Reproductive Endocrinology

Hypothalamus: Gonadotropin Releasing Hormone (GnRH) Pituitary: Follicle Stimulating Hormone (FSH) Luteinizing Hormone (LH) Ovary: Estradiol Progesterone Testes: Testosterone

10 aa peptide Secreted in pulsatile fashion (2-3 hr cycle) Higher frequency stimulates FSH secretion Lower frequency stimulates LH secretion Sexual maturity results from activation of GnRH secretion

Heterodimeric glycoproteins α-subunit – shared by FSH, LH, TSH, and hCG ß-subunit – provides unique actions of hormones FSH - MW ~34,000 LH – MW ~28,000 Each have trophic functions in males and females

Up to 8 weeks gestation, embryos contain primordial genital ducts of both sexes: Wolffian – male Mullerian – female At 8 weeks, testes begin production of: Testosterone – supports development of Wolffian: Epididymis, vas deferens and seminal vesicles Anti-mullerian hormone – blocks Mullerian growth: Fallopian tubes, uterus, upper vagina Lack of testosterone action leads to Wolffian degeneration and Mullerian development

~400,000 primordial follicles at puberty 300-400 will reach maturity and ovulate Remainder “die” by atresia throughout life Puberty: Adrenarche – onset of adrenal androgen synthesis Onset at 6-7 years Androstendione, DHEA and DHEAS Dec. sensitivity of HP axis to negative feedback GnRH and gonadotropin secretion Menarche – onset of menstrual cycles

GnRH stimulates FSH and LH release FSH – follicular maturation and estradiol synthesis LH – follicular rupture and progesterone synthesis Estradiol (E2) Endometrial proliferation Pos and neg feedback Progesterone (P4) E ndometrial support

Estradiol(-17ß) – E2 18 carbon aromatic steroid Promotes secondary sexual characteristics Increases HDL, some proteins (eg, TBG) Synthesized in ovary and placenta Progesterone – P4 21 carbon steroid Precursor of many steroids Some influence on breast development Primarily involved in pregnancy

Estradiol Reference is interval age and menstrual cycle dependent 39-375 pg/mL (follicular phase) 49-440 pg/mL (luteal phase)

Progesterone Ref. interval is age, cycle & pregnancy stage dependent 0-2.7 ng/mL (follicular phase) 3.0-31.4 ng/mL (luteal phase) Pregnancy: 11.0-45.0, 26.0-89.0, 46.0-423 ng/mL by trimester Immunoassay (competitive) LC-MS/MS

Immunoassay (usually sandwich assays) Reference ranges sex, age and cycle variable Ultrasensitive assays available – necessary for prepubertal evaluations

Release of egg from follicle

Late luteal phase (of prev. cycle) E2 and P4 decline, FSH secretion increases (loss of negative feedback) FSH stimulates follicular proliferation and E2 Day 1-4 – several follicles recruited and develop Granulosa cells synthesize and secrete E2 Day 5-7 – dominant follicle selected, suppressing others E2 stimulates endometrial (uterine lining) proliferation E2 negative feedback suppresses FSH secretion E2 synthesis continues Antral follicle is final product

Rising follicular E2 stimulates LH surge at day 12-13 via positive feedback LH peaks 24-36 hours later Ovulation – 10-12 hrs post LH peak (day 14) • –Follicular rupture • –Ovum release LH stimulates follicular synthesis of P4 Ovum captured by fallopian tubes

Ruptured follicle transforms to corpus luteum Corpus luteum (CL) synthesizes P4 and E2 -P4 rises ~3 days post ovulation -P4 suppresses LH and FSH secretion -P4 peaks about 8-9 days post ovulation Fertilized ovum implants in uterine lining -hCG synthesis by trophoblast maintains CL -CL P4 maintains endometrium Without hCG, CL begins regression ~day 9 -Decreasing P4 promotes endometrial sloughing

Defined as 12 months of amenorrhea —Mean age at 51 years —No correlation with age of menarche Primary depletion of ovarian follicles Decreased estradiol (10% of normal levels) Increased FSH & LH (no negative feedback) —FSH 10-15x due to longer half-life (4 hrs) —LH 4-5x (half-life 30 minutes)

Pseudohermaphroditism: • –Gonadal sex different than genital sex • –46,XX karyotype with ambiguous genitalia • Congenital adrenal hyperplasia (CAH) Precocious puberty: • –Secondary sexual characteristics before age 8 • –GnRH-dependent – early activation of HP axis • ——-nc. LH using ultrasensitive immunoassay GnRH-independent: • Usually CAH • Tumors of adrenals or ovaries • Steroid measurement, imaging Primary amenorrhea • –No menses by age 16 • –Turner’s syndrome (45,X(O) karotype) • –Pure gonadal agenesis • –Mullerian duct agenesis/dysgenesis • -Absent uterus or vagina • –Androgen insensitivity (testicular feminization) • –Congenital adrenal hyperplasia • —Hypothalamic or pituitary Elevated FSH indicates ovarian non-response Chromosomal testing indicated Low FSH/LH suggest 2° or 3° issue

X-linked defect of androgen receptor Lack of androgen cellular effects Wolffian development fails ---Testosterone ineffective Mullerian development “normal” --Anti-mullerian factor present -------Blocks upper genital tract development Genotypic XY, phenotypic female Intra-abdominal testes Normal to high testosterone, high LH

Secondary amenorrhea Loss of normal menses for ≥6 months Pregnancy Polycystic ovary syndrome (PCOS) Ovarian tumors, premature ovarian failure Late-onset CAH, Cushing’s syndrome, adrenal tumors Pituitary disorders, incl. hyperprolactinemia Hypothalamic, excessive exercise, stress Drugs History very important Lab testing similar to primary amenorrhea except no genetic testing

Polycystic Ovary Syndrome (PCOS) May comprise 80-90% of anovulatory infertility Prevalence up to 20% More common in Hispanic and South Asian women Less common in women of Chinese or Japanese descent Diagnosis requires two of the following: Presence of hyperandrogenism and/or hyperandrogenemia Irregular or absent ovulation Presence of polycystic ovaries by ultrasound

Hyperandrogenism: Hirsutism – male hair pattern (beard, trunk) Virilization – inc. muscle mass, deepening voice More common in androgen-secreting tumors

Hyperandrogenemia: ASD, DHEA and/or testosterone increased DHEA-S normal; elevated indicates adrenal origin 50% are obese, many have acne Insulin resistance LH elevated, FSH normal to low LH:FSH >2.5 suggestive (with symptoms)

GnRH stimulates FSH and LH release FSH – Sertoli cells -Spermatogenesis -Inhibin secretion (dont worry about it) (↓ FSH) LH – Leydig cells -Synthesize testosterone Testosterone -2° sexual characteristics -Anabolic actions -Spermatogenesis

Testosterone (T) -Secondary sexual characteristics -Inc. muscle and bone mass (anabolic) -Libido -Promotes spermatogenesis Dihydrotestosterone (DHT) -5α-reductase in prostate and skin -Biologically active form of testosterone ---Similar to T3 ---Rarely measured Dehydroepiandrosterone (DHEA) Androstanedione (ASD) ----Both are precursors to T and DHT

Bound to plasma proteins Sex-hormone binding globulin (SHBG) – ~60% Low capacity, high affinity Estradiol also bound Albumin – high capacity, low affinity - ~35% Free – 2-3% Controversy as to whether only free (2-3%) or weakly bound (37-38%) are biologically active