Circamensal Rhythmicity and Muscle Function: The Role of Reproductive Hormones in the Regulation of Strength

The human female menstrual cycle is characterised by fluctuations in reproductive and pituitary hormones which regulate the monthly release of an ovum for fertilisation. The circamensal changes in the hormonal milieu may influence exercise performance. The generation of maximal voluntary muscle strength, mediated by changes in the steroid hormones, has been the focus of recent research, particularly ergogenic effects of oestrogen. Peak force of the adductor pollicis, normalised for muscle size, has been reported mid-cycle in concert with the rise in oestrogen. The removal of an oestrogen and progesterone environment results in muscle weakness in humans and animals. These hormones decline concomitantly following natural ovarian failure (i.e., the menopause) and surgical extraction of the ovaries (i.e., bilateral oophorectomy). To overcome the problem of controlling for rapid cyclical changes in reproductive hormones across the menstrual cycle, and to isolate the effects of oestrogen when measuring strength, other models have been adopted. Treatment of in vitro fertilisation patients involves, in part, the down-regulation of gonadotropin releasing hormone receptors followed by up-regulation with exogenous pituitary hormones. This presents a very low and very high oestrogenic milieu while progesterone remains rel atively stable. Under these conditions, maximal strength of the first dorsal interosseus muscle has been unchanged. The rapid loss in strength observed post-menopause is preserved, and possibly restored, in women taking hormone replacement therapy. These findings are significant for the preservation of skeletal and muscular health of post-menopausal women. There is increasing evidence to support the role of reproductive hormones in the regulation of muscle strength. Since the link between the hormone milieu during the menstrual cycle and strength changes is weak, other models must be employed. Strength declines rapidly at the menopause, and offsetting muscle weakness in post-menopausal women has implications in reducing the risk of muscloskeletal injury. Female athletes who are prone to amenorrhoea constitute another target group. A hormone-deficient state may not be beneficial to performance, but may compromise muscle function.     

The Menstrual Cycle and Human Performance: An Overview

Physiological events during the normal menstrual cycle are determined by feedback loops within the hypothalamic-pituitary-ovarian axis. Hormonal changes within the menstrual cycle have potential impact on human performance. Relevant stages to consider are pre-menses and menses, the follicular and luteal phases separated by an abrupt elevation in lutenizing hormone and characterised by a sharp rise in body temperature coinciding with ovulation. Strenuous athletic training may affect the normal menstrual cycle. Such disruptions include delayed menarche in ballet dancers and gymnasts, shortened luteal phase and secondary amenorrhea associated with high training loads and competitive stress. Amenorrhea is also noted in flight attendants, linked with an inhibiting effect of disrupted circadian rhythm on lutenizing hormone. The so-called 'athlete triad' considers secondary amenorrhea, abnormal eating behaviour and osteoporosis (attributed to chronic hypoestrogenia). The normal cycle may also be disrupted when circadian rhythms are disturbed, for example in rapid time-zone transitions. Fluctuations in the steroid hormones have been associated with changes in muscle strength. There is evidence also of elevations in heart rate: changes may be partly specific to time of day. Effects on muscle strength may be determined at selected stages of the menstrual cycle, using whole-body performance, local muscle groups or isolated individual muscles. Whilst oestrogen has been implicated in the ergogenic effect of steroid hormones, there is accumulating evidence that a role for progesterone cannot be discounted. The isolation of the ovarian hormones separately is feasible with studies of IVF patients or groups on hormone replacement therapy.     

The Menstrual Cycle and Human Performance: An Overview

Physiological events during the normal menstrual cycle are determined by feedback loops within the hypothalamic-pituitary-ovarian axis. Hormonal changes within the menstrual cycle have potential impact on human performance. Relevant stages to consider are pre-menses and menses, the follicular and luteal phases separated by an abrupt elevation in lutenizing hormone and characterised by a sharp rise in body temperature coinciding with ovulation. Strenuous athletic training may affect the normal menstrual cycle. Such disruptions include delayed menarche in ballet dancers and gymnasts, shortened luteal phase and secondary amenorrhea associated with high training loads and competitive stress. Amenorrhea is also noted in flight attendants, linked with an inhibiting effect of disrupted circadian rhythm on lutenizing hormone. The so-called 'athlete triad' considers secondary amenorrhea, abnormal eating behaviour and osteoporosis (attributed to chronic hypoestrogenia). The normal cycle may also be disrupted when circadian rhythms are disturbed, for example in rapid time-zone transitions. Fluctuations in the steroid hormones have been associated with changes in muscle strength. There is evidence also of elevations in heart rate: changes may be partly specific to time of day. Effects on muscle strength may be determined at selected stages of the menstrual cycle, using whole-body performance, local muscle groups or isolated individual muscles. Whilst oestrogen has been implicated in the ergogenic effect of steroid hormones, there is accumulating evidence that a role for progesterone cannot be discounted. The isolation of the ovarian hormones separately is feasible with studies of IVF patients or groups on hormone replacement therapy.     

