Starting from puberty, ovarian sex hormones induce a series of cyclical changes in the female reproductive system, with the most prominent being the cyclical changes in the endometrium.
Cyclical Changes in the Endometrium
These consist mainly of cyclical histological and biochemical changes in the endometrial tissue.
Histological Changes in the Endometrium
The endometrium is morphologically divided into two layers: the functional layer and the basal layer. The functional layer serves as the site for embryo implantation and undergoes cyclical proliferation, secretion, and shedding under the regulation of sex hormones. The basal layer, located near the myometrium, remains unaffected by sex hormones and does not undergo shedding. Following menstruation, the basal layer regenerates and repairs the endometrial surface, forming a new functional layer. Based on these histological changes, the menstrual cycle is divided into three phases: the proliferative phase, the secretory phase, and the menstrual phase (using a typical 28-day cycle as an example).
Proliferative Phase
This phase occurs from days 5 to 14 of the menstrual cycle and corresponds to the follicular phase of the ovarian cycle. As ovarian follicles develop, estrogen secretion increases, leading to proliferative changes in the endometrial surface epithelium, glands, stroma, and blood vessels. During this phase, the thickness of the endometrium grows from 1–2 mm to approximately 12 mm. The proliferative phase can be further divided into early, mid, and late phases.
Early Proliferative Phase (Days 5–7)
During this stage, the endometrium is thin (1–2 mm). The glands are short, straight, narrow, and sparse, with glandular epithelial cells appearing cuboidal or low columnar in shape. The stroma is dense, containing star-shaped stromal cells and small, straight arterioles with thin walls.
Mid Proliferative Phase (Days 8–10)
The number of glands increases, and they become longer and slightly coiled. Glandular epithelial cells exhibit active proliferation, with cells appearing columnar and undergoing mitosis. Stromal edema becomes more prominent, while spiral arterioles start to develop and thicken.
Late Proliferative Phase (Days 11–14)
The endometrium further thickens to about 12 mm, acquiring an uneven, wavy surface. The glandular epithelium becomes tall columnar and forms pseudostratified epithelium with increased mitosis. The glands lengthen further and develop a more coiled structure. Stromal cells become stellate and connect to form a network. Edema within the tissue is pronounced, and small arterioles proliferate, their lumina enlarge, and they become coiled.
A key change during this stage involves an increase in ciliated cells and microvilli in the glandular epithelium. Ciliated cells, which first appear on days 7–8, are predominantly distributed around glandular openings, facilitating the flow and distribution of endometrial secretions. Microvilli increase the surface area of epithelial cells, enhancing their excretory and absorptive capacities. Proliferating glandular and stromal cells are rich in free and bound ribosomes, mitochondria, Golgi complexes, and primary lysosomes, which are involved in protein synthesis, energy production, and enzyme storage.
Secretory Phase
This phase occurs from days 15 to 28 of the menstrual cycle and corresponds to the luteal phase of the ovarian cycle. After ovulation, the corpus luteum forms and secretes progesterone and estrogen, allowing the endometrium to continue thickening. The glands elongate further, becoming more coiled, and begin to secrete substances. Blood vessels proliferate rapidly and become more coiled, accompanied by stromal loosening and edema. During this phase, the endometrium is thick and soft, containing abundant nutrients, creating favorable conditions for the implantation and development of a fertilized ovum. The secretory phase can also be divided into early, mid, and late stages.
Early Secretory Phase (Days 15–19)
During this stage, endometrial glands elongate further with marked coiling, and glandular epithelial cells begin to form subnuclear vacuoles containing glycogen, which is a characteristic histological feature of this stage. Stromal edema continues, and spiral arterioles proliferate and coil.
Mid Secretory Phase (Days 20–23)
The endometrium thickens further and acquires a serrated appearance. The apical membranes of glandular epithelial cells rupture, releasing glycogen into the glandular lumen, a process referred to as apocrine secretion. Additional endometrial secretions include plasma exudate, which contains critical immunoglobulins that bind with epithelial-secreted binding proteins and enter the endometrial cavity. Secretion activity peaks seven days after the LH surge, coinciding with blastocyst implantation. Stromal cells become even more loose and edematous, while spiral arterioles further proliferate and coil.
