Atypical Development

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Atypical Development
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Gonadal Intersexuality ("True Hermaphroditism")
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Gonadal Intersexuality

• Either 2 ovotestes or 1 ovary and 1 testis
• Very rare, appear more feminine masculine.
• Usually, XX with an SRY gene translocated on one
  X. Tissue in which that X is expressed is
  masculinized.
  
• Sometimes, an XX and XY conceptus fuse or 1 sperm
  fertilizes the oocyte and 1 fertilizes the polar
  body, which fails to degenerate.
  
• Several have become pregnant and delivered
  children one fathered a child.

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Chromosomal Anomalies

• Turners syndrome
  Klinefelters syndrome

XXY genotype SRY male Internal sex OK Small t
estes
Low T Low sperm gynecomastia
X0 genotype Poor ovaries Low hormone Immature s
ex
infertile
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Metaphase
Nondisjunction
Normal Anaphase
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Turners syndrome

• X0
• Lack normal ovaries granulosa cells need
  oocytes, just as oocytes need granulosa cells.
  (gap junctions)
  
• Infertile, no puberty, deficits in visuospatial
  skills
  
• Treated with GH testosterone for growth, and
  with E P for breast development, menstrual
  cycles, and can bear children with donated eggs.
  

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Klinefelters syndrome

• XXY, XXXY
• Male SRY trumps any number of DAX-1 genes, as
  long as they are on different X chromosomes
  
• Tall, small testes, breast development, sparse
  body hair, low T, low sperm count, low libido
  
• Learning disabilities, especially for language
• Can be treated with T

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Congenital Adrenal Hyperplasia

• Genetic defect
• Corticoid synthesis
• Adrenal cortex
• Deficit corticoids
• Excess T
• XX
• No MIH
• Wolffian Duct
• External genitals
• masculinized

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Congenital adrenal hyperplasia

• Lack of enzyme ? cortisol (21 hydroxylase)
  therefore, decreased feedback ? excess ACTH ?
  adrenal cortex hypertrophies (hyperplasia)
  produces more of whatever it can, including
  androgens
• Recessive trait, treated with corticosteroids
• In male differentiation OK, but early puberty
  and cessation of growth.
  
• In female enlarged clitoris and fused labia.
• Play more with boys toys, less interested in
  motherhood, more inclined to male-typical
  activities and careers, more likely to be
  attracted to women, but more hetero- than
  lesbian, excel in visuospatial tasks

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5alpha-Reductase Deficiency

• Child at birth
  Appearance at puberty

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5-alpha reductase deficiency

• Normal internal genitalia testes secrete T, MIH
  causes Mullerian ducts to degenerate.
  
• Lack of DHT leads to inadequate masculinization
  of external genitalia at birth
  
• Testes in labia or inguinal canal
• Urogenital sinus urethra blind vagina
• Prostate gland small or absent
• At puberty, lots of T ? testes descend, scrotum
  darkens, phallus enlarges, muscular, deep voice

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Androgen Insensitivity Syndrome

• Nongonadal
• XY
• Mutation T-receptor
• Insensitive to T
• Normal testes
• MIH T
• Woffian fail
• External fail
• Complete/partial

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Androgen Insensitivity Syndrome

• XY, normal testes, secrete T
• Due to mutation in gene for androgen receptor
• Sometimes only partial insensitivity to
  androgens
  
• Convert T ? E ? breast development
• Do not menstruate or have pubic or underarm hair

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Neural differentiation
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Third interstitial nucleus of the anterior
hypothalamus (INAH3)
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INAH3

• Larger in heterosexual men than in women or gay
  men, though considerable overlap
  
• Same was true in men who did not die of AIDS
  therefore, not due to AIDS
  
• Function not clear

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Sexual differentiation in hypothalamus
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SDN-POA of rats

• Same size in male and female fetuses before day
  18 of gestation
  
• T surges in males (day 18 of gestation and again
  birth) ? larger SDN in males females
  
• Neurons die in females due to lack of T during
  early development cant be rescued by T
  injections after 1 week postnatal.
  
• T ? E directly in MPOA is necessary.
• Castration in adulthood ? no effect

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Development of sexual dimorphism of rat spinal
nucleus of the bulbocavernosus
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SNB in rats

• Spinal nucleus of bulbocavernosus
• Male and female fetuses have similar SNBs and
  similar bulbocavernosus muscles.
  
• Muscles, but not neurons, have androgen receptors
  and depend on androgen.
  
• Females lack the T surge, so muscles atrophy
• Male muscles send trophic factors to neurons,
  which survive. Therefore, indirect effect of T.

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Hormones and sexual behavior in rats
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