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.     

Neuroendocrine changes in the aging reproductive axis of female rhesus macaques (Macaca mulatta)

Femalerhesus macaques show monthly menstrual cycles and eventually enter menopause at approximately 25 yr of age. To help identify early biomarkers of menopause in this nonhuman primate, we monitored reproductive hormones longitudinally from aged female macaques during the transitions from premenopause to perimenopause and postmenopause and found that, indeed, elevated plasma FSH was a better predictive factor of menopause onset than age. In a second experiment, we compared reproductive hormone profiles of young adult macaques (8-10 yr old) with those of regularly cycling old macaques (approximately 24 yr old). Indwelling vascular catheters were used for remote blood collection for at least 100 consecutive days, thereby covering three complete menstrual cycles in each macaque. Plasma levels of estradiol, progesterone, LH, FSH, follicular phase inhibin B, and anti-müllerian hormone (AMH) were determined during each menstrual cycle and were averaged for each animal; group mean differences were analyzed using one-way ANOVA. Old premenopausal macaques showed regular menstrual cycles that were qualitatively indistinguishable from those of young macaques; peak plasma levels of estradiol, progesterone, and LH were not significantly different. In marked contrast, peak plasma FSH concentrations were significantly higher, while inhibin B and AMH levels were generally lower, in the old premenopausal macaques compared with those in the young macaques. These data provide further evidence that rhesus macaques serve as an excellent model to study underlying mechanisms of human menopause. Furthermore, the data suggest that an age-related change in FSH, inhibin B, and AMH secretion may be the first endocrine manifestation of the transition into perimenopause, potentially having value in predicting the onset of the perimenopausal transition.     

Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause.

To obtain more insight into the relationship between cyclic and regional changes in steroid receptor expression and function-related changes in the various types of cell of the normal human uterus, we performed an immunocytochemical study on paraffin-embedded sections. The distribution and intensity of immunostaining for the oestrogen receptor and the progesterone receptor in the various types of cell were semiquantitatively scored. The data were statistically compared for the different phases of the menstrual cycle and after the menopause, and for the different regions of the corpus and (endo)cervix uteri. During the menstrual cycle, significant changes in oestrogen receptor score were observed in glandular and stromal cells of endometrium basalis and functionalis and in smooth muscle cells of the myometrium. In all types of cell, oestrogen receptor expression reached a maximum in the late proliferative phase. During the early secretory phase, oestrogen receptor staining declined sharply in stromal and smooth muscle cells, whereas, in glandular epithelium, oestrogen receptor expression decreased more gradually. During mid- and late-secretory phases, an increase in oestrogen receptor staining was also observed in predecidualizing stromal cells and smooth muscle cells. Progesterone receptor numbers changed significantly in glandular epithelium but not in stromal and smooth muscle cells. Glandular progesterone receptor expression reached a maximum in the early secretory phase and was then drastically reduced. During mid- and late-secretory phases stromal cells were moderately stained for progesterone receptor in contrast to epithelial gland cells which showed no or very weak staining. No regional variations in steroid receptor distribution in endometrium and myometrium were found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circamensal Rhythms in Physical Performance

The eumenorrheic menstrual cycle represents a clear inherent biological rhythm that might interact with both physical performance, and/or the physiological response to performance. The predominant hormonal fluctuations throughout the cycle are in the ovarian steroids oestrogen and progesterone. Progesterone has both a thermogenic and ventilatory effect leading to a potential increase in minute ventilation and body temperature during exercise. Oestrogen has been linked to fluctuations in blood flow and heart rate via a vasodilatory mechanism, plus potential variation in muscle strength. If these hormones do indeed influence physical performance, or the physiological response to performance, female athletes might choose to manipulate the cycle through an endogenous hormonal mechanism. Furthermore, researchers utilizing a female population must control for these fluctuations in their research design.     

