Gametogenesis, fertilisation and the first two weeks of development

From the Department's gametogenesis and early embryology slides (photographed), rewritten as a clinical story: how the gametes are made, how they meet, and how the embryo implants. The clinical payoff is infertility, ectopic pregnancy, molar pregnancy and early pregnancy loss.

The reasoning chain: meiosis halves the chromosomes (46 → 23) in the testis and the ovary → one sperm penetrates one secondary oocyte in the ampulla of the tube → the zygote cleaves and becomes a blastocyst → the blastocyst implants in the posterior upper wall of the uterus by about day 7 → the bilaminar disc forms in week 2 and the placental circulation begins. A fault at any step gives infertility, an ectopic pregnancy or an early loss.

1. Gametogenesis: making sperm and eggs

Gametogenesis converts diploid germ cells (46 chromosomes, 2N) into haploid gametes (23, 1N) by meiosis. The primordial germ cells arise in the wall of the yolk sac in week 4 and reach the gonadal ridges by week 6.

Male: spermatogenesis (from puberty, continuous)

Three phases:

1. Spermatocytogenesis: at puberty, primordial germ cells become type A spermatogonia (46, 2N). Some type A cells divide by mitosis to keep a continuous stem-cell supply for the whole reproductive life; others become type B spermatogonia (46, 2N), which enter meiosis as primary spermatocytes.
2. Meiosis: a primary spermatocyte (46, 4C) completes meiosis I to form two secondary spermatocytes (23, 2N), and meiosis II to give four haploid spermatids (23, 1N).
3. Spermiogenesis: each spermatid matures into a sperm (acrosome forms, nucleus condenses, tail develops, excess cytoplasm is shed). No cell division occurs here.

The whole process takes about 64–74 days in the seminiferous tubules, supported by Sertoli cells (blood-testis barrier, nutrition) and driven by FSH, LH and testosterone from Leydig cells. Sperm are stored and matured in the epididymis (about 2 weeks) and gain motility there. One primary spermatocyte gives four sperm.

Female: oogenesis (starts before birth, finishes at fertilisation)

• Fetal life: oogonia multiply by mitosis, become primary oocytes, and start meiosis I but stop in prophase I (diplotene) from about month 5 of fetal life until puberty. About 7 million germ cells at 20 weeks fall to about 1–2 million at birth and about 400,000 at puberty; only about 400–500 are ovulated.
• At puberty: each cycle 5–15 primary oocytes begin to mature, usually only one completes maturation.
• Just before ovulation (triggered by the LH surge): the primary oocyte completes meiosis I, giving a secondary oocyte (23, 2N) and the first polar body, which degenerates. The secondary oocyte starts meiosis II and stops at metaphase II.
• Meiosis II is completed only if a sperm penetrates, producing the mature ovum and the second polar body.
• One primary oocyte gives one ovum (and three polar bodies). Advancing maternal age raises the chance of non-disjunction (for example trisomy 21), because the oocyte has been arrested for decades.

2. Week 1: fertilisation, cleavage and the blastocyst

Where: in the ampulla of the uterine tube, within 12–24 hours of ovulation. Sperm remain able to fertilise for about 3–5 days.

Three phases of fertilisation

1. Penetration of the corona radiata with the help of the sperm's enzymes and tail movements (capacitation in the female tract first).
2. Binding and penetration of the zona pellucida: sperm glycosyltransferases bind to ZP3 receptors; binding triggers the acrosome reaction (fusion of the outer acrosomal and the sperm cell membranes, releasing acrosin and other enzymes), which digests a path through the zona.
3. Fusion of the sperm and oocyte membranes triggers the cortical reaction: cortical granules (lysosomes) release enzymes that change the zona and inactivate the sperm receptors. This is the zona (polyspermy) block: no second sperm can enter.

Results of fertilisation: the secondary oocyte completes meiosis II; the male and female pronuclei fuse into the zygote (46); sex is determined (an X-bearing sperm gives a girl, a Y-bearing sperm a boy); cleavage begins.

Clinical points: failure to fertilise causes infertility (IVF and ICSI bypass it). Dispermy gives a triploid conception (partial mole). An empty egg fertilised by a duplicated sperm gives a complete mole (46,XX of paternal origin).

