Menstrual Cycle

Human Reproduction and Development in Health and Disease

Week 2 Lecture 3-4 by Phil Knight

Learning Objectives

  • By the end of this session, students should be able to:

    • Describe the roles of different parts of the female reproductive system.

    • Describe the menstrual cycle and explain the relationship between the ovarian cycle and uterine (endometrial) cycle.

    • Explain the roles of gonadotrophins and ovarian hormones in regulating menstrual cycles.

    • Outline the pubertal transition and menarche.

    • Outline reproductive ageing, fertility decline, and menopause.

    • Outline mammary gland development, thelarche, lactation, and explain the milk ejection reflex.

Menstrual Cycle Overview

  • The menstrual cycle spans from menarche (the first period) to menopause.

  • Comprises two interlinked cycles:

    • Ovarian (ovulatory) cycle

    • Uterine (endometrial) cycle

  • Conventionally taught as a 28-day cycle with:

    • Day 1 being the first day of menstrual flow

    • Ovulation on approximately Day 14.

  • Actual cycles can vary from 21 to 35 days with ovulation occurring between days 8 and 20.

Variability in Menstrual Cycle Length

  • Substantial variability in menstrual cycle length across the reproductive lifespan:

    • Mean cycle length: 28 days ± 90% confidence intervals.

    • Cycle length can vary considerably over approximately 12 years from menarche to menopause.

Ovarian Cycle

  • The ovarian cycle consists of two main phases:

    • Pre-ovulatory Phase (Follicular Phase): Day 1 to Day 14.

    • Post-ovulatory Phase (Luteal Phase): Day 14 to Day 28.

Hormonal Regulation of Ovarian Cycle

  • Hormones involved:

    • Hypothalamus releases Gonadotropin-Releasing Hormone (GnRH).

    • Anterior pituitary gland secretes Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH).

    • Ovaries produce Estrogen, Progesterone, and Inhibin.

  • Feedback mechanisms regulate hormonal levels affecting ovaries and endometrium.

    • Negative feedback loop controls GnRH, FSH, and LH levels.

    • Positive feedback loop contributes to LH surge mid-cycle.

Gonadotropin-Releasing Hormone (GnRH)

  • Released in pulses from the hypothalamus.

  • Size and frequency of pulses influence the secretion of FSH and LH:

    • Pre-ovulation estrogen increases pulse frequency (positive feedback).

    • Post-ovulation estrogen and progesterone decrease pulse frequency (negative feedback).

Luteinizing Hormone (LH)

  • Mid-cycle GnRH/LH surge promotes ovulation.

  • Acts on LH receptors on theca cells to stimulate androgen synthesis.

    • Some of the androgen enters systemic circulation; some converts to estrogen in granulosa cells.

  • This process involves the enzyme P450 aromatase, which is upregulated by FSH.

Follicle-Stimulating Hormone (FSH)

  • Most active during the pre-ovulatory phase (follicular phase).

  • Stimulates growth of approximately 6-20 small ovarian follicles:

    • Follicles secrete estrogen and inhibin.

    • Mid-follicular phase inhibin and estrogen suppress FSH to ensure only one follicle becomes dominant.

  • Post-ovulation, FSH levels are inhibited to prevent the maturation of further follicles.

Ovarian Reserve

  • Refers to the pool of quiescent primordial follicles in the ovarian cortex.

  • The process of follicle development takes over 6 months, occurring continuously across multiple menstrual cycles.

  • Initial stimulus arises from inter-cycle rises in FSH promoting further follicle development during the start of each cycle.

FSH Threshold Hypothesis

  • A transient rise in FSH initiates the growth of multiple antral follicles.

  • The most FSH-sensitive follicle responds first by proliferating and secreting more estrogen and inhibin, leading to its selection as the dominant follicle.

    • Subordinate follicles lack sufficient FSH support and do not mature further, leading to atresia.

Dominant Follicle Selection

  • The dominant follicle exhibits higher FSH sensitivity due to:

    • Greater numbers of FSH receptors on granulosa cells.

    • Enhanced production of co-stimulatory factors synergistic with FSH (e.g., IGF1, activin).

Estrogen (E2) Role in Reproduction

  • Produced by maturing follicles in response to FSH.

  • Functions include:

    • Development of secondary sexual characteristics at puberty.

    • Thickening of uterine lining before ovulation.