The influence of hormonal changes during menstrual cycle on serum adiponectin concentrations in healthy women

Adiponectin is an adipocyte-derived hormone involved in the regulation of carbohydrate and lipid metabolism. Its concentrations are decreased in patients with obesity, type 2 diabetes and atherosclerosis and are higher in females than in males. Gender differences of adiponectin levels raise the possibility that sex hormones directly regulate its serum concentrations, which may in turn influence insulin sensitivity in different phases of the menstrual cycle. To test this hypothesis we measured serum adiponectin, estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone concentrations daily throughout the menstrual cycle in six healthy women. Mean adiponectin levels strongly positively correlated with serum cortisol concentrations [R=0.94286; p=0.0048 (Spearman correlation test)], but were not significantly related to other anthropometric, biochemical and hormonal characteristics of the subjects (BMI, blood glucose, insulin, testosterone, prolactin, cholesterol, HDL cholesterol, LDL cholesterol, triglycerides concentrations, or atherogenic index). Furthermore, no significant changes of serum adiponectin levels were found throughout the menstrual cycle. We conclude that changes in sex hormones during the menstrual cycle do not affect total circulating adiponectin levels in healthy women. Therefore, the differences in insulin sensitivity in various phases of the menstrual cycle are not due to changes of circulating adiponectin levels.     

A delay differential equation model of follicle waves in women

This article presents a mathematical model for hormonal regulation of the menstrual cycle which predicts the occurrence of follicle waves in normally cycling women. Several follicles of ovulatory size that develop sequentially during one menstrual cycle are referred to as follicle waves. The model consists of 13 nonlinear, delay differential equations with 51 parameters. Model simulations exhibit a unique stable periodic cycle and this menstrual cycle accurately approximates blood levels of ovarian and pituitary hormones found in the biological literature. Numerical experiments illustrate that the number of follicle waves corresponds to the number of rises in pituitary follicle stimulating hormone. Modifications of the model equations result in simulations which predict the possibility of two ovulations at different times during the same menstrual cycle and, hence, the occurrence of dizygotic twins via a phenomenon referred to as superfecundation. Sensitive parameters are identified and bifurcations in model behaviour with respect to parameter changes are discussed. Studying follicle waves may be helpful for improving female fertility and for understanding some aspects of female reproductive ageing.     

Circamensal Rhythms in Physical Performance

The eumenorrheic menstrual cycle represents a clear inherent biological rhythm that might interact with both physical performance, and/or the physiological response to performance. The predominant hormonal fluctuations throughout the cycle are in the ovarian steroids oestrogen and progesterone. Progesterone has both a thermogenic and ventilatory effect leading to a potential increase in minute ventilation and body temperature during exercise. Oestrogen has been linked to fluctuations in blood flow and heart rate via a vasodilatory mechanism, plus potential variation in muscle strength. If these hormones do indeed influence physical performance, or the physiological response to performance, female athletes might choose to manipulate the cycle through an endogenous hormonal mechanism. Furthermore, researchers utilizing a female population must control for these fluctuations in their research design.     

Hormonal profiles after the menopause.

The endocrinological changes of the climacteric have been defined by studying the concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), androstenedione, testosterone, oestrone, and oestradiol in 60 normal postmenopausal women of different menopausal ages. The women were studied in six groups, according to the number of years since their menopause. One year after the menopause androstenedione, oestrone, and oestradiol concentrations were reduced to about 20% of the values recorded during the early proliferative phase of the menstrual cycle. At the same time the mean concentration of FSH had risen by a factor of 13-4 and that of LH by a factor of 3-0. Concentrations of both gonadotrophins reached a peak of 18-4 and 3-4 times the proliferative phase value respectively after two to three years, and then gradually declined in the next three decades to values that were 40-50% of these maximal levels. Testosterone concentrations remained mostly in the normal range for premenopausal women but were depressed to 60% of these levels two to five years after the menopause, and the mean androstenedione levels showed a significant increase in the same group of women. The concentrations of both oestrone and oestradiol remained consistently low for 10 years after the menopause, but oestradiol concentrations inexplicably increased in the last two decades, with levels at the lower end of normal range for reproductive women in six patients.     

Focus: Sex and Gender Health: Marijuana,the Endocannabinoid System and the Female Reproductive System

Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.     

