Normal reproductive physiology

Before one can understand the hormonal and endocrine changes associated with menopause, it is important to briefly review normal, pre‐menopausal reproductive physiology. During the follicular phase, FSH is secreted by the pituitary in order to stimulate follicle growth and granulosa cell development. The granulosa cells convert androgens to estradiol, stopping the anti‐follicular effect of androgen and inhibiting FSH secretion; it is this balance that leads to the development of a single follicle ready for ovulation. The ovary also produces both Inhibin A and Inhibin B, which fine‐tune negative feedback inhibition of FSH by acting on the pituitary gonadotrophes [2]. As the follicle(s) near maturation the rising estrogen levels trigger the luteinizing hormone (LH) surge and ovulation; the luteal phase then ensues, including progesterone and estradiol; progesterone assists in preparation of the uterine endometrium for pregnancy, while also inhibiting gonadotrophin releasing hormone analogue (GnRH) pulse frequency [3]. If a woman becomes pregnant, beta human chorionic gonadotrophin (bHCG) maintains the corpus luteum past its usual two‐week lifespan, until the implanted embryo’s placenta takes over. In the absence of conception, the corpus luteum involutes, and progesterone and estradiol levels fall and menstruation ensues. The pulses of GnRH secretion become more frequent and smaller, raising the levels of circulating FSH and stimulating the already activated follicles that will contribute to the coming follicular phase of the cycle. Had pregnancy ensued, the progesterone and estrogen from the embryo‐placenta would have blocked menstruation and the rise of hypothalamic‐pituitary secretion [4].

Ovarian aging with menopause

One of the first hormonal indications of perimenopause is a rising FSH; this is secondary to decreasing production of Inhibin B by granulosa cells in antral follicles. As ovarian function and antral follicle count declines, Inhibin B levels fall, allowing for rising levels of gonadotropins [5]. Rising FSH drives increased recruitment of follicles, with consequential increase in the rate of follicle loss during perimenopause [6, 7].

In addition, estradiol levels also fall with decline in functional ovarian reserve; this results in further disinhibition of GnRH pulsatility, increased sensitivity of gonadotropins to GnRH, and increased levels of FSH as mentioned [8]. Rance et al. suggest that the increase in GnRH may be mediated by increases in neurokinin B and kisspeptin, both stimulatory peptides, and decreasing levels of dynorphin, an inhibitory neuropeptide [2, 9].

In addition to Inhibin A and B, anti‐Müllerian hormone (AMH) is a glycoprotein also produced by granulosa cells in preantral and small antral follicles [10]. AMH inhibits the stimulatory actions of FSH follicle recruitment [11]; as the number of antral follicles decreases with age, so too do AMH levels also decrease, reaching undetectable levels at menopause [12]. As such, AMH has become increasingly popular as a measure for ovarian reserve and as an index for menopause [13].

Hypothalamic changes with menopause

Beyond ovarian aging and its hormonal consequences, several studies have also suggested that the hypothalamic‐pituitary unit itself is affected by aging and also contributes to menopause independent of gonadal feedback. Studies by Hall et al. suggest that in menopause, GnRH pulse frequency decreases, while overall levels of GnRH increase in a compensatory manner [14]. Additionally, LH and FSH levels fall significantly in the post‐menopausal patient, independent of ovarian steroid response [15]. The pituitary itself also becomes less sensitive to GnRH, with significant decreases in both LH and FSH responses in older versus younger postmenopausal women [8]. Interestingly, estrogen‐negative feedback appears to remain intact in postmenopausal women, while estrogen‐positive feedback may be lost during perimenopause [16, 17].

In sum, the hormonal and neuro‐endocrine changes associated with menopause are complex and are still being studied currently. What we believe we understand to date is that with aging, follicle count, and ovarian reserve decreases. This leads to falling levels of Inhibin B and estradiol, which in turn leads to rising levels of FSH in an attempt to preserve normal ovarian function. Eventually, these mechanisms fail as ovarian reserve diminishes, and menopause ensues.

