Comprehensive Study Guide on the Menstrual Cycle and Ovarian Cycles

Anatomical Considerations of the Uterus

To comprehend the phenomena participating during the menstrual (sexual) cycle and pregnancy, it is necessary to identify specific anatomical aspects of the uterus. This organ measures approximately $7\,cm$ in length; however, it can reach up to $32\,cm$ when a pregnancy is at term. The uterus is destined to house, protect, and nourish the new being during a prolonged lapse of time; additionally, it allows the fetus to move freely, grow, and increase in weight.

The uterus presents three principal components: the fundus, the body, and the neck (cervix). The fundus corresponds to the superior extreme of the uterine body. Extending from each side of the fundus are the Fallopian tubes, at the distal end of which the ovaries are located. The body is the major segment of the organ and is the site where the implantation of the conceptus occurs. The uterine body terminates in a narrower region called the cervix, which opens into the vagina.

The Uterine Wall and the Endometrium

The wall of the uterus is composed of three layers which, from the inside out, are the endometrium, the miometrium, and the perimetrio. The endometrium is the mucosa that lines the interior of the uterus, and its function is to house and nourish the new being. Its histological components include the epithelium, stroma, glands, and blood vessels. These are organized into three distinct layers: the compact layer, the spongy layer, and the basal layer.

The compact layer is the most superficial region of the endometrium and serves as the boundary for the uterine cavity. It is formed by simple columnar epithelium containing both ciliated and non-ciliated cells. The spongy layer is localized between the compact and basal layers; it is formed by glands and blood vessels surrounded by loose connective tissue. Together, the compact and spongy layers constitute the functional layer of the endometrium, which is eliminated during menstruation and renewed during each menstrual cycle.

The basal layer is the deepest part of the endometrium and is located adjacent to the miometrium. This layer is very dense due to the large amount of connective tissue. It contains the base of the glands and blood vessels and possesses its own vascularity. The basal layer is responsible for renewing the functional layer of the endometrium.

Myometrium and Perimetrio

The miometrium is the thickest wall of the uterus and is formed by three poorly defined layers of smooth muscle. The miometrium performs an essential function as its contractions are responsible for carrying out the labor of childbirth. The perimetrio is the outermost layer of the uterus and is formed by the visceral peritoneum; therefore, it is considered a mesothelium.

Regulation of the Menstrual Cycle

The menstrual cycle, also known as the sexual cycle, comprises the changes that happen in an ordered and periodic manner within the female reproductive apparatus. Its purpose is to prepare for the possibility of pregnancy. It begins at puberty with the presentation of the first menstruation, also called menarche. These cycles finish between the ages of $45$ and $50$ years with the last menstruation, known as menopause. Each regular and spontaneous cycle has an average duration of $28\,days$, though they vary between women; cycles between $24$ and $35\,days$ are considered normal and occur with certain frequency.

The menstrual cycle is regulated precisely by hormones produced in three organs: the hypothalamus, the anterior pituitary (adenohypophysis), and the ovary. These organs integrate to form the hypothalamic-pituitary-gonadal axis. The hypothalamus is the region of the diencephalon that contains specialized neurons for the synthesis of gonadotropin-releasing hormone (GnRH). GnRH is released in a pulsatile manner toward the pituitary portal system to then bind to a receptor localized in the gonadotrophs of the anterior pituitary.

The function of GnRH is to activate the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are called gonadotropins. Once released into the bloodstream, gonadotropins produce significant morphological and physiological changes in the ovary, which repercuss throughout the organism, especially in the uterus, Fallopian tubes, vaginal epithelium, and the mammary gland.

The Ovarian Cycle: Follicular Phase

The ovarian cycle is divided into two phases: the follicular (estrogenic) phase, which comprises the first $14\,days$ of the cycle, and the luteal (progestational) phase, which corresponds to the subsequent $14\,days$. The follicular phase is characterized by the process of maturation of the ovarian follicles, also called folliculogenesis. This phase is dominated by FSH. After being released by the anterior pituitary, FSH passes into the circulatory system and reaches the ovary, where it acts on developing follicles to promote maturation and growth until the formation of a mature follicle.

During the follicular phase, the granulosa cells synthesize increasing amounts of estrogens, which is why this stage is also known as the estrogenic phase. Estrogens are a set of hormones necessary for the growth of the endometrium. Furthermore, high levels of estrogen favor the sudden increase of LH, a phenomenon that happens between $12$ and $24\,hours$ before the maturation of the follicle is complete.

LH is responsible for reactivating the maturation of the primary oocyte, after which it finishes its first division, constituting a secondary oocyte and a polar body. Later, the oocyte initiates the second meiotic division until reaching metaphase II, where meiosis is inhibited again. At this point, the follicle is considered mature (preovulatory) and contains a large amount of follicular fluid in the antrum. Subsequently, the stigma appears on the surface of the ovary, due in part to the pressure exerted by the follicular fluid. It must be remembered that the most developed follicle becomes independent of FSH activity and becomes the dominant follicle, which synthesizes inhibin, a protein that interrupts the maturation of the rest of the follicles, which then atrophy.

