Reproductive life events and sexual functioning in women: case reports

Are reproductive life events in women associated with an increased risk of sexual dysfunction? Female sexual dysfunction effects up to 40% of women in the United States between 18 and 59 years of age. Sexual dysfunction may be accompanied by fluctuations in gonadal hormone secretion, making women more vulnerable to sexual symptoms, especially during times of reproductive life events. Reproductive life events, such as the use of birth control pills, various phases of the menstrual cycles, postpartum and lactation states, and perimenopause, are highly correlated with changes in sex steroids. As an understanding of the role of sex steroids on sexual functioning is elucidated, clinicians will be able to offer more specific and effective treatment options for women during various phases of reproductive life. Several case studies are presented to illustrate the unique clinical considerations that a clinician must consider when treating the biologic component of female sexual dysfunction.     

The influence of 17beta-oestradiol on corticotrophin-releasing hormone induced suppression of luteinising hormone pulses and the role of CRH in hypoglycaemic stress-induced suppression of pulsatile LH secretion in the female rat

Corticotrophin-releasing hormone (CRH) released during stress has been implicated in the disruption of the reproductive neuroendocrine axis, and 17beta-oestradiol (E2) has been shown to enhance stress-induced suppression of pulsatile gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH) release. The aims of the present study were to examine the role of CRH in hypoglycaemic stress-induced suppression of LH pulses, and to investigate the influence of E2 on the inhibitory effect of CRH on pulsatile LH secretion in the female rat. Suppression of LH pulses by insulin-induced hypoglycaemic (IIH) stress was completely prevented by intracerebroventricular (icv) administration of a CRH antagonist. Central administration of CRH (5 microg) resulted in an interruption of LH pulses in E2 treated animals, but had little or no effect in the absence of this gonadal steroid. These results provide evidence of a pivotal role for CRH in mediating the suppressive effect of IIH stress on pulsatile LH secretion in the female rat, and highlight a sensitising role for E2 in CRH-induced suppression of LH pulses.     

Mechanisms for ovarian cycle disruption by immune/inflammatory stress

This review summarizes highlights of our experiments investigating mechanisms, mediators and sites by which endotoxin disrupts reproductive neuroendocrine activity and interferes with the estrous cycle of sheep. Endotoxin, or lipopolysaccharide (LPS), is a commonly used model for immune and inflammatory stress. When administered to ovary-intact ewes, endotoxin interrupts the follicular phase of the cycle by interfering with several steps in the preovulatory chain of endocrine events. One such step is the development of high frequency LH pulses, which provide an essential stimulus for the preovulatory increase in estradiol secretion from the ovarian follicle. Follow-up experiments in ovariectomized ewes demonstrate that endotoxin inhibits pulsatile LH secretion at both the hypothalamic and pituitary levels, suppressing pulsatile GnRH secretion and reducing pituitary responsiveness to GnRH. This disruption of GnRH and LH pulsatility is mediated by pathways that include the synthesis of prostaglandins and cortisol, both of which are increased by endotoxin. It is postulated that a prostaglandin-mediated pathway disrupts the cycle during immune and inflammatory stress, whereas a separate cortisol-mediated pathway reinforces this disruption and also participates more generally in suppressing cyclicity during other stressful situations that activate the hypothalamo-pituitary-adrenal axis.     

Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats

Sex differences in hypothalamic-pituitary-adrenal (HPA) function were examined in gonadectomized male and female rats given equivalent sex hormone replacement regimens either using subcutaneous silastic implants (Experiment 1) or cannula implants in the medial preoptic area (MPOA) (Experiment 2) containing either dihydrotestosterone (DHT), testosterone propionate (TP), estradiol benzoate (EB), or left empty (control). Plasma was obtained before and after 20 min of restraint stress to determine plasma ACTH, corticosterone, and CBG levels as measures of HPA function. Consistent with the literature, androgens decreased, and estrogen increased these measures of HPA function, although peripheral implants were more effective than MPOA implants. Gonadectomy and sex hormone treatment did not eliminate sex differences; overall, females had higher levels than males on measures of HPA function. Analyses of variance (ANOVA) indicated interactions of sex and sex hormone treatment on CBG levels and post-stress corticosterone levels in Expt. 1. The results suggest that sexual dimorphisms influence HPA function even when males and females are given equivalent physiological doses of gonadal steroids, and that the relevant sexual dimorphisms involve both the periphery and the CNS.     

