WHAT ARE THE PHASES OF MENSTRUAL CYCLE?

 Author: Akau B. Z.

What is the Menstrual Cycle?

The menstrual cycle is a cyclical pattern of physiological changes in the ovaries, uterus, and other sexual structures that occur from the start of one menstrual cycle to the beginning of the next. Its duration is approximately 28 days (ranges 21 – 35 ). It starts with removing the endometrium and releasing FSH (follicle-stimulating hormone) by the anterior pituitary. The menstrual cycle depends on: 

• Complex interaction and interplay of neuroendocrine systems from the hypothalamus to the pituitary, the ovaries, and the end organs. 
• The hypothalamus itself is under the influence of the CNS and environmental stimuli.
• Chemical messengers – endocrine and paracrine.
• End organ response.
• Outcome of pregnancy or menstruation.

The hypothalamus-pituitary-ovarian axis controls the required physiologic changes of the menstrual cycle that occur both in the ovaries and the uterus. The hypothalamic-pituitary-ovarian axis, ovarian cycle, and Uterine cycle all make up the menstrual cycle.

What is Menstruation?

Menstruation is the visible manifestation of cyclic physiologic uterine bleeding due to the shedding of the endometrium, following the invisible interplay of hormones mainly through the hypothalamic-pituitary-ovarian axis (H-P-O axis). It occurs when there is failure of fertilization of the oocyte or failure of implantation. This suggests that in the absence of pregnancy, the uterus cries. Conventionally, the first day of the menstrual cycle is recognized as the first day of menstruation.

How does the Hypothalamic- Pituitary-Ovarian Axis Commence?

With the onset of puberty, the hypothalamus secretes the Gonadotrophin-releasing hormone (GnRH) in a pulsatile manner. It is synthesized and transported from the nerve cells in the hypothalamus to the hypophyseal pituitary portal vein and the anterior lobe of the pituitary gland. GnRH stimulates the basophil cells in the anterior pituitary leading to synthesis and release of the gonadotrophic hormones FSH and LH.

• FSH – Follicle Stimulating Hormone.
• LH – Luteinizing Hormone.

Both hormones are glycoproteins, which exert their major effects on the ovary to produce estrogen and progesterone. Low estrogen levels inhibit the synthesis of LH (negative feedback) and vice versa. High estrogen levels in the late follicular phase of the ovary cause the pituitary to release a surge of LH during the periovulatory phase through a positive feedback mechanism.

Low progesterone levels have a positive feedback effect on pituitary LH and FSH secretion. This is seen immediately before ovulation. High progesterone levels in the luteal phase inhibit pituitary LH and FSH production. Other hormones are involved in pituitary gonadotrophin secretion.

• Inhibin, a peptide hormone produced in the ovaries by granulosa cells, inhibits pituitary FSH secretion.
• Activin, a peptide hormone also produced by granulosa cells, stimulates pituitary FSH secretion.

Phases of Menstrual Cycle

The menstrual cycle is divided into two (2):

1. The ovarian cycle: consists of 3 phases

• Follicular phase
• Ovulation phase
• Luteal phase

1. The uterine cycle: consists of 3 phases

• Menses
• Proliferative phase
• Secretory phase

These ovarian and uterine phases are intimately linked by the production and release of hormones.

The Ovarian Cycle 

Ovaries with developing oocytes are present in the female fetus from an early stage of development. The number of oocytes reaches a maximum by the end of the second trimester and is arrested during the first prophase stage of meiotic division. A female does not produce fresh oocytes during her lifetime. The ovary has reproductive and endocrine functions. 