Cleavage and the blastocyst: the zygote divides (2, 4, 8 cells) with no growth, forms the morula (16 cells, about day 3) and becomes a blastocyst (about day 4–5), with an inner cell mass (embryoblast) and an outer trophoblast; it hatches from the zona pellucida. If the zona is defective or the tube is damaged, the embryo may implant in the tube (ectopic pregnancy).

3. Implantation (about day 6–7)

• The blastocyst implants in the endometrium, usually in the posterior superior wall of the uterus, about day 7 after fertilisation.
• It happens in the functional layer of the endometrium during the secretory (progestational) phase of the cycle.
• Trophoblast differentiates into two layers: the cytotrophoblast (inner, mitotic) and the syncytiotrophoblast (outer, multinucleated, invasive; it secretes hCG).
• hCG from the syncytiotrophoblast keeps the corpus luteum producing progesterone, which is why pregnancy tests turn positive about 8–10 days after fertilisation.
• Clinical: implantation low in the uterus gives placenta praevia; implantation in the tube, ovary, cervix or caesarean scar gives an ectopic pregnancy; bleeding at implantation can be mistaken for a light period.

4. Week 2 (days 8 to 14)

The embryoblast: the bilaminar disc

• It splits into two layers: a dorsal epiblast (columnar cells) and a ventral hypoblast (cuboidal cells). Together they form a flat oval disc, the bilaminar embryonic disc.
• Clefts appear in the epiblast and join to form the amniotic cavity.
• Hypoblast cells migrate and line the inner surface of the cytotrophoblast to form the exocoelomic (Heuser's) membrane, which encloses the exocoelomic cavity (primitive yolk sac).
• At the future site of the mouth, hypoblast cells become columnar and fuse with the epiblast to form a circular midline thickening, the prochordal plate.

The trophoblast and the start of the placental circulation

• The syncytiotrophoblast invades the endometrium, eroding blood vessels and glands.
• Lacunae appear in the syncytiotrophoblast and fill with maternal blood and glandular secretions.
• Decidual cells at the implantation site fill with glycogen and lipids and nourish the embryoblast.
• The lacunae fuse into a lacunar network, and maternal blood flows through it, establishing the early uteroplacental circulation (about day 12). At this stage the embryo is fed by diffusion only.
• By the end of week 2 primary chorionic villi begin to form.

Clinical pearls

• The first two weeks are the "all-or-none" period: a toxic insult either kills the embryo or leaves it unharmed; structural malformations arise from weeks 3–8.
• Failure of the trophoblast to invade properly (week 2 and later) underlies pre-eclampsia; over-invasion gives placenta accreta.
• Chromosomal errors at fertilisation are the commonest cause of early miscarriage (see the notes on abortion).

Examiner questions

1. Compare spermatogenesis and oogenesis in a table.
2. Describe the three phases of fertilisation and the cortical reaction.
3. Where and when does implantation occur, and what is the role of hCG?
4. Describe the changes in the embryoblast and trophoblast in week 2.

Practice questions

1. In a woman, primary oocytes are arrested in: A. Prophase of meiosis II · B. Prophase (diplotene) of meiosis I · C. Metaphase of meiosis I · D. Anaphase of mitosis · E. Interphase Answer: B. They stay arrested from fetal life until the LH surge.

2. Meiosis II of the oocyte is completed: A. At birth · B. At puberty · C. At ovulation · D. When a sperm penetrates the secondary oocyte · E. At implantation Answer: D.

3. The usual site of fertilisation is: A. The uterine cavity · B. The cervix · C. The ampulla of the uterine tube · D. The ovary · E. The fimbriae Answer: C.

4. The cortical reaction: A. Starts the acrosome reaction · B. Forms the morula · C. Blocks polyspermy by altering the zona pellucida · D. Produces hCG · E. Forms the amniotic cavity Answer: C.

5. The cells of the trophoblast that make hCG are the: A. Cytotrophoblast · B. Syncytiotrophoblast · C. Epiblast · D. Hypoblast · E. Decidual cells Answer: B.