Reproductive Physiology, Pathology, and Development

Reproductive And Development Reasoning Map

The reproductive axis depends on pulsatile hypothalamic GnRH. GnRH stimulates pituitary gonadotrophs through Gq signaling to release LH and FSH. Pulse frequency and amplitude shape the relative secretion of LH and FSH; continuous GnRH exposure downregulates receptors and suppresses both gonadotropins, which is why continuous GnRH agonists or antagonists can treat hormone-sensitive conditions. Prolactin inhibits GnRH, so hyperprolactinemia causes decreased LH and FSH, anovulation, infertility, amenorrhea, and hypogonadism.

Dopamine inhibits prolactin, while TRH stimulates prolactin, explaining why primary hypothyroidism can produce galactorrhea and menstrual dysfunction.

Ovarian steroidogenesis follows a two-cell, two-gonadotropin model. LH stimulates theca interna cells to convert cholesterol into androgens. FSH stimulates granulosa cells to express aromatase, converting theca-derived androgens into estradiol. Before ovulation, estradiol proliferates endometrium and thins cervical mucus. Sustained high estradiol switches from negative to positive feedback on the pituitary, producing the LH surge. The LH surge causes completion of meiosis I in the oocyte, follicular rupture, and luteinization.

The corpus luteum secretes progesterone, which converts proliferative endometrium into secretory endometrium with tortuous glands, stromal edema, and nutrient-rich secretions. If implantation does not occur, luteolysis decreases progesterone and estradiol, causing spiral artery constriction, ischemia, and menstruation. If implantation occurs, syncytiotrophoblast secretes hCG, an LH analog that rescues the corpus luteum until the placenta produces sufficient progesterone.

The menstrual cycle is best anchored by ovulation. The follicular phase varies in length and is dominated by recruitment of follicles under FSH, selection of a dominant follicle, rising estradiol, and proliferative endometrium. Ovulation occurs about 14 days before menses, regardless of total cycle length, because the luteal phase is relatively fixed. The luteal phase is dominated by progesterone. Basal body temperature rises after ovulation because progesterone has a thermogenic effect.

Primary amenorrhea is failure of menses by expected age and is approached with secondary sexual characteristics, uterus presence, and gonadotropins. Secondary amenorrhea first requires exclusion of pregnancy, then evaluation of hypothalamic, pituitary, ovarian, thyroid, and uterine causes. Polycystic ovary syndrome involves increased GnRH pulse frequency favoring LH, theca androgen production, peripheral estrone from adipose aromatase, chronic anovulation, insulin resistance, hirsutism, acne, and risk of endometrial hyperplasia from unopposed estrogen.

Testicular physiology parallels ovarian compartmentalization. LH stimulates Leydig cells to produce testosterone. FSH stimulates Sertoli cells to support spermatogenesis, secrete androgen-binding protein, produce inhibin B, and make anti-Mullerian hormone during fetal life. Testosterone maintains male internal ducts and secondary sex characteristics; dihydrotestosterone, made by 5alpha-reductase, drives external genitalia, prostate development, facial and body hair, and prostate growth. Inhibin B selectively suppresses FSH. Primary testicular failure causes low testosterone with high LH and FSH.

Androgen insensitivity syndrome is an XY condition with functional testes and normal AMH, so paramesonephric structures regress, but androgen receptor failure prevents male internal and external differentiation. Patients have female external genitalia, absent uterus, sparse pubic hair, and undescended testes. 5alpha-reductase deficiency causes undervirilized external genitalia at birth with virilization at puberty when testosterone rises.

Embryology questions often ask what structure a duct or tissue becomes. Paramesonephric ducts form fallopian tubes, uterus, cervix, and upper vagina unless AMH induces regression. Mesonephric ducts form epididymis, vas deferens, seminal vesicles, and ejaculatory ducts when testosterone is present. The lower vagina derives from the urogenital sinus. Ovaries descend to the pelvis, and gubernaculum remnants become the ovarian ligament and round ligament.

Testes descend through the inguinal canal, guided by the gubernaculum, and the processus vaginalis normally obliterates; persistence can cause indirect inguinal hernia or hydrocele. Hypospadias results from failure of urethral folds to fuse and is associated with ventral urethral opening. Epispadias is a dorsal urethral defect associated with bladder exstrophy. Urachal remnants can produce urine discharge from the umbilicus, cysts, or sinus tracts.

