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Editors: Robert Rubin Donald Pfaff. Hardcover ISBN: Imprint: Academic Press. Published Date: 20th July These characteristics could contribute to several of the discrepancies in the literature and include age, stage of reproductive aging, duration of hypogonadism, and the presence of symptoms. A better understanding of the nature of these discrepancies will inform future studies of the clinical relevance of ovarian steroids and hormone therapies in women.
This section will first review the physiology of reproductive aging in women. Emphasis will be placed on the considerable variability in ovarian hormone secretion characterizing the menopause transition compared with the relatively stable endocrine milieu of the postmenopause see section by A. Differences in observed outcomes in these measures will be identified. Finally, questions of clinical relevance will be presented that remain to be answered and that may help to reconcile some of the otherwise discordant findings in the current literature.
Hormone/Behavior Relations of Clinical Importance
The process of reproductive aging in women has several unique features that distinguish it from reproductive senescence in most animal species described below in the section by A. Although the average age of the menopause in women is 51 years, the transition from normal reproductive life to the last year after the final menstrual period referred to as either the menopause transition or the perimenopause may be 10—15 years in duration.
The endocrinology of the menopause transition has yet to be fully characterized and represents a complex interplay of actions at all levels of the hypothalamic—pituitary—ovarian axis Santoro, Nonetheless, evidence suggests that this phase of reproductive aging occurs in stages. The early menopause transition is associated with lower ovarian inhibin secretion, which in turn reduces the restraint on both the hypothalamus and pituitary and results in elevated pituitary gonadotropin [follicle-stimulating hormone FSH ] secretion.
In addition to reduced ovarian inhibin secretion, age-related increases in gonadotropin-releasing hormone GnRH production could contribute to the elevated pituitary gonadotropin levels Maffucci and Gore, ; Yin and Gore, Importantly, ovarian estradiol secretion is normal or at times elevated during this early stage of the menopause transition Santoro, As ovarian aging proceeds into the late menopause transition, despite occasional episodes of normal cycling, women are exposed to periods of estrogen withdrawal, fewer ovulatory cycles, and prolonged hypogonadism, ultimately leading to the last menstrual period.
Five to 10 years after the menopause, the activity of the HPG axis becomes relatively more stable and is characterized by persistent hypogonadism and relatively tonic not phasic elevated gonadotropin secretion Hall and Gill, In addition to changes in ovarian estradiol and progesterone secretion, production rates of several other hormones e. These findings emphasize that, if the impact of reproductive hormones on brain function and behavior during the menopause transition is to be examined, then it makes no sense to collapse the process of reproductive aging into a single physiologic event.
The evidence in women that ovarian steroids play a regulatory role in cognitive function, at first glance at least, has gone from all good for the brain to all bad. Both observational- and clinic-based studies have suggested that combined HT and unopposed ET in hypogonadal women improve cognition, lessen the risk for the development of dementia, and, possibly, improve the severity and course of dementia. Preclinical studies have identified biologically plausible mechanisms by which estrogen could enhance neuronal function, improve neuronal resilience, and serve as a neuroprotective agent see below, sections by J.
Epidemiological surveys prospectively monitoring women as they progress through the menopause transition have suggested that self reports of decreased concentration and poor memory are frequent accompaniments of this phase of life and the postmenopause Woods et al. Additionally, the possibility that declining ovarian estrogen secretion could exacerbate the age-related decrement in episodic memory Maki et al.
These trials demonstrated the beneficial effects of short-term i. However, to date, studies have not consistently identified deficits in performance corresponding to self reports of cognitive impairment in perimenopausal women. Specifically, cognitive benefits were observed in symptomatic perimenopausal women and in women in whom hypogonadism was recently induced by medical or surgical interventions.
In addition to the potential beneficial effects of estrogen on episodic memory, some evidence suggested that HT reduced the risks of both dementia including AD and mild cognitive impairment MCI.
In contrast, several recent findings Shumaker et al. For example, recent randomized placebo-controlled trials RCTs sponsored by the WHI investigated the effects of HT in community-dwelling women between the ages of 65 and 79 years Rossouw et al. HT was in the form of continuous conjugated equine estrogens CEEs 0. ET consisted of CEE 0. Indeed, in contrast to the observational studies, the WHIMS observed an increased risk of dementia with HT [consistent with the WHI observations of increased rates of cerebrovascular disease and thrombotic phenomena related to combined HT Rossouw et al.
