An Update on Menopause HP Pattanaik, PC Mahapatra
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Endocrinology of Menopause1

Behram S Anklesaria
Rajesh M Soneji
 
INTRODUCTION
A casual review of the Endocrinology and the pathophysiology of Menopause leave the average clinician much dissatisfied on account of his or her clinical experiences and ends up being a very dry subject.
It also is understood to be a story of HPO axis which undergoes major reproductive endocrine changes several times during the life of a normal female.
Our endeavor is to take you to a journey beyond the traditional dry understanding of Endocrinology and to expand your horizons beyond the narrow street between the ovaries and the hypothalamus.
After all, how can one hope to describe the multifaceted perimenopausal experience restricting oneself to the HPO region, without involving the higher centers of the brain?
In fact, recent research has identified receptors for gonadal steroids in the amygdala, hippocampus, cortex, midbrain rafe nuclei, glial cells and central gray matter, confirming an involvement of sex hormones in controlling wellbeing, cognitive functions and memory processes in physiological as well as in pathological conditions.13
 
THE ENDOCRINOLOGY OF LATE REPRODUCTIVE AGING
“Perimenopause” means changes in ovarian hormones, feedback relationships, and clinical experiences beginning in women of age 35-50 with or without regular menstrual blood flow and ending 1 yr after the final menstrual flow.
A key observation-estradiol levels are increased in perimenopause.
The changes here along with lower inhibin B level probably cause higher follicular phase FSH levels — “endogenous ovarian hyper 2stimulation” results. The positive estradiol feedback on LH is also disturbed—midcycle LH peaks and midluteal slow-frequency; high-amplitude LH pulses are less frequent. In addition to higher levels, estradiol receptors may increase in tissues of symptomatic women.
Despite hyperstimulation of follicles, progesterone levels and luteal phase lengths are paradoxically decreased —reasons probably include LH peak disruptions and estrogen-stimulated greater corticotrophin-mediated reproductive suppression. In summary, disturbed feedback relationships causing higher and unpredictable estrogen and lower progesterone levels occur throughout perimenopause, especially during regular cycles.5
For many gynecologists, regular cycles are, by definition, ovulatory—irregular cycles are considered synonymous with anovulation.6 But the fact remains that anovulation and short luteal phase cycles commonly occur in regularly cycling perimenopausal women.7 Data show that flow onset does not require dropping progesterone levels,8 and also that 5-10% of regularly menstruating women across all reproductive life phases is non-ovulatory.9 Finally, this concept also indicates the difficulties with the Staging of Reproductive Aging and menopausal transition.10
 
THE ENDOCRINOLOGY OF MENOPAUSE TRANSITION
Irregular cycles herald the onset of Menopause transition and precede the final menstrual period by 2-5 years11 mainly due to diminishing pool of ovarian follicles.
There is fall in primordial follicle numbers and the resultant decrease in the number of antral follicles which in turn influence the hormonal communication of HPO unit.1214 The most common manifestation of fall in follicle numbers is ovarian failure and high FSH with high inhibin-B. This rise in FSH becomes more pronounced and variable with late reproductive age whereas LH becomes more consistently elevated.1521
Elevated estradiol levels with variable progesterone levels at this juncture are a very interesting phenomenon. As ovulatory follicles decline there is increased ovarian refractoriness to gonadotrophin stimulation. Given that inhibin-B is a marker of ovarian reserve it is likely that ovarian refractoriness is reflected by low inhibin-B levels.223
 
BRIEF REMARKS ON INDIVIDUAL COMPONENTS OF THE ENDOCRINE LOOP (HPO AXIS)
Overall, the results of fundamental changes in hypothalamic-pituitary-ovarian feedback loops are changes in the ovulatory menstrual cycle pattern of estradiol secretion, increases in ovarian estradiol production, more rapid loss of primary ovarian follicles, and an increase in disturbances of ovulation including short luteal phase cycles and anovulation.
It is also likely that higher estradiol levels up-regulate target tissue estradiol receptors.
Finally, it is also to be remembered that genetic influences on the expression of feedback and gonadal steroid changes in women's perimenopausal health experiences also is an important factor.
 
