MENARCHE

The underlying major endocrinological change is that the hypothalamus begins to secrete releasing hormones. These lead to the release into the circulation of adrenal androgens and pituitary human growth hormone (hGH). It is hGH that causes the growth spurt which begins 3–4 years before the menarche, and which is maximal in the first 2 years (Fig. 2.1). The physical growth slows down as the first menstruation (menarche) approaches. This is because increasing quantities of oestrogen are secreted by the ovaries and feed back negatively, reducing hGH secretion. Shortly after the secretion of hGH starts, the hypothalamus begins to release gonadotrophin-releasing hormone (GnRH) in an episodic pulsed manner. At first, the pulses are greater in amplitude during sleep, but after 2 years they occur by day and night at about 2-hour intervals. GnRH induces the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, which in turn bind to receptors in the ovaries and induce the secretion and release of oestrogen and progesterone into the circulation. The quantity of FSH and LH increases as the girl matures.

Fig. 2.1 The menarche in relation to growth and breast development in adolescence.

Until the age of 8 years, only small quantities of oestrogen are secreted (and less of progesterone). After that age oestrogen secretion begins to rise, slowly at first, but after the age of about 11 years the rise is quite rapid. The FSH levels reach a plateau when the girl is aged about 13. LH levels rise more slowly until 1 year before menarche, at which time a rapid rise occurs (Fig. 2.2). By this time, the GnRH pulses occur every 90 minutes. These hormonal changes persist until after the age of 40, when changes presaging the menopause begin (see Ch. 42).

Fig. 2.2 Pubertal changes in levels of FSH and LH in girls.

It is thought that the rapid rise of LH induces the onset of menarche, but other factors are also involved. These include an increase in the fat : lean ratio of body composition, which in turn is related to good nutrition and the absence of debilitating diseases.

Between the early 1800s and the mid 1900s the average age at menarche fell from 15–17 years to 13–13.5 years. There has been little change over the past 30 years the mean age being around 12.5 years with the exception that obese girls tend to enter puberty earlier than those of normal weight. The initial reduction is believed to be due to better childhood nutrition. It is hypothesized that the greater amount of body fat in girls today permits the greater aromatization of androgens to oestrogens. Rapidly rising levels of oestrogens feed back positively to the hypothalamus and pituitary gland, leading to the LH surge that precedes the menarche.

The menarche may be delayed in women who are of low body weight, such as ballet dancers, women who have anorexia nervosa, or those who are compulsive exercisers.

EFFECTS OF OESTROGEN AND PROGESTERONE ON BODY TISSUES

More than 20 oestrogens have been isolated, the three considered the most important being oestrone, oestradiol and oestriol. Oestrone is a relatively weak oestrogen and interconverts with 17-β oestradiol, which is the most active and the predominant oestrogen in the reproductive years. Oestradiol is rapidly transported in the blood to tissues that have oestrogen-binding receptors. In the blood, 60% is bound to albumin, 37% to sex hormone-binding globulin, and 3% is free. The tissues of the genital tract and the lobular elements of the breasts have the highest concentration of cells containing specific oestrogen-binding receptors, and consequently are most affected by circulating oestradiol.

Once attached to the specific binding sites oestradiol is transferred to the cell’s nucleus, where it activates genes, leading to RNA synthesis. This process is regulated to some extent by progesterone, which blocks the formation of new receptors and induces intracellular enzyme production; these enzymes also regulate oestrogen metabolism. Following nuclear gene activation, oestradiol is rapidly converted to the relatively inactive oestriol, which is transported to the liver where it is conjugated with glucuronic acid. The conjugate is then excreted, mostly in the urine. This leaves the cell receptors free to bind more oestradiol.