Dynamics of Blood Serum Levels of Follicle-Stimulating Hormone, Luteinizing Hormone, Prolactin, Estradiol, and Progesterone in Right- and Left-Handed Women

The dynamics of follicle-stimulating hormone (FSH) luteinizing hormone (LH), prolactin (PRL), estradiol (E₂), and progesterone were studied in left- and right-handed women having a stable 28-day menstrual cycle. The hormones were determined by enzyme immunoassays on days 3, 8, 10, 13, 16, 22, 26, and 28 of the menstrual cycle. The data showed that bllod serum levels of FSH, LH, PRL, and E₂are higher in left-handed in comparison to right-handed women (p< 0.001). On days 10 through 28 of the cycle, the level of progesterone is also higher in left-handed women (p< 0.001). The dynamic of these hormones in left-handed and right-handed women appeared to remain within the normal limits. These findings indicate that the handedness correlates with the dynamucs of serum levels of these hormones. Higher serum levels of hormones in left-handed women suggests that they have higher levels of the functional activity of the hypophysis–ovarian axis and prolactin axis.     

The reproductive endocrinology of the menopausal transition

The menopause transition is a dynamic process that begins with the first appearance of menstrual irregularity and ends with a woman's final menstrual period. As ovarian follicle numbers dwindle, the hypothalamic-pituitary-ovarian axis enters a state of compensated failure. In this state, elevated FSH is capable of maintaining relatively regular folliculogenesis and ovulation, but fertility is reduced. Eventually, this state of compensated failure cannot be sustained, and the ovary becomes unable to produce functioning follicles. Recent multicenter studies from several countries have addressed the pattern of change in hormones and a model form reproductive aging has been developed that helps explain the changes in hormone patterns and fertility that accompany menopause. Perhaps more important, the hormonal changes of the menopausal transition may be predictive of future disease risk. This review will undertake an explanation of the current literature on this topic.     

Oestrogen and progesterone interactions in the control of gonadotrophin and prolactin secretion

Oestrogen and progesterone have marked effects on the secretion of the gonadotrophins and prolactin. During most of the oestrous or menstrual cycle the secretion of gonadotrophin is maintained at a relatively low level by the negative feedback of oestrogen and progesterone on the hypothalamic-pituitary system. The spontaneous ovulatory surge of gonadotrophin is produced by a positive feedback cascade. The cascade is initiated by an increase in the plasma concentration of oestradiol-17 beta which triggers a surge of luteinizing hormone releasing hormone (LHRH) and an increase in pituitary responsiveness to LHRH. The facilitatory action of oestrogen on pituitary responsiveness is reinforced by progesterone and the priming effect of LHRH. How oestrogen and progesterone exert their effects is not clear but the facilitatory effects of oestrogen take about 24 h, and the stimulation of LHRH release is produced by an indirect effect of oestradiol on neurons which are possibly opioid, dopaminergic or noradrenergic and which modulate the activity of LHRH neurons. In the rat, a spontaneous prolactin surge occurs at the same time as the spontaneous ovulatory gonadotrophin surge. The prolactin surge also appears to involve a positive feedback between the brain-pituitary system and the ovary. However, the mechanism of the prolactin surge is poorly understood mainly because the neural control of prolactin release appears to be mediated by prolactin inhibiting as well as releasing factors, and the precise role of these factors has not been established. The control of prolactin release is further complicated by the fact that oestradiol stimulates prolactin synthesis and release by a direct action on the prolactotrophes. Prolactin and gonadotrophin surges also occur simultaneously in several experimental steroid models. A theoretical model is proposed which could explain how oestrogen and progesterone trigger the simultaneous surge of LH and prolactin.     

The effects of aging on hormone and reproductive cycles in female chimpanzees (Pan troglodytes)

In contrast to those for human females, observational cycle data available for chimpanzees suggest that menstrual cycling, and thus reproductive potential, continues until near death. This study documents age-related changes in estrous cycling and hormone profiles in 14 female chimpanzees (Pan troglodytes) ranging in age from 31 to 50 y. Estrous data were analyzed from daily cycle charts, averaging 13.3 y of cycle data per subject, after omission of gestational and postpartum amenorrhea. Concentrations of total luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and other hormones were assayed in serum samples taken biannually. Sample collection times were chosen to avoid the ovulatory LH and FSH peaks of the female's cycle and yielded a mean of 19.6 serum samples over an average of 14.4 y per subject. Analysis of cycle charts revealed a negative relationship between age and the percentage of cycle days at maximal tumescence. There also were positive relationships between age and the length of the estrous cycle and age and the percentage of cycle days at complete detumescence. Analysis of hormonal data revealed curvilinear relationships between age and both LH and FSH. These cycle and hormonal changes mirror those in perimenopausal and menopausal women. Our data provide evidence of perimenopause (at 30 to 35 y) and menopause (at 35 to 40 y) in the chimpanzee.     