Changes in Ovarian Regulatory Proteins—Inhibins, Activins and Follistatin
Although research on “inhibin” a pleomorphic ovarian and testicular protein, began over 30 years ago, only recently have the two major, discrete types in women, inhibin B relating to the ovarian follicle pool23 and inhibin A relating to LH and luteal phase events,24 been sufficiently studied and characterized to be of clinical usefulness.25,26 Inhibin B levels, stimulated by FSH, normally increase early in the menstrual cycle to inhibit further FSH-related recruitment of follicles.27 However, follicular-phase inhibin B levels are lower in regularly menstruating midlife women—this change is associated with higher FSH and estradiol levels.28 There are negative correlations between inhibin B levels and FSH and estradiol.27 Furthermore, inhibins, not well characterized by type, also appear to act as intragonadal paracrine regulators.29
Inhibin A levels are not as well characterized but decreases appear to occur later in perimenopause, 30,31 although some authors have shown small increases in follicular phase levels in older women.32 Inhibin A appears to be important in regulation of events relating to ovulation, and to decrease over time.24,30
In addition to the effects of inhibins, other ovarian proteins such as activin and follistatin are important in the net changes in ovarian control during perimenopause.4
 
Changes in FSH Feedback Control and Levels
Follicle-stimulating hormone (FSH) is secreted in pulses by the anterior pituitary under the influence of gonadotrophin-releasing hormone with direct inhibitory feedback by estradiol and inhibin B and stimulatory actions of activin A.
The key question is—what is an increased FSH level?
Based on prospective, population-based data from 150 women sampled in the early follicular-phase yearly over 6 years, Burger and colleagues concluded, “There is no single reliable hormonal marker of menopausal status for an individual woman”.33 In addition, the usual premenopausal follicular-phase FSH normal range is wide, often has a middle gray zone, or it overlaps the menopausal range. For example, in a cohort sampled yearly over 4-9 yr before menopause, serum FSH levels averaged from weekly samples over 4 wk were 13.1 (2.3-75) in prolonged cycles compared with 6.7 (2.2-20.7) IU/L in regular ovulatory cycles.34
The big picture is that FSH levels increase with age or across perimenopause—the primary reason appears to be inconsistent or decreased estradiol suppression. That, in turn, is probably related to lower levels of inhibins and perhaps higher activins. However, it appears to take very little elevation of FSH, only into the 15-20 IU range, to produce heavy flow, endometrial thickening and hyperplasia, multiple moderate-sized ovarian cysts, and estradiol levels over 2000 pmol/L.35
Hence, levels seen commonly in both ovulatory and nonovulatory cycles from midlife women are sufficient to cause ovarian hyper stimulation.
 
Changes in LH Feedback Control and Levels
It is known that when FSH levels are already higher, LH levels may remain normal in the perimenopausal transition.36 However, some studies show LH levels are also statistically higher in older women37 and higher in those with greater estrogen excretion levels.39 The most important changes in LH appear to relate to the dynamics of the midcycle LH peak.
Although data remain preliminary, exogenous estrogen appears to unreliably produce an LH peak in older women.39 Also, although estradiol levels were not significantly different, cycling women ages 40-50 appeared to lack the slow-frequency, high-amplitude LH pulsatility characteristic of the luteal phase.37 Therefore, changes in positive and perhaps also the negative feedback control of LH appear to occur in perimenopause.5
 
Changes in Estradiol Feedback and Levels
Higher premenstrual estradiol levels in midlife women are associated with heavy flow4042 and with abnormal proliferation of the endometrium.47 The symptom of heavy flow causes about 25% of perimenopausal women to seek medical help43,44 and commonly occurs, if not before, as cycles change from being regular to irregular.45 Part of the pathophysiology of abnormal vaginal bleeding may be that endometrial estradiol receptors are up-regulated in women with heavy flow.46
High estradiol levels before flow may also explain premenstrual front-of-breast tenderness that is commonly reported in regularly cycling women who may also have cyclic night sweats.47 Often perimenopause presents as increasing “premenstrual syndrome” with increased mood, fluid, appetite, and breast tenderness symptoms before flow.48 High estradiol levels have also been shown experimentally to amplify stress hormone responses to situational stress.49 It is possible, although other feedback effects are less efficient, that higher estradiol-related corticotrophin-releasing hormone causes suppressive effects on pituitary control of the ovary.50 These hypothalamic responses to high estradiol may account for the feelings of being out of control, palpitations, and chest pressure some perimenopausal women experience.
 
Changes in Ovulation and Progesterone Levels
Ovulation and premenstrual endocrinology of perimenopause are less well understood than early follicular phase changes. The major epidemiological prospective study of hormonal levels did not measure premenstrual levels.51
Nevertheless, weekly overnight urines for pregnanediol, in three cycles per woman in 31 women considered to be in the menopausal transition, showed that only 52% of cycles that were 18-260 d apart (median 29) were ovulatory.52 The longer cycles were significantly less likely to be ovulatory than the ones of normal length.52,53
In general, short luteal phase cycles and lower progesterone levels occur, even in regularly cycling women in their mid-late 40s.54 This means that the ratio of estradiol to progesterone levels increases.55 These ovulatory changes may result from the disturbed positive feedback of estradiol on LH.566
 
