NS 3410 1st Edition Lecture 12Outline of Last LectureI. HormonesII. Endocrine Gland Stimuli: Humoral StimulusIII. Parathyroid GlandIV. Hormonal StimuliV. Vitamin D Synthesis Outline of Current LectureI. Sex- Steroid Production in MenII. Sex-Steroid Production in WomenIII. Mutations in Aromatase EnzymeIV. Aromatase Deficient MenV. Receptor MutationsCurrent LectureI. Sex-Steroid Production in Men- Androgens are critical for differentiation of the reproductive system, sexual function, spermatogenesis-95% androgen from Leydig cells of testes and 5% from adrenal gland-98% of testosterone bound to sex hormone binding globulin and 2% free- GnRH (hypothalamus), LH/FSH (pituitary), testes-LH stimulates testosterone production in Leydig cells-FSH impacts spermatogenesis- Adrenal cortex produces androstenedione- can be converted into either testosterone or estrogenThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- Peripheral conversion of androstenedione from the adrenal cortex into estrogen takes place in many tissues including skin, muscle, adipose tissue and bone- Production of adrenal androstenedione is governed by ACTH, production of gonadal androstenedione is under control by gonadotropinsII. Sex- Steroid Production in Women- Estrogen- endometrial development, ovulation- Estrogen is synthesized primarily by the ovary; adipocytes are secondary source- Most estrogen also bound to SHBG/ little is free- GnRH (hypothalamus) > LF/FSH (pituitary) > ovary-LH surge triggers ovulation and corpus luteum development-FSH initiates follicular growth- Androgens- in premenopausal women, the adrenal glands and ovaries each produce about half of the total androstendione. After menopause, androstenedione production is about halved due to the loss of the steroid secreted by the ovaryIII. Mutations in Aromatase Enzyme- Aromatase deficiency in humans is rare- If fetus does not have aromatase, androgens from fetal adrenal glands can’t be converted to estrogen by placenta so they are converted to testosterone peripherallyand leads to virilization of the mother and fetus- Females are identified at birth due to pseudohermaphroditism. Can get cystic ovariesand delayed bone maturation during childhood and at puberty- primary amenorrhea, failure of breast development, virilization and hypergonadotrophic hypogonadism- Males are diagnosed much later, no obvious defects at birth, have tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity- Estrogen replacement therapy reverses symptoms in males and females- Aromatase encoded by CYP19A1 gene- Aromatase activity in various tissues including the testicular Leydig cells of testis, adipose tissue, ovary, skin, placenta, brain- Aromatase deficiency is inherited via autosomal recessive mode of transmission; all by 2 cases to date are consanguineous - Virilization of mother during pregnancy is common; high 5-DHT testosterone and androstenedione with low estradiol, estriol- Female fetus is severely masculinized external genital IV. Aromatase Deficient Men- Undetectable estrogens- Normal to high levels of testosterone and gonadotropins- Tall stature- Delayed skeletal maturation- Eunuchoid body proportions- Osteoporosis and bone pain- Progressive genu valumV. Receptor Mutations- Mutations in the glucocorticoid, androgen, thyroid hormone and vitamin D receptors have been identified- These mutations cause hormone resistance by usually changing either the ability of the hormone to bind to the receptor or causing a conformational change in the HR complex so they cannot elicit genomic or non-genomic effects- No mutation for the estrogen receptor had been reported suggesting that it would be lethal, perhaps by affecting embryo implantation- Historically believed that estrogen was not important hormone in