1. Male and Female Reproductive System Review MARIEL ARVIZU, MD DOCTOR OF SCIENCE CANDIDATE NUTRITION DEPARTMENT HARVARD SCHOOL OF PUBLIC HEALTH

2. Reproductive Hormones  Sex hormone synthesis  Sex hormone regulation  Sex hormone effects

3. Puberty  Early puberty social implications  Early age menarche associated:  Cancer – Breast/Endometrial  Obesity  Cardiovascular disease (CVD)

6. Tanner Stages of Puberty: 1969

7. Precocious Puberty secondary characteristics 2.5-3 SD to median age Before 1999: 10 yrs girsl and 12 boys After 1999: 7 years girls and 6 yrs boys Causes Disorders involving hypothalamus Tumors Androgen or Estrogen secreting Infectious Developmental abnormalities Delayed Puberty Absence or incomplete development of secondary sex characteristics by age at which 95% children of that sex and age have reached sexual maturation - 14 boys - 12 for girls (breast development)

8. Normal Puberty  FSH and LH:  Initiate spermatogenesis  Follicule stimulation  Release of sex hormones:  Testosterone  Estrogen Maturation of reproductive system and behavior  Progesterone

9. The hypothalamus-pituitary-gonadal axis (HPG)  Sex hormones are under regulation of pulsatile release of GnRH = Gonadothropin- releasing hormone.  Adenohypofisis(anterior pituitary) GnRH stimulates the release of luteinizing hormone (LH) and follicule-stimulating hormone (FSH) LH – binds to Leyding cells in males and teca cells in ovary Increases the expression of sTAR-steroidogenic acute regulatory protein StAR promotes transfer of cholesterol inside the mitochondria to initiate steroid production

10. Estradiol/Progesterone synthesis =Steroidogenesis

11. Androgen synthesis in males  Androgens: are steroid hormones that control the expression and maintenance of male sexual characteristics.  They are synthesized zona reticulate & fasciculate of the adrenal cortex  DHEA:dihidriepiandristenedione  androstenedione  Testosterone: produced in Leyding cells in the testes but DHT is the biological active hormone

12. Androgen synthesis in females  They are typically = “male hormones” but have important role in female  50% of androgen in women are produced by peripheral circulating DHEA  Other 50% comes from ovary and adrenal glands  DHT is also present but in smaller amounts than in males – virilization hormone  Main source are androgen precursors: 1. DHEA-S = dihidroepiandrostsrone-sulfate zona reticularis adrenal glands 2. DHEA: zona reticularis, ovarian teca cells, and periphery from DHEAS. 3. Androstenedione: zona fasciculate adrenal glands, ovarian stroma, and peripheral DHEAS. aromatase Testosterone → Estradiol in peripheral tissues and important source of estradiol in postmenopausal women

13. Estrogen synthesis in females

14. Estrogen synthesis in males  Estrogens are present in men  Peripheral tissue: circulating aromatase that facilitates conversion of testoster one → est radiol adrostenedi one → est rione  Limited systemic effect, more local effect

15. Progesterone  Synthetized from pregnenolone through 3β-HSD  Ovary  Placenta during pregnancy  Adrenal glands as part of mineralocorticoid production Menstrual cycle Estradiol → main product of FSH stimulation Progesterone → main product of LH following ovulation

16. Hormonal Regulation of Sex Hormones  HPG axis differ by gender  Males: previous slides LH and FSH  Pretty straight forward  Inhibin feeds back only on anterior pituitary release of FSH. + - + + + - - - -

17. http://www.bbc.co.uk/schools/gcsebitesize/science/aqa_pre_2011/human/hormonesrev3.shtml