• Reproduction: development and maturation of follicle and ovulation
• Endocrine: estrogens, progesterone, and testosterone

With the onset of menarche, the primordial follicles containing oocytes will activate and grow cyclically, causing ovulation and subsequent menstruation in the absence of fertilization. The process of follicular maturation, ovulation, formation of the corpus luteum, and its subsequent regression if pregnancy does not occur is accompanied by the production of steroid hormones from the ovarian cells. There are three (3) phases of the ovarian cycle, as above:

1. Follicular Phase: A rise in FSH levels in the first days of the menstrual cycle stimulates a cohort of small antral follicles on the ovaries to grow. The follicle has two cell types: the granulosa and theca cells respond to FSH and LH, respectively. Theca cells use LH to increase the synthesis of androgens from cholesterol. These androgens are converted into estrogens in the granulosa cells under the influence of FSH. Both FSH and LH are required to generate a normal cycle with an adequate amount of estrogen. Increased secretion of estrogen due to follicular growth results in negative feedback on the pituitary to decrease FSH secretion. This assists in the dominant follicle selection while the smaller follicles undergo atresia. The dominant follicle continues producing estrogen and inhibin (which enhances androgen synthesis under LH control). This phase lasts from days 1-14. Other autocrine and paracrine mediators play a role in the follicular phase of the menstrual cycle.

• Inhibin: is secreted by the granulosa cells within the ovaries. Participates in feedback to the pituitary to downregulate FSH release and also appears to enhance androgen synthesis.
• Activin: is also produced in granulosa cells and the pituitary and increases FSH binding on the follicles.
• Insulin-like growth factors (IGF-I, IGF-II) act as paracrine regulators. 

The Development and Maturation of Follicles

• Primordial follicle: dormant, immature, small oocytes surrounded by a flat layer of squamous granulosa cells and basal lamina and arrested in the diplotene (or dictyate) stage of meiosis. They are quiescent, showing little to no biological activity. Measures 0.03–0.05 mm in diameter.

• Preantral follicle: Primordial follicles transform into primary follicles during ovarian follicle activation, forming a single layer of cuboidal structure about 0.1 mm in diameter. The oocyte genome is activated, and paracrine signaling pathways form. Primary follicles express FSH receptors during shape change and mitotic activities. A zona pellucida separates the oocyte from the surrounding granulosa cells. Normal menstrual cycle plasma FSH levels do not affect granulosa responses.

• Secondary follicle: preantral follicles with multiple layers of about 2–10 layers of cuboidal or low columnar cells that form. Stroma-like theca cells are gathered by oocyte-secreted signals and surround the follicle's outermost layer, basal lamina. They undergo cytodifferentiation to form theca externa and interna, with a network of capillary vessels circulating blood.  The development of the antrum also starts taking place in the secondary follicle stage. The transition from primary to secondary follicles involves a second layer of granulosa cells, regulated by granulosa mitosis. A novel oocyte-derived growth factor called growth differentiation factor-9 (GDF-9) is present in rodents.  In GDF-9-deficient mice, follicle growth stops at the primary stage, leading to infertility. The oocyte plays a crucial role in regulating folliculogenesis.

•  Tertiary follicle: Five structural elements make up a preantral follicle when it has completed the secondary stage: a zona pellucida, six to nine layers of granulosa cells, a basal lamina, a theca externa, and a theca interna. The onset of tertiary follicle development is indicated by the appearance of a cavity in granulosa cells, called cavitation or early antrum formation. Cavitation is characterized by fluid accumulation between the granulosa cells, causing a cavity. This process establishes the basic plan of the Graafian follicle and ensures proper cell positioning for differentiation and proliferation. The late tertiary and preovulatory phases of the menstrual cycle involve the death of most follicles, known as atresia, due to radical apoptosis. High concentrations of FSH prevent atresia, and a rise in pituitary FSH causes the recruitment of five to seven class 5 follicles to participate in the next cycle. These follicles, called antral follicles, compete for growth-inducing FSH. The dominant follicle grows up to 20 mm in diameter and becomes the preovulatory follicle.

• Graafian follicle: a family of large follicles (0.4-23mm in diameter) with a cavity or antrum containing follicular fluid or liquor folliculi. The antrum is the characteristic structural unit of Graafian follicles. The follicular fluid contains granulosa cells and oocytes, and regulatory molecules pass through it. Despite their absence in birds and amphibians, their presence in all mammalian species demonstrates their physiologic importance.

