Phases. The prototype menstrual cycle of primates (ie., humans) is 28 days in modal length (cycle lengths are longer and more irregular at the beginning and ending of catamenial life). By convention the first day of menses is considered the first day of the cycle. Menses endures for about five days. The following follicular phase is approximately nine days, culminating in ovulation (Day 14). The luteal phase lasts for two weeks (Figure 4-47).

Comparison to the estrous cycle. Most aspects of the menstrual cycle are strikingly similar to those of the estrous cycle, with a few exceptions: higher primates exhibit a bloody vaginal discharge associated with shedding of the uterine lining; sexual receptivity (although certainly heightened near ovulation) is not circumscribed (it has been argued that among some orders of primates submissions to matings outside of fertile periods is a tactic employed by females to decrease male aggression and serves as an incentive for a male to remain within a social group); and the follicular phase of the menstrual cycle is prolonged (no secondary surge of FSH has been detected). The human CL produces substantial quantities of estradiol - unlike luteal tissues of lower mammals and anthropoid (human-like) primates.

Menstrual bleeding. In humans, Old World (Eurasian and African) monkeys, and apes uterine spiral arteries become exposed with sloughing of the endometrium (Figure 4-48); bleeding is visible. Menstruation in tree-dwelling (prehensile) primates/New World (South American) monkeys and prosimians is microscopic. Cycle lengths of New World monkeys tend to be shorter than for higher primates (Table 4-7). Only two nonprimate species are known to menstruate - the elephant shrew and bat.

The mechanism of menstrual bleeding involves PGF2a. Endometrial PGF2a is highest before the onset of menses. Vasoconstriction induced by PGF2a causes ischemia, accumulation of toxic catabolites, tissue necrosis, and desquamation. Myometrial contractility and abdominal discomfort (cramping) associated with menses are also caused by PGF2a (therapeutics that suppress synthesis of prostaglandins are utilized to alleviate symptoms of dysmenorrhea). Coiled arteries dilate and bleed into the uterine lumen as levels of PGF2a subside.

(Use of highly absorbent tampons during menstruation predisposes a very small percentage of women to toxic shock syndrome; the condition is related to production of toxins by a vaginal bacterium (staphylococcus aureus) that becomes harbored and reproduces within the tampon. Toxins enter the circulation causing fever, rash, gastrointestinal upset, hypotension, and even death.)

Premenstrual syndrome. Premenstrual syndrome (PMS) consists of a set of variable symptoms including tension, mood swings, weight gain, and breast tenderness. As many as 30% of women of reproductive age experience PMS symptomatology; the condition can be debilitating. Symptoms of PMS predominant during the luteal phase. The pathophysiology of PMS is poorly understood. Several causal theories of PMS have been propose - steroidal imbalance, vitamin B6 deficiency, hypoglycemia, hyperprolactinemia, dysfunctional metabolism of prostaglandins, and(or) elevation/withdrawal of EOPs. Although specific symptoms of PMS can be treated, no single form of therapy is universally effective. A severe form of PMS, premenstrual dysphoric disorder (PMDD), is characterized by depression.

Contraceptive steroids. Most modern oral contraceptives are low-dose combinations of a synthetic estrogen and progestin (Figure 4-49) taken daily for three weeks; endometrial sloughing and withdrawal bleeding occurs during the following one week - when the steroids are not administered (some prescriptions contain a placebo with an iron supplement). Irregular patterns of uterine bleeding are more prevalent when progestin-only contraceptive methods are used (in the absence of an estrogen, diminished endometrial growth and blood flow leads to hypoxia and tissue sloughing).

Several mechanisms of contraceptive action oblige the pill. Uninterrupted exposure to the negative feedback effects of steroids blocks the midcycle surge of gonadotropins and ovulation. Viscosity of the cervical mucus and poor motility of the uterus and oviducts provide an effective impedance to sperm transport. And even in the unlikely case that fertilization does occur, development of the endometrium is altered so to be detrimental to implantation. Indeed, emergency contraception can be achieved using steroidal pills (taken within 72 hours of unprotected intercourse and 12 hours later).

