Premenopausal Hormonal Regulation of Ovarian Function

The menstrual cycle is controlled by the hypothalamic–pituitary–ovarian axis, which, apart from its mid-cycle gonadotropin surge, acts as a negative feedback system, whereby peptide gonadotropins stimulate steroid hormone production in the ovaries, which in turn inhibits gonadotropin secretion, thus allowing cycles to occur [1–3].

The hypothalamus secretes gonadotropin-releasing hormone (GnRH). This acts on the pituitary gland in a pulsatile manner, which leads to the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [1, 2]. It is the frequency and amplitude of these pulses which determine the quantity of each hormone ultimately secreted. Slower frequencies appear to precipitate FSH secretion, whereas LH secretion has a predilection for higher frequencies of GnRH stimulation [2].

At the start of the menstrual cycle, the ovary contains several antral follicles. These follicles consist of an oocyte separated from a fluid-filled sac called the antrum, both of which are surrounded by a layer of granulosa cells (cumulus cells and mural cells). These cells are surrounded by a basal membrane, around which lies another layer of theca cells. Theca cells develop LH receptors if they are part of the dominant follicle and produce androgens (progesterone or testosterone) from cholesterol. Conversely, granulosa cells have FSH receptors; androgens are absorbed by these cells and aromatized to estradiol (E2). Granulosa cells also produce the glycoprotein hormone inhibin, which includes two isoforms, A and B [1, 2].

In the late luteal phase (prior to menstruation) and the early follicular phase, levels of circulating FSH rise. This in turn stimulates follicular development and leads to selection of a dominant follicle. Whilst it is not known exactly how a dominant follicle is selected, it is thought that through varying follicular sensitivity, the most sensitive follicle goes on to mature, whilst the other follicles undergo atresia (degeneration). With its development, the dominant follicle secretes increasing levels of E2; this acts on the endometrium to stimulate proliferation. At the hypothalamus and pituitary gland, rising levels of E2 and inhibin B act to reduce FSH secretion through a negative feedback mechanism [1–3].

During the early and mid-follicular phases, E2 also exerts negative feedback on LH secretion, which ensures basal levels during this period. However, about 36 hours prior to ovulation (i.e. in the late follicular phase), E2 reaches levels in the circulation which switch this negative feedback effect to a positive feedback effect. This leads to a surge in LH (which is accompanied by a smaller surge in FSH) over a 24-hour period in the 24 hours prior to ovulation. This LH surge leads to rupture of the dominant follicular wall and release of the oocyte [2, 3].

Following ovulation, there is an abrupt fall in E2 production from the ruptured follicle. The follicle undergoes a series of changes which convert it into an endocrine structure called the corpus luteum (‘yellow body’). This produces E2 and progesterone, which act on the endometrium to promote implantation. LH maintains the corpus luteum in the week following ovulation, but if pregnancy does not occur, then this begins to degenerate, leading to a gradual reduction in the production of steroid hormones. With falling E2 and progesterone levels, the loss of negative feedback leads to a subsequent rise in FSH, heralding the start of a new menstrual cycle. A summary of these processes is shown in Figure 1.1 [1, 2].

Figure 1.1 Endocrine changes during the menstrual cycle.

Definitions and Staging in Reproductive Aging

In order to understand the context in which the physiological changes of the menopausal transition are happening, it is necessary to consider the definitions and stages associated with reproductive aging.

The premenopause is typically defined as the phase of a woman’s life from the menarche (onset of menstruation) until the beginning of the perimenopausal stage. The perimenopause comprises the time from a woman’s mature reproductive state at the point when she begins to experience variability in the length of her cycle or characteristic symptoms of the menopausal transition to the year following her final menstrual period (FMP). It is only following this 12-month period of amenorrhea that a diagnosis of menopause can be made. The term menopausal transition also refers to the time when a woman’s cycle changes or she experiences clinical symptoms, but ends with the FMP. The terms menopause and postmenopause are often used interchangeably to describe the phase of a woman’s life from the FMP [1–11].