Role of estrogen in balancing contributions from multiple memory systems

In addition to modulating memory per se, estrogen alters the learning strategy used to solve a task, thereby regulating the quality of information processed by the brain. This review discusses estrogen's actions on cognition within a memory systems framework, highlighting our work with a variety of paradigms showing that learning strategy is sensitive to estrogen even when learning rate is not. Specifically, high levels of gonadal steroids, in particular, elevations in estrogen, bias female rats toward using hippocampal-sensitive approaches while low levels of gonadal steroids promote the use of non-hippocampal sensitive strategies. In light of findings from a variety of approaches involving the hippocampus in allocentric and the striatum in egocentric response patterns, it is likely that estrogen alters the relative participation of these, and most undoubtedly other, neural systems during cognition. Changes in neuromodulators such as acetylcholine that regulate other processes such as inhibitory tone and excitability reflect one mechanism by which estrogen may orchestrate learning and memory.     

Lipid reactivity to stress: II. Biological and behavioral influences.

This study examined behavioral and physiological influences on lipid concentrations during acute and chronic stressors. One hundred men (n = 92) and women (n = 8) were tested during a chronic stressor and during 2 acute stressors. During chronic stress, diet, physical activity, exercise, and sleep were examined. During the acute stressors, catecholamines, cortisol, plasma volume, and cardiovascular responses were examined. None of the behavioral influences could explain the lipid response to chronic stress. Responses of the atherogenic lipids to acute stressors were not solely reflecting hemoconcentration of the plasma but were moderately correlated with cardiovascular, epinephrine, and cortisol reactivity. Diastolic blood pressure reactors to the acute stressors had larger lipid responses to the chronic stressor than did nonreactors. Elevations in blood lipids during stress are not artifacts and may be clinically significant.     

Neuroendocrine responses to psychological stress in eumenorrheic and oligomenorrheic women

Neuroendocrine adaptive responses to psychological stress include activation of the hypothalamic-pituitary-adrenal (HPA) axis and sometimes suppression of the hypothalamic-pituitary-gonadal (HPG) axis. In women who experience chronic stress, these responses are probably responsible for disturbances in the menstrual cycle. In the present experiment, we investigated the effect of an acutely stressful situation on the physiological and neuroendocrine responses in college age women. We hypothesized that females who are experiencing some degree of abnormal menstrual function or women who have less-robust cycles (oligomenorrheic females) would exhibit differences in gonadotropin secretion from eumenorrheic females when exposed to psychological stressors. Fifteen women completed this study: eumenorrheic (n = 5) and oligomenorrheic women (n = 5) who experienced a series of psychological stressors, and eumenorrheic controls (n = 5). Blood samples were taken at 10 min intervals for 8 h (09:00-17:00) in each woman during the mid-follicular phase of the menstrual cycle. The psychological stressors were administered for 1 h beginning at 13:00 h. Luteinizing hormone (LH), growth hormone (GH) and cortisol were measured in each sample to assess the effect of stress on secretion of these hormones. Deconvolution analysis was used to analyze pulsatile hormone secretion and the approximate entropy (ApEn) statistic analyzed the regularity of release of each hormone. Although, there were significant changes in heart rate (HR), skin resistance (SR) and cortisol levels in the stressed women during the psychological stressor compared to resting baseline values but not in the controls, there was no difference in either LH or GH secretion between women who experienced stress and those who did not. Furthermore, there were no differences in the LH or GH secretion patterns in the oligomenorrheic and eumenorrheic women exposed to the psychological stressor.     