Oestradiol stimulates the growth of the vulva and the vagina after the menarche, the hormone causing proliferation of both the epithelial and the muscular layers. This oestrogen also stimulates the formation of more blood vessels, which supply the organs. The uterus is particularly stimulated by oestradiol, which increases its vascularity. Oestradiol causes endometrial proliferation, stimulating the growth of the glands and stroma as well as the growth of the muscular layers of the uterus, so that the uterus grows from its prepubertal size to its adult size in the perimenarchal years (Fig. 2.3). The great increase in circulating oestrogen in pregnancy causes the rapid growth of the uterus, and the lack of this hormone after the menopause leads to uterine atrophy.

Fig. 2.3 The prepubertal uterus compared with the adult uterus. Note particularly the change in ratio of the corpus and cervix.

Progesterone acts on tissues that have oestrogen receptors, but only if they are first sensitized by oestrogen. Progesterone hinders the maturation of the vaginal epithelial cells and renders the cervical mucus viscous, while also increasing the thickness and succulence of an oestrogen-primed endometrium, preparing it to accept a fertilized egg. Progesterone aids in fat deposition and is thermogenic, raising the body temperature by 0.2–0.5 °C.

MENSTRUATION AND OVULATION

At puberty each ovary contains about 200 000 oogonia surrounded by mantles of theca lutein cells, many of which have developed fluid-filled cavities (antra) to become primary follicles.

From now on until their disappearance at the time of the menopause, and in the absence of pregnancy, severe weight loss or of certain other conditions, between 15 and 20 of these follicles are stimulated to grow each month by FSH and LH secreted by the anterior pituitary gland. One (occasionally more) of the follicles grows more rapidly than the others and, reaching the ovarian surface, causes the release of an ovum. If an ovum is released and pregnancy does not occur, menstruation follows.

The control of this system is complex and reciprocating. The initial stimulus originates in the hypothalamus with the release of GnRH into the hypophyseal portal vessels. As mentioned, GnRH released in a pulsatile manner reaches the pituitary gland, where it stimulates the growth and maturation of gonadotrophs, which secrete FSH and LH. FSH acts on 10–20 ‘selected’ primary follicles, by binding onto the theca granulosa cells that surround them. The effect of the rising amounts of FSH is to cause fluid to be secreted into the cavity of the follicles, one of which grows more rapidly than the remainder. Simultaneously the theca granulosa cells that surround the selected follicles secrete increasing amounts of oestradiol, which enters the circulation.

The endocrinological effect of the rising levels of oestradiol is that it exerts a negative feedback on the anterior pituitary and the hypothalamus, with the result that the secretion of FSH falls whereas that of oestradiol rises to a peak (Fig. 2.4). Some 24 hours later a sudden large surge of LH and a smaller surge of FSH occur. This positive feedback leads to the release of an ovum from the largest follicle. Ovulation has occurred. (If large amounts of FSH are produced by the anterior pituitary gland, or usually if FSH injections are given, superovulation occurs, seven or more follicles reaching maturity, a technique used in in-vitro fertilization.)

Fig. 2.4 Hormone levels in the normal menstrual cycle – considerable variations are compatible, however, with normal menstrual function. Here, the inter-relationship of ovarian steroids and hypothalamic–pituitary gonadotrophins is shown. After menstruation, rising levels of oestrogen exert a negative feedback, reducing FSH release. Towards midcycle still higher oestrogen levels exert a positive feedback, causing a sudden peak release of LH, which induces ovulation. An increased release in FSH also occurs. Failure of this sequence will lead to anovulation and irregular cycles. In the luteal phase, LH levels must be sufficiently high to maintain the corpus luteum until the conceptus has implanted and commenced hCG secretion, which then maintains corpus luteum function. If conception fails to occur the corpus luteum deteriorates after about 7 days, with the resulting falling levels of progesterone and oestrogen. As a consequence menstruation occurs and FSH levels rise, initiating a new menstrual cycle.

