Disorders of Sexual DevelopmentDr G CornwallBIO 390P – Human Reproductive Biology

Introduction• Disorders of Phenotypic Sex

– Result in a mismatch between gonadal and phenotypic sex• Changes in sex chromosome #• Hormone Biosynthesis Disorders• Receptor mutations

– Pseudohermaphroditism – In chapter 4 we discussed errors in sex determination

• sex-reversal • true hermaphroditism

• Disorders that affect the timing of puberty– Acceleration of puberty– Delaying puberty

Sex Chromosome Abnormalities• Result from non-disjunction in either the spermatocytes or oocytes during meiosis• Chromosomes do not separate during anaphase of either meiosis I or meiosis II• Aneuploidy - One extra or one less chromosome– Trisomy – Monosomy

• Turner Syndrome X0 1/2,500 female births– Features

• Infertile females, small stature, reduced secondary sex characteristics,

• Low hairline, broad shoulders, short webbed neck• Small ovaries containing no follicles

– Atretic loss by the time birth• Cardiovascular and renal defects, osteoperosis, inverted

nipples

– Hormomally• Low estrogen and Androgen levels• Elevated FSH and LH• Estrogen therapy to get female body form

– 75% of cases have to do w/ non-disjunction in sperm

• Klinefelter’s Syndrome (XXY)– 1/800 male births– Develops after puberty – Presentation

• Disproportionately long long bones• Seminiferout tubule disorganization• Androgen deficiency leading to

– Lack of facial and body hair– Small testes and penis– Infertility and erectile dysfunction– Gynocomastia & low muscle mass

– Many show few symptoms– Primarily due to nondisjunction in egg (67%)– Treatment with androgen therapy

• Cannot restore fertility

Hormone Biosynthesis Disorders• Can result from missing enzymes in the hierarchical biosynthetic pathway of steroid hormones

– Mutations in the genes that encode a particular enzyme involved in the conversion of one product to another

– Deficiency of one hormone leads to deficiencies of others downstream

Androgen Deficiency • Testosterone and DHT have qualitatively different functions in formation of internal and external

genitalia– Defects in their synthesis result in different phenotypic changes– Great variability in the expression due to varied the disparity in

androgen levels between individuals

• DHT deficiency results from a deficiency of 5-α reductase– The phenotype depends on the extent of DHT deficiency– Abnormalities in both internal and external genitalia

• Prostate not formed• Clitoral-like phallus instead of a penis • Labia and vaginal opening rather than a scrotum• Testes remain in abdominal cavity

– T levels are normal - Mesonephric duct development is almost normal• Ejaculatory ducts empty into a blind vagina

– APH levels are normal – no paramesonephric duct formation

• Guevedoces: an example of 5-α reductase deficiancy– XY “female then male”– Seen in Dominican republic, Turkey, and Papua, New Guinea– external genitalia appear at birth as female; clitoral-like penis, undescended tests so scrotum (bifid)

appears like labia • Range of expression from partial to complete DHT deficiency• Raised as girls if full female expression

– at puberty, penis enlarges, testes descend, male characters appear• Due to huge influx of T at puberty• Psychosexual orientation is male

• Testosterone deficiency results from a deficiency in the production of 17-hydroxysteroid dehydrogenase– External genitalia are female in appearance– Cryptorchid testes– Improper formation of the scrotum

Testosterone Elevation• Congenital Adrenal hyperplasia (CAH)

– An increase in T at the same time as a deficiency in glucocorticoids– 21-hydroxlase deficiency– In XX embryos – masculinization of internal and external genitalia

• Vide range of expressions• Ovaries, uterus and uterine tubes are present• Mesonephric duct development is variable

Other Hormone Deficiencies • APH Deficiency (rare)

– Results, in males, from a mutation in the gene encoding APH– Persistent Mullerian Duct Syndrome (PMDS)

• Presence of uterus and uterine tubes in males• External genitalia are normal• Often exhibit chriptorchidism

• Estrogen Deficiency– Results from an aromatase deficiency– In Males - Normal external genitalia, normal development of secondary sex characteristics +

Osteoperosis at a young age.– In females

• Exposed to higher than normal androgen levels during development• Virilzation of external genitalia (surgery necessary)• At puberty – increased virilization, high FSH and LH• Estrogen replacement therapy results in normal puberty

– Both exhibit the expected psychosexual orientation • May indicate estrogen does not play a role in ‘brain sex’

Hormone Receptor Disorders • Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS)

– Aka testicular feminization syndrome– A mutation in the gene that codes for the androgen receptor results in defective T-receptors

• gene is on the X chromosome– Results in XY “females”

• Plenty of T present, but no receptor, thus no T dependent processes are activated– Female external genitalia & psychological orientation– Individuals have testes & produce testosterone

• Estrogen insensitivity syndrome (EIS)– Very rare– Presents in the same way as a male with an aromatase deficiency

Disorders Leading to Precocious Puberty• GnRH dependent precocious puberty– Results from premature activation of the pulse generator (most cases are idiopathic)– Complete precocious puberty (CPP)– Treatment with long-acting GnRH agonists

• Causes down-regulation of GnRH receptor production by pituitary gonadotrophs • Suppresses the onset of changes associated with puberty• Stop treatment at ‘normal’ age of puberty

• GnRH independent– Secondary sex characteristics appear without GnRH stimulation– Incomplete precocious puberty (IPP)– Isolated activation of the pituitary, adrenal or gonads, resulting in increased secretion of their

respective hormones– Results in some but not all pubertal changes occurring early– Causes

• Estrogen producing ovarian or adrenal tumors in girls• Androgen producing adrenal or leydig cell tumors in boys• Pituitary tumors• Mutations in the LH receptor gene that to constitutively active LH receptors

Disorders Leading to Delayed Puberty• Hypogonadotropic hypogonadism

– Gonadal dysfunction due to very low gonadotropin levels– May be due to hypothalamic dysfunction due to failure or suppression of the GnRH pulse generator

• Induced by Stress or CNS tumors• Can be treated with pulsatile GnRH administration

– Maintains fertility & induces and maintains ovulatory cycles– May be due to pituitary defects

• Isolated LH and FSH deficiencies

• Hypergonadotropic hypogonadism

– Gonadal dysfunction in the presence of high gonadotropin levels• Similar to menopause

– Can be due to gonadal dysfunction resulting in low gonadal steroids, and thus reduced negative feedback, which causes gonadotropin levels to rise• Leisions to leydig or granulosa cells• Deficiencies in enzymes involved in the biosynthesis of the steroid hormones• Mutations in the LH receptor gene which prevents it from responding to LH