Menstrual Cycle

Objectives

Upon completion of this module, students should be able to:

• Reproductive Physiology

  • Describe the ovarian and endometrial cycles, including hormone effects on target tissues.

  • Define primary follicle, dominant follicle, ovulation, corpus luteum, and corpus albicans.

  • Name reproductive hormones secreted by the hypothalamus, anterior pituitary gland, ovaries, and trophoblast.

  • Name the phases of the menstrual cycle.

  • Describe the function of the corpus luteum.

  • Describe the sonographic appearance of ovaries and endometrium during different menstrual cycle phases.

  • Describe the sonographic appearance of developing follicles, the dominant follicle, and the corpus luteum.

  • Identify developing follicles, the dominant follicle, and the corpus luteum on pelvic sonograms.

  • Define proliferative and secretory endometrium.

  • Identify proliferative, mid-cycle, and secretory endometrium on pelvic sonograms.

  • Describe the effect of progesterone on basal body temperature.

  • Describe the effects of fertilization on corpus luteum function.

  • State the normal timing of human blastocyst implantation.

  • Briefly explain the function of gonadotropic-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, progesterone, and human chorionic gonadotropin (hCG).

  • State the physiological effects of estrogen and progesterone.

• Uterine and Ovarian Doppler During the Menstrual Cycle

  • Describe the Doppler characteristics of blood flow in the uterine arteries during the normal menstrual cycle.

  • Describe the Doppler characteristics of blood flow in the ovarian arteries during the normal menstrual cycle.

  • Describe the colour Doppler characteristics of blood flow in the corpus luteum.

Terminology

• (Menses/Periods): Normal menstrual bleeding, occurring every $28$ days approximately, between puberty and menopause (except during pregnancy and lactation), lasting about $5$ days.

• Menarche: The first menstruation, occurring as early as the $9^ ext{th}$ or as late as the $16^ ext{th}$ year.

• Puberty: The stage when secondary sex characteristics appear, and reproduction becomes possible.

• Menopause: The cessation of menstruation, marking the end of reproductive function.

• Climacteric: Signals the advent of menopause, characterized by menstrual cycles becoming less frequent. Typically begins between ages $40$ and $50$ (with wide variations) due to the ovaries' failure to respond to gonadotropic hormones. This leads to a gradual decrease in folliculogenesis and progressive atrophy of the ovaries, uterus, vagina, external genitalia, and breasts.

Reproductive Physiology

• Between ages $9$ and $16$, females experience cyclic changes in the ovaries and uterus, driven by endocrinologic activities. These are collectively known as the menstrual cycle, representing the reproductive phase.

• The hypothalamus acts as the biological clock, controlling the hormonal cycle which, in turn, regulates the menstrual cycle through feedback from ovarian hormones.

• Ovarian Cycle: Refers to changes within the ovary, aiming to provide a suitable ovum for fertilization.

• Endometrial Cycle: Refers to changes in the endometrium, aiming to create a suitable site for blastocyst implantation and development.

• The two cycles are intimately related because endometrial changes are regulated by ovarian hormones.

• The typical menstrual cycle is described as $28$ days for descriptive purposes, although variations are common and normal.

• The first day of menstruation is assigned as Day $1$ of the cycle.

Ovarian Cycle

• At the onset of each menstrual cycle, several small, immature primary (primordial) follicles begin to grow and develop.

• This follicular process is activated by Follicle-Stimulating Hormone (FSH), secreted by the anterior pituitary gland.

• Usually, only one mature follicle, called the dominant or Graafian follicle, develops and moves to the ovarian surface, appearing as a transparent cyst.

• The mature preovulatory follicle contains the ovum at one end and a cystic cavity (antrum) at the other.

• Specialized theca and granulosa cells surround the follicle and secrete estrogen, progesterone, and luteinizing substances.

• Ovulation: Release of the ovum from the mature follicle, normally occurring on Day $14$ (mid-point of the idealized cycle).

• Corpus Hemorrhagicum: The ruptured dominant follicle immediately following ovulation.

• Corpus Luteum (CL): Forms from the corpus hemorrhagicum and secretes progesterone (and estrogen), which is essential for maintaining the endometrium for successful implantation.

