Human Reproductive System and Hormonal Regulation

Human Reproductive System

  • Overview of the human reproductive system and the regulation of reproductive cyclicity.

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

  • The production of gametes and sex hormones is controlled by a sequence of hormonal events involving the hypothalamus, anterior pituitary gland, and ovaries/testes.
  • This regulatory system is known as the hypothalamic-pituitary-gonadal (HPG) axis.
  • The interacting hormones include:
    • Female and male hypothalamus: GnRH (Gonadotropin-Releasing Hormone)
    • Female and male pituitary: FSH (Follicle-Stimulating Hormone), LH (Luteinizing Hormone)
    • Female ovaries: Estrogen, inhibin, and progesterone
    • Male testes: Testosterone, inhibin

Interactions along the Hypothalamic-Pituitary-Gonadal (HPG) Axis

  • Hypothalamus
    • Releases GnRH into the portal blood.
  • Anterior Pituitary
    • Releases LH and FSH in response to GnRH.
  • Gonads (Testes or Ovaries)
    • Secrete sex hormones (and inhibin) in response to LH and FSH.
  • Target Cells
    • Respond to sex hormones.
  • Stimulatory and Inhibitory Effects
    • GnRH stimulates the anterior pituitary.
    • LH and FSH stimulate the gonads.
    • Sex hormones stimulate target cells.
    • Estrogen and progesterone (from ovaries) and testosterone (from testes) inhibit the hypothalamus and anterior pituitary.

Activation of the HPG Axis at Puberty

  • Puberty: The period when reproductive organs mature and become functional, marking the earliest time reproduction is possible.
  • Before Puberty: Low circulating levels of sex steroid hormones suppress GnRH secretion by the hypothalamus.
  • Approaching Puberty: 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.

Activation of the HPG Axis at Puberty (cont.)

  • The anterior pituitary responds to increased GnRH levels by releasing 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 increased release of sex hormones until the adult pattern of hormone interaction is achieved.

Hormonal Regulation of Testicular Function by the HPG Axis

  • The hypothalamus releases GnRH, which travels to the anterior pituitary via the hypophyseal portal veins.
  • GnRH causes the anterior pituitary gonadotropic cells to release FSH and LH.
  • FSH indirectly stimulates spermatogenesis by causing sustentocytes to release ABP (Androgen-Binding Protein), which maintains a high local concentration of testosterone.
  • LH stimulates interstitial endocrine cells to secrete testosterone, which is essential for spermatogenesis.
  • Testosterone acts at other body sites to stimulate maturation of sex organs, development and maintenance of secondary sex characteristics, and libido (sex drive).
  • Negative feedback by testosterone inhibits FSH and LH release from the anterior pituitary and GnRH release from the hypothalamus.
  • Inhibin, released by sustentocytes, feeds back on the anterior pituitary, decreasing FSH release.

Plasma Testosterone and Sperm Production Levels Versus Age in Males

  • Before birth, the male fetus has testosterone levels that are approximately two-thirds of adult levels.
  • After a brief rise in early infancy, blood levels recede and remain low throughout childhood.
  • As puberty nears, higher levels of testosterone are required to suppress hypothalamic release of GnRH, and the adult pattern is established.

Mechanism and Effects of Testosterone Activity

  • Testosterone is synthesized from cholesterol.
  • It stimulates spermatogenesis and targets accessory organs.
  • Testosterone has multiple anabolic effects throughout the body.
  • Deficiency leads to atrophy of accessory organs, a decline in semen volume, and impaired erection/ejaculation.
  • Treatment includes testosterone replacement therapy.

Male Secondary Sex Characteristics

  • Features induced in nonreproductive organs by male sex hormones (mainly testosterone).
  • Appearance of pubic, axillary, and facial hair.
  • Enhanced growth of hair on the chest or other areas.
  • Larynx enlargements causing a deepening of voice.
  • Skin thickens and becomes oily.
  • Bones grow and increase in density.
  • Skeletal muscles increase in size and mass.
  • Boosts basal metabolic rate.
  • Basis of sex drive (libido) in males.

The Ovarian Cycle

  • The ovarian cycle is a monthly (~28 day) series of events associated with the maturation of an egg.
  • It consists of two consecutive phases, with ovulation occurring midcycle between the phases.
    • Follicular phase: Period of follicle cohort recruitment and growth. Vesicular follicle growth continues, and it is the follicle that ovulates (days 1–14).
    • Luteal phase: Period of corpus luteum activity (days 14–28).
  • Only 10–15% of women have a 28-day cycle.
  • The follicular phase varies in length, but the luteal phase is consistently 14 days from ovulation to the end of the cycle.

Events of Oogenesis and Follicle Development

  • Before Birth:
    • All primordial follicles are already present and contain primary oocytes arrested in prophase I.
    • Oogonia (stem cells) undergo mitosis to produce primary oocytes.
  • At Birth:
    • All primordial follicles are present, each containing a primary oocyte arrested in prophase I.
  • Throughout Life Until Menopause:
    • Primordial follicles begin to grow and develop. Before puberty, all developing follicles undergo atresia (degeneration).
  • From Puberty to Menopause:
    • After puberty, some vesicular follicles are rescued from atresia each month, and the primary oocyte in one follicle (the dominant follicle) completes meiosis I.
    • Meiosis begins but arrests.
  • Meiosis I Completed:
    • Occurs in a vesicular follicle just before ovulation.
    • A secondary oocyte and a first polar body are produced.
  • Ovulation:
    • The secondary oocyte is arrested in metaphase II.
  • Meiosis II Completed:
    • Only occurs if the sperm penetrates the oocyte, resulting in an ovum and a second polar body.
  • Fate of Polar Bodies:
    • All polar bodies degenerate.