    • Positive feedback inducing LH and FSH surge to trigger ovulation.

Mid-Cycle LH Surge and Ovulation

  • High estrogen levels reach a threshold triggering the LH surge, leading to:

    • Ovulation of the secondary oocyte.

    • Conversion of the empty follicle into corpus luteum, marking the start of the luteal phase.

  • The corpus luteum secretes progesterone, estrogen, and inhibin, collectively suppressing FSH and LH, thus preventing further follicle maturation.

Summary of Endocrine Regulation

  • Ovarian hormone production is tightly regulated by the hypothalamus and anterior pituitary:

    • During the follicular phase, FSH stimulates the follicle to produce more estrogen.

    • Threshold estrogen levels prompt the GnRH/LH surge that triggers ovulation.

    • Post-ovulation, LH fosters the formation of the corpus luteum which secretes hormones to maintain the endometrium while suppressing further follicle development.

The Uterine (Endometrial) Cycle

  • Taught as a quasi-28 day cycle with Day 1 marking the commencement of menstrual flow.

  • Phases include:

    • Menstrual Phase: Menstruation occurs if pregnancy does not ensue.

    • Proliferative Phase: Corresponds with the pre-ovulatory phase.

    • Secretory Phase: Corresponds with the luteal phase.

Menstrual Phase Details

  • Menstruation represents the shedding of the unnecessary thickened uterine lining due to decreased progesterone following corpus luteum regression.

  • Lasts typically 3-5 days with total fluid loss ranging from 25-120 mL, consisting of endometrial cells, blood, and secretions.

Proliferative Phase Details

  • Occurs post-menstruation, lasting approximately 10 days, where:

    • Estrogen stimulates endometrial proliferation.

    • Endometrium becomes increasingly vascular and develops mucus-secreting glands in preparation for a potential fertilization.

Secretory Phase Details

  • The corpus luteum secretes progesterone and estrogen, enhancing the endometrium for possible implantation:

    • Uterine lining thickens and secretes glycogen, lipids, and proteins.

    • Cervical mucus thickens, becoming hostile to sperm.

  • Corpus luteum degenerates after roughly 10-16 days if no pregnancy, resulting in menstrual phase initiation.

Pregnancy Establishment and Zygote Formation

  • If fertilization occurs, the zygote travels to the uterus where it implants approximately 6 days post-ovulation.

  • The embryo secretes human chorionic gonadotropin (hCG), which:

    • Mimics LH, maintains corpus luteum, and keeps progesterone levels elevated for early pregnancy.

    • Suppresses FSH secretion to prevent further maturation of follicles.

Puberty and Menopause

  • Puberty involves significant physiological changes driven by metabolic factors, with menarche typically occurring between 11 and 15 years of age.

  • Menopause represents the endpoint of reproductive capability, characterized by variability in signs and symptoms, including irregular periods, hot flushes, vaginal dryness, and mood changes.

  • Notable evidence indicates that average age of menarche has decreased by about 4 years from the 19th century to now.

Menopause Characteristics

  • Involves a significant decline in germ cell numbers, leading to loss of ovarian reserve:

    • At birth, ovaries contain roughly 1.5 million primordial follicles.

    • By puberty, this decreases to about 300,000 oocytes.

  • Effects include increased risk for health conditions such as osteoporosis and cardiovascular diseases due to a lack of estrogens.

Mammary Gland Development and Lactation

Thelarche and Breast Development Stages

  • Thelarche marks the onset of breast development, typically starting after ages 8-9 with growth stages defined by Tanner stages.

    • Stage 1: No breast development.

    • Stage 2: Breast budding, mean age 11.2.

    • Stage 3: Continued enlargement, mean age 12.2.

    • Stage 4: Distinct areola and papilla formation, mean age 13.1.

    • Stage 5: Mature breast development, mean age 15.3.

Breast Changes During Pregnancy

  • Under the influence of hormones like Prolactin, Progesterone, and hPL, breasts undergo hyperplasia during pregnancy.

  • Estrogen promotes duct proliferation while inhibiting lactation until childbirth, where a sudden drop allows for lactation to commence.

Suckling Reflex and Milk Ejection

  • Suckling induces prolactin release via reduced dopamine levels, facilitating milk synthesis.

  • Oxytocin mediates both uterine contractions during labor and stimulates milk ejection by contracting myoepithelial cells surrounding milk lobules.