• If fertilization does not occur, the CL regresses, progesterone output diminishes, and by the end of the cycle, complete regression occurs. This failing CL triggers endometrial sloughing and menstrual bleeding.

• Corpus Albicans: The end-point of a regressing CL, appearing as a small fibrous area in the ovarian cortex.

Endometrial Cycle

• In sync with ovarian activity, the functional layer of the endometrium undergoes cyclic changes: regeneration, proliferation, secretory activity, necrosis, and sloughing.

• During menstruation, the functional layer of the endometrium, along with blood, is sloughed off into the vagina.

• After menstruation, a new functional layer begins to form from the basal layer, stimulated by ovarian estrogen. The endometrium progressively thickens during the proliferative and secretory phases.

• After ovulation and CL formation, endometrial glands become secretory.

• If fertilization does not occur, the CL regresses, and the endometrium, no longer supported by ovarian hormones, begins to "shrink." This shrinking results from the loss of tissue fluids and secretions due to a drop in estrogen.

• Estrogen has a water-retaining effect on tissues, while progesterone promotes secretory activity.

• As the endometrium shrinks, spiral arteries kink, leading to vascular stasis, followed by ischemia, necrosis, sloughing, and bleeding.

• The menstrual cycle is continuous but is divided into specific phases based on hormonal levels and events in the ovary and endometrium.

Phases of the Menstrual Cycle

Menstrual Phase (DAY $1$ TO $5$)

• Synonyms: Menstruation, menses, period.

• Characteristics: Uterine bleeding and endometrial sloughing.

• Hormonal Activity:

  • Serum estrogen is low at the beginning of the cycle.

  • Low estrogen signals the hypothalamus (biologic clock) to release gonadotropin-releasing hormone (GnRH).

  • GnRH is secreted in pulsatile manner (approx. every $90$ minutes), inducing cyclical FSH and LH secretion from the pituitary.

  • FSH and LH act directly on the ovary to promote mature follicle development and cause ovulation.

  • Under FSH influence, numerous primordial follicles begin to develop, grow, and secrete estrogen.

• Sonographic Features:

  • Ovary: Typically few or no visible developing cystic follicles.

  • Endometrium: Thin, or may appear thick with fluid and tissue debris (menstrual blood and sloughed endometrium) in the endometrial cavity, endocervical canal, and vagina.

Follicular / Proliferative Phase (DAY $6$ TO $13$)

• Characteristics: Development and growth of primordial follicles (folliculogenesis) and reorganization and proliferation of the functional layer of the endometrium.

• Hormonal Activity:

  • Developing follicles secrete increasing amounts of estrogen.

  • A single dominant follicle emerges, while other developing follicles regress and become atretic.

  • The dominant follicle continues to grow towards the ovarian surface.

  • Increasing serum levels of ovarian hormones (estrogen) create a negative feedback loop on the hypothalamus and pituitary, decreasing GnRH, FSH, and LH secretions.

  • Just before ovulation, rising estrogen levels induce a surge in pituitary LH output (an "extra squirt" of LH), which is crucial for ovulation.

  • LH also promotes progesterone secretion by the dominant follicle and corpus luteum.

• Sonographic Features:

  • Ovaries: Numerous growing cystic follicles, enlarging to about $10$ to $15 ext{ mm}$.

    • Near the end of this phase, a single dominant follicle emerges; others regress.

    • The mean diameter of the dominant follicle prior to ovulation is $20 ext{ mm}$ (range: $18$ to $25 ext{ mm}$).

    • Oral contraceptives suppress folliculogenesis, keeping follicles small.

  • Endometrium: Thin initially, then progressively thickens.

    • Appears as an echogenic band surrounding a brighter central cavity echo.

    • In late proliferative phase, typically displays a multilayered echo pattern, with the basal endometrium appearing more echogenic than the superficial functional zone.

Ovulation (DAY $14$)

• Characteristics: Release of the mature oocyte (ovum).

• The ruptured dominant follicle becomes the corpus hemorrhagicum, then the corpus luteum.

• Oral contraceptives primarily suppress ovulation by preventing dominant follicle emergence, thus inhibiting corpus luteum formation.

