Human Reproductive System: Cyclicity and Regulation

Human Reproductive System

An overview of the human reproductive system, focusing on reproductive cyclicity and its regulation.

Reproductive Hormone Secretion: The Hypothalamic-Pituitary-Gonadal (HPG) Axis

The production of gametes and sex hormones is orchestrated by a sequence of hormonal events involving the hypothalamus, anterior pituitary gland, and ovaries (in females) or testes (in males). This regulatory system is known as the hypothalamic-pituitary-gonadal (HPG) axis.

Key Hormones Involved:
  • Hypothalamus:
    • GnRH (Gonadotropin-Releasing Hormone): Released by both female and male hypothalami.
  • Anterior Pituitary:
    • FSH (Follicle-Stimulating Hormone): Released in both females and males.
    • LH (Luteinizing Hormone): Released in both females and males.
  • Female Gonads (Ovaries):
    • Estrogen
    • Inhibin
    • Progesterone
  • Male Gonads (Testes):
    • Testosterone
    • Inhibin

Interactions within the HPG Axis

The HPG axis operates through stimulatory and inhibitory feedback loops:

  • The hypothalamus releases GnRH, which travels via the portal blood system to the anterior pituitary.
  • GnRH stimulates the anterior pituitary to release LH and FSH.
  • LH and FSH stimulate the gonads (ovaries or testes) to produce sex hormones (and inhibin).
  • Sex hormones exert effects on target cells throughout the body.
  • Estrogen and progesterone (from ovaries) and testosterone (from testes) inhibit the hypothalamus and anterior pituitary, creating negative feedback.
  • Inhibin (from both ovaries and testes) also inhibits the anterior pituitary.

Activation of the HPG Axis at Puberty

  • Puberty: The period when reproductive organs mature and become functional, marking the earliest point at which reproduction is possible.
  • Prior to puberty, low levels of circulating sex steroid hormones are sufficient to suppress GnRH secretion by the hypothalamus.
  • As puberty approaches, the hypothalamus becomes less sensitive to the inhibitory effects of sex hormones, leading to an increase in GnRH secretion.
  • The hypothalamus releases GnRH in a pulsatile manner.
  • In response to increased GnRH levels, the anterior pituitary releases FSH and LH.
  • FSH and LH stimulate the gonads to release more sex hormones.
  • The threshold for inhibition of GnRH continues to rise, resulting in a progressive increase in sex hormone release until an adult pattern of hormone interaction is achieved.

Hormonal Regulation of Testicular Function (HPG Axis in Males)

  • The hypothalamus releases GnRH, which reaches the anterior pituitary via the hypophyseal portal veins.
  • GnRH stimulates anterior pituitary gonadotropic cells to release FSH and LH.
  • FSH indirectly stimulates spermatogenesis by causing sustentocytes (also known as Sertoli cells) to release androgen-binding protein (ABP), which maintains a high local concentration of testosterone.
  • LH stimulates interstitial endocrine cells (also known as Leydig cells) to secrete testosterone, which is essential for spermatogenesis.
  • Testosterone acts at other body sites to:
    • Stimulate maturation of sex organs.
    • Promote the development and maintenance of secondary sex characteristics.
    • Influence libido (sex drive).
  • Negative feedback mechanisms:
    • Testosterone inhibits FSH and LH release from the anterior pituitary and GnRH release from the hypothalamus.
    • Inhibin, released by sustentocytes, inhibits FSH release from the anterior pituitary.

Plasma Testosterone and Sperm Production Levels Versus Age in Males

  • Before birth, testosterone levels in a male fetus reach approximately two-thirds of adult levels.
  • Following a brief increase in early infancy, blood levels decrease and remain low throughout childhood.
  • As puberty nears, higher levels of testosterone are required to suppress hypothalamic release of GnRH, leading to the establishment of the adult hormonal pattern.

Mechanism and Effects of Testosterone Activity

  • Testosterone, synthesized from cholesterol, plays several critical roles:
    • Stimulates spermatogenesis.
    • Targets accessory reproductive organs.
    • Exerts anabolic effects throughout the body.
  • Testosterone deficiency leads to:
    • Atrophy of accessory organs.
    • Decline in semen volume.
    • Impaired erection and ejaculation.
  • Treatment for testosterone deficiency involves testosterone replacement therapy.

Male Secondary Sex Characteristics

  • Male secondary sex characteristics are features induced in nonreproductive organs by male sex hormones, primarily testosterone.
    • Appearance of pubic, axillary, and facial hair.
    • Enhanced hair growth on the chest and other areas.
    • Larynx enlargement, leading to a deepening of the voice.
    • Thickening and increased oiliness of the skin.
    • Bone growth and increased density.
    • Increased size and mass of skeletal muscles.
    • Boost in basal metabolic rate.
    • Basis for sex drive (libido) in males.

The Ovarian Cycle

  • Ovarian Cycle: A monthly series of events associated with the maturation of an egg, typically lasting around 28 days.
    • Follicular Phase (Days 1-14): The period of follicle cohort recruitment and growth, culminating in the selection of a dominant follicle that will ovulate. Vesicular follicle growth continues.
    • Luteal Phase (Days 14-28): The period of corpus luteum activity following ovulation. The luteal phase is consistently 14 days long, from ovulation to the end of the cycle.
  • Cycle length varies among women; only 10-15% have a 28-day cycle.