Do Background Stressors Influence Reactivity to and Recovery From Acute Stressors?1

This review examines the effect of background stressors with acute stressor reactivity and recovery in the 19 available studies. Background stressors were associated with increased acute stressor reactivity in slightly over half of the studies of ongoing stressors. However, a substantial minority of studies demonstrated reduced acute stressor reactivity, suggesting habituation for certain people in certain situations. Background stressors were associated with delayed blood-pressure and immunological recovery from acute stressor events, but were not associated with delayed heart-rate recovery. Possible mechanisms underlying the association between background stressors and acute stressor reactivity and recovery are discussed. Background stressors should be measured thoroughly in future acute stress research to understand the meaning of the acute stress responses.     

The effects of acute stress and pubertal development on metabolic hormones in the rat

A dramatic change in stress responsiveness occurs during pubertal development such that stress-induced corticosterone secretion in prepubertal animals takes 45-60 min longer to return to baseline compared to adults. Though corticosterone is known to influence energy mobilization, it is presently unknown whether stressors affect other hormones important in energy utilization and metabolism differentially in animals before and after pubertal development. Therefore, we exposed prepubertal (28 days of age) and adult (77 days of age) male rats to a single 30 min session of restraint stress in either the light or dark phase of the animals' light-dark (LD) cycle and measured plasma glucose, insulin and thyroid hormones (thyroxine (T4) and triiodothyronine (T3)). We found similar stress-induced increases in plasma glucose levels in prepubertal and adult animals in the LD phase of the LD cycle. We also found that prepubertal animals have lower circulating insulin and total and free T4 levels, but higher total and free T3 levels compared to adults in both the light and dark phases (LD). Interestingly, insulin and thyroid hormone levels were unaffected by acute stress at either age or time of day. These data indicate that, despite prepubertal animals showing an extended glucocorticoid stress response after a single acute exposure to stress, glucose levels are similarly affected by acute stress in prepubertal and adult animals. Furthermore, though stage of development significantly affects the levels of peripheral metabolic hormones such as insulin, T4 and T3, acute stress does not appreciably influence their secretion before or after puberty.     

Effects of daily and acute restraint stress during lactation on maternal aggression and behavior in mice

A decreased reactivity to stressors during lactation might heighten the expression of maternal care (including defense of offspring) by minimizing the extent to which stress can impact maternal care. Although stressors applied during pregnancy have variable effects on maternal aggression (or defense of offspring), to date no study has examined the effects of stress applied during the postpartum period on maternal aggression. In this study, we examined the effects of both daily and acute restraint stress (30 min) applied postpartum on maternal aggression and other maternal behaviors. Daily restraint (ending 2 h before testing) did not alter any measure of maternal behavior, including nursing, licking and grooming of pups and pup retrieval, or any measure of maternal aggression. In contrast, acute stress significantly impaired total time aggressive and number of attacks, but pup retrieval was normal. c-Fos levels were significantly elevated in a number of brain regions in association with acute stress, including lateral septum (LS), caudal periaqueductal gray and medial amygdala (MeA), suggesting possible sites where stress reactivity could alter aggression. Together, the results indicate that acute restraint stress impairs maternal aggression and provide a starting point for future studies examining how stress reactivity pathways may intersect with maternal aggression pathways.     

Acute stress persistently enhances estrogen levels in the female rat

Here we tested whether exposure to either tailshock or swim stress alters ovarian hormone levels, estrogen and progesterone, in females and whether the effects are persistent. Adrenal hormone levels were also measured in males and females. Estradiol levels were elevated in unstressed females during proestrus relative to females in other stages of estrous, and exposure to the stressors enhanced estradiol beyond basal levels. For females stressed during diestrus 2, estradiol levels were elevated immediately after stressor cessation and up to 24 hrs. Exposure to tailshock, but not swim-stress, transiently enhanced progesterone in females stressed during the stage of proestrus and estrus. Glucocorticoid levels were elevated in response to both stressors and were supraelevated in females under both basal and stress conditions relative to males, particularly in blood from females exposed to acute swim stress. These results indicate that exposure to a relatively acute stressful event immediately and persistently enhances serum estradiol and are discussed in the context of reports that exposure to the same stressors immediately and persistently impairs associative learning in the female rat.     

