MCB 135E Discussion October 3, 2005

Sex Differentiation: Male 6th Embryonal Week Bipotential gonad differentiates as a testis & secretes testosterone (T) from Leydig cells T secretion promotes: Wolffian ducts differentiation Male secondary sex organs T secretion promotes: Regression of Mullerian ducts by Mullerian Inhibitory Substance (MIS) from Sertoli Cells) T secretion promotes: Activity of 5 alpha reductase to produce dihydrotestosterone (DHT) and formation of external genitalia

Major Intersexual Conditions with NORMAL Chromosome Complement Pseudohermaphroditism A) Female Congenital virilizing adrenal hyperlasia of the fetus Maternal androgen excess: Endogenous: virilizing adrenal or ovarian tumor Exogenous: treatment with androgens or progestins B) Male: Androgen resistance Defective testicular development Congenital steroid enzyme deficiency (lack of 5 alpha reductase)

Major Intersexual Conditions with ABNORMAL Chromosome Complement 1.Only one X or more than XX Chromosomes (female) Ovarian dysgenesis XO (Turner’s Syndrome) Superfemales XXX 2. With a Y and XX chromosome (male) Seminiferous tubule dysgenesis XXY (Klinefelters’s Syndrome) 3. Mosaics True hermaphroditism

Example of Experimental Protocol

During Prenatal Growth Studies from experimental animals show that removal of the pituitary gland (no GH, no T3, T4) or damage to the hypothalamus (no GHRH, GHIH, no TRH) FAIL to impair somatic body growth

During Prenatal Growth in humans Infants born with: *Pituitary aplasia *Anencephaly *Congenital GH deficiency are all of normal size at birth Maternal GH does NOT cross the placenta Therefore maternal GH does not substitute for fetal GH

Fetal GH GH is secreted & circulates in blood reaching a peak at midgestation What is the function of fetal GH? Perhaps GH develops/differentiates those hypothalamic centers regulating GHRH and GHIH in readiness for their function after birth Another example of the organizational actions of hormones

If GH does not regulate fetal growth then what does? Insulin may have an regulatory action on growth *Detectable insulin blood levels at 11-12 weeks *Insulin receptors present by 15 weeks *Levels rise progressively throughout gestation *By 34 weeks, levels are more than 6x adult values

Insulin Insufficiency Pancreatic agenesis (failure of pancreas development) Leprechaunism (resembling elves) Reduced intrauterine growth due to extreme insulin resistance In both cases, the fetus at birth has low body weight (decreased fat & decreased muscle mass) These infants are hyperinsulinemic but their cells do not respond to insulin: few receptors less receptor binding abnormal receptors post receptor defects

Insulin-like Growth Factors (IGF1, IGF2) IGFs: insulin-like peptides mediate effect of GH on growth postnatally. In adult, they are produced mostly in the liver, simulated by GH. In the human fetus levels of IGF1 are low. However, fetal levels of IGF2 are as high as adult levels. IGF1 levels are correlated with body weight and increase at birth.