Beyond the HPO axis-Role of higher centers and neuropeptides on menopausal transition
As mentioned in the introduction steroid receptors have now been discovered at many higher centers including the central grey matter. The mechanism of action of these steroids in the CNS is similar to the one observed in the peripheral target organs, producing both genomic and nongenomic effects.
In the genomic mechanism, steroids induce relatively long-term action on neurons by activating specific intracellular estrogen receptors (ERα and ERβ) that modulate gene transcription and protein synthesis. Thus, gonadal steroids modulate the synthesis, release and metabolism of many neuropeptides and neuroactive transmitters, and the expression of their receptors.57 Moreover, sex steroids exert very rapid effects in the brain that cannot be attributed to genomic mechanisms.58 These rapid nongenomic effects of steroids modulate electrical excitability, synaptic functioning and morphological features.
Thereby, mood changes, sweating, anxiety, depression, insomnia and alterations of cognitive functions are some possible clinical consequences of the reduced regulatory effects exerted by gonadal and adrenal hormones on neurotransmitters and neuropeptides in postmenopausal women.59,60
We have all observed some weird levels and varieties of symptoms unrelated to the biochemical picture in our wide experience of menopausal patients. Certainly, the evidence that gonadal steroids modulate neurosteroids levels open new possibilities in the study of neuroendocrinological menopause related changes.
 
CONSEQUENCES OF THE CHANGES IN REPRODUCTIVE HORMONAL SECRETION
There are few recognized symptoms associated with the subtle hormonal changes in late reproductive age, but with the onset of irregular cycles in the menopause transition, hormonal changes become more marked, and experiences such as breast tenderness, menorrhagia, vasomotor symptoms, sleep difficulties, and labile mood become common.61,62 Breast tenderness is associated with the early menopause transition63 basically because of high estradiol. High estradiol with luteal phase defect with low progesterone leads to DUB and endometrial hyper plasia.6467
Vasomotor symptoms are normally associated with low estrogen and are most common in late menopause transition. It can also occur during ovulatory cycles in menopause transition perhaps due to fluctuating 7oestrogen levels.63,68 Many symptoms like poor concentration, labile mood and memory disturbances69 have not been investigated in relation to hormonal dynamics.
Given the complexity of changes occurring during the transition further investigation of peri-menopausal experiences would be best studied by measuring day-to-day and cycle-to-cycle hormone levels with simultaneous record of experiences.
 
CLINICAL CORELATION OF MENOPAUSAL ENDOCRINOLOGY
In perimenopause, FSH increases early in the follicular phase as a result of net positive change as inhibition decreases and stimulation increases. This lack of normal inhibition of FSH probably leads to increased follicle numbers and the increased incidence of dizygotic twinning in older women,70 more rapid depletion of follicles in autopsy studies,71 and higher estradiol levels.72,73 In turn, higher estradiol levels are associated with heavy flow41 in some perimenopausal women and menstrual problems in 32% of menstruating midlife women,74 as well as increased endometrial thickness75 and proliferative histology.41 Higher estradiol levels, through hypothalamic effects, also appear to increase cortisol and catecholamine responses to situational stresses.49 Premenstrual symptoms increase, perhaps as a consequence, and in turn predict more difficult hot flush/night sweat symptoms later in perimenopause.76
Ovulation, although commonly present, is often not normal in amount or duration of progesterone.73,77 The definite trend is for the ratio of estradiol to progesterone to increase.55 These perimenopausal hormonal changes likely have major, although poorly understood, effects on women's experiences.
The effect of the decreased coordination of feedback loops in perimenopause is that high estradiol levels may and often co-exist with elevated gonadotrophin levels. Therefore, exogenous estrogen levels may not reliably suppress endogenous estradiol. These data suggest that symptomatic treatment of heavy flow, vasomotor symptoms, premenstrual symptoms, and sleep disturbances should avoid estrogen. However, progesterone may be effective perimenopausal therapy—it is a steroid that is relatively or absolutely low in perimenopause.
Sociodemographic characteristics,74 weight and waist circumference changes, cycle intervals, and length of flow also need to be documented during clinical evaluation.8
Using an instrument like the Daily Perimenopause Diary,47 patterns of breast tenderness, stretchy cervical mucus, hot flushes/night sweats, mood symptoms, and sleep across normal and long intermenstrual intervals can be characterized.
Finally, there is need for other prospective population-based studies of perimenopause that include measures of progesterone and luteal-phase lengths.
 
SUMMARY
In summary, the complex, interactive and always variable endogenous ovarian hyper stimulation with ovulation disturbances characteristic of perimenopause is much better known now than two decades ago.
However, we still need to integrate the endocrinology with symptoms and to be able to define the onset of perimenopause when cycles are regular and estradiol levels have already increased. It has already been stressed time and again in this chapter that biochemical levels and symptomatology are often at odds with each other partially due to our traditional, oversimplified and pedantic obsession with the HPO axis.
The future lies in further dissecting the crucial involvement of the higher centers and putting in perspective the role of neurotransmitters and neuropeptides in finally arriving at a comprehensive understanding of that fantastic complex of physiology and pathology that we all call-MENOPAUSE.
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