The collapse of the follicle from which the ovum has been released leads to a change in its nature. The theca granulosa cells proliferate, become yellow in colour (luteinized) and are referred to as theca-lutein cells. The collapsed follicle becomes a corpus luteum. The lutein cells of the corpus luteum secrete progesterone as well as oestrogen. Progesterone secretion reaches a plateau about 4 days after ovulation and then rises progressively should the fertilized ovum implant into the endometrium. The trophoblastic cells of the implanted embryo immediately secrete hCG, which maintains the corpus luteum so that the secretion of oestradiol and progesterone continues. On the other hand, if pregnancy fails to occur the theca-lutein cells degenerate and produce less oestradiol and progesterone. This reduces the negative feedback on the gonadotrophs, with a rise in the secretion of FSH. The falling circulating levels of oestradiol (Table 2.1) and progesterone cause changes in the endometrium (see p. 14), which leads to menstruation.

Table 2.1 Plasma oestradiol levels during the menstrual cycle

ENDOMETRIAL CYCLE

Menstruation is the periodic discharge from the uterus of blood, tissue fluid and endometrial cellular debris, in varying amounts. The quantity of tissue fluid is the greatest variable. This means that some women who complain of heavy periods do not become anaemic as might be expected (see Ch. 28). The mean blood loss during menstruation is 30 mL (range 10–80 mL). Menstruation normally occurs at intervals of 22–35 days (counted from day 1 of the menstrual flow to day 1 of the next) and the menstrual discharge lasts from 1 to 8 days.

A convenient way to describe the endometrial menstrual cycle is to start just after menstruation ceases and follow the cycle to the next menstruation as it passes through the proliferative and secretory (luteal) phases.

Proliferative phase

As each area of the endometrium is shed during menstruation, regenerative repairs begin, the endometrial surface being reformed by the metaplasia of stromal cells and by an outgrowth of epithelial cells of the endometrial glands. Within 3 days of menstruation ceasing, the repair of the entire endometrium is complete.

In the early proliferative phase the endometrium is thin, the glands few, narrow, straight, and lined with cuboidal cells, and the stroma is compact (Fig. 2.5). The early regenerative phase lasts from day 3 of the menstrual cycle to day 7, when proliferation speeds up. The epithelial glands increase in size and grow down perpendicular to the surface. Their cells become columnar with basal nuclei. The stromal cells proliferate, remaining compact and spindle shaped (Fig. 2.6). Mitoses are common in glands and stroma. The endometrium is supplied by basal arteries in the myometrium which send off branches at right angles to supply the endometrium. At first, as each artery penetrates the basal endometrium it is straight, but in the middle and superficial layers it becomes spiral. This coiling permits the artery to supply the growing endometrium by becoming uncoiled. Each spiral artery supplies a defined area of endometrium.

Fig. 2.5 Endometrium – early proliferative phase. Note that the glands are straight, short and narrow. The surface epithelium is thin.

Fig. 2.6 Endometrium – late proliferative phase. The glands have become longer and tortuous and, in a few, early secretory changes may be observed. The stroma remains dense.

Luteal phase

If ovulation occurs, as is usual except at the extremes of the reproductive years, the endometrium undergoes marked changes. The changes start in the last 2 days of the proliferative phase, but increase dramatically after ovulation. Secretory vacuoles, rich in glands, appear in the cells lining the endometrial glands. At first the vacuoles are basal and displace the cell’s nucleus superficially (Fig. 2.7). They rapidly increase in number and the glands become tortuous. By the sixth day after ovulation the secretory phase is at its peak. The vacuoles have streamed past the nucleus. Some have discharged mucus into the cavity of the gland; others are full of mucus, leading to a saw-toothed appearance (Fig. 2.8). The spiral arteries increase in length by uncoiling (Fig. 2.9).

Fig. 2.7 Endometrium – early luteal phase. The tortuosity of the glands, and the subnuclear vacuoles, can be seen.

Fig. 2.8 Endometrium – day 6 after ovulation. The glands are now very tortuous, with secretion in the lumen and increasing fluid separating the stromal cells. In a fertile cycle day 6 is when the ovum reaches the uterine cavity.