The results of the observational studies, therefore, were essentially dismissed as being flawed by several confounds, including a healthy user bias and a masking of initial mortality rates attributable to the limited frequency of follow-ups in the early phases of the observational studies. Recent preclinical studies reviewed below highlight the importance of timing of ET in this report.
Research and Perspectives in Endocrine Interactions
Historically, there has been a presumption that declining reproductive function plays no role in the onset of mood disorders that occur during midlife in women. For example, depression that occurred during the menopause transition was presumed to be either secondary to the disruptive effects of hot flushes on sleep or a coincidental occurrence of an otherwise recurrent mood disorder.
The symptoms of depression during the menopause transition also were assumed to be transient and of such minor severity that they were dismissed to be of little clinical consequence. Recent studies, however, suggest that these presumptions are incorrect. First, several community-based longitudinal studies have reported the relative independence of depressions during the menopause transition and hot flushes: both occur at this stage of life, but depression is not simply caused by hot flushes Avis et al.
Second, recent longitudinal studies that followed women with no past history of depression demonstrated an increased risk of first-onset depressions during the late menopause transition Schmidt et al. Finally, both major and minor depressions are clinically significant to women at midlife, because both are associated with an increased risk for several other medical conditions Wassertheil-Smoller et al. The majority of women do not develop depression during the menopause transition, and, therefore, reproductive aging is not uniformly associated with either depressive symptoms or the syndrome of depression.
Nonetheless, despite numerous studies concluding that the menopause is not associated with an increased risk for developing depression in women, several other longitudinal, community-based studies reported an association between the menopause transition and an increased risk for depression Schmidt, Indeed, five recent longitudinal studies all have documented an increased risk for depression during the menopause transition, with odds ratios ranging from 1.
In particular, two recent studies Cohen et al. These studies differ from previous surveys in their use of criteria to distinguish the menopause transition from either the premenopause or postmenopause. Additionally, several of these studies used syndromal measures of depression, including structured diagnostic interviews. It warrants emphasis that the majority of the women in these studies remained asymptomatic throughout the menopause transition.
However, these data suggest that events surrounding the final menstrual period may predispose some women to develop clinically significant depressive illness. Although several factors could precipitate depression in these women, endocrine events are suggested by the stage of the menopause transition i. The late transition is characterized by more prolonged hypogonadism than the early perimenopause, during which estradiol secretion may be increased.
The antidepressant efficacy of estradiol has been examined in three relatively recent RCTs of women meeting standardized diagnostic criteria for major and minor depression, who were randomly assigned to enter double-blind, placebo-controlled trials Schmidt et al. In perimenopausal women, short-term administration 3—8 weeks of estradiol significantly decreased depression scores compared with both baseline and placebo conditions.
The efficacy of ET in perimenopausal depression is consistent with the observed effect size 0.
The Teenage Brain: Surging Hormones—Brain-Behavior Interactions During Puberty
The therapeutic response to estradiol was observed in both major and minor depression as well as in women with and without hot flushes. Thus, the efficacy of ET in perimenopausal depression is not solely a product of its ability to reduce the distress of hot flushes. In contrast to these studies in perimenopausal depression, the administration of estradiol under similar conditions failed to improve mood in depressed women who were 5—10 years postmenopause Morrison et al.
Thus, the effects of estradiol on depression may be limited to perimenopausal women. In summary, the majority of women do not develop depression during or after the menopause transition. Nevertheless, recent prospective studies monitoring both reproductive status and mood have documented that, for some women, perimenopause-related events increase the risk for the onset of depression. The role of ovarian function in these episodes of depression is suggested, albeit indirectly, by both the timing of their onset relative to the last menstrual period and the antidepressant efficacy of short-term ET.
In addition to the role of ovarian steroids in cognitive function and affective adaptation, another behavior, sexual function, is highly valued, intricately related to social behavior, and presumed to be regulated by ovarian steroids. Preclinical studies have clearly documented both the neurocircuitry of sexual behavior and the important regulatory role estrogen serves in many aspects of this behavior Pfaff, A recent study evaluated the effects of GnRH agonist-induced hypogonadism on sexual functioning in 20 young healthy women Schmidt et al.
Several recent RCTs reported improvements in libido after testosterone therapy in hypogonadal women Shifren et al. Thus, it is likely that androgen secretion, which was partially suppressed by the GnRH agonist, accounted for the reported decline in libido. Interestingly, baseline level of sexual function, but not hormone levels, predicted the response to hypogonadism.
Those women with the highest libido at baseline experienced the greatest decline during hypogonadism.
Related Hormones and the Brain (Research and Perspectives in Endocrine Interactions)
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