Sexual Differentiation Lecture 2023 PDF

SEXUAL DIFFERENTIATION Master of Arts in Biomedical Sciences Dr. Kelly Roballo LEARNING OBJECTIVES 01 02 03 04 05 Describe the development of chromosomal sex Describe the sequence of events and hormonal regulation that is essential for the normal development of male and female phenotype....

SEXUAL DIFFERENTIATION Master of Arts in Biomedical Sciences Dr. Kelly Roballo LEARNING OBJECTIVES 01 02 03 04 05 Describe the development of chromosomal sex Describe the sequence of events and hormonal regulation that is essential for the normal development of male and female phenotype. Describe the disorders of chromosomal sex including Klinefelter’s Syndrome and Turner ’s syndrome. Describe the pathogenesis and clinical presentation of Kallmann syndrome. Describe how congenital adrenal hyperplasia causes ambiguity in the external genitalia HUMAN CHROMOSOMES Which would be female and which would be male? XX XY SEX DETERMINATION: OVERVIEW • Dimorphism: • Males ® sperm • Females ® eggs • Chromosomes • Autosomes • Sex Chromosomes • X - chromosome • Y - chromosome • During fertilization, egg and sperm fuse, producing a cell with 46 chromosomes (22 pairs of autosomes and 1 pair of sex chromosomes) • The sperm determines the sex of the embryo – If the sperm that fertilizes the egg has an X chromosome, the embryo will be XX (female) – If the sperm that fertilizes the egg has a Y chromosome, the embryo will be XY (male) 22+X 22+X XX 22+X 22+Y XY CHROMOSOMAL SEX DIFFERENTIATION • Sex chromosomes contain “master switch” genes that initiate a sequence of events leading to development of male or female gonads • Y chromosome: SRY gene, acts to promote male reproductive differentiation. • X chromosome: DSS gene (region that may contain several genes, still being researched), acts to promote female reproductive differentiation. SEXUAL DIFFERENTIATION • Action of the Y-chromosomal region is preceded by “upstream” gene action that is evidently a prerequisite for Y-chromosomal function in gonadal determination GONADAL DIFFERENTIATION • Gonads: male and female sex glands (ovaries and testes). • Male and female gonads are the same until about 6 weeks after conception. • Genetic signals determine whether the gonads will develop into ovaries or testes. • After the testes or ovaries develop, they begin releasing sex hormones that continue the process of sexual differentiation. NORMAL PRENATAL DEVELOPMENT: INTERNAL & EXTERNAL GENITALIA • Undifferentiated stage: • 0-7 weeks gestation • male and female external genitals the same • urogenital fold • genital groove • genital tubercle • labioscrotal swelling • male and female internal genitalia the same undifferentiated sex glands N O R M A L P R E N ATA L D E V E L O P M E N T: INTERNAL & EXTERNAL G E N I TA L I A • Sexual differentiation: Gonadal development • 8 weeks gestation • Y chromosome synthesis of H-Y antigen • Male: H-Y antigen causes undifferentiated sex glands to develop into testes • Female: lack of H-Y antigen causes undifferentiated sex glands to develop into ovaries • The key event in testis differentiation is the expression of Sry / SRY in the developing Sertoli cells within the indifferent gonad, and the subsequent downstream pathways that complete the process of testicular differentiation. H-Y antigen is a male tissue specific antigen (a male histocompatibility antigen that causes rejection of male skin grafts by female recipients). We thought it would trigger the formation of testes but may be activated by the formation of testes NORMAL PRENATAL DEVELOPMENT: INTERNAL & EXTERNAL GENITALIA • Sexual differentiation: Duct development • both sexes start out with two systems: • Mullerian ducts - will develop into fallopian tubes, uterus, inner vagina • Wolffian ducts - will develop into epididymis, vas deferens, and seminal vesicles • Male (XY) • Testes secrete testosterone and Mullerian-inhibiting hormone • Testosterone - Wolffian ducts begin to develop • Mullerian-inhibiting hormone - inhibits further development of Mullerian ducts - they shrink and degenerate • Female (XX) • absence of Mullerian-inhibiting hormone - Mullerian ducts develop • absence of testosterone - Wolffian ducts degenerate NORMAL PRENATAL DEVELOPMENT: INTERNAL & EXTERNAL GENITALIA • Sexual differentiation: Genital development • Male (XY): testosterone causes unisex genitalia to develop into penis and scrotum • testosterone converted to dihydrotestosterone • dihydrotestosterone causes the external appearance of scrotum and penis • Female (XX): absence of testosterone causes unisex genitalia to develop into clitoris, labia, vaginal opening, etc. • NOTE:The default is the develop as a female. Male hormones are needed to promote differentiation into a male SEXUAL DIFFERENTIATION: INTERNAL EMBRYONIC DEVELOPMENT SEXUAL DIFFERENTIATION: EXTERNAL GENITALIA • Bipotential tissues: genital tubercle, urethral folds, urethral groove and labioscrotal swellings SEXUAL DIFFERENTIATION: EXTERNAL GENITALIA Growth and development of the external male genitalia depend on conversion of testosterone to dihydrotestosterone (DHT) and the presence of androgen receptors in the target tissues. The congenital absence of androgen receptors in target tissues causes androgen insensitivity syndrome in which the external genitalia develop into the female phenotype and the wolffian and müllerian ducts regress. PATHWAY FOR SEXUAL DEVELOPMENT: REVIEW FOR GENES TO ORGANS OVERVIEW OF GAMETOGENESIS: PRODUCING EGGS OR SPERM REGULATION OF REPRODUCTION: GENERAL PATHWAYS CONGENITAL ADRENAL HYPERPLASIA • Results from impaired synthesis of cortisol and sex hormones. • Can be deficiency of any one of five total enzymes CAH: 17-HYDROXYLASE DEFICIENCY • Loss-of-function mutation in CYP17 gene. • Decreased production of glucocorticoids and sex steroids. • Increased synthesis of mineralocorticoids. • Causes hypertension and hypokalemia • Males: 46, XY present with ambiguous genitalia • Females: Sexual infantilism- external genitalia does not mature as normally KALLMANN SYNDROME • Deficient secretion of GnRH from the hypothalamus. • Patients may experience delayed puberty or no puberty. • More common in males: • S/Sx • Anosmia (lack of smell) • Decreased libido • Amenorrhea • Decreased muscle mass and aggressiveness in males • Infertility • Treatment: • gonadal hormone replacement therapy • Fertility treatments ORIGINS OF ATYPICAL PRENATAL DIFFERENTIATION • Sex chromosome disorders: individuals born with one or more extra sex chromosomes or missing one sex chromosome. • Turner’s syndrome (XO) • Klinefelter’s Syndrome (XXY) • Disorders affecting prenatal hormonal processes: • Androgen Insensitivity Syndrome (AIS) • Fetally androgenized female • DHT-deficient male SEX CHROMOSOME DISORDERS: TURNER’S SYNDROME • Turner’s syndrome (XO): • 1 in 2000 female births • Normal external female genitalia • Internal female anatomy not developed; no functional ovaries, therefore no breast development, menstruation, or fertility. • Often have other health problems, including heart, kidney, thyroid problems, and diabetes. SEX CHROMOSOME DISORDERS: KLINEFELTER’S SYNDROME • Klinefelter’s syndrome (XXY): • 1 in 500 male births • Undersized penis and testes • Typically sterile • Low interest in sex • Somewhat feminized physical characteristics • If desired, the XXY boy can increase male secondary sex characteristics (body hair, reduced breast development, increased muscle development) w/testosterone treatment THANK TOU