07 - Reproductive Systems

sexual differentiation

causes sex difference and specificity of reproductive systems

• formed during fetal development

• puberty to establish its functional and structural maturation as a function of hypothalamic-pituitary-gonadal axis

  • sex hormone synthesis and control mechanisms

  • menstrual cycle

• genetic sex → determined by sex chromosomes

  • Y chromosome is determinant for male gonadal and phenotypic sex, since testis-determining gene is located on Y chromosome

• gonadal sex → testes or ovaries

• phenotypic sex → physical appearance of internal and external genitalia

  • differentiation of male phenotype determined by presence of testes and the hormones they produce

  • differentiation of female phenotype is independent on presence of ovaries, but is dependent on absence of testes and the hormones they produce

gonads and hormones

• testes 

  • Leydig cells → secretes testosterone for male differentiation

  • Sertoli cells → secretes antimullerian hormone for regression of Mullerian ducts

• ovaries

  • theca cells → produce progesterone and androgen precursors

  • granulosa cells → converts androgens to estrogen via aromatase

duct development

before differentiation, both Mullerian and Wolffian ducts are present

• testosterone → stimulates Wollfian duct

• antimullerian hormone → regresses Mullerian duct 

• no testosterone/AMH → Wolffian duct regresses, Mullerian duct develops

sex hormone synthesis

cholesterol → progesterone → testosterone → estrogen (E2) → estriol (E3)

• 17⍺-hydroxylase and 17,20-lyase → progesterone to testosterone

• 5⍺-reductase → testosterone to potent dihydrotestosterone (DHT)

  • deficiency alters development of targeting organs

• aromatase → testosterone to estrogen (E2)

  • located in gonads and peripheral tissues

  • in males, E2 functions in spermatogenesis in testes

  • in females, E2 circulation released from ovaries

  • estrogen promotes survival of osteoblasts and inhibits osteoclasts, where deficiency causes osteoporosis

• 16⍺-hydroxylase → E2 to E3

  • major product in placenta

male — hypothalamic-pituitary-gonadal (HPG) axis

hypothalamic neurons secrete GnRH in a pulsatile manner that stimulate pituitary gonadotropes to secrete LH and FSH

• LH acts on Leydig cells to produce progesterone and then testosterone

  • degerming male phenotype in embryogenesis

  • spermatogenesis 

  • all androgenic responses

• FSH acts on Sertoli cells

  • provide antimullerian hormone for male phenotype development in embryogenesis

  • provide structural support and nutritional support for germ cell development

  • convert testosterone to estrogen via aromatase for spermatogenesis

  • produce inhibin to control/inhibit pituitary release of FSH

female — hypothalamic-pituitary-gonadal (HPG) axis

• LH acts on both theca and granulosa cells to produce progesterone

  • theca cell → progesterone converted to androgens via 17⍺-hydroxylase and 17,20-lyase

    • androgens diffuse from theca cell to granulosa cell

  • granulosa cell → progesterone diffuses into theca cell

• FSH acts on granulosa cells to produce estrogen 

  • aromatase → converts androgens to estrogens

GnRH during puberty

secretion of GnRH begins at gestational week 4, with secretion of FSH and LH around 10-12 weeks of gestation at low levels until puberty

• puberty starts with predominant release of GnRH in pulsatile manner during child sleeping

  • allows for time frame for receptor replenishment

• stimulates FSH and LH release from pituitary

feedback mechanisms

• negative feedback (both sexes) → testosterone, estrogen, progesterone, and inhibin decrease GnRH, LH, and FSH levels

  • Leydig cells feedback on LH and FSH

  • Sertoli cells feedback on FSH

  • estrogen feedbacks on hypothalamus and pituitary

• positive feedback (females only) → high estrogen will increase GnRH and LH levels, leading to LH surge

  • estrogen feedforwards to hypothalamus and pituitary

ovarian cycle

• follicular phase → days 1-14

  • increased FSH promotes estrogen synthesis

  • activin released to convert all androgens to estrogen via aromatase

  • follicle growth, endometrial proliferation

• ovulation phase → day 14

  • LH surge, triggered by increased estrogen

    • positive feedback of estrogen 

  • theca and granulosa cells become luteal cells

• luteal phase → days 14-28

  • increased progesterone from corpus luteum

  • low levels of 17,20-lyase and release of inhibin to lower estrogen

  • luteal cells regress from having lowered LH and FSH

    • high progesterone and estrogen for negative feedback

uterine/endometrial cycle

• proliferative phase → 11 days

  • high levels of estrogen

  • endometrial growth

  • cervical mucus is thin and alkaline

• secretory phase → 12 days

  • high levels of progesterone

  • glandular secretion and vascularization

  • cervical mucus is thick and acidic for sperm-blocking

• menstrual phase → 5 days

  • endometrial necrosis and shedding

  • prostaglandins (PGs) cause vasoconstriction in uterus and vasodilation in systemic circulation

gonadal cells summary

in males:

• Leydig cells → secretes testosterone

  • LH receptor

  • drives spermatogenesis and male phenotype

• Sertoli cells → secretes estrogen and inhibin

  • FSH receptor

  • supports spermatogenesis, inhibits FSH

in females:

• theca cells → converts androgens to progesterone

  • LH receptor

  • substrate for granulosa conversion

• granulosa cells → secretes estrogen, inhibin, and activin

  • FSH and LH receptors

  • promotes follicle maturation

  • positive feedback mechanism for estrogen