Sexual differentiation begins with chromosomal sex and SRY-driven testes formation. Sertoli cells produce AMH to regress paramesonephric ducts. Leydig cells produce testosterone to preserve mesonephric ducts. DHT masculinizes external genitalia. Without testes, internal female structures develop by default from paramesonephric ducts and external genitalia follow a female pattern. Congenital adrenal hyperplasia in an XX fetus can virilize external genitalia while internal female organs remain because ovaries do not produce AMH.

Kallmann syndrome causes failed GnRH neuron migration with anosmia and hypogonadotropic hypogonadism. Turner syndrome, usually 45,X, causes streak ovaries, primary ovarian failure, short stature, webbed neck, coarctation of the aorta, and primary amenorrhea with high FSH.

Pregnancy physiology is endocrine and vascular. hCG from syncytiotrophoblast maintains the corpus luteum early and can stimulate the TSH receptor, sometimes lowering TSH in early pregnancy. The placenta produces progesterone to maintain decidua and uterine quiescence, estrogens to support uterine growth, human placental lactogen to induce maternal insulin resistance and lipolysis, and CRH involved in timing labor. Maternal plasma volume increases more than red cell mass, causing dilutional anemia. Systemic vascular resistance falls, increasing cardiac output.

Glomerular filtration rate rises, lowering serum creatinine. Hypercoagulability increases venous thromboembolism risk. Preeclampsia reflects abnormal placentation with inadequate spiral artery remodeling, placental ischemia, endothelial dysfunction, hypertension, proteinuria, and end-organ injury. Eclampsia adds seizures. HELLP syndrome includes hemolysis, elevated liver enzymes, and low platelets. Gestational diabetes is driven by placental hormones that increase insulin resistance.

Contraception mechanisms are common Step 1 targets. Combined estrogen-progestin contraceptives suppress GnRH, LH, and FSH through negative feedback, preventing the LH surge and ovulation; progestin also thickens cervical mucus and thins endometrium. Progestin-only methods rely more heavily on cervical mucus and endometrial effects and may suppress ovulation depending on formulation. Emergency levonorgestrel primarily delays or inhibits ovulation before the LH surge. Copper intrauterine devices create a local inflammatory reaction toxic to sperm and ova.

Levonorgestrel intrauterine systems thicken cervical mucus and produce endometrial atrophy. Selective estrogen receptor modulators vary by tissue: clomiphene blocks estrogen feedback at the hypothalamus, increasing GnRH, LH, and FSH to induce ovulation; tamoxifen antagonizes breast estrogen receptors but can stimulate endometrium.

Reproductive pathology is organized by cell of origin. Endometrial hyperplasia and endometrioid carcinoma are linked to prolonged unopposed estrogen, obesity, anovulation, estrogen-secreting tumors, or tamoxifen. Leiomyomas are benign estrogen-sensitive smooth muscle tumors of myometrium and can cause abnormal bleeding, infertility, and a whorled gross pattern. Endometriosis is ectopic endometrial glands and stroma, commonly in ovaries, pelvic peritoneum, or uterosacral ligaments, causing cyclic pain, infertility, and chocolate cysts.

Ovarian epithelial tumors are often cystic and occur in older patients; serous tumors may have psammoma bodies, mucinous tumors are multiloculated, and Brenner tumors have transitional-type epithelium. Germ cell tumors include dysgerminoma, yolk sac tumor with alpha-fetoprotein and Schiller-Duval bodies, choriocarcinoma with hCG, and mature teratoma. Sex cord-stromal tumors include granulosa cell tumors producing estrogen and Call-Exner bodies, and Sertoli-Leydig tumors producing androgens.

Testicular germ cell tumors include seminoma with radiosensitivity and placental alkaline phosphatase, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Prostate adenocarcinoma usually arises in the peripheral posterior zone, while benign prostatic hyperplasia arises in the periurethral transition zone through DHT-mediated stromal and glandular growth.

Trophoblastic disease illustrates abnormal fertilization and placental proliferation. Complete hydatidiform mole usually has an empty egg fertilized by one sperm that duplicates or by two sperm, producing a 46,XX or 46,XY conceptus with diffuse villous swelling, trophoblastic proliferation, very high hCG, and no fetal tissue. Partial mole usually is triploid with some fetal tissue and focal villous changes. Choriocarcinoma is malignant trophoblastic proliferation without chorionic villi, produces high hCG, and spreads hematogenously.

Ectopic pregnancy most often implants in the fallopian tube and presents with pain, bleeding, and lower-than-expected hCG rise; rupture can cause intraperitoneal hemorrhage.