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Menopause

Overview of Menopause

Genevieve Neal-Perry, MD, PhD 
Reviewed on July 22, 2024
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Introduction

Menopause is a retrospectively diagnosed defined amenorrhea (i.e., lack of menstrual bleeding) for 12 consecutive months due to ovarian follicular depletion. Menopause can be spontaneous or as a consequence of medical interventions (e.g., bilateral oophorectomy, chemotherapy, radiotherapy) – in which case it is referred to as iatrogenic menopause. The term menopausal transition, or perimenopause, denotes a period of approximately 4 to 7 years which begins with the onset of menstrual irregularities in the later reproductive years and extends until one year after the final menstrual period.

The Stages of Reproductive Aging Workshop (STRAW)held in 2001 aimed to define terminology and devise a precise system for characterizing the menopausal transition using menstrual and quantitative hormonal criteria. The initial staging system underwent a revision in 2012 (renamed STRAW + 10), which became and remains the gold standard for defining reproductive lifespan. The STRAW + 10…

Introduction

Menopause is a retrospectively diagnosed defined amenorrhea (i.e., lack of menstrual bleeding) for 12 consecutive months due to ovarian follicular depletion. Menopause can be spontaneous or as a consequence of medical interventions (e.g., bilateral oophorectomy, chemotherapy, radiotherapy) – in which case it is referred to as iatrogenic menopause. The term menopausal transition, or perimenopause, denotes a period of approximately 4 to 7 years which begins with the onset of menstrual irregularities in the later reproductive years and extends until one year after the final menstrual period.

The Stages of Reproductive Aging Workshop (STRAW) held in 2001 aimed to define terminology and devise a precise system for characterizing the menopausal transition using menstrual and quantitative hormonal criteria. The initial staging system underwent a revision in 2012 (renamed STRAW + 10), which became and remains the gold standard for defining reproductive lifespan. The STRAW + 10 classification categorizes reproductive, perimenopause and (post)menopause into seven stages (Figure 1-1), following the four stages of reproductive years (Stages -5, -4, -3a and -3b).

Enlarge  Figure 1-1: The STRAW + 10 Staging System for Reproductive Aging in Women. Perimenopause includes Stages -2, -1, 0 and +1a, while postmenopause comprises Stages +1a, +1b, +1c and +2. See text for more detail. Source: Adapted from: Harlow SD, et al. <em>J Clin Endocrinol Metab</em>. 2012;97(4):1159-1168.
Figure 1-1: The STRAW + 10 Staging System for Reproductive Aging in Women. Perimenopause includes Stages -2, -1, 0 and +1a, while postmenopause comprises Stages +1a, +1b, +1c and +2. See text for more detail. Source: Adapted from: Harlow SD, et al. J Clin Endocrinol Metab. 2012;97(4):1159-1168.

Stages -2, -1 and 0 respectively represent the early menopausal transition, late menopausal transition and final menstrual period. The early transition (Stage -2) is characterized by a ≤7-day deviation from previously regular menstrual cycles or the occurrence of a skipped menstrual period, while the late menopause transition (Stage -1) is marked by a cycle of ≥60 days. The initial 12 months following the final menstrual period correspond to Stage +1a, the second 12 months to Stage +1b, and the following 3-6 years are identified as Stage +1c. During all +1 Stages, there is an absence of vaginal bleeding due to ovulation. The rest of the woman's life is categorized as late postmenopause, or Stage +2.

One drawback associated with STRAW + 10 is that, although data were sourced from more ethnically diverse cohorts, the clinical sites were confined to North America and Australia. Furthermore, it has limited applicability for women experiencing irregular menstrual cycles, such as those with polycystic ovarian syndrome, hysterectomy, endometrial ablation, or the utilization of a progestin intrauterine device (IUD).

Physiology of Menopause

The timing of menopause is the result of an intricate interplay involving genetic, epigenetic, socioeconomic and lifestyle factors. The ultimate determinant of menopause timing are the ovaries and the follicles themselves. The number of follicles is established before birth, with the number of oocytes reaching a typical maximum of 6-7 million at mid-gestation. The number shrinks dramatically during later fetal development and childhood, with apoptosis reducing the number of oocytes to 700,000 at birth and 300,000 at puberty. During the reproductive years of life, ongoing apoptosis coupled with follicular recruitment during menstrual cycles (approximately 400–500 cycles in a typical reproductive lifespan, sometimes with multiple follicles recruited per cycle), ultimately depletes all oocytes by the age of 45-55.

Pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), along with locally produced hormones, regulate ovarian follicles. They act as a negative feedback system. Gonadotropins induce the production of steroid and peptide hormones in the ovaries, which in turn inhibit gonadotropin secretion. This process enables the occurrence of menstrual cycles. In the early perimenopausal stage, ovarian physiological changes are typically associated with a low antral follicle count, leading to alterations in estradiol levels and an elevation in FSH, as well as changes in LH. The most consistent and linear endocrine change during the menopausal transition is the gradual decline of inhibin B and anti-Mullerian hormone (AMH), indicating the reduction in granulosa cell mass and/or functionality. A schematic overview of perimenopausal physiological changes is shown in Figure 1-2.