Glucocorticoid sensitivity in humans-interindividual differences and acute stress effects

The hypothalamus pituitary adrenal (HPA)- axis is one of the major output systems of the neuroendocrine stress response. Its major end products, glucocorticoids (GCs), have a plethora of effects throughout the organism, most of which are believed to be protective against disturbances of homeostasis. However, negative effects have also been described under specific conditions of hyper- or hypo(re)activity of the HPA axis. Both beneficial and adverse effects of GCs ultimately depend on the target tissue sensitivity to these steroids. Recent findings suggest that GC sensitivity (a) may vary between different target tissues in the same organism, (b) shows large individual differences and (c) can be acutely changed in times of acute stress. In the present review, data are summarized which show differences in GC sensitivities in patients suffering from diverse somatic and psychiatric diseases, as well as chronically stressed individuals. Furthermore, studies are presented that show a rapid modulation of GC sensitivity in response to exercise or psychosocial stress in healthy adults. The response pattern of acute GC sensitivity modulation seems to be influenced by age and sex hormone status of the individual. While the GC signalling cascade may be subject to modulation at several levels, the pathway for acute modulation of GC sensitivity remains to be elucidated.     

High blood pressure and marital discord: not being nasty matters more than being nice

Theories linking anger and blood pressure (BP) reactivity to cardiovascular disease must be able to identify naturally occurring stressors that arouse emotion with sufficient frequency to cause chronic physiologic stress. We examine the impact of normal family arguments on 43 patients (24 women, 19 men) with essential hypertension. Patients and their partners discussed a threatening disagreement for 10 min while BP and conversation were recorded. Discussing problems increased BP, but the causal pathways differed by sex. In women, hostile interaction and marital dissatisfaction were associated with increased BP; "supportive" or "neutral" exchanges were unrelated to BP. In men, BP fluctuations were related only to the patient's speech rate. These findings are consistent with other research on sex differences in communication and social problem-solving styles and implicate different mechanisms (frequent anger, active coping) through which marital discord could increase risk. Implications for intervention are considered.     

Central noradrenergic mechanisms underlying acute stress responses of the Hypothalamo-pituitary-adrenal axis: adaptations through pregnancy and lactation

Hypothalamo-pituitary-adrenal axis responses to stress are attenuated perinatally, and may contribute towards conservation of energy stores and/or prevention of overexposure to glucocorticoid and its adverse effects in the developing fetus/neonate. Previous work has shown that reduced central drive to the hypothalamo-pituitary-adrenal axis is responsible, since parvocellular paraventricular nucleus neurone responses are reduced. One of the main input pathways to the paraventricular nucleus that is activated by the majority of stressors is the brainstem noradrenergic system. This review outlines key noradrenergic mechanisms that mediate hypothalamo-pituitary-adrenal axis responses to acute stress, and addresses aspects of their adaptation in pregnancy and lactation that can explain the stress hyporesponsiveness at that time. In summary, reduced noradrenaline release and adrenergic receptor expression in the paraventricular nucleus may lead to reduced sensitivity of the hypothalamo-pituitary-adrenal axis to adrenergic antagonists and agonists and its responses to stress. While there are subtle differences in these changes between pregnancy and lactation, it would appear that reduced effectiveness of the noradrenergic input can at least partly account for the reduced hypothalamo-pituitary-adrenal axis responses both pre- and post-natally.     

The roles of carbon monoxide and nitric oxide in the control of the neuroendocrine stress response: complementary or redundant