Ovulation and the Luteal Phase

Ovulation is defined as the process by which the secondary oocyte, together with the follicular cells that form the corona radiata, is expelled from the ovary. Ovulation happens on day $14$ of a regular ovarian cycle and is induced by the elevated concentration of LH and FSH.

The second phase of the ovarian cycle, the luteal phase, is characterized by the formation of the corpus luteum (yellow body). This is formed from the follicular cells of the granulosa as well as the cells of the theca interna. The formation of the corpus luteum occurs after ovulation and depends on LH. The corpus luteum is a specialized endocrine gland that secretes large amounts of progesterone, principally during the first week of the luteal phase. It also secretes estrogens, but in a smaller quantity. Estrogens in this phase are synthesized by the cells of the theca interna from androstenedione.

If fertilization does not occur, the corpus luteum begins to degenerate seven or eight days after ovulation, giving rise to the corpus albicans (white body), which is a whitish nodule of connective tissue. Follicles that did not finish maturation also degenerate and remain as atretic follicles (atretic bodies).

The Endometrial Cycle: Menstrual and Proliferative Phases

Under the action of the ovarian hormones estrogen and progesterone, the endometrium undergoes cyclic structural modifications called the endometrial cycle. In case fertilization or implantation does not occur, the cycle culminates with menstruation. The endometrial cycle is divided into three phases: menstrual, proliferative, and secretory.

The menstrual phase, or menstruation, is due to the desquamation of the functional layer of the endometrium (compact and spongy layers). This phase has a duration of $3$ to $6\,days$ and manifests with the exit of blood through the vagina, approximately $30\,ml$. The first day of menstruation is considered day $1$ of the menstrual cycle.

At the end of menstruation, the proliferative phase begins, with the objective of restoring the functional layer of the endometrium. This phase is characterized by an increase in the number of mitoses, causing the stroma cells, glands, and blood vessels to proliferate from the basal layer, increasing endometrial volume. The proliferative phase depends on estrogens secreted during the ovarian follicular phase. At the beginning of the phase, the endometrial glands are straight with cuboidal epithelium; however, by the end of this stage, the glands become voluminous and the epithelium is pseudostratified with columnar cells. At the moment of ovulation, the endometrium possesses its three layers: compact, spongy, and basal.

The Endometrial Cycle: Secretory Phase

The secretory phase initiates after ovulation and coincides with the luteal phase of the ovary, as it depends on the progesterone produced by the corpus luteum. This phase lasts approximately $14\,days$ and involves changes that prepare the endometrium for the anidation of the conceptus. This involves the synthesis and storage of sufficient nutrients to sustain the life of the new being during the first weeks of development.

In the secretory phase, the apocrine cells of the glandular epithelium begin to synthesize nutrients such as glycogen, which is stored in intracytoplasmic vacuoles. Progesterone causes the relaxation of the smooth muscle of the blood vessels, leading to vasodilation and an increased blood supply to the endometrial glands. By day $19$ of the cycle, the apical portion of the glandular epithelium cells detaches, and its content, rich in glycoproteins and glycogen, is deposited inside the glands.

By day $21$ of the cycle ($7\,days$ after ovulation), the luteal phase reaches its maximum expression and the secretion of glycoproteins and glycogen ceases. At this point, the glands are turgid and tortuous, prepared for implantation. This coincides with the arrival of the blastocyst if fertilization occurred.

If there was no fertilization, serum levels of LH fall, and consequently, progesterone levels also decrease. As progesterone diminishes, the stimulus to the smooth muscle of the endometrial vessels is suspended, resulting in local vasoconstriction and tissue ischemia. Ischemia manifest as edema, lysis of the glandular connective tissue, and extravasation of blood. Finally, the functional layer of the endometrium detaches, and a new cycle begins.

Effects on Cervical Mucus and Fallopian Tubes

The cervical mucus undergoes various modifications during the phases of the menstrual cycle. Under the action of estrogen, its quantity increases, and it becomes watery, transparent, elastic, filante, and crystalline, favoring the ascent of sperm. Conversely, under progestational action, the cervical mucus is scarce, thick, opaque, and has little filancia.

Ovarian hormones also exert effects on the smooth muscle of the Fallopian tubes. Estrogen increases contractility (peristalsis) to capture the recently ovulated secondary oocyte. Progesterone decreases contractility, modifying the transport time of the fertilized oocyte toward the uterine cavity.

Irregular Cycles and the Fertile Period

While the duration of the cycle varies between women, the second phase always remains stable at $14\,days$. Therefore, regardless of cycle length, ovulation always occurs fourteen days before the next menstruation. Regular cycles present in the same lapse of time (e.g., every $28$, $30$, or $32\,days$). Irregular cycles are those where the length varies between one period and another and may be accompanied by reproductive problems.

The fertile period is the lapse of time in which the oocyte can be fertilized. It is determined by the characteristics of the cycle and the gametes. Considering the median life of sperm is $72\,hours$ ($3\,days$) and the oocyte is $24\,hours$ ($1\,day$), the fertile period is considered to be three days before and three days after ovulation. The rest of the cycle is considered non-fertile.