2009 BGD-B Lecture Sexual Differentiation

Introduction

This lecture is still available online with links to powerpoint slides as PDF for printing online lecture.

This current page is only in the early developmental stage and not complete.

BGD Genital 2009 Lecture Slides

The links below to PDF versions of lecture slides.

• 1 slide/page (52 pages 1.25 Mb)
• 4 slides/page (13 pages, 803 Kb)
• 6 slides/page (18 pages, 776 Kb)
• Lecture Handout (5 pages 172 Kb)

Lecture Overview

• Gonad
• Internal Genitalia
• Reproductive Tract
• External Genitalia
• Development
• Function
• Abnormalities

Background Reading

UNSW Embryology

• Gonad Development

NIH Bookshelf

• Developmental Biology (Gilbert) Chapter 17
• Endocrinology (Nussey and Whitehead) The Gonad

Textbook References

• Human Embryology (3rd ed.) Larson Chapter 10 pp266-313
• The Developing Human (6th ed.) Moore & Persaud Chapter 13 p303-346
• Before We Are Born (5th ed.) Moore & Persaud Chapter 14 p289-326
• Essentials of Human Embryology, Larson Chapter 10 p173-205
• Human Embryology, Fitzgerald and Fitzgerald Chapter 21-22 p134-152

Genital System Development

3 stages

1. Differentiation of gonad (sex determination)
2. Differentiation of internal genital organs
3. Differentiation of external genital organs

2nd and 3rd stages dependent on endocrine gonad

• Long Maturation Time-course
  • Begins in embryo
  • Continues through fetal
  • Finishes in puberty

Sex Chromosomes

X Chromosome

• 1400+ genes
• 150 million base pairs
• 95% determined

Y Chromosome

• 200+ genes
• 50 million base pairs
• 50% determined

Gonad

• gastrulating mammalian embryo
• cells signaled by neighbours
• form primordial germ cells (pgc)
• migrate into genital ridges which develop into gonads

Primordial germ cells develop into

• eggs, if gonad is becoming an ovary
• sperm, if gonad is becoming a testis

Gonad will develop into an ovary unless its somatic cells contain a Y chromosome

Sex Determination

• Humans (week 5-6)
  • Germ cells migrate into gonadal ridge
  • Gonads (male/female) identical at this stage (Indifferent)

Gonad development dependent on sex chromosome

• Y present testes
• No Y ovary

DNA with SRY Protein SRY protein binds DNA

Testes determining factor (TDF)

• Transcription factor
• Bends DNA 70–80 degrees

Internal Genital Tract

• Female - paramesonephric - uterus
• Male - mesonephric - ductus deferens

External Genital Organs

• All embryos initially same (indifferent)
• Testosterone - differentiates male
  • Male Hormone dependent anatomy

Genital Abnormalities

• Chromosomal
• Hermaphroditism
• Gonadal Dysfunction
• Tract Abnormalities
• External Genitalia
• Gonadal Descent

Chromosomal

• Turner’s Syndrome (Monosomy XO)
  • 99% non-viable embryos
  • Fail to sexually mature at puberty

• Klinefelter’s Syndrome (47, XXY)
  • Begin normal male, become infertile
  • Tall, mental dullness, behaviour problems

• Males (46, XX)
  • Develop as male, infertile adults
  • Part of SRY gene located on one X (see Sex Reversal in Humans)

Hermaphroditism

• True Hermaphroditism (46,XX)
  • Gonads both ovary and teste tissues
  • Ovotestes or ovary and testes

• Male Pseudohermaphrodites (46,XY)
  • Gonads of one sex, external genitalia of opposite
  • Various causes

• Female Pseudohermaphrodites (46,XX)
  • Gonads are ovaries, external genitalia ambiguous
  • Hyperplastic adrenals secrete androgens

Gonadal Dysfunction

Gonads fail to develop properly

• Gonadal Dysgenesis
  • Swyer’s syndrome
  • 46,XX

Mixed Gonadal Dysgenesis (45,X/46,XY)

• Primary Hypogonadism
  • Affected females 46,XX

Primary Hypogonadism

• • Defective anterior pituitary production of gonadotropin
  • Lack of gonadotropin-releasing hormone

Tract Abnormalities

Many different forms

Uterine

• Associated with other anomalies
• Paramesonephric duct (0.1-0.5% of women)
• several classifications
• Unicornuate, bicornuate uterus

Vagina

• Agenesis, atresia
• See also endocrine disruptors

Ductus Deferens

• Uni- or bilateral absence
• Failure of mesonephric duct to differentiate

External Genitalia

• Multi-factoral
• Chromosomal, single gene, environmental
• Developmental arrest gives ambiguous

Hypospadias

• Common male (1 in 300)
• failure of urogenital folds to fuse
• results in a proximally displaced urethral meatus

Gonadal Descent

Cryptorchidism

• One or both testes fail to descend into scrotum
• 1:30 live male births
• May be associated with other abnormalities

Undescended Ovaries

• reasonably rare, also be associated with other uterine malformations (unicornuate uterus)

Virilization of a Genetic Female with Ovaries

• Fetal androgens
  • congenital adrenal hyperplasia (CAH)
  • adrenal adenoma or hyperplasia
• Maternal androgens
  • ovarian or adrenal tumors
• Latrogenic
  • exogenous androgens or progestagens with androgenic activity

Androgen Insensitivity Syndrome

• XY karyotype and presence of testes
• Externally - develop female secondary sex characteristics
• Internally - women lack Müllerian duct derivatives, have undescended testes

Puberty

• Hormone Axis LH & FSH
• Difference in timing
• increased gonadotrophin secretion and stimulate gonadal maturation
• rise in testosterone and estradiol secretions in males and females respectively
• positive feedback of estradiol in females also occurs during puberty

Tanner Stages

• External Genitalia
• Mammary

Sex and Brain Differentiation

• Brains of males and females differ
  • regions specialized for reproduction
  • Also in other regions (controlling cognition, etc) where sex differences are not necessarily expected
• Differentially susceptible to neurological and psychiatric disease
• 2 sources of sexually dimorphic information
• complement of sex chromosome genes
• mix of gonadal hormones
• sex differences in brain attributed to differential action of gonadal hormones
• evidence for sex chromosome effects on both neural and non-neural systems
• XX and XY cells differentiate even before they are influenced by gonadal hormones
  • even if exposed to similar levels of gonadal steroids