There is widespread evidence in favour of nitric oxide (NO) acting as a gaseous neurotransmitter in the central nervous system, diffusing from its cells of origin and affecting surrounding neuronal tissue in evanescent three-dimensional waves. This is also true of the hypothalamus, where amongst other activities NO inhibits stimulation of corticotrophin-releasing hormone (CRH) and vasopressin release by inflammatory stressors, effects thought to be mediated by binding with soluble guanylate cyclase (sGC). Carbon monoxide is being increasingly recognised as another gaseous neuromodulator, but with principal effects on other hemoproteins such as cyclo-oxygenase, and a distinctly different profile of localisation.NO is predominantly a pro-inflammatory agent in the periphery while CO is often anti-inflammatory. In the hypothalamus, the actions of CO are also distinct from those of NO,with marked antagonistic effects on the inflammatory release of vasopressin, both in vitro and in vivo, but with little involvement in the regulation of CRH. Thus, it would appear that these apparently similar gases exert quite distinct and separate effects, although they cause broadly similar overall changes in the secretion of neuroendocrine stress hormones. We conclude that these two gases may play significant but different roles in the control of the neuroendocrine stress response, but one common feature may be attenuation of inflammation-induced release of stress hormones.     

Persistent neuroendocrine changes in multiple hormonal axes after a single or repeated stressor exposures

Many researchers have studied acute responses to stress in animals and how they are modified by prior stressor exposure, but relatively few have examined whether responses to stressors might last for prolonged periods of time. We have previously demonstrated that trough plasma corticosterone levels in rats are elevated for three to five days after single or repeated exposures to mild restraint and inescapable tailshock. The current study measured other aspects of the adrenal axis, and activity in other neuroendocrine systems, 24 hours after one or three consecutive exposures to the same stress paradigm. The data indicated persistent activation of the adrenal axis and prolactin levels, whereas the thyroid and reproductive hormone axes were inhibited after either one or three stress sessions. These changes are remarkable in that one would have expected acute responses to even intense stressors to have ended within hours after the end of the stressor. It will be important to understand the interactions among these responding neuroendocrine systems and to know how long such persistent changes last. Finally, it will be critical to understand the relative contributions of neuroendocrine and psychological factors in maintaining these persistent neuroendocrine changes after exposure to intense stressors.     

Hypoglycemia-induced suppression of luteinizing hormone (LH) secretion in intact female rhesus macaques: role of vasopressin and endogenous opioids

The first objective of this study was to determine whether insulin-induced hypoglycemia (IIH) inhibits LH secretion in unrestrained female macaques during the follicular phase of the menstrual cycle. There was a consistent inhibitory effect of hypoglycemia on LH secretion within 3 h in these females. This inhibition was likely an indirect effect since low glucose levels did not inhibit GnRH secretion from GT1-1 neurones in vitro. We next investigated whether administration of a vasopressin antagonist (AVPa) either alone, or with naloxone could reverse the IIH-induced inhibition of LH release. Females were studied in the follicular phase during 10 h periods with blood samples collected every 10 min. Experimental groups were IIH (n=6), IIH+AVPa (n=5) and IIH+AVPa+naloxone (n=4). The first 5 h of each study served as a control and hypoglycemia was then induced with insulin. The AVPa was given as a bolus (180 microg) just before the insulin and was followed by a continuous infusion (180 microg/h) for 5 h. Naloxone (5 mg/kg) was given with the AVPa and followed by a continuous infusion (5 mg/kg/h) for 5 h. In the IIH group, LH reached its lowest value 3-4 h after insulin. Neither AVPa nor AVPa+naloxone infusion reversed the inhibitory action of hypoglycemia on LH release. These data suggest that if there are inhibitory actions of vasopressin and endogenous opioids on GnRH release induced by hypoglycemia, they are not sufficient to explain the suppression of GnRH/LH release in intact female primates.     

Variations in sex-related cognitive abilities across the menstrual cycle

Sex differences in human cognitive and motor skills may in part be due to organizational or activational effects of sex hormones on the brain. In this study, an extensive battery of cognitive and motor tests was administered to normally cycling women at two phases of the menstrual cycle, in order to detect any hormone-mediated changes in performance. Results confirmed changes across the menstrual cycle on a variety of speeded manual and articulatory measures, and on some nonverbal/spatial tests. The results provide qualified support for the hypothesis that the high levels of gonadal steroids provide qualified support for the hypothesis that the high levels of gonadal steroids present at the luteal phase of the cycle may facilitate skills favoring females, but be detrimental to skills favoring males. The implications of these results for research in the area of human sex differences are discussed.