• Clinical Detection: A shift in basal body temperature (BBT) from a lower preovulatory level to a slightly higher postovulatory level (typically $0.3^ ext{o} ext{C}$ rise) is a practical method. This increase is due to the thermogenic action of progesterone and indicates corpus luteum development and progesterone secretion.

• Sonographic Features (best observed in serially scanned patients in follicle monitoring/ovulation induction programs):

  • Ovary: Direct evidence includes changes in the dominant follicle's appearance.

    • Prior to ovulation: Simple, round, thin-walled cyst measuring between $18$ and $25 ext{ mm}$.

    • With ovulation: Becomes corpus hemorrhagicum/corpus luteum, appearing more irregular (crenated), thick-walled, and containing low-amplitude internal echoes (secondary to hemorrhage).

  • Endometrium: Sonographic evidence of secretory endometrium (thick, uniformly echogenic) is indirect proof of ovulation, as it results from circulating progesterone levels.

    • A mid-cycle endometrial appearance is often seen right after ovulation.

  • Pelvic Free Fluid: An increased volume of free fluid in the pelvis at mid-cycle in a serially monitored patient is an indirect sign of ovulation.

  • No reliable, detectable uterine, cervical, or vaginal changes are directly associated with ovulation.

• Indirect Clinical Evidence of Ovulation: Includes a documented rise in BBT, elevated serum progesterone levels (exceeding $3 ext{ mg/ml}$), and a secretory endometrial pattern via biopsy analysis.

Luteal / Secretory Phase (DAY $15$ TO $25$)

• Characteristics: Formation of the corpus hemorrhagicum and corpus luteum, and secretory activity of the endometrial glands.

• Hormonal Activity:

  • The corpus luteum (CL) secretes progesterone and estrogen.

  • The functional layer of the endometrium thickens and secretes large amounts of lubricating mucus.

  • If fertilization does not occur, the CL begins to regress after Day $20$–$21$, and estrogen and progesterone levels gradually decrease.

  • If fertilization occurs, implantation of the conceptus into the uterus happens on Day $20$ of a $28$-day cycle (typically $6$ days post-fertilization).

  • Human chorionic gonadotropin (hCG), secreted by the trophoblastic cells of the blastocyst, signals the CL to maintain its hormonal output of progesterone and estrogen. hCG is essential for maintaining the CL's hormonal output, which supports the decidual reaction of the endometrium.

  • Later in pregnancy (around $3$ months), the placenta takes over, secreting sufficient estrogen and progesterone to maintain the decidua, and the CL atrophies into a corpus albicans.

• Sonographic Features:

  • Ovary: Corpus luteum appears as an irregular cystic structure (approx. $20 ext{ mm}$ in diameter) generally containing debris echoes.

  • Endometrium: Thick and uniformly echogenic due to the tortuous structure of endometrial glands and abundant mucin secretion, creating more interfaces compared to the proliferative phase. Endometrial thickness peaks around Day $21$ (implantation period).

Ischemic Phase (DAY $26$ TO $28$)

• Synonym: Premenstrual phase.

• Characteristics: Further regression of the corpus luteum and shrinking of the endometrium, accompanied by vascular stasis and ischemia.

• Hormonal Activity:

  • Estrogen and progesterone levels rapidly diminish, leading to loss of tissue fluids and secretory activity.

  • The endometrium shrinks, causing kinking of the spiral arteries.

  • This results in vascular stasis, ischemia, and necrosis.

  • Tissue necrosis and associated hemorrhaging initiate menstrual bleeding, starting a new cycle.

• Sonographic Features: No specific unique features; corpus luteum and endometrium may be seen regressing.

Uterine and Ovarian Doppler During the Menstrual Cycle

• Uterine Arteries:

  • Doppler indices (Resistive Index [RI] and Pulsatility Index [PI]) tend to decrease after ovulation.

  • End-diastolic velocities are often absent or low during the early proliferative phase and higher during the secretory phase.

• Ovarian Arteries:

  • Prior to ovulation, Doppler indices of both ovarian arteries are relatively high, though the ovary destined to ovulate typically has lower values.

  • After ovulation, Doppler indices in the active (ovulating) ovary decrease.