2. Ovulation: On day 14 of a 28-day cycle or two weeks before the subsequent menstrual cycle, ovulation (the release of a mature egg from the ovary) occurs. Individual differences may exist in this based on hormone rhythms. Ovulation marks the midpoint of every menstrual cycle and is triggered by a surge in luteinizing hormone and rising estrogen levels. when the egg is released, it moves into the fallopian tube towards the uterus and lasts 24 hours in the uterus. During this phase, individuals may experience heightened libido and changes in cervical mucus consistency, which becomes thin and slippery, facilitating sperm transport. Pregnancy can occur during this period if sexual intercourse occurs. Sperm have a five-day maximum shelf life in the uterus. This suggests that you are probably going to be pregnant if you have unprotected sexual activity five days before your ovulation.

3. Luteal Phase: Following the release of the oocyte, the remaining granulosa and theca cells form the corpus hemorrhagicum, then the corpus luteum. Granulosa cells have a vacuolated appearance with accumulated yellow pigment, hence the corpus luteum (yellow body). Corpus luteum has a rich blood supply aided by local Vascular Endothelial Growth Factor (VEGF) production. Progesterone production rises due to pituitary LH  and granulosa cell activity. During the luteal phase, progesterone levels peak, and the corpus luteum eventually transforms into corpus albicans. The luteal phase lasts 14 days in most women, and its duration is more regular. In the absence of fertilization and production of beta-human chorionic gonadotropin, the corpus luteum regresses – called luteolysis. Progesterone production decreases and leads to the shedding of endometrium – menstruation. Low levels of E2, progesterone, and inhibin feeding back to the pituitary cause increased secretion of gonadotrophic hormones, particularly FSH. Therefore, new preantral follicles begin to be stimulated, and the cycle begins anew.

The Uterine Cycle 

Estrogen and progesterone act on the uterine endometrium to produce changes to its structure, thickness, and vascularity. These changes in the uterine cycle result in three phases, as above. Three layers form the endometrium: the stratum basalis, stratum spongiosum, and stratum compactum (stratum functionalis). The stratum functionalis is the only tissue shed during menstruation.

3. Menstruation: with the failure of fertilization, circulating levels of progesterone and estrogen fall. This leads to:

• Loss of tissue fluid
• Vasoconstriction of spiral arterioles, distal ischemia, and degeneration of stratum functionalis.
• The arteries rupture, and the rapid blood flow dislodges the necrotic functional layer, which is lost.
• Enhanced fibrinolysis reduces clotting. 

Menstruation begins on day 1 and ends between days 2 and 7 when the endometrium starts to repair and arterioles narrow.

2. Proliferative phase: corresponds with the latter half of the follicular phase in the ovarian cycle. Under the influence of estrogen, endometrial thickness increases from 0.5mm to 3.5 – 5.5 mm. Glandular and stromal regeneration, as well as angiogenesis, occur. Epidermal growth factor seems to be responsible for the mediation of estrogen-induced glandular and stromal regeneration. Factors involved in angiogenesis include VEGF and FGF (fibroblast growth factor). In the stratum functionalis, simple tubular glands protrude onto the surface. The epithelium lining the endometrial glands changes from a single layer of columnar cells to a pseudostratified epithelium with frequent mitoses. Cells from the bone marrow infiltrate the stroma.

3. Secretory Phase: It lasts for two (2) weeks and corresponds to the luteal phase of the ovarian cycle. The thickness of the endometrium reaches 5 – 6 mm. Following the stimulation of ovulation by progesterone and LH, a secretory endometrium is produced with the following features:

• Stroma becomes loose and oedematous.
• Slood vessels entering the endometrium become thickened and twisted (spiral arteries). 
• The endometrial glands become more tortuous and corkscrew-shaped.
• They secrete a glycogen-rich secretion and filled with glycogen.
• Fluid is secreted into the glandular cells and the uterine lumen.

Later in the secretory phase, progesterone induces the formation of a temporary layer known as the decidua in the endometrial stroma. Recently, apical membrane projections of the endometrial epithelial cells called pinopodes appear after days 21-22 and seem to be a progesterone-dependent stage in making the endometrium receptive for embryo implantation. Immediately before menstruation, the stratum basalis shows minimal changes in the menstrual cycle. The stratum spongiosum has oedematous stroma and exhausted glands. The stratum compactum has prominent decidualized stromal cells.