Fig. 2.9 Endometrial vascular patterns.

In the absence of pregnancy, the secretion of oestrogen and progesterone falls as the corpus luteum ages. The fall leads to an increase in endometrial free arachidonic acid and endoperoxidases. These enzymes induce stromal cell lysosomes to synthesize and secrete prostaglandins (PGF_2α and PGE₂) and prostacyclin. PGF_2α is a powerful vasoconstrictor and causes uterine contractions; PGE₂ causes uterine contractions and some vasodilatation; prostacyclin is a vasodilator, causes muscle relaxation and inhibits platelet aggregation. During menstruation the ratio of PGF_2α to the other two prostaglandins increases. This change reduces the blood flow through the endometrial capillaries and leads to a shift of fluid from the endometrial tissues into the capillaries, with a resulting decrease in endometrial thickness. This leads to increased coiling of the spiral arteries and a further decrease in blood flow. The area of endometrium supplied by the spiral artery becomes hypoxic, and ischaemic necrosis occurs. The vasoconstriction occurs in different spiral arteries at different times, alternating with vasodilatation. The necrotic area of the endometrium is shed into the uterine cavity, accompanied by blood and tissue fluid. Menstruation has begun.

In the past decade molecular biology has identified at least 50 proteins secreted by the endometrium that may be involved in controlling menstruation. For example, endothelin causes marked vasoconstriction of the spiral arteries and consequently reduced blood flow in them. Other proteins promote cell division, which could help in repairing the endometrium.

Menstrual phase

During menstruation the superficial and middle layers of the endometrium are shed, the deep basal layer being spared (Fig. 2.10). The shedding occurs in an irregular, haphazard manner, some areas being unaffected and others undergoing repair, while simultaneously other areas are being shed. The shed endometrium, with tissue fluid and blood, forms a coagulum in the uterine cavity. This is immediately liquefied by fibrinolysins and the liquid, which does not coagulate, is discharged through the cervix by uterine contractions. If the quantity of blood lost in the process is considerable, there may be insufficient fibrinolysins and clots are expelled through the cervix.

Fig. 2.10 Endometrium – early menstrual phase. The section shows the beginning of focal necrosis in the superficial zone of the endometrium, with small areas of haemorrhage into the stroma and infiltration with neutrophils.

The blood vessels supplying the area beneath the shed endometrium are sealed with a haemostatic plug consisting of aggregated platelets and by fibrin fibres, which infiltrate the platelet aggregations to form a stable occlusive plug. In addition, vasoconstriction occurs. The basal layer of the endometrium regenerates and new epithelium covers the denuded area. When regeneration exceeds necrosis and repair is complete or nearly complete, menstruation ceases and a new menstrual cycle begins.

CERVICAL CYCLE

During the follicular phase the glands lining the clefts of the cervical canal proliferate and secrete a thick mucus, which forms a complex mesh in the cervical canal. Just before ovulation, the sudden surge of oestrogen changes the character of the cervical mucus, which becomes thin and forms long strands through which helical channels appear. Following ovulation, progesterone alters the nature of the cervical mucus, which again becomes thick and impenetrable.

VAGINAL CYCLE

Cyclic changes occur in the vaginal epithelium which are dependent on the ratio between oestrogen and progesterone. In the follicular phase, superficial and large intermediate cells predominate. As ovulation approaches the proportion of superficial cells increases and few leucocytes can be seen (Fig. 2.11). Following ovulation a marked change occurs as progesterone is secreted. The superficial cells are replaced by intermediate cells and leucocytes increase in number, causing the smear to look dirty (Fig. 2.12).

Fig. 2.11 Vaginal exfoliative cytology – late proliferative phase. Note the discrete cells with small nuclei and the clear background.

Fig. 2.12 Vaginal exfoliative cytology – luteal phase. The cells have clumped and the background infiltration of leucocytes has begun.