Events of Oogenesis

Oogenesis involves the development of oocytes (female gametes) within the ovarian follicles:

  • Before Birth:
    • Oogonia (stem cells) undergo mitosis to produce primary oocytes.
    • Primary oocytes begin meiosis I but arrest in prophase I. All primordial follicles containing primary oocytes are present at birth.
  • Childhood to Menopause:
    • Primordial follicles begin to grow and develop throughout life until menopause. Before puberty, all developing follicles undergo atresia (degeneration).
    • From puberty to menopause, some vesicular follicles are rescued from atresia each month, and the primary oocyte in one dominant follicle completes meiosis I.
  • Meiosis I Completion:
    • Meiosis I completes in the vesicular follicle just before ovulation, resulting in a secondary oocyte and the first polar body (which may or may not undergo meiosis II).
  • Ovulation:
    • The secondary oocyte is ovulated and arrested in metaphase II.
  • Fertilization:
    • Meiosis II is completed only if the secondary oocyte is penetrated by a sperm, resulting in an ovum and the second polar body. The polar bodies degenerate.

Development and Fate of Ovarian Follicles

The progression of follicle development:

  1. Primordial Follicles: The earliest stage, containing a primary oocyte.
  2. Primary Follicle: Characterized by a primary oocyte surrounded by a single layer of granulosa cells.
  3. Secondary Follicle: Includes a primary oocyte and multiple layers of granulosa cells. The theca folliculi begins to form.
  4. Early Vesicular (Antral) Follicle: Development of the antrum, a fluid-filled cavity.
  5. Mature Vesicular (Antral) Follicle: A large antrum and a secondary oocyte. The follicle is ready to be ovulated and carries out meiosis I.
  6. Ovulation: The follicle ruptures, releasing the secondary oocyte.
  7. Corpus Luteum: Forms from the ruptured follicle after ovulation, secreting hormones like progesterone and estrogen.
  8. Corpus Albicans: If pregnancy does not occur, the corpus luteum degenerates into the corpus albicans.

Hormonal Regulation of the Ovarian Cycle

Establishing the Ovarian Cycle
  • Before puberty, the ovaries secrete small amounts of estrogen, which inhibits hypothalamic GnRH release.
  • As puberty nears, adequate leptin levels decrease the hypothalamus's sensitivity to estrogen, increasing GnRH release. This stimulates FSH and LH release by the pituitary, acting on the ovaries.
  • These events continue until an adult cyclic pattern is achieved, marked by menarche (the first menstrual period).
  • Estrogen supports follicle development and the development of female secondary sex characteristics.
  • Progesterone (high during pregnancy) stimulates breast maturation and milk production.
Menopause
  • Menopause marks the end of the reproductive period, typically in the late 40s or early 50s.
  • The number of follicles becomes insufficient to produce the high estrogen levels needed to trigger the GnRH surge, LH peak, and subsequent ovulation.
  • Hormone replacement therapy (estrogen replacement) can be used to manage menopausal symptoms.
Regulation of the Ovarian Cycle
  1. GnRH Stimulation: GnRH stimulates FSH and LH secretion.
  2. Follicle Maturation: FSH and LH stimulate follicles to grow, mature, and secrete sex hormones:
    • LH stimulates thecal cells to produce androgens (specifically, testosterone).
    • FSH stimulates granulosa cells to produce aromatase, which converts androgens (testosterone) to estrogen.
  3. Negative Feedback: Increasing levels of plasma estrogen exert negative feedback inhibition on FSH and LH release. Inhibin from granulosa cells also inhibits FSH release.The dominant follicle is able to survive the dip in FSH levels. Other recruited follicles will perish.
  4. Positive Feedback: As estrogen levels continue to rise from the dominant follicle, a brief positive feedback occurs on the brain and anterior pituitary when estrogen levels reach a critical high value. This triggers the LH surge.
  5. LH Surge and Ovulation: The LH surge triggers ovulation and the formation of the corpus luteum. High estrogen levels trigger the release of stored LH (and some FSH) by the anterior pituitary at midcycle. Shortly after ovulation, estrogen levels decline, and the corpus luteum secretes progesterone and some estrogen.
  6. Negative Feedback: Progesterone and estrogen from the corpus luteum exert negative feedback, which inhibits LH and FSH release, helping to prevent the development of new follicles during the luteal phase.
Brain GnRH Centers
  • The female brain has both surge and tonic GnRH centers, which regulate the pulsatile release of GnRH necessary for the LH surge and ovulation.
  • The male brain has only a tonic GnRH center, resulting in a more consistent, non-cyclic release of GnRH.
Hormonal Events Leading to Ovulation
  • Increase in estrogen leads to GnRH surge and LH spike, which ultimately causes ovulation.

The Uterine (Menstrual) Cycle

  • Uterine (Menstrual) Cycle: A cyclic series of changes in the endometrium (the lining of the uterus) that occur in response to fluctuating ovarian hormone levels.
Three Phases:
  1. Menstrual Phase (Days 1-5): The functional layer of the endometrium is shed, resulting in menstruation.
  2. Proliferative (Preovulatory) Phase (Days 6-14): The functional layer of the endometrium is rebuilt in response to increasing estrogen levels.
  3. Secretory (Postovulatory) Phase (Days 15-28): The endometrium prepares to receive an embryo through enrichment of the blood supply and glandular secretion of nutrients. This phase occurs after ovulation.
Correlation of Ovarian and Uterine Cycles
  • The ovarian cycle (follicular and luteal phases) and the uterine cycle (menstrual, proliferative, and secretory phases) are synchronized by fluctuating hormone levels.
    • The menstrual and proliferative phases occur before ovulation and correspond to the follicular phase of the ovarian cycle.
    • The secretory phase corresponds to the luteal phase of the ovarian cycle.
  • Hormone Fluctuations:
    • Fluctuating levels of pituitary gonadotropins (FSH and LH) regulate the events of the ovarian cycle.
    • Changes in ovarian hormone levels (estrogen and progesterone) cause the endometrial changes of the uterine cycle.
    • High estrogen levels trigger the LH/FSH surge.