In 2001, the Stages of Reproductive Ageing Workshop (STRAW) met to propose criteria for defining the stages of reproductive life. They generated a staging system which provided guidance on ovarian aging in women. Prior to this, there was no generally accepted staging system. The aim of this was to improve research in women transitioning from a reproductive to a non-reproductive state by standardizing nomenclature and outlining the characteristic changes of each stage to aid consistency across studies. In a clinical context, the STRAW staging system provides health care providers and women with a guide to assessing fertility and contraceptive requirements. In 2006, the ReSTAGE collaboration assessed the validity and reliability of STRAW’s criteria and made several recommendations. Ten years later, this collaboration and a greater understanding of ovarian aging have led to a revision of the STRAW staging system. The STRAW + 10 staging system is shown in Tables 1.1 and 1.2 [4].

The STRAW + 10 staging system is divided into three phases: the reproductive phase, the menopausal transition and the postmenopausal phase. The reproductive phase is subdivided into three stages (−5 to −3). The early reproductive stage (−5) refers to the period immediately following the menarche, before menstrual cycles become regular. During the peak reproductive stage (−4), menstrual cycles are regular. The late reproductive stage (−3) marks the time when fertility begins to go into decline and is subdivided into two stages. During stage −3b, menstrual cycles are regular, but anti-Müllerian hormone (AMH) levels continue to fall (a process which starts from the menarche) as a result of a gradual depletion in the antral follicle count (AFC) [1, 4, 6]. Stage −3a is characterized by subtle changes in menstrual cycle length and flow. Cycles tend to become shorter and periods heavier [1, 3, 7]. FSH levels rise with increasing variability, whilst AFC, AMH and inhibin B are low [4].

From the onset of the early menopausal transition, also known as the perimenopause (−2), cycle variability increases with a persistent difference of 7 days or more in the length of consecutive cycles. Anatomical and biochemical changes are similar to those of stage −3a, but with increasing variability in FSH levels. The late menopausal transition (−1) is characterized by an interval of amenorrhea lasting at least 60 days [4]. There is an increased prevalence of anovulation and further variability in cycle length and hormonal levels [4, 7, 8]. Indeed, during this stage, FSH levels are typically defined as being greater than 25 IU/L and are often associated with high E2 levels. However, E2 does start to fall [3, 4, 6, 8]. This stage is expected to last between 1 and 3 years, and it is during this time that menopausal symptoms, and in particular vasomotor symptoms (VMS), usually arise [4].

The late menopausal transition concludes with the final menstrual period (FMP) (0) and gives way to the postmenopausal phase (+1 to +2). Stage +1 is defined as the early postmenopausal stage and is subdivided into three stages. Stage +1a lasts 1 year following the FMP, and the end of this stage is defined as the menopause (a period of amenorrhea lasting 12 months). The end of this stage marks the end of the perimenopause, and 1 year into the postmenopausal phase, although this diagnosis can only be made retrospectively [4]. During stages +1a and +1b (which also lasts 1 year), FSH levels continue to rise, whilst E2 levels continue to fall [3, 4, 6, 8]. Thereafter, stabilization of these hormones occurs. Menopausal symptoms, and particularly VMS, are most likely to occur during these stages. Stage +1c marks a period of stabilization in levels of FSH and E2 which lasts between 3 and 6 years. The late postmenopausal stage (+2) lasts for the remaining lifespan of a woman, during which FSH levels tend to fall gradually. Generalized somatic aging processes rather than reproductive aging characterize this period. The prevalence of urogenital symptoms increases at this time [4].

Whilst the STRAW + 10 system is regarded as the gold standard of reproductive aging given its broad applicability to women regardless of age, ethnicity, BMI and smoking status, there remain three key areas where the model cannot be applied. The first is women who are either using hormonal contraception, have had endometrial ablation or have had a hysterectomy. In these instances we must rely on hormonal and clinical criteria alone. The second is women with polycystic ovarian syndrome (PCOS), who have oligomenorrhea as well as a higher AFC and AMH. The final example is those with chronic illness, such as those undergoing chemotherapy for cancer or those living with HIV [4, 10].