The Menstrual Cycle
Gametogenesis and steroidogenesis proceed in
a continuous fashion in the postpubertal human male. In contrast, the
postpubertal human female exhibits repetitive cyclic changes in the
hypothalamic–pituitary–ovarian axis that allow: (i) the maturation and release
of gametes from the ovary; and (ii) the development of a uterine environment
prepared to support a pregnancy should fertilization occur. In the absence of
conception, each cycle ends in menstrual bleeding. The pituitary gonadotropins,
luteinizing hormone (LH) and follicle-stimulating hormone (FSH), link the
hypothalamus and the ovary and mediate these cyclic changes.
The menstrual cycle is best
understood if divided into the four phases of functional and morphologic
changes in the ovary and endometrium: (i) follicular, (ii) ovulatory, (iii)
luteal and (iv) menstrual (Fig. 14.1).
Follicular phase
Conventionally considered the
first phase, this is the phase of the menstrual cycle leading up to ovulation.
In a typical 28-day menstrual cycle, it comprises the first 14 days. In
ovulatory cycles of more or less than 28 days’ duration, the deviation from the
average is largely caused by differences in the length of the follicular phase.
During this phase of the
menstrual cycle, a cohort of ovarian follicles will rapidly mature, although
only one typically becomes the dominant follicle,
called the Graafian follicle. Those follicles that undergo final
maturation in a given cycle have likely been growing for several months prior
to that cycle. Progression from the primordial or resting state to the small
antral stage is largely gonadotropin-independent. During the few days prior to
the start of menstruation, a small cohort of these growing follicles, now at
the small antral stage, is recruited for further gonadotropin-dependent growth.
As one cycle ends, the scheduled demise of the corpus luteum results in a rapid
decline in its hormonal secretion. The resultant fall in serum estradiol
releases the central negative feedback inhibition on FSH secretion. Associated
declines in progesterone and inhibin Aare involved to a lesser degree.
Increases in FSH secretion during the late luteal phase are accompanied by an
increase in the pulse frequency of LH secretion.
Day 1 of menstrual bleeding is
considered the first day of the follicular phase. During days 4–5 of this
phase, development of the recruited ovarian follicle cohort is characterized by
FSH-induced granulosa cell proliferation and aromatase activity. The theca
cells of the developing follicle produce androgen precursors. These are
converted into estradiol within neighboring granulosa cells. The process has
been called the two-cell hypothesis (Chapter 2). Estradiol levels increase. The
recruited follicles have several layers of granulosa cells surrounding their
oocytes and a small accumulation of follicular fluid. FSH induces synthesis of additional FSH receptors on granulosa cells,
expanding its own effects. FSH also stimulates synthesis of new LH receptors on
the granulosa cells, thereby initiating LH responsiveness.
By days 5–7 of the menstrual
cycle, a single, selected follicle pre- dominates to the detriment of the
others in the selected cohort, and will mature and ovulate between days 13 and
15. The predominant follicle is characterized by the highest mitotic index of
all the recruited follicles, an optimal capacity for FSH retention in its
follicular fluid, and high estradiol and inhibin B synthesis. Nondominant
follicles have elevated androgen : estrogen ratios in their follicular fluid, suggesting
suboptimal induction of aromatase activity, and will undergo atresia.
Androgens appear to be key to the atresia process, as granulosa cells treated
with androgen in vitro undergo apoptosis.
During the mid to late follicular
phase, continued elevations in circulating estradiol and inhibin B suppress FSH
secretion, so preventing new follicular recruitment. Continuous high elevations
of circulating estradiol exert a somewhat unexpected effect on the pituitary
gland; exponential increases in LH secretion. The ovary also exhibits increased
responsiveness to the gonadotropins. Lastly, high estrogen levels cause growth
of the endometrial tissue lining the uterus. These changes in the endometrium
can be distinguished microscopically and are defined as the “proliferative
phase” (Chapter 10).
Ovulatory phase
This phase of the menstrual cycle
is characterized by a surge in pituitary LH secretion, culminating in extrusion
of the mature ovum through the capsule of the ovary. In the 2–3 days preceding
the onset of the LH surge, circulating estradiol and inhibin B rise rapidly and
in parallel. Estradiol synthesis is at a maximum and no longer dependent on
FSH. Progesterone begins to rise as the surging LH induces progesterone
synthesis by the granulosa cells.
Key to ovulation is the midcycle
positive feedback effect of estrogen on LH secretion. Proof that rising ovarian
estrogens are central to ovulation lies in the observation that a gonadotropin
surge can be elicited when prolonged elevated circulating estradiol concentrations
are produced experimentally by 2–3 days of exogenous estrogen administration in
women. The effects of elevated circulating estrogen are further augmented by
the presence of ovarian progesterone. The site of the positive feedback actions
of midcycle estrogen on LH secretion appears to be in both the hypothalamic
neuroendocrine cells and the pituitary gonadotropes. The exact mechanism by
which estrogen induces the midcycle LH surge is uncertain, but dopaminergic and
β-endorphinergic neuronal modulation of the gonadotropin-releasing hormone
(GnRH) pulse generator are involved. In fact, at midcycle, there is a 20-fold
increase in sensitivity of the pituitary gonadotropes to GnRH. Further, the
GnRH pulse generator can be inhibited by both synthetic and naturally occurring
opioids, suggesting that opioids have a pivotal role in the neuronal control of
the midcycle LH surge. A small rise in FSH occurs simultaneously with the
pronounced rise in LH at midcycle, presumably in response to the GnRH signal.
Ovulation appears to require LH.
The exact mechanism of this effect is unknown, although prostaglandins are
thought to be at least one of the mediators. To this point, LH has been shown
to stimulate prostaglandin biosynthesis by ovarian cells and inhibitors of
prostaglandin synthesis inhibit ovulation in animals.
Luteal phase
After ovulation, the dominant
morphologic and functional feature of the ovary is the formation and
maintenance of the corpus luteum. In humans,
the luteal cells make large amounts of estrogen and inhibin. In fact, the
circulating estrogen concentrations during the luteal phase are in the
preovulatory, positive feedback range. Characteristic of the luteal phase,
however, are the uniquely high concentrations of progesterone and 17-hydroxyprogestrone
secreted by the corpus luteum. Progesterone at these elevated levels prevents
estrogen from stimulating another LH surge from the pituitary. Instead, in the
presence of the combination of high concentrations of progesterone and
estrogen, the preovulatory GnRH pulses are reduced in frequency, resulting in
only baseline FSH and LH secretion.
The length of the luteal phase is
more consistent than that of the follicular phase, normally 14 ± 2 days. If
pregnancy does not ensue, the corpus luteum spontaneously regresses and
follicular development proceeds for the next cycle. Only small amounts of LH
are necessary to maintain the corpus luteum in a normal cycle. However, after
14 days, even basal LH secretion will not support the endocrine function of the
gland. If pregnancy ensues, maintenance of the corpus luteum and progesterone
production is critical to the success of the early gestation. Human chorionic
gonadotropin (hCG) is a hormone homologous to LH. hCG is secreted by the
placental tissues (trophoblast) of a developing pregnancy. Therefore, in the
presence of pregnancy, hCG secreted by gestational trophoblast can maintain the
corpus luteum until the trophoblast assumes the role of progesterone secretion
(Chapter 18). High progesterone elevelsal so create the“secretoryphase” of theen dometrium,
which is marked by endometrial maturation that can allow implantation of the
embryo (Chapter 16). The exact trigger for the demise of the corpus luteum in a
cycle that does not result in pregnancy is unknown. DNA fragmentation patterns
characteristic of apoptosis appear in the corpus luteum as early as the mid to
late luteal phase.
The rise in FSH secretion near
the end of the luteal phase is reliant on a concomitant drop in the high
circulating levels of progesterone, estradiol and inhibin. It is clinically
significant that an estrogen antagonist such as clomiphene citrate,
administered in the luteal phase, causes a rise in circulating FSH levels and
initiation of follicular recruitment.
Menstrual phase
The first day of menstruation
marks the beginning of the next cycle. A new wave of follicles has been
recruited and will progress toward maturation and, for one, ovulation. The
phenomenon known as menstruation is largely an endometrial event, triggered by
the loss of progesterone support from the corpus luteum in nonconception
cycles. Dramatic structural changes occur in the endometrium during menstruation,
driven by complex and only partially understood mechanisms. Hormonally
regulated matrix-degrading proteases and lysosomes appear to be involved.
Matrix-degrading proteases are part of the metalloproteinase (MMP) family of
enzymes whose substrates include collagen and other matrix proteins. Of the MMP
family, seven members are expressed in cell- and menstrual cycle-specific
patterns. Also, the endothelins, which are potent vasoconstrictors, appear to
have maximum activity at the end of the luteal phase. Finally, the premenstrual
fall in progesterone is associated with a decline in 15-hydroxyprostaglandin
dehydrogenase activity. This results in an increase in the availability of
prostaglandin PGF2α, a potent stimulator of myometrial
contractility. Prostaglandin and thromboxane homeostasis direct myometrial and
vascular contractions within the uterus. Control of such contractility is
central to the creation of endometrial ischemia, the promotion of endometrial
sloughing and the cessation of menstrual bleeding.
