Spermatogenesis

Structural setting: Sertoli cells and the blood-testis barrier

• Basal compartment - contains diploid spermatogonia
• Luminal (adluminal) compartment - contains haploid spermatocytes and spermatids, immunologically shielded from the bloodstream

The three phases

• Each primary spermatocyte (46 chromosomes, diploid) undergoes meiosis I, a division lasting up to ~22 days, producing two secondary spermatocytes.
• Each secondary spermatocyte then quickly (within hours) undergoes meiosis II, producing spermatids with a haploid, reduced chromosome number (23 chromosomes, 1n, 1d).
• Guyton & Hall notes this is where the diploid chromosome complement is halved, with 23 chromosomes going to each spermatid - Guyton and Hall Textbook of Medical Physiology, p. 998-999.

• Condensation and elongation of the nucleus
• Formation of the acrosomal cap (a lysosome-like organelle containing enzymes for ovum penetration)
• Development of the flagellum (tail), with mitochondria helically wrapping its proximal segment
• Loss of most cytoplasm

Hormonal regulation

• Hypothalamic GnRH stimulates the anterior pituitary to release LH and FSH.
• LH acts on Leydig cells to produce testosterone.
• FSH and locally high testosterone act on Sertoli cells (which bear the relevant receptors), making Sertoli cells the primary regulators of the process.
• Intratesticular testosterone concentration can reach roughly 200 times circulating levels - necessary for spermatogenic cell proliferation and differentiation.
• Sertoli cells also secrete androgen-binding protein (ABP) to maintain high local androgen levels, and inhibin, which provides negative feedback on pituitary FSH secretion - Histology: A Text and Atlas, p. 2086-2087.

Clinical relevance

Functions of Testosterone

1. Fetal development

• From about the 7th week of gestation, the SRY gene triggers testicular differentiation and testosterone secretion.
• Drives development of the penis, scrotum, prostate, seminal vesicles, and male genital ducts, while suppressing female genital organ formation.
• Causes descent of the testes into the scrotum during the last 2-3 months of gestation.

2. Puberty - primary and secondary sexual characteristics

• Enlarges the penis, scrotum, and testes (roughly 8-fold by age 20).
• Body hair: growth over pubis, abdomen (linea alba), face, chest.
• Male pattern baldness: reduces scalp hair growth in genetically predisposed men.
• Voice: causes laryngeal hypertrophy and enlargement, producing the deeper adult male voice.
• Skin: thickens skin and increases sebaceous gland secretion (can contribute to acne).
• Larynx, pelvis: narrows and lengthens the pelvic outlet into a funnel shape and strengthens it for load-bearing (versus the broad female pelvis).

3. Protein and musculoskeletal effects

• Protein anabolism: increases muscle mass (~50% greater than in females) and protein deposition generally.
• Bone: increases bone matrix and calcium retention, thickens bones; also promotes epiphyseal closure, which ultimately limits final height despite an earlier growth spurt.

4. Metabolic effects

• Increases basal metabolic rate by roughly 5-10% (up to 15% with high doses), likely via its protein-anabolic action.
• Increases red blood cell count (~15-20%, accounting for men having ~700,000 more RBCs/mm³ than women on average) - this appears to be an indirect effect (not via direct erythropoietin stimulation), possibly related to increased metabolic rate.
• Mild effect on electrolyte and water balance: increases renal sodium reabsorption, contributing to a 5-10% increase in blood and extracellular fluid volume after puberty (much weaker effect than mineralocorticoids).

5. Reproductive/gametogenic function

• Maintains spermatogenesis via high intratesticular concentrations (up to ~200x circulating levels), acting through Sertoli cells.
• Sustains libido and other CNS-mediated sexual behaviors.

Mechanism of action

Regulation and clinical notes

• Secretion is controlled by the hypothalamic-pituitary-gonadal axis: GnRH -> LH -> Leydig cell testosterone production, with negative feedback from testosterone/inhibin.
• Levels decline modestly with age; only about 10-20% of men over 60 and 50% of men over 80 have testosterone below the "low" threshold (<300 ng/dL). Obesity and type 2 diabetes accelerate age-related decline.
• Testosterone replacement in elderly men has been associated with possible increased cardiovascular risk in some studies, so use requires caution.