Ovarian aging and menopause: current theories, hypotheses, and research models

Aging of the reproductive system has been studied in numerous vertebrate species. Although there are wide variations in reproductive strategies and hormone cycle components, many of the fundamental changes that occur during aging are similar. Evolutionary hypotheses attempt to explain why menopause occurs, whereas cellular hypotheses attempt to explain how it occurs. It is commonly believed that a disruption in the hypothalamic-pituitary-gonadal axis is responsible for the onset of menopause. Data exist to demonstrate that the first signs of menopause occur at the level of the brain or the ovary. Thus, finding an appropriate and representative animal model is especially important for the advancement of menopause research. In primates, there is a gradual decline in the function of the hypothalamic-pituitary-gonadal (HPG) axis ultimately resulting in irregularities in menstrual cycles and increasingly sporadic incidence of ovulation. Rodents also exhibit a progressive deterioration in HPG axis function; however, they also experience a period of constant estrus accompanied by intermittent ovulations, reduced progesterone levels, and elevated circulating estradiol levels. It is remarkable to observe that females of other classes also demonstrate deterioration in HPG axis function and ovarian failure. Comparisons of aging in various taxa provide insight into fundamental biological mechanisms of aging that could underlie reproductive decline.     

Wild fulvous fruit bats (Rousettus leschenaulti) exhibit human-like menstrual cycle

We investigated the menstrual cycle of wild fulvous fruit bats (Rousettus leschenaulti), focusing on changes in the endometrial and ovarian structure and pituitary and steroid hormones. The menstrual cycle lasts for 33 days in bats studied in their natural habitat and in captivity. Vaginal bleeding was restricted to a single day (Day 1). A preovulatory follicle was found in the ovary on Day 18 when the levels of LH and FSH reached their maxima, accompanied by a thickened endometrium. On Day 24, serum levels of progesterone and estradiol-17 were also maximal, and uterine glands increased in size. After that, the levels of progesterone dropped precipitously, leading to menstrual bleeding. Both the morphologic and hormonal changes observed in fulvous fruit bats during the menstrual cycle resemble similar changes in humans. Fulvous fruit bats may be useful nonprimate laboratory models to study menstruation and menstrual dysfunction.     

Prolactin levels in Western Lowland gorillas

Hyperprolactinemia is known to cause menstrual irregularity and infertility in humans. However, little is known about the role of prolactin in menstruation and fertility in Western Lowland gorillas. To create a database of prolactin values in gorillas, we have performed immunoassays on serum specimens dating back to 1983 from nine female gorillas at the Brookfield Zoo. We matched these samples with documented behavioral data to correlate menstrual timing. In addition, we ran other reproductive hormones both to aid in determining the phase of the menstrual cycle and to evaluate the effect of the prolactin on suppression of these hormones during the premenarchal and postpartum phases. We found that values for luteinizing hormone, follicle-stimulating hormone, estradiol and progesterone cycle in very similar patterns to humans. Based on the 59 available samples, prolactin was found to be higher in gorillas than in humans in nearly every phase of the menstrual cycle (range 49.9-93.7 ng/mL) and such levels do not appear to alter the reproductive axis as it does in humans. Thus, prolactin may have a different impact on fertility in gorillas than it does in humans.     

Oestrogen receptor content of normal breast cells and breast carcinomas throughout the menstrual cycle

To examine the presence and distribution of oestrogen receptors in the normal breast during the menstrual cycle cytological samples obtained by fine needle aspiration from 69 premenopausal women with normal breasts were analysed immunocyto-chemically with a monoclonal antibody to oestrogen receptor; samples from 15 postmenopausal women were also analysed. The receptor content of breast cancers from 83 premenopausal women was also determined in relation to when during the menstrual cycle excision was performed. In the normal premenopausal women oestrogen receptors were detected in the nuclei of epithelial cells in 21 out of 68 (31%) assessable samples. All 21 of these samples were obtained from the 35 women who were studied during the first half of their menstrual cycle (days 28 to 14). None of the 33 samples obtained during the second half of the cycle contained oestrogen receptors. Samples were assessable in eight of the postmenopausal women, six giving a positive result for oestrogen receptor. Fifty one of the 83 carcinomas were positive for oestrogen receptor, 24 having been excised during the first half of the cycle and 27 during the second half.Production of oestrogen receptor protein is suppressed at the time of ovulation in the normal breast epithelium of premenopausal women. In contrast, breast carcinoma cells either synthesise this protein continuously throughout the cycle or fail to express it despite fluctuations of serum hormone concentrations.