Reproductive Embryology & Development

Sex determination and differentiation

Default is female; SRY makes testes. The early gonad is bipotential, and the embryo is programmed to develop as female by default. The SRY gene on the Y chromosome encodes testis-determining factor, which converts the bipotential gonad into a testis. Without a Y chromosome, the gonad becomes an ovary; a 46,XY gonad lacking SRY becomes a fibrous streak (Swyer syndrome).

Sertoli and Leydig cells steer the ducts. Sertoli cells secrete Müllerian inhibitory factor (MIF, also called anti-Müllerian hormone), which makes the Müllerian ducts regress. Leydig cells make testosterone, which stabilizes the Wolffian ducts. A male who lacks MIF or its receptor retains a uterus and tubes despite otherwise normal male development.

Sertoli = MIF (removes the female ducts); Leydig = testosterone (builds the male ducts).

Testosterone internal, DHT external. Testosterone itself builds the internal male ducts. 5α-reductase converts testosterone to dihydrotestosterone (DHT), which forms the external genitalia (penis and scrotum) and the prostate and later drives male-pattern hair growth. Without DHT these structures fail to masculinize.

Ducts, external genitalia and descent

Müllerian vs Wolffian. The Müllerian (paramesonephric) ducts form the female internal tract: fallopian tubes, uterus, cervix and upper one-third of the vagina; the lower vagina comes from the urogenital sinus. The Wolffian (mesonephric) ducts form the male internal structures, remembered as SEED: Seminal vesicles, Epididymis, Ejaculatory duct and ductus (vas) Deferens. Each sex keeps small remnants of the other's duct, such as the Gartner duct cyst in females (Wolffian) and the appendix testis in males (Müllerian).

Gonadal descent. The gubernaculum pulls the testis down into the scrotum, preceded by an outpouching of peritoneum, the processus vaginalis. Failure of the processus to close allows an indirect inguinal hernia or a hydrocele. An undescended testis (cryptorchidism) impairs spermatogenesis and raises the risk of infertility and seminoma. In females the gubernaculum becomes the ovarian ligament plus the round ligament of the uterus, which passes through the inguinal canal.

Hypospadias vs epispadias. Hypospadias, the more common anomaly, places the urethral opening on the ventral (under) surface because the urethral folds fail to fuse; it often accompanies cryptorchidism. Epispadias places the opening on the dorsal (upper) surface because the genital tubercle is positioned abnormally, and it is associated with bladder exstrophy. Hypospadias is repaired before any circumcision because the foreskin may be needed for the reconstruction.

Gametogenesis

Oocytes arrest, sometimes for decades. Primary oocytes begin meiosis I during fetal life and arrest in prophase I until ovulation. The LH surge completes meiosis I, producing a secondary oocyte and the first polar body; the secondary oocyte then arrests in metaphase II until fertilization, when meiosis II finishes and releases the second polar body. The long prophase I arrest is why nondisjunction, and therefore Down syndrome, becomes more likely with maternal age.

"An egg met a sperm": meiosis I finishes at ovulation, meiosis II at fertilization.

Spermatogenesis is continuous from puberty. In the seminiferous tubules, spermatogonia give rise to primary spermatocytes, which divide into secondary spermatocytes and then spermatids; spermiogenesis remodels spermatids into spermatozoa. The full cycle takes about 64–74 days, Sertoli cells nurse the developing cells, and there is no prolonged meiotic arrest.

Disorders of sexual development

Complete androgen insensitivity. A 46,XY person has a defective X-linked androgen receptor. The testes make MIF, so there is no uterus or tubes, and they make testosterone, but tissues cannot respond. The result is female external genitalia with a blind-ending vaginal pouch, scant pubic and axillary hair, and breast development from aromatized estrogen. It presents as primary amenorrhea, like the 16-year-old with testes in the groin. Testes may be intra-abdominal or inguinal and are removed after puberty because of their malignancy risk.

5α-Reductase deficiency. In this autosomal recessive 46,XY condition, DHT cannot be made, so external genitalia are ambiguous or female-appearing at birth, but they virilize at puberty with the testosterone surge. Internal Wolffian structures are normal, and testosterone is normal or high with an elevated testosterone-to-DHT ratio.

Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser). A 46,XX female has an absent uterus and upper vagina but normal ovaries, so secondary sex characteristics and (female-range) testosterone are normal. It presents as primary amenorrhea and is often accompanied by renal anomalies.

Klinefelter syndrome (47,XXY). Meiotic nondisjunction produces the most common cause of primary male hypogonadism. Dysgenetic, hyalinized seminiferous tubules leave small, firm testes with infertility and low inhibin, so FSH rises; Leydig cell failure lowers testosterone, so LH rises and estrogen is relatively high, causing gynecomastia. Patients are tall with long limbs, carry a Barr body, and have a higher risk of male breast cancer.

Turner syndrome (45,XO). The most common cause of primary amenorrhea: short stature, streak ovaries (premature ovarian failure), webbed neck from fetal cystic hygroma, shield chest with widely spaced nipples, lymphedema of hands and feet, bicuspid aortic valve and coarctation of the aorta, and horseshoe kidney. Estrogen is low and FSH and LH are high, and there is no Barr body. Intelligence is usually normal.