Oogenesis: Steps and Hormonal Regulation

Prenatal phase (before birth)

1. Migration and mitosis: Primordial germ cells migrate from the yolk sac to the developing ovary and proliferate by mitosis, becoming oogonia. By gestational weeks 20-24, there are roughly 6-7 million oogonia.
2. Entry into meiosis I: Starting around gestational weeks 8-9 (continuing through mid-fetal life), oogonia enter meiotic prophase I and become primary oocytes. Each primary oocyte becomes surrounded by a single layer of granulosa cells, forming a primordial follicle.
3. Meiotic arrest: Meiosis I arrests at the diplotene/dictyate stage of prophase I. This arrest persists for years to decades - not resuming until just before ovulation, potentially 13-50 years later.
4. Attrition: Oocyte numbers fall dramatically through programmed atresia - about 2 million remain at birth, and only around 300,000-400,000 remain by puberty.

Postnatal/reproductive phase (puberty onward)

1. Follicular development (in three stages, paralleling the menstrual cycle):
   • Stage 1 (years-long): primordial follicle -> primary follicle; granulosa cells proliferate, theca interna forms.
   • Stage 2 (~70-85 days): antral fluid (containing steroids, FSH) accumulates; follicle becomes a graafian follicle (2-5 mm).
   • Stage 3 (5-7 days, the final follicular phase of a cycle): one dominant follicle is selected, grows rapidly to ~20 mm, while others become atretic.
2. Completion of meiosis I: Just before ovulation (day 14 of a 28-day cycle), the primary oocyte completes its first meiotic division, producing a haploid secondary oocyte (23 duplicated chromosomes) and a small, non-functional first polar body.
3. Ovulation: The dominant (graafian) follicle ruptures, releasing the secondary oocyte into the fallopian tube.
4. Meiosis II - arrested again: The secondary oocyte begins meiosis II but arrests at metaphase II, and stays arrested unless fertilization occurs.
5. Fertilization completes meiosis: If a sperm fertilizes the oocyte, meiosis II completes, producing the mature haploid ovum (23 chromosomes) plus a second polar body, which degenerates. If fertilization does not occur, the oocyte degenerates unfertilized.
6. Corpus luteum formation: The ruptured follicle's remnants (granulosa + theca cells, capillaries, fibroblasts) form the corpus luteum, which secretes progesterone and estrogen to support a possible pregnancy; it regresses (~14 days) if fertilization doesn't occur, or is sustained by hCG if it does.

Hormones involved

Follicular Development: Steps and Hormones

Steps of follicular development

• Converts granulosa/theca cells toward progesterone secretion (estrogen falls, progesterone rises just before ovulation)
• Triggers release of proteolytic enzymes that digest the follicular capsule
• Stimulates new blood vessel growth and local prostaglandin release, causing capsule rupture at the stigma
• Results in ovulation: release of the oocyte (with its surrounding corona radiata cells) into the peritoneal cavity/fallopian tube, on approximately day 14 of a 28-day cycle. Meiosis I completes just before this release.

Hormones involved

Male vs Female Gametogenesis: Comparison Table

Key conceptual differences to remember

• Continuous vs. cyclical: Spermatogenesis is an ongoing assembly line; oogenesis is cyclical and tied to the ~28-day ovarian/menstrual cycle.
• Quantity vs. quality/scarcity: Males produce millions of sperm daily from a renewable stem cell pool; females are born with a finite, depleting oocyte reserve and typically ovulate only one mature oocyte per cycle.
• Symmetric vs. asymmetric division: Meiosis in the male yields four equivalent gametes; meiosis in the female is deliberately asymmetric to concentrate cytoplasm/organelles into a single large, viable ovum.
• Timing of meiotic completion: Sperm complete meiosis entirely within the testis before release. Oocytes only complete meiosis II after fertilization - meaning the "final" female gamete (a true haploid ovum) technically only exists transiently at the moment of fertilization.

Follicular Development: Steps and Hormones (Guyton and Hall Textbook of Medical Physiology, 15th ed., Ch. 82, "Female Physiology Before Pregnancy and Female Hormones")

Steps

• A preovulatory LH surge (6- to 10-fold rise, peaking ~16 hours before ovulation) is essential; FSH also rises 2- to 3-fold.
• LH converts granulosa/theca cells to progesterone-secreting cells, so estrogen falls and progesterone rises just before ovulation.
• Proteolytic enzymes digest the follicular capsule; new blood vessels and prostaglandins promote swelling and rupture.

Hormones involved