Estrogen and Progesterone

Overview

Introduction

• Female hormones
  • in follicular phase of menstrual cycle, follicle synthesizes estrogens
    • major product is 17β-estradiol
  • in luteal phase of menstrual cycle, corpus luteum synthesizes progesterone and estrogen
• major product is progesterone

Estrogen

• Sources of estrogens 
  • ovary (17β-estradiol)
  • placenta (estriol)
  • blood (aromatization)
• Estrogens biosynthesis
  • two-cell, two-gonadotropin model
    • 17β-estradiol synthesis requires granulosa cells and theca cells
      • theca cells do not express aromatase
        • aromatase catalyzes conversion of androstenedione to 17β-estradiol
    • biosynthetic pathway
      • LH acts on theca cells
        • increases activity of cholesterol desmolase
          • increases synthesis/secretion of androstenedione
          • androstenedione freely diffuses from theca cells to granulosa cells
      •  FSH acts on granulosa cells
        • increases activity of aromatase
          • increases synthesis/secretion of 17β-estradiol
• Estrogens potency
  • 17β-estradiol > estrone > estriol
• Estrogen receptor
  • estrogen receptor (ER) functions as a homodimer and resides in cell cytoplasm
  • estrogen-ER complex translocates to cell nucleus, interacts with steroid response elements on chromatin, and rapidly induces transcription of target genes
• Function of estrogens
  • at puberty, functions in development of female sex characteristics
    • genitalia, breasts, and female fat distribution
  • functions in proliferation and development of ovarian granulosa cells of follicles
  • functions in maturation and maintenance of uterus
    • proliferates endometrium of uterus
    • lowers uterine threshold to contractile stimuli
      • increases myometrial excitability
  • upregulates estrogen, progesterone, and LH receptors
  • negatively feeds back on anterior pituitary in follicular phase of menstrual cycle 
    • ↓ FSH and ↓ LH
  • positively feeds back on anterior pituitary at midcycle in response to LH surge
    • ↑ FSH and ↑ LH
  • stimulates prolactin secretion
    • blocks action of prolactin on breasts
  • upregulates transport proteins
    • in blood plasma, estrogens are mostly bound to carrier proteins
      • e.g., albumin and sex hormone-binding globulin (SHBG)
  • upregulates HDL cholesterol and downregulates LDL cholesterol
• Notes
  • pregnancy
    • 50-fold ↑ in 17β-estradiol and estrone
    • 1,000-fold ↑ in estriol
• increase in estriol levels is an indicator of well-being of fetus

Progesterone

• Sources of progesterone
  • corpus luteum, placenta, adrenal cortex, and testes
• Function of progesterone 
  • stimulates endometrial glandular secretions
  • stimulates development of spiral arteries
  • maintains pregnancy
  • raises uterine threshold to contractile stimuli during pregnancy
    • decreases myometrial excitability
  • relaxes uterine smooth muscle
    • prevents contractions
  • produces thick cervical mucus that inhibits sperm entry into uterus
  • increases basal body temperature
    • increases hypothalamic temperature set-point
  • negatively feeds back on anterior pituitary in luteal phase of menstrual cycle
    • ↓ FSH and ↓ LH
  • downregulates estrogen receptors
• Notes
  • increase in biosynthesis of progesterone is characteristic of mid cycle or ovulation
• “PROGESTerone is PRO-GESTation”

Estrogen and Progesterone in Pregnancy

• Overview
  • estriol is major estrogen in pregnancy
• Maternal-placental-fetal unit
  • elevated levels of estrogens and progesterone are necessary for maintaining pregnancy
  • corpus luteum is not adequate to generate very high hormone levels
  • placenta emerges as major source of estrogens and progesterone
  • placenta is an imperfect endocrine organ
    • placenta cannot synthesize sufficient cholesterol
      • cholesterol is a precursor for hormone synthesis
    • placenta lacks necessary enzymes for estrogen synthesis
  • maternal-placental-fetal unit overcomes shortcomings of placenta to very high hormones levels
• Progesterone synthesis
  • mother provides cholesterol (LDL particles) to placenta
  • placenta converts cholesterol to pregnenolone then to progesterone
  • placenta provides high progesterone levels to mother
• Estriol synthesis
  • mother provides cholesterol (LDL particles) to placenta
  • placenta converts cholesterol to pregnenolone to progesterone
  • placenta provides high progesterone levels to fetus
  • fetal adrenal cortex converts progesterone to DHEA-sulfate
  • fetal liver hydroxylates DHEA-sulfate to 16-OH DHEA-sulfate
  • fetus provides high levels of 16-OH DHEA-sulfate to placenta
  • placenta converts 16-OH DHEA-sulfate to estriol
  • placenta provides high estriol levels to mother