin was significantly lower in EAA (1.7 +/- 0.2 ng/ml) than in ECA (2.9 +/- 0.3 ng/ml), RCA (5.8 +/- 0.9 ng/ml), and ROC (7.4 +/- 1.3 ng/ml). Hypoleptinemia in EAA was paralleled by reductions (P < 0.05) in caloric intake, insulin, estradiol, and thyroid hormones. Leptin increased by 40-46% (P < 0.05) in the luteal phase of the menstrual cycle in RCA and ECA. Plasma leptin was similar in the placebo and active pill phases in ROC despite a significant increase in ethinylestradiol. Leptin correlated (P < 0.05) with triiodothyronine and insulin but not with estrogen, energy intake, or exercise energy expenditure. These data suggest that in female athletes 1) leptin may be a metabolic signal that provides a link between adipose tissue, energy availability, and the reproductive axis and 2) sex hormones do not directly regulate leptin secretion.     

Dietary influences on growth and sexual maturation in premenarchial rhesus monkeys

The effect of a high-fat diet on growth, sexual maturation, and developmental changes in serum levels of estradiol (E2), growth hormone (GH), somatomedin-C (Sm-C), and insulin were examined in outdoor-housed premenarchial rhesus monkeys. From 16 to 32 months of age, females were fed either a high-fat diet (HFD, N = 5) with 31% calories from fat or a control diet (commercial laboratory chow, N = 10) with 12% of the calories from fat. Maintenance on a HFD did not accelerate physical growth, as all animals exhibited similar increments in body weight, crown-rump length, and weight/height ratios. In contrast, the HFD group exhibited an earlier onset of perineal swelling and menarche despite lower body weights during that time. Moreover, 80% of the HFD animals exhibited an early first ovulation (31-32 months of age) compared with 40% of control animals. These reproductive changes were associated with significant differences in the endocrine profiles of HFD animals. Fasting serum levels of insulin were significantly elevated within 2 months of diet treatment and remained elevated throughout the study period. Levels of Sm-C were elevated relative to those of controls after 3 months of diet treatment, but not thereafter. Serum GH increased after 6 months on the HFD and, overall, concentrations were higher in HFD animals. A significant rise in E2 was observed after only 45 days on the HFD treatment. These concentrations did not differ from 18 to 21 months of age but again were elevated at 27 months in the HFD females. Since these endocrine and physical changes associated with reproductive physiology occurred in the absence of enhanced growth, these data suggest that a high-fat diet may influence the rate of sexual maturation through changes in certain metabolic factors which may act on the developing neuroendocrine system.     

Does Estradiol Modulate Sexual Solicitations in Female Rhinopithecus roxellana?

Studies of the relationship between sexual behavior and reproductive endocrinology in females offer critical insight into sexual selection, mate choice, and female reproductive strategies in primates. We examine the relationship between sexual solicitations and urinary estradiol in female Sichuan golden monkeys (Rhinopithecus roxellana) living under semiwild conditions at the Shanghai Wild Animal Park, China. We collected data on the frequency of sexual solicitations and urinary samples on 4 adult females during 2 mating seasons. We determined urinary estradiol levels via radioimmunoassay. Our results indicate that during the ovarian cycle, solicitation focused on the periovulatory period around the estradiol peak. The frequency of female solicitations rose to a peak after the peak of estradiol level, suggesting that ovarian steroids modulate sexual behavior during the fertile phase of the ovarian cycle. We also found that females frequently solicited matings during pregnancy, most of which the α male accepted and that resulted in copulations. During pregnancy, however, there was no obvious relationship between sexual solicitation and urinary estradiol. We conclude that in Rhinopithecus roxallana, sexual behavior and estradiol production do not strictly correlate during different parts of the reproductive cycle. We discuss additional relationships between social interactions, dominance, sexual behavior, and endocrine function.