The ageing female reproductive axis II ovulatory changes with perimenopause

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Jerilynn C. Prior

Division of Endocrinology and Metabolism, University of British Columbia, Vancouver Hospital andHealth Sciences Centre, Vancouver, BC, Canada V5Z 1C6

A bstract. Perimenopause, a complex physiological transition for midlife women, begins with changes in experiences many years before cycles become irregular, oestradiol levels decrease or follicle-stimulating hormone levels increase. Erratic and average higher oestradiol levels as well as shorter luteal phase lengths and lower progesterone levels occur during perimenopause. These ovarian changes may be causally related to lower inhibin production but the dynamic prospective inter-relationships within women are not well documented. This review will first define perimenopause and then explore the limited published data on ovulatory characteristics in perimenopause. In addition, it will report preliminary prospective observational data on menstrual cycles and ovulation in initially ovulatory women followed through the perimenopause. Prospective data suggest that ovulation disturbances begin early in perimenopause and increase with irregular cycles. Combined with higher oestradiol levels they may cause menorrhagia. It is not yet known whether disturbances of ovulation relate to bone loss in perimenopausal, as in premenopausal, women. It is also not known whether progesterone therapy can effectively counteract the end organ (breast, endometrial, brain) effects of higher/erratic oestradiol levels and effectively treat perimenopausal vasomotor and other symptoms.

2002 Endocrine facets of ageing. Wiley, Chichester (Novartis Foundation Symposium 242) p 172-192

Each woman is born with an average of over a million follicles in her two ovaries, and each follicle contains an egg that could potentially be released and fertilized. The life cycle of each woman's cohort of follicles is not well known but includes continuous maturation (that may manifest as ovarian cysts; Merrill 1963) and atresia of immature follicles that begin long before puberty. Therefore, independent of pituitary stimulation or ovulation, follicle numbers steadily decrease. Prior to puberty, the ovaries enlarge and cystic activity increases but the first 10—12 years following menarche is required before the majority of women consistently and normally ovulate (Vollman 1977). This review of ovulation will focus on ovulation during perimenopause, the final portion of the life cycle of ovarian follicles.

Change in Experience

Irregular periods

Final Menopause period

2-5 years

Phase A B

3 years D

1 year

FIG. 1. This time line diagram shows the approximate time intervals for the characteristic changes of the perimenopause. Phases A and B occur before irregular periods begin. Phases C and D occur before the year of final menstrual flow that is phase E of the perimenopausal transition (Prior 1998).

Perimenopause is understood to begin when the number of remaining ovarian follicles reaches some (unknown) low point. Cross-sectional ovarian histological studies suggest that the rate of follicle 'loss' accelerates abruptly in the late 30s or early 40s (Richardson et al 1987). On the face of it, that information suggests that ovulation becomes more prevalent during perimenopause. Perimenopause, for this review, begins when a woman reports a change in experience (such as increased breast tenderness and premenstrual symptoms with or without night sweats and sleep disturbances, Fig. 1). That the ovaries become depleted of follicles fits with the prevalent notion that perimenopause is a time of ovarian senescence during which 'oestrogen deprivation' develops. In fact, cross-sectional data have been interpreted to support such an oestradiol decline (Burger et al 1995) although a meta-analysis of all controlled studies in which oestradiol levels have been systematically measured in perimenopausal and premenopausal control women shows that oestradiol levels are significantly higher in perimenopausal women (Prior 1998). These higher and erratic oestradiol levels are postulated to be due to decreasing ovarian inhibin production (Burger et al 2002, this volume) and others (Klein et al 1996, Welt et al 1999). These lower inhibin levels allow follicle-stimulating hormone (FSH) levels to rise slightly but not significantly, which stimulates multiple follicles each of which secretes some oestradiol. The resulting oestradiol levels are not only higher but because of disturbed pituitary—ovarian feedback, are also non-suppressible (Fig. 2) (Prior 1998).

Rising and uninhibited FSH levels stimulate maturation and oestradiol production by more follicles but it is not clear whether or not ovulation and progesterone production are also hyperstimulated. More ovarian cysts, that suggest anovulation, appear to be present (Djerassi et al 1995). These women, were they to become pregnant, would more likely produce non-identical twins (Gilfillan et al 1996). However, all of the few studies in which ovulation has been

Premenopausal Ovaries: PériménopausaI Ovaries:

fol il eu far phase follicular phase

Female Reproductive Axis

FIG. 2. Diagram of the ovaries in the follicular phase and the inter-relationships among ovarian oestradiol, inhibin and FSH productions during the premenopausal and perimenopausal years. Lacking adequate inhibin production from ovarian follicles (dark ovoids), perimenopausal FSH levels rise slightly and the increasing oestradiol levels are not sufficient, with lower inhibin levels, to suppress them. Dotted line, inhibition; solid line, stimulation; shaded ovoids, growing follicles, striped bodies, atretic corpus luteum. Reprinted from Prior (1998) with permission of the Endocrine Society.

FIG. 2. Diagram of the ovaries in the follicular phase and the inter-relationships among ovarian oestradiol, inhibin and FSH productions during the premenopausal and perimenopausal years. Lacking adequate inhibin production from ovarian follicles (dark ovoids), perimenopausal FSH levels rise slightly and the increasing oestradiol levels are not sufficient, with lower inhibin levels, to suppress them. Dotted line, inhibition; solid line, stimulation; shaded ovoids, growing follicles, striped bodies, atretic corpus luteum. Reprinted from Prior (1998) with permission of the Endocrine Society.

documented prospectively and some cross-sectional studies indicate that disturbances of ovulation are an integral part of the ageing of the reproductive system for women.

The purpose of this review is to examine reproductive ageing in women as it relates to ovulation and progesterone production throughout the several postulated phases of the perimenopause (Table 1) (Prior 1998). This paper will focus not only on available data concerning ovulation in perimenopause, but also highlight the potential physiological and clinical consequences of such ovulation disturbances. Finally, it will review the potential data from studies in progress and propose therapy with progesterone for symptomatic perimenopausal women.

It is important first, to define ovulation disturbances and indicate how they are diagnosed. The term 'ovulation disturbance' includes a spectrum of changes in progesterone production by the corpus luteum including short luteal phase (SLP) and anovulatory cycles (Anov) (Prior et al 1990a). An SLP lasts less than 12 days from the luteinizing hormone (LH) peak or has fewer than 10 days of significant basal temperature elevation (Vollman 1977). Ovulation disturbances and luteal phase length can be documented by quantitative basal temperature measurement methods using least squares or mean temperature analysis to determine whether and where in the cycle a significant temperature increase occurs (Prior et al 1990b). Ovulation disturbances can also be diagnosed using daily or intermittent measurements of blood (Welt et al 1999), saliva or urinary progesterone breakdown products such as pregnanediol corrected for creatinine

(PdG) (Santoro et al 1996). However, no single gold standard for ovulation exists and criteria for diagnosing ovulation and luteal phase length with each method are not well described and validated. Importantly, no ovulation documentation methods are suitable for continuous monitoring over long periods of time and in random participants from populations.

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