1. What are the clinical symptoms associated with menopause?

Much of our information regarding the clinical manifestations of menopause comes from longitudinal studies of perimenopausal patients, one of the largest being the Study of Women’s Health Across the Nation (SWAN), a multi‐site longitudinal study of mid‐life aging in over 3000 women of diverse racial and ethnic groups [18]. In addition, a “state‐of‐the‐science” meeting in 2005 gathered the world’s experts to determine which midlife symptoms were most likely to be caused by menopause as compared to aging alone; symptoms were evaluated on their proximity to the menopause as well as their relationship to estrogen [19, 20].

The symptoms associated with menopause actually begin in the perimenopausal period, which begins approximately two to eight years preceding menopause and continues to approximately one year after the final menses [21]. Symptomatology varies widely in onset, duration, and quality, and an individualized approach should be taken when managing patients.

Uterine bleeding

Mirroring the hormonal fluctuations occurring during perimenopause, menstrual cycles are also in flux at this time and become increasingly irregular. A change in menstrual pattern is the most common symptom of perimenopause [22]. More specifically, cycles tend to become shorter, leading to increasing frequency of menses. However longer cycles are also possible [23], and as perimenopause proceeds, the tendency toward oligomenorrhea increases [24].

Bleeding tends to be heavier in early perimenopause, becoming increasingly lighter as the transition progresses toward the final menstrual period. It is important to note that despite this irregularity, heavy, prolonged bleeding as well as heavy inter‐menstrual bleeds are not normal and warrant further clinical evaluation.

Vasomotor symptoms

Vasomotor symptoms are the second‐most common symptom of perimenopause/menopause, with as many as 85% of perimenopausal women experiencing night sweats, hot flushes, and sleep disturbances secondary to vasomotor symptoms [19]. Also known as hot flushes or hot flashes, vasomotor symptoms (VMSs) are generally defined as episodes of intense heat and sweating, accompanied by flushing of the head, neck, chest, and/or upper back [25]. The intensity, quality, and duration of hot flushes vary widely among patients from several minutes of extreme heat in the upper body and face to perspiration, chills, clamminess, anxiety, and palpitations [26].

Vasomotor symptoms are generally milder in early perimenopause and tend to worsen significantly throughout the late perimenopausal period [27]. A recent study by Avis et al. found that the earlier that VMS began in the pre/perimenopausal transition, the longer the total duration of symptoms, while women who were post‐menopausal when vasomotor symptoms began had the shortest duration of vasomotor symptoms (median 3.4 years); on average, VMS lasted more than seven years for more than half of subjects and persisted for 4.5 years after their final menses [28]. In addition, several studies have shown a correlation between vasomotor symptoms and cardiovascular disease as well as greater degree of bone loss and increased bone turnover [29, 30]. Hot flashes generally stop within four to five years of onset; however, some women report continuation of vasomotor symptoms for many years, and their impact on quality of life should not be underestimated.

Genitourinary syndrome

Estrogen receptors are present along the vulva, vagina, bladder, and pelvic floor; in these organs, estrogen plays an important role in collagen synthesis and turnover [31]. As such, as estrogen levels decrease during the menopausal state, changes in the vulva, vagina, and pelvic floor are common. In 2014, a consensus conference was held, bringing together the International Society for the Study of Women’s Sexual Health and the North American Menopause Society with the goal of reviewing terminology to more accurately encompass the genitourinary symptoms of menopause [32]. Members created the term “genitourinary syndrome of menopause” to describe the collection of symptoms associated with the genitourinary changes of menopause. These include loss of vaginal rugae and elasticity, thinning of vaginal epithelium, vulvar or vaginal irritation, burning, or itching, increased tissue friability and bleeding, and shortening/narrowing of the vagina and entroitus. Other symptoms include genital dryness, decreased lubrication, discomfort with sexual activity, post‐coital bleeding, and decreased arousal, as well as urinary symptoms such as urinary frequency/urgency and dysuria. Vaginal pH becomes more alkaline, increasing risk for infection. Altogether, these symptoms may significantly affect quality of life, from pain, and bleeding to sexual dissatisfaction. These atrophic changes can be treated effectively and safely with very low dose estrogens delivered to the vagina.

Sleep disturbances, depressed mood, cognitive changes

Women report difficulty sleeping more frequently than men; this appears to worsen with aging, with women reporting increasing sleep symptoms associated with aging as compared to men [33]. Hot flashes occur more commonly during the night, causing sleep disturbance. However, studies suggest that approximately 40% of perimenopausal women experience sleep disturbance even in the absence of hot flashes [34].

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