  • Doppler indices in the non-ovulating ovary remain relatively constant.

• Colour Doppler:

  • Demonstrates increased vascularity in the dominant follicle around the time of the LH surge and in the corpus luteum post-ovulation.

  • This increased vascularity is attributed to neoangiogenesis (formation of new blood vessels) during luteinization.

  • The "ring of fire" term describes the rich colour Doppler vascular pattern associated with a normally functioning corpus luteum.

Gynecological Endocrinology

Structures Involved

• Hypothalamus

• Pituitary gland

• Ovary

• Trophoblast of the early blastocyst (if pregnant)

Hormones

• Gonadotropic-Releasing Hormone (GnRH)

  • Secreted by the hypothalamus; controls FSH and LH release.

  • Secreted in a pulsatile manner; amplitude and frequency vary throughout the cycle:

    • Follicular phase: $1$ pulse every hour.

    • Luteal phase: $1$ pulse every $2$–$3$ hours.

  • Amplitude and frequency are regulated by feedback from estrogen, progesterone, and brain neurotransmitters.

  • Stimulates synthesis and release of both FSH and LH from the same anterior pituitary cells.

  • GnRH stimulation leads to a rapid ($30$ min) increase in serum FSH and LH, with a later ($90$ min) release of LH.

  • Improper amplitude or frequency of GnRH can be a factor in infertility.

• Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH)

  • Secreted by the anterior pituitary.

  • FSH:

    • Receptors primarily in the cell membrane of granulosa cells lining ovarian follicles.

    • Acts on granulosa cells to stimulate follicular growth and promotes the formation of LH receptors.

    • Increases FSH and LH receptor content in granulosa cells, an action enhanced by estrogen.

  • LH:

    • Receptors exist in theca cells throughout the cycle and on granulosa cells once the follicle matures under FSH and estrogen influence.

    • With sufficient LH receptors on granulosa cells, LH directly acts on them to cause luteinization (corpus luteum formation) and progesterone formation.

    • LH levels steadily increase until a mid-cycle surge, accompanied by a lesser FSH surge.

    • Initiates luteinization and progesterone production in granulosa cells.

    • The preovulatory rise in progesterone facilitates the positive feedback of estrogen and is needed to induce the mid-cycle FSH peak.

• Estrogen

  • At least six estrogens exist, but three are significant: beta-estradiol (estradiol), estrone, and estriol. Estradiol is the principal estrogen.

  • Secreted by the granulosa cells of ovarian follicles and the corpus luteum.

  • Functions:

    • Stimulates follicle growth and enhances FSH action on granulosa cells.

    • The dominant follicle secretes the most estrogen, increasing FSH receptor density on granulosa cells.

    • Rising estrogen causes negative feedback on FSH secretion, halting the development of other follicles, which then become atretic.

    • During the late follicular phase, the follicular rise in estrogen exerts positive feedback on LH secretion, causing LH levels to rise steadily, peaking approximately $24$–$36$ hours before ovulation.

    • FSH induces the appearance of LH receptors on granulosa cells.

  • Major Physiological Effects:

    • Development and maintenance of female reproductive structures.

    • Development of female secondary sex characteristics.

    • Development of breasts.

    • Control of fluid and electrolyte balance.

    • Increase protein anabolism.

• Progesterone

  • Secreted by the maturing follicle just before ovulation and by the corpus luteum after ovulation.

  • Peak levels are reached $8$–$9$ days after ovulation, coincidental with blastocyst implantation.

  • Also synthesized by the placenta from the end of the first trimester until term.

  • Major Physiological Effects:

    • Prepares the endometrium for implantation.

    • Maintains the decidua during pregnancy.

    • Prepares breasts to secrete milk for lactation.

• Human Chorionic Gonadotropin (hCG)

  • Biochemically similar to LH.

  • Secreted in early pregnancy by the trophoblast of the blastocyst.

  • The trophoblast forms the chorion, which differentiates into the villous chorion (chorion frondosum, becoming the placenta) and the smooth chorion (chorion laeve, joining with the amnion to form the amniochorionic membrane).

  • Maintains corpus luteal function until the placenta is established and can produce sufficient estrogen and progesterone.