Development and Fate of Ovarian Follicles

  • Primordial Follicles:
    • Consist of an oocyte surrounded by pre-granulosa cells.
  • Primary Follicle:
    • Characterized by a zona pellucida around the oocyte.
  • Secondary Follicle:
    • Has a theca folliculi forming.
  • Early Vesicular Follicle:
    • Develops an antrum (fluid-filled cavity).
  • Mature Vesicular Follicle:
    • Carries out meiosis I and is ready to be ovulated.
    • Contains a secondary oocyte, corona radiata, and a well-formed antrum.
  • Ovulation:
    • The follicle ruptures and the secondary oocyte is ovulated.
  • Corpus Luteum:
    • Forms from the ruptured follicle.
    • If fertilization occurs, it produces hormones to maintain pregnancy.
  • Corpus Albicans:
    • The corpus luteum degenerates into the corpus albicans if fertilization does not occur.

Hormonal Regulation of the Ovarian Cycle

  • Establishing the Ovarian Cycle:
    • Before puberty, ovaries secrete small amounts of estrogen, inhibiting hypothalamic release of GnRH.
    • As puberty nears, if leptin levels are adequate, the hypothalamus becomes less estrogen-sensitive, so GnRH is released, stimulating FSH and LH release by the pituitary, which then acts on the ovaries.
    • Events continue until an adult cyclic pattern is achieved, and menarche (the first menstrual period) occurs.
      • Estrogen supports follicle development.
      • Estrogen affects the development of female secondary sex characteristics.
      • Progesterone (high during pregnancy) stimulates breast maturation and milk production.
  • Menopause: End of the reproductive period.
    • In the late 40s/early 50s, the number of follicles is insufficient to produce the high estrogen levels needed to trigger a GnRH surge, LH peak, and ovulation ceases.
      • Treatment may include estrogen replacement therapy.

Hormonal Regulation of the Ovarian Cycle (Detailed)

  1. GnRH Stimulates FSH and LH Secretion:

    • The hypothalamus releases GnRH, which stimulates the anterior pituitary to secrete FSH and LH.

  2. FSH and LH Stimulate Follicle Growth, Maturation, and Secretion of Sex Hormones:

    • LH stimulates thecal cells to produce androgens (e.g., testosterone).
    • FSH stimulates granulosa cells to make aromatase, an enzyme that converts testosterone to estrogen.

  3. Negative Feedback Inhibits Gonadotropin Release:

    • Increasing levels of plasma estrogen exert negative feedback inhibition on FSH and LH release.
    • Inhibin from granulosa cells also inhibits FSH release.
    • Only the dominant follicle can withstand the dip in FSH levels; other recruited follicles perish.

  4. Positive Feedback Stimulates Gonadotropin Release:

    • Estrogen levels continue to rise due to continued release by the dominant follicle.
    • When estrogen levels reach a critical high value, a brief positive feedback occurs on the brain and anterior pituitary.
    • This triggers the LH surge.

  5. LH Surge Triggers Ovulation and Formation of the Corpus Luteum:

    • High estrogen levels trigger the release of stored LH, and some FSH, by the anterior pituitary at midcycle.
    • The LH surge triggers ovulation.
    • Shortly after ovulation, estrogen levels decline, and the corpus luteum secretes progesterone and some estrogen.

  6. Negative Feedback Inhibits LH and FSH Release:

    • The combination of progesterone and estrogen secreted by the corpus luteum exerts negative feedback on the hypothalamus and anterior pituitary, inhibiting LH and FSH release.

Brain Centers

  • The female brain has surge and tonic GnRH centers, while the male brain has only a tonic GnRH center.

  • Increase in estrogen leads to GnRH surge which causes a LH spike and then ovulation.

The Uterine (Menstrual) Cycle

  • The uterine (menstrual) cycle is 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 menstrual flow.

    2. Proliferative (Preovulatory) Phase (Days 6–14):

      • The functional layer of the endometrium is rebuilt under the influence of estrogen.

    3. Secretory (Postovulatory) Phase (Days 15–28):

      • The endometrium prepares to receive an embryo, with enrichment of the blood supply and glandular secretion of nutrients, influenced by progesterone and estrogen from the corpus luteum.
      • If fertilization does not occur, the corpus luteum degenerates, hormone levels drop, and the cycle starts again with the menstrual phase.

Correlation of Ovarian and Uterine Cycles

  • Fluctuating levels of pituitary gonadotropins (FSH and LH) regulate the events of the ovarian cycle.
  • Structural changes in ovarian follicles and the corpus luteum correlate with changes in the endometrium during the uterine cycle.
  • Fluctuating levels of ovarian hormones (estrogen and progesterone) cause the endometrial changes of the uterine cycle.
  • The menstrual and proliferative phases occur before ovulation, corresponding to the follicular phase of the ovarian cycle.
  • The secretory phase corresponds in time to the luteal phase of the ovarian cycle.