Late Secretory Phase (Days 24–28)
The endometrium adopts a sponge-like appearance, with glandular openings directed toward the uterine cavity and secretions such as glycogen becoming more prominent. Stroma becomes looser and more edematous. Beneath the surface epithelial cells, stromal cells differentiate into large decidual-like cells, alongside small round granulocytes with prominent nuclear lobes and eosinophilic granules. Spiral arterioles grow rapidly, exceeding the thickness of the endometrium, becoming highly coiled, and their lumina dilate. If fertilization occurs, the endometrium continues thickening. If fertilization does not occur, the corpus luteum in the ovary degenerates, leading to a decline in progesterone and estrogen levels, causing the endometrium to shed and transition into the menstrual phase.
Characteristic ultrastructural changes during the secretory phase include the appearance of giant mitochondria and the formation of the nucleolar channel system (NCS). The NCS consists of spiral foldings of the nuclear membrane that extend into the nucleoplasm or nucleolus. It is only observed after ovulation.
Menstrual Phase
The menstrual phase corresponds to days 1 to 4 of the menstrual cycle. During this period, the spongy functional layer of the endometrium breaks down and sheds from the basal layer, which is the final outcome of corpus luteum regression and the withdrawal of progesterone and estrogen. In the 24 hours preceding menstruation, spiral arteries of the endometrium undergo rhythmic contraction and relaxation, followed by increasingly intense vasospastic contractions. These processes result in ischemia, necrosis, and detachment of the distal vascular walls and tissues. The shed endometrial fragments and blood flow out together through the vagina, marking the onset of menstruation.
Biochemical Changes in the Endometrium
Steroid Hormone and Protein Hormone Receptors
Steroid Hormone Receptors
Both endometrial glandular cells and stromal cells in the proliferative phase are rich in estrogen and progesterone receptors. Estrogen receptor levels in the endometrium peak during the proliferative phase and decrease significantly after ovulation. Progesterone receptor levels peak around ovulation. Afterward, progesterone receptors in glandular epithelium gradually decrease, while stromal cells display a relative increase in progesterone receptor expression. Smooth muscle cells in the spiral arteries of the endometrium also express estrogen and progesterone receptors. These receptors exhibit cyclical variations, with both types reaching their highest levels during the luteal phase, suggesting that uterine blood flow may be influenced to some extent by steroid hormones.
Protein Hormone Receptors
Endometrial and glandular epithelium express hCG/LH receptors, though their specific functional roles remain unclear. Growth hormone receptors and growth hormone-binding proteins are also expressed in the endometrium, potentially playing a role in regulating its development.
Enzymes
Various hydrolases, such as acid phosphatase and β-glucuronidase, are capable of breaking down proteins, nucleic acids, and mucopolysaccharides. These enzymes are typically confined within lysosomes and remain inactive. After ovulation, if fertilization does not occur, the corpus luteum undergoes regression over time, leading to a decline in estrogen and progesterone levels. As a result, the permeability of lysosomal membranes increases, allowing hydrolases to be released into the tissue. This release impacts endometrial metabolism and contributes to the breakdown and sloughing of tissue, resulting in endometrial shedding and bleeding. Other systems, such as the matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinases (TIMP) system and the tissue plasminogen activator (tPA)/plasminogen activator inhibitor (PAI) system, are also involved in regulating the detachment of the endometrium.
Acid Mucopolysaccharides
Under the influence of estrogen, endometrial stromal cells produce carbohydrate-protein complexes known as acid mucopolysaccharides (AMPS). Estrogen promotes the concentration and polymerization of AMPS in the stroma, forming a foundational material that acts as a scaffold for the growth of the proliferative endometrium. Following ovulation, progesterone inhibits the synthesis and polymerization of AMPS while promoting their breakdown. This reduction in the viscous stromal matrix of the endometrium increases vascular permeability, facilitating the exchange of nutrients and metabolic byproducts. These changes prepare the endometrium for the implantation and development of a fertilized ovum.
Vasoconstrictors
In the 24 hours preceding menstruation, the ischemia and necrosis of the endometrium trigger the release of vasoconstrictors such as prostaglandin F2α and endothelin-1. These factors reach their peak levels during menstruation. Additionally, thromboxane A2 (TXA2), produced by platelet aggregation, also exhibits vasoconstrictive effects. Such factors induce rhythmic contractions of uterine blood vessels and the myometrium. Throughout the menstrual period, vascular contractions progressively intensify, leading to ischemia, necrosis, breakdown, and eventual shedding of the functional layer of the endometrium.
