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AN77.1-6 | Gametogenesis and fertilization — Part 1

The Menstrual Cycle: Uterine and Ovarian Phases

The menstrual cycle is the recurring monthly process of endometrial preparation for pregnancy, coordinated by hormonal signals from the ovary. The average cycle length is 28 days (normal range 21-35 days), counted from the first day of menstrual bleeding (day 1) to the day before the next period begins. The cycle has two parallel components: the uterine (endometrial) cycle describing changes in the endometrium, and the ovarian cycle describing changes in the ovary. These are synchronised by the same hormones.

Figure: The Menstrual Cycle: Uterine and Ovarian Phases

The Uterine Cycle (AN77.1) has three phases:

1. Menstrual phase (Days 1-5): In the absence of pregnancy, the corpus luteum degenerates, causing a sharp decline in oestrogen and progesterone levels. Without hormonal support, the spiral arteries of the endometrium undergo vasoconstriction, leading to ischaemia and necrosis of the functional layer. The necrotic tissue, along with blood from the ruptured vessels and uterine secretions, is shed as menstrual flow (menses). The average menstrual blood loss is 30-80 mL (>80 mL is considered menorrhagia). The basal layer remains intact and provides the stem cells for endometrial regeneration. Importantly, menstrual blood does not clot normally because it contains fibrinolysins released from the endometrial tissue — this is why menstrual blood appears fluid rather than coagulated. If clots are present, it may indicate heavy menstrual bleeding exceeding the fibrinolytic capacity.

2. Proliferative (follicular/oestrogen) phase (Days 6-14): Under the influence of rising oestrogen levels produced by the developing ovarian follicle, the endometrium regenerates and proliferates. The glands of the basal layer grow and elongate (straight, narrow glands), the stroma becomes dense and vascularised, and the spiral arteries grow into the thickening endometrium. The endometrium grows from approximately 1 mm (at the end of menstruation) to 3-4 mm by ovulation. Oestrogen stimulates the synthesis of oestrogen receptors (amplifying its own effect) and progesterone receptors (preparing the endometrium for the next phase). The cervical mucus becomes thin, watery, and elastic (spinnbarkeit), forming a fern-like crystallisation pattern when dried on a slide — these properties facilitate sperm penetration. This phase varies in length (it is the variable component of the cycle — cycles shorter or longer than 28 days differ primarily in the length of the proliferative phase).

3. Secretory (luteal/progesterone) phase (Days 15-28): Following ovulation, the corpus luteum produces progesterone (and oestrogen). Progesterone transforms the proliferated endometrium into a secretory endometrium ready for implantation. The glands become coiled and tortuous (corkscrew-shaped), their lumina dilate with glycogen-rich secretions (which nourish the early embryo before placental circulation is established), the stroma becomes oedematous (decidualisation — stromal cells enlarge and accumulate glycogen and lipid), and the spiral arteries become maximally coiled. The endometrium reaches its maximum thickness of 5-7 mm. The cervical mucus becomes thick, viscid, and impenetrable to sperm (a natural barrier that contributes to the infertile period). The secretory phase is remarkably constant in duration — approximately 14 days — because it is determined by the fixed lifespan of the corpus luteum. If implantation does not occur, the corpus luteum degenerates (luteolysis), progesterone and oestrogen levels fall, and the cycle begins again with menstruation.

If implantation occurs (approximately day 6-7 after fertilisation, corresponding to approximately day 20-22 of the menstrual cycle), the trophoblast of the implanting blastocyst produces human chorionic gonadotropin (hCG), which rescues the corpus luteum from degeneration. The corpus luteum of pregnancy continues to produce progesterone and oestrogen, maintaining the secretory endometrium (now called the decidua) until the placenta takes over steroidogenesis at approximately 10-12 weeks. This is the basis of pregnancy testing — detection of hCG in urine or blood.

The Ovarian Cycle (AN77.2) runs in synchrony with the uterine cycle and has two phases separated by ovulation:

1. Follicular phase (Days 1-14): At the beginning of each cycle, a cohort of primordial follicles (approximately 15-20) is recruited from the ovarian reserve. Under the influence of FSH from the anterior pituitary, these follicles begin to grow, progressing through primary, secondary, and antral stages. By approximately day 5-7, a single dominant follicle is selected (the follicle with the most FSH receptors and the highest oestrogen production), while the remaining recruited follicles undergo atresia. The dominant follicle grows rapidly, reaching approximately 20-25 mm diameter by the time of ovulation. It produces increasing amounts of oestrogen, which initially exerts negative feedback on FSH (causing the decline in FSH that leads to atresia of non-dominant follicles) but then, at high sustained levels (>200 pg/mL for >48 hours), switches to positive feedback, triggering the LH surge from the anterior pituitary.

2. Ovulation (Day 14): The LH surge (a 10-20 fold increase in LH) triggers a cascade of events: resumption of meiosis I in the oocyte (which has been arrested in prophase I since foetal life), cumulus expansion (the cumulus cells surrounding the oocyte become loosened by hyaluronic acid production), follicular wall weakening (by collagenases and prostaglandins), and finally rupture of the follicle with extrusion of the oocyte surrounded by the zona pellucida and corona radiata. The oocyte is at the secondary oocyte stage (having completed meiosis I and arrested in metaphase of meiosis II). Ovulation occurs approximately 36 hours after the onset of the LH surge. The released oocyte is captured by the fimbriae of the fallopian tube and transported along the tube by ciliary action and peristalsis.