Enlarge  Figure 1-2: Menopausal Loss of Ovarian Function. Hypothalamic ageing leads to desynchronized gonadotropin-releasing hormone (GnRH) pulsing patterns and dysfunction luteinizing hormone (LH) pulsatility from the pituitary gland. These central nervous system changes, together with ovarian ageing, impair ovarian follicle responsiveness to gonadotropins, hormone production (inhibin B, anti-Müllerian hormone (AMH) and estradiol) and follicular development. This leads to cycle irregularities and follicle-stimulating hormone (FSH) upregulation. Source: Adapted from: Davis SR, et al. Nat Rev Dis Primers. 2015;1:15004.
Figure 1-2: Menopausal Loss of Ovarian Function. Hypothalamic ageing leads to desynchronized gonadotropin-releasing hormone (GnRH) pulsing patterns and dysfunction luteinizing hormone (LH) pulsatility from the pituitary gland. These central nervous system changes, together with ovarian ageing, impair ovarian follicle responsiveness to gonadotropins, hormone production (inhibin B, anti-Müllerian hormone (AMH) and estradiol) and follicular development. This leads to cycle irregularities and follicle-stimulating hormone (FSH) upregulation. Source: Adapted from: Davis SR, et al. Nat Rev Dis Primers. 2015;1:15004.

In the years leading up to menopause, elevations in FSH can be detected well before noticeable declines in estradiol or menstrual irregularities occur. This characteristic rise in FSH may exhibit variability, initially trending upward in a step-wise manner as follicle counts decrease, and then sharply increasing within one year of menopause. The early menopausal transition is characterized by the fluctuating levels of FSH on cycle day 2-5, while in the late menopausal transition FSH is more consistently elevated (serum level of >25 IU/L). During the +1a and +1b menopausal stages, FSH continues to rise before stabilizing at an elevated level in the +1c stage.

Luteal phase follicular recruitments result in early follicular estradiol level increases in the years preceding the perimenopause. The early menopausal transition is marked by fluctuations in estradiol levels, with cycles remaining ovulatory. In the late menopausal transition, the levels typically start to drop. Around 45% of women experience a rapid decrease in estradiol within one to two years of menopause, while others either undergo a gradual decline or maintain a relatively steady level. During Stage +1a and +1b, estradiol levels further decrease, eventually stabilizing at a low level in Stage +1c.

Vasomotor symptoms (VMS), including hot flashes (HFs) and cold/night sweats, sleep disturbance and genitourinary syndrome of menopause (GSM) are two of the most common (peri)menopausal symptoms with a negative influence on quality of life (QoL) and wellbeing (see below). Hot flashes or cold/night sweats usually involve vasodilation and sweating on the head, chest and neck. During an HF, skin temperature typically rises, particularly in the fingers and toes, while core body temperature drops. Since estrogen therapy is effective in reducing HF symptoms, hormonal changes are mechanistically implicated in HFs, although the details of the causal relationship are not fully elucidated. The kisspeptin/neurokinin B/dynorphin (KNDy) neuronal signaling system in the hypothalamus is a thermoregulatory pathway that is also required for the production of gonadotropin-releasing hormone, providing a neuromechanistic link between the hypothalamic-pituitary-gonadal axis and the heat dissipation response which characterizes VMS. An estrogen-deficient state potentiates the activity of KNDy signaling. Studies in rodents and humans have demonstrated that administration of neurokinin B increases cutaneous vasodilation and conversely, that ablation of KNDy neurons reduces it. Several lines of evidence suggest that the calcitonin gene-related peptide (CGRP) is the primary vasodilator that mediates hot flashes (including higher expression in menopausal women and HF-associated release), but this has not yet been conclusively established. The hypoestrogenic environment of menopause is also responsible for GSM, inducing changes in vaginal epithelial thickness, smooth muscle atrophy and loss of tissue elasticity, and reduced blood flow in the vaginal area.

Prevalence and Demographics of Menopause

On average, women spend about 40% of their lives post-menopause. The median age for natural menopause is 51 years, with 90% of women experiencing menopause between the age of 45 and 56 years. Natural menopause is considered premature when it occurs before the age of 40, which is observed in about 1.9% of women. When menopause occurs between the ages of 40 and 45 it is considered early, while menopause with an onset beyond the age of 55 is considered late.

Research suggests a tendency for a slightly delayed onset of natural menopause in the developed world. The highest mean age at final menstrual period was noted in high income regions/countries, including Europe and Australia (50.5 and 51.3 years, respectively). Similar ages were observed in Japanese women. However, in regions like Africa, Latin America and the Middle East, the mean age tends to be lower, with regional means ranging from 47.2 to 48.4 years. The United States falls in between, at approximately 49.1 years. In India, the mean age of the final menstrual period is 45 to 46.2 years, suggesting a correlation between economic vulnerability and earlier onset of menopause.

Within the variation noted above, the age of menopausal onset appears to be relatively stable across different world regions and through recorded history. While genetics may play a large part in the timing and variability of menopause onset observed among individual women, environmental factors, nutrition and other influences may contribute to the regional patterns. Across various cultures and ethnic and racial groups, research underscores the influence of lower educational attainment, economic insecurity, rural residence and lifestyle factors (e.g., smoking) in lowering the age at which menopause occurs.

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