Birth control pills on the market today are relatively safe; however, there are risk factors. The most serious side-effect is the development of blood clots (estrogen/progestins can cause clotting/fibrinolytic imbalances and increase circulatory LDL/cholesterol) leading to venous thrombosis and embolism. There is no increased hazard of heart attack or stroke in healthy nonsmoking women. Women predisposed to cardiovascular disease or are over 35-years-old and smoke cigarettes (the most important independent risk factor for myocardial infarction) should not use oral contraceptives (a synergistic factor). There is no convincing data to indicate that oral contraceptives increase the danger of any type of cancer. Metabolic side-effects (usually mild) of the pill are not uncommon (nausea, breast tenderness, fluid retention). Noncontraceptive benefits of oral contraceptives include diminished incidences of ovarian and endometrial cancers (associated with the progestin component of the pill), dysmenorrhea, PMS, cystic ovaries, endometriosis, intermenstrual (break-through) bleeding, iron deficiency anemia (due to reduced blood loss at menses), and androgen-dependent acne.

A major advantage of long-acting progestin preparations (Depo-Provera or Implanon) is that execution is not contingent on a daily conscious effort; problems with these techniques are that the normal pattern of uterine bleeding is disrupted and amenorrhea after discontinuation (sometimes more than a year) is common. Break-through bleeding is more prevalent with "extended/continuous" contraceptive systems.

Menopause. A midlife depreciation in reproductive function and sexual activity is characteristic of mammals. A virtual loss in capacity to ovulate occurs in most mammalian females (an exception is the bush baby, in which mitotic expansion of immature ova continues throughout adulthood); more subtle changes in fertility take place in older males. The oldest documented age of a woman conceiving naturally and giving birth to a normal baby is 57 (a 63-year-old woman recently achieved a successful pregnancy following oocyte donation/IVF). Men have been reported to father children into their 90s.

The most explored paradigm of aging is the so-called menopause. Menopause is reached (median age = 50) with the complete cessation of menstrual bleeding (this is actually a gradual process that begins between the ages of 35 and 40). The period from the onset of reproductive aging through the early postmenopausal years is called the climacteric.

The primary determinant of menopause resides with the ovary. The ovaries become progressively less responsive to gonadotropins during the climacteric; this involves a shortage and eventual depletion of the limited reserve of follicles available for recruitment (Figure 4-50). Thus, ovarian and endometrial cyclicity are ultimately terminated. Because ovarian outputs of steroid hormones and inhibin are diminished (ie., intensity of negative feedback), plasma concentrations of gonadotropins remain elevated in postmenopausal women. Hypersecretion of hMG (FSH:LH @ 10:4) has been documented through 90 years (extracts of urinary hMG [pergonal] can be used to induce multiple ovulations in ovarian-competent women). (A fault in hypothalamic function [eg., catecholamine depletion], eventually leading to ovarian failure, is the driving force responsible for the reproductive decline with age in rodents.)

Symptoms that accompany the climacteric include menstrual irregularities (persistent periods of estrus and diestrus are typical in murine rodents), urogenital atrophy, emotional upset, hot flashes (peripheral vasodilation), and osteoporosis; these problems are attributed to follicular exhaustion and estrogen deficiency. Specific mechanisms underlying emotional and vasomotor alterations are not clear. Because estradiol stimulates calcification of bone (ie., uptake of calcium), in the face of chronically low levels of estradiol, bones become brittle and weak. Spiral arteries atrophy following chronic estrogen withdrawal.

The use of estrogens for treatment of the postmenopausal syndrome has been routine in the United States. Unfortunately, unopposed (by progestin) long-term estrogenic therapy increases risks of endometrial and ovarian cancers. Incidences of breast cancer, heart attack, and stroke are increased when estrogen is used in combination with a progestin (colorectal cancer risk is decreased). Some findings have indicated that low-dose estrogens can protect against cardiovascular thrombosis (improved HDL/cholesterol profile) and reduce occurrences of dementia (antioxidant effect). Other studies suggest that long-term use of estrogen or estrogen-progestin increases the risk of dementia. To minimize the pitfalls of HRT (hormone replacement therapy), the FDA recommends the lowest possible dose for the shortest possible duration. It appears that risks escalate with age.

Early menopause (cessation of menstrual cycles before the age of 40) occurs in women with premature ovarian failure (POF). In POF, an autoimmune disease, antibodies are produced against ovarian antigens.

Age of menopause is not affected by prolonged periods of anovulation (eg., with use of oral contraceptives or due to multiple pregnancies); this is because atresia, not ovulation, is the dominant follicular process of the ovary (in women < 0.1% of the some one-half million ova present at puberty will ever ovulate).