Cyclical Changes in Other Reproductive Organs
Under the cyclical influence of ovarian sex hormones, the vaginal epithelium, cervical mucus, fallopian tubes, and breast tissue undergo corresponding changes.
Cyclical Changes in the Vaginal Epithelium
The vaginal mucosa consists of non-keratinized stratified squamous epithelium, which is relatively thick. During the menstrual cycle, the vaginal mucosa undergoes cyclical changes, most prominently in the upper part of the vagina. Before ovulation, estrogen promotes the proliferation of basal cells, which gradually differentiate into intermediate and superficial cells, resulting in the thickening of the vaginal epithelium. This thickening reaches its peak during ovulation. These cells become rich in glycogen, which is metabolized by lactobacilli within the vagina to produce lactic acid. This maintains a certain level of acidity in the vaginal environment, inhibiting the growth of pathogenic bacteria. After ovulation, progesterone primarily induces the shedding of superficial cells. Clinically, changes in vaginal exfoliated cells can provide information about estrogen levels and ovulation status. Following menopause, estrogen levels decrease, causing the vaginal epithelium to thin, the number of exfoliated cells to reduce, and the vaginal pH to rise, which increases the risk of vaginal infections.
Cyclical Changes in Cervical Mucus
The cervical mucosa does not undergo cyclical shedding. However, the glandular cells of the cervix, under the influence of ovarian sex hormones, secrete mucus with cyclical changes in its physical and chemical properties, as well as in its quantity. Estrogen stimulates the secretory function of cervical glandular cells. During the early follicular phase, estrogen levels are low, and only a small amount of cervical mucus is secreted. As the follicles develop and estrogen levels rise, the volume of mucus secretion increases. During ovulation, cervical mucus becomes thin, transparent, and stretchable, with an elasticity of over 10 cm. When analyzed using a smear test, the dried mucus exhibits fern-like crystallization. This pattern first appears around days 6–7 of the menstrual cycle and becomes clearest and most typical during ovulation. After ovulation, progesterone reduces mucus secretion, resulting in thicker, more turbid mucus with reduced stretchability. Smear tests during this phase show the gradual disappearance of crystallization, which is completely absent by approximately day 22 of the cycle, replaced instead by elliptical bodies arranged in rows. Clinically, the examination of cervical mucus is used to assess ovarian function.
Cervical mucus is a hydrogel composed of glycoproteins, plasma proteins, sodium chloride, and water. The sodium chloride content of cervical mucus varies across the menstrual cycle, accounting for only 2%–20% of its dry weight during the premenstrual and postmenstrual periods but rising to 40%–70% during ovulation. Because cervical mucus is isotonic, the increased proportion of sodium chloride also leads to increased water content, making cervical mucus thinner and more abundant during ovulation. The glycoproteins in cervical mucus form a network, with the mesh size enlarging under the influence of estrogen prior to ovulation, which facilitates sperm passage during this period. Progesterone reduces mucus secretion from glandular cells and increases its viscosity, forming a gel-like consistency that inhibits the entry of sperm and microorganisms into the uterus. Through their respective effects, estrogen and progesterone allow cervical mucus to act as a biological gate regulating sperm penetration during the menstrual cycle.
Cyclical Changes in the Fallopian Tubes
The cyclical changes in the fallopian tubes involve both morphological and functional aspects. Estrogen promotes the growth of ciliated epithelial cells in the fallopian tube mucosa, leading to an increase in their size. It also enhances fluid secretion by non-ciliated cells, which provides nutrients for the transport and preimplantation development of the ovum. Estrogen further stimulates the development of the fallopian tubes and increases the amplitude of rhythmic contractions in the muscular layer of the tubes. In contrast, progesterone reduces the amplitude of rhythmic contractions in the fallopian tube musculature, inhibits the growth of ciliated epithelial cells, and decreases mucus secretion from non-ciliated cells. The combined effects of estrogen and progesterone ensure the normal transport of the fertilized ovum through the fallopian tubes.
Cyclical Changes in the Breasts
Estrogen stimulates the proliferation of mammary ducts, while progesterone promotes the growth of mammary lobules and alveoli. Some women experience breast swelling and tenderness during the premenstrual phase, which may be caused by the dilation of mammary ducts, vascular congestion, and stromal edema of the breast. These symptoms largely subside after menstruation due to the withdrawal of estrogen and progesterone.