3. Luteal phase (Days 15-28): The ruptured follicle collapses and is transformed into the corpus luteum under the continuing influence of LH. The granulosa cells luteinise (accumulating lipid and the yellow pigment lutein — hence 'corpus luteum' = 'yellow body') and produce progesterone as their primary product (also oestrogen and inhibin A). The corpus luteum has a programmed lifespan of approximately 14 days unless rescued by hCG from an implanting embryo. Its degeneration produces the corpus albicans (a white scar of connective tissue).

Spermatogenesis and Oogenesis

Spermatogenesis (AN77.3) is the process by which spermatogonia (diploid stem cells) differentiate into mature spermatozoa (haploid gametes) within the seminiferous tubules of the testis. It begins at puberty and continues throughout life, with a complete cycle taking approximately 64-74 days.

Figure: Spermatogenesis and Oogenesis

The process occurs in three phases: (1) Spermatogonial phase (mitotic): Type A spermatogonia undergo mitotic divisions, with some remaining as stem cells (maintaining the spermatogonial pool) and others differentiating into type B spermatogonia, which divide to form primary spermatocytes (2n, 46 chromosomes). (2) Meiotic phase: Primary spermatocytes undergo meiosis I (the reduction division), producing two secondary spermatocytes (1n, 23 chromosomes, each with two chromatids). Secondary spermatocytes rapidly undergo meiosis II (the equational division), producing four spermatids (1n, 23 chromosomes, each with one chromatid). (3) Spermiogenesis (maturation phase): Spermatids undergo dramatic morphological transformation into spermatozoa without further cell division. This involves: nuclear condensation (chromatin compaction with replacement of histones by protamines), acrosome formation (from the Golgi apparatus — the acrosome contains hydrolytic enzymes essential for penetrating the zona pellucida), flagellum development (from the centriole — the tail contains the axoneme with the characteristic 9+2 microtubule arrangement), mitochondrial sheath formation (around the midpiece — providing ATP for motility), and cytoplasmic reduction (shedding excess cytoplasm as residual bodies, phagocytosed by Sertoli cells).

The seminiferous tubule has a highly organised architecture. Sertoli cells (sustentacular cells) are large, non-dividing cells that span from the basement membrane to the lumen, providing structural support and nourishment to developing germ cells. They form the blood-testis barrier through tight junctions between adjacent Sertoli cells, creating a basal compartment (containing spermatogonia) and an adluminal compartment (containing spermatocytes and spermatids) that is immunologically privileged. Sertoli cells also produce: androgen-binding protein (ABP — concentrating testosterone in the tubular lumen), inhibin B (negative feedback on FSH), anti-Müllerian hormone (AMH — in the foetus, causing regression of Müllerian ducts), and fluid that transports spermatozoa to the rete testis. Leydig cells (interstitial cells) lie between the seminiferous tubules and produce testosterone in response to LH. Testosterone is essential for spermatogenesis (acting through Sertoli cells) and for maintenance of male secondary sexual characteristics.

Oogenesis (AN77.3) is the process of ovum formation, which begins in foetal life and is not completed until fertilisation — spanning decades.

(1) Foetal period: Primordial germ cells migrate to the developing ovary and undergo rapid mitotic proliferation as oogonia, reaching a peak of approximately 6-7 million by the 5th month of foetal life. Oogonia then enter meiosis I and become primary oocytes, arresting in the diplotene stage of prophase I (also called the dictyotene stage). Each primary oocyte is surrounded by a layer of flat follicular (granulosa) cells, forming a primordial follicle. By birth, the number of oocytes has already declined to approximately 1-2 million through atresia (programmed cell death), and no new oocytes are formed after birth (recent stem cell research has challenged this dogma, but it remains the accepted teaching).

(2) From puberty to menopause: At each menstrual cycle, a cohort of primordial follicles is recruited into the growing pool. The primary oocyte remains arrested in prophase I throughout this period — an arrest that can last from 12 years (puberty) to over 50 years (menopause). This prolonged arrest is one reason for the increased risk of non-disjunction with advancing maternal age. The LH surge triggers resumption of meiosis I: the primary oocyte completes its first meiotic division, producing a large secondary oocyte (which retains most of the cytoplasm) and a small first polar body (which receives minimal cytoplasm and eventually degenerates). The secondary oocyte immediately begins meiosis II but arrests in metaphase II. It is this secondary oocyte (arrested in metaphase II) that is ovulated.

(3) At fertilisation: Penetration of the secondary oocyte by a spermatozoon triggers completion of meiosis II, producing the mature ovum (female pronucleus) and the second polar body.

Key differences between spermatogenesis and oogenesis include: (1) spermatogenesis produces four functional gametes from each primary spermatocyte, while oogenesis produces only one ovum and two or three polar bodies; (2) spermatogenesis is continuous from puberty, while oogenesis begins in foetal life and is completed only at fertilisation; (3) spermatogenesis involves extensive cytoplasmic reduction, while oogenesis involves cytoplasmic accumulation (the ovum is one of the largest cells in the human body, approximately 120 μm diameter); (4) the prolonged meiotic arrest in oogenesis (decades) predisposes to non-disjunction errors with maternal aging.