Medical Physiology, 3rd Edition

The Endometrial Cycle

In the human female fetus, the uterine mucosa is capable of responding to steroid hormones by the 20th week of gestation. Indeed, some of the uterine glands begin secreting material by the 22nd week of gestation. Endometrial development in utero apparently occurs in response to estrogens derived from the maternal placenta. By the 32nd week of gestation, glycogen deposition and stromal edema are present in the endometrium. As estrogenic stimulation is withdrawn after delivery, the endometrium regresses, and at ~4 weeks after birth, the glands are atrophic and lack vascularization. The endometrium remains in this state until puberty.

The ovarian hormones drive the morphological and functional changes of the endometrium during the monthly cycle

The ovarian steroids—primarily estradiol and progesterone—control the cyclic monthly growth and breakdown of the endometrium. The endometrial cycle has three major phases: the menstrual, proliferative, and secretory phases.

The Menstrual Phase

If the oocyte was not fertilized and pregnancy did not occur in the previous cycle, a sudden diminution in estradiol and progesterone secretion will signal the demise of the corpus luteum. As hormonal support of the endometrium is withdrawn, the vascular and glandular integrity of the endometrium degenerates, the tissue breaks down, and menstrual bleeding ensues; this moment is defined as the start of day 1 of the menstrual cycle (Fig. 55-11 ). After menstruation, all that remains on the inner surface of most of the uterus is a thin layer of nonepithelial stromal cells and some remnant glands. However, epithelial cells remain in the lower uterine segments as well as regions close to the fallopian tubes.

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FIGURE 55-11 Endometrial cycle. The ovarian cycle includes the follicular phase (in which the follicle develops) and the luteal phase (in which the remaining follicular cells develop into the corpus luteum). The endometrial cycle has three parts: the menstrual, the proliferative, and the secretory phases.

The Proliferative Phase

After menstruation, the endometrium is restored by about the fifth day of the cycle (see Fig. 55-11) as a result of proliferation of the basal stromal cells on the denuded surface of the uterus (the zona basalis) as well as the proliferation of epithelial cells from other parts of the uterus. The stroma gives rise to the connective tissue components of the endometrium. Increased mitotic activity of the stromal and glandular epithelium continues throughout the follicular phase of the cycle and beyond, until ~3 days after ovulation. Cellular hyperplasia and increased extracellular matrix result in thickening of the endometrium during the late proliferative phase. The thickness of the endometrium increases from ~0.5 mm to as much as 5 mm during the proliferative phase.

Proliferation and differentiation of the endometrium are stimulated by estrogen that is secreted by the developing follicles. Levels of estrogen rise early in the follicular phase and peak just before ovulation (see Fig. 55-6). ER levels in the endometrium also increase during the follicular phase of the menstrual cycle. Levels of endometrial ER are highest during the proliferative phase and decline after ovulation in response to changing levels of progesterone.

Estradiol is believed to act on the endometrium in part through its effect on the expression of proto-oncogenes (see p. 70). Estradiol also stimulates the synthesis of growth factors such as insulin-like growth factors (IGFs; see p. 996), transforming growth factors (TGFs), and epidermal growth factor (EGF) by endometrial cells that then act in an autocrine and paracrine manner to induce maturation and growth of the endometrium. Estradiol also induces the synthesis of PRs in endometrial tissue. Levels of PRs peak at ovulation, when estradiol levels are highest, to prepare the cells for the high progesterone levels of the luteal phase of the cycle.

Progesterone, in contrast, opposes the action of estradiol on the epithelial cells of the endometrium by inhibiting ER expression and stimulating expression of 17β-HSD and sulfotransferase. 17β-HSD converts estradiol to estrone (see Fig. 55-8), which is a weaker estrogen. Sulfotransferase conjugates estrogens to sulfate, making them biologically inactive.

The Secretory Phase

During the early luteal phase of the ovarian cycle, progesterone further stimulates the 17β-HSD and sulfation reactions (see above) and decreases ER levels in endometrial cells. These three antiestrogenic effects halt the proliferative phase of the endometrial cycle. Progesterone also stimulates the glandular components of the endometrium and thus induces secretory changes in the endometrium. The epithelial cells exhibit a marked increase in secretory activity, as indicated by increased amounts of endoplasmic reticulum and mitochondria. These increases in synthetic activity occur in anticipation of the arrival and implantation of the blastocyst. The early secretory phase of the menstrual cycle (see Fig. 55-11) is characterized by the development of a network of interdigitating tubes within the nucleolus—the nucleolar channel system—of the endometrial epithelial cells.

During the middle to late secretory phase, the secretory capacity of the endometrial glands increases. Vascularization of the endometrium increases, the glycogen content increases, and the thickness of the endometrium increases to 5 to 6 mm. The endometrial glands become engorged with secretions. They are no longer straight; instead, they become tortuous and achieve maximal secretory activity at approximately day 20 or 21 of the menstrual cycle.

The changes in the endometrium are not limited to the glands; they also occur in the stromal cells between the glands. Beginning 9 to 10 days after ovulation, stromal cells that surround the spiral arteries of the uterus enlarge and develop eosinophilic cytoplasm, with a prominent Golgi complex and endoplasmic reticulum. This process is referred to as predecidualization. Under the influence of progesterone, spindle-shaped stromal cells become rounded decidual cells and form an extracellular matrix consisting of laminin, fibronectin, heparin sulfate, and type IV collagen. Multiple foci of decidual cells spread throughout the upper layer of the endometrium and form a dense layer called the zona compacta (see Fig. 55-11). This spreading is so extensive that the glandular structures of the zona compacta become inconspicuous. Inflammatory cells accumulate around glands and blood vessels. Edema of the midzone of the endometrium distinguishes the compact area from the underlying zona spongiosa, where the endometrial glands become more prominent.

Together, the superficial zona compacta and the midlevel zona spongiosa make up the so-called functional layer of the endometrium. This functional layer is the region that proliferates early in the monthly endometrial cycle, that later interacts with the embryo during pregnancy, that is shed after pregnancy, and that is also shed each month during menstruation. The deepest layer of the endometrium—the zona basalis—is the layer left behind after parturition or menstruation. The cells of the zona basalis give rise to the proliferation at the beginning of the next endometrial cycle.

During the late luteal phase of the menstrual cycle, just before the next menstruation, levels of both estrogens and progestins diminish, and these decreased ovarian steroid levels lead to eventual demise of the upper two thirds of the endometrium. During this period, the spiral arteries rhythmically go into spasm and then relax. This period of the cycle is sometimes referred to as the ischemic phase. As cells begin to die, hydrolases are released from lysosomes and cause further breakdown of the endometrium. Prostaglandin production increases as a result of the action of phospholipases liberated from lysosomes. Necrosis of vascular cells leads to microhemorrhage. The average loss of blood, tissues, and serous fluid amounts to ~30 mL. Menstrual blood does not clot because of the presence of fibrolysins released from necrotic endometrial tissue.

The effective implantation window is 3 to 4 days

Based on studies of embryo transfer to recipient mothers in oocyte donation programs (see Box 56-1) when both the age of the donated embryo and the time of the endometrial cycle of the recipient are known, the period of endometrial receptivity for implantation of the embryo is estimated to extend from as early as day 16 to as late as day 19 of the menstrual cycle. Of course, because implantation must normally follow the ovulation that occurs on day 14 and because fertilization normally occurs within 1 day of ovulation, the effective window is <4 days, from day 16 to day 19. In contrast, when embryos are transferred on cycle days 20 through 24, no pregnancies are achieved. image N55-7

N55-7

Implantation Window

Contributed by Ervin Jones

The numerical values presented on page 1126 for the implantation window (days 16 to 19 of the cycle) come from embryo-transfer studies in which the woman has received gonadotropins to overstimulate the ovary to enhance the development of many ova, and then received hCG to mimic the LH surge (see Box 56-1). As discussed on pages 1132–1133, in a natural menstrual cycle that involves fertilization, the implantation takes place 6 to 7 days after ovulation, that is, between days 20 and 21.

Although the mechanisms underlying endometrial receptivity remain unclear, the formation of microvilli and pinopods (i.e., protrusions of endometrial cells near gland openings) during the midluteal phase and the secretion of extracellular matrix composed of materials such as glycoproteins, laminin, and fibronectin may provide a surface that facilitates attachment of the embryo (see pp. 1135–1136).

LESION

REFLEXOGENIC ERECTION

PSYCHOGENIC ERECTION

EFFECT ON EJACULATION

Upper motor neuron

Present

Absent

Significantly impaired

Lower motor neuron

Absent

Present

Less impaired