18. Hormonal Regulation in Females More complicated……MENSTRAUL CYCLE!

19. Estrogen EffectMenWomen Female sexual characteristics: Breast development, growth and differentiation of sexual organs Liver disease who have an excess of estrogen because of the inability of their liver to metabolize it develop gynecomastia, palmar erythema, and spider angiomas. Estradiol promotes uterine endometrium and breasts. In the absence of progesterone, endometrial thickening will proceed unopposed, potentially leading to endometrial hyperplasia and cancer. High exposure to estadiol has also been shown to increase risk for certain breast cancers. Energy homoestasis and metabolism Estrogen deficiency can develop Metabolic Syndrome Aromatase deficiency has been associated with the development of metabolic derangement characterized by increased circulating LDL, decreased glucose tolerance, hyperinsulinemia, and hepatic steatosis. In women, estrogen deficiency has been associated with an increase in adipose cell volume and the growth of peripheral fat pads. Prevention bone loss: estrogens act on osteoblasts and osteoclasts to decrease resorption of bone :(1) increasing expression of factors on osteoblasts which promote osteoclast apoptosis; (2) increasing osteoprotegrin expression and decreasing RANK-RANK ligand signalling Men with estrogen insensitivity or aromatase deficiency are at increased risk of loss in bone density and osteoporosis Menopausal women are at increased risk of bone fractures and bone loss Vasoprotection: estrogens may decrease the risk of atherogenesis in males and females. Premature atherosclerosis in men aromatase-deficient Animal studies have demonstrated a role for estrogen in preventing the formation of new atherosclerotic plaques, but this role has not yet been demonstrated in humans. But premonopausal women have less CVD risk than postmenopausal women and men.

20. Progesterone EffectMenWomen Female menstrual cycle: -- Estradiol promotes uterine endometrium and breasts. In the absence of progesterone, endometrial thickening will proceed unopposed, potentially leading to endometrial hyperplasia and cancer. High exposure to estadiol has also been shown to increase risk for certain breast cancers. After fertilization Maintains pregnancy --- Organizes endometrial vasculature prepare for implantation Inhibits contractions uterine wall by inhibiting oxytocin Allows implantation of oocyte Promotes lobuloalveolar growth in the breasts to prepare for lactation Homoestasis antagonist of the mineralocorticoid receptor (Aldosterone), reducing sodium retention when present, and increasing sodium retention when progesterone is withdrawn. Some of the effects of progesterone may be related to its ability to antagonize estrogen by decreasing expression of estrogen receptors, e.g. the ability of progesterone to inhibit estrogen-mediated endometrial proliferation

21. Androgen Effect: Mainly Testosterone MenWomen Male sexual characteristics: development of the male sexual organs as well as secondary sexual characteristics Men with liver disease who have an excess of estrogen because of the inability of their liver to metabolize it develop gynecomastia, palmar erythema, and spider angiomas. Estradiol promotes uterine endometrium and mammary glands of the breasts. In the absence of progesterone, endometrial thickening will proceed unopposed, potentially leading to endometrial hyperplasia and cancer. High exposure to estadiol has also been shown to increase risk for certain breast cancers. Mood, sexual drive and desire stimulatory effect on libido in both women and men. increased testosterone is associated with an increase in sexual drive and the drop in testosterone with age is associated with a decreasing libido. In women with adrenal insufficiency and consequent low androgen levels, replacement with DHEA has been found to increase energy and improve libido and sexual thoughts Bone formation: increase bone thickness and periosteal bone formation. The effect of testosterone on bone, via aromatisation to estrogen, is thought to account for increased bone strength in men over women. Testosterone increased bone mineral density in women with hypopituitarism but this may have been due to the effects of aromatization to estrogen. Metabolism: muscle deposition. Testosterone increases basal metabolic rate and muscle mass. In women with hypopituitarism, testosterone supplementation increased fat-free mass and muscle. Erythropoiesis: promotes red blood cell formation and protects against anemia. Replacing testosterone in males with hypogonadism results in increases in red blood cell mass. Low levels of testosterone in older women may increase the risk of anemia. Estrogen precursor: testosterone and androstenedione can be aromatized to form estrogens. peripheral aromatization of testosterone plays an important role in estrogen production in bones and the reproductive tract, where it plays an important role in normal physiology. In postmenopausal women, aromatization of circulating androgens is an important source of estrogens and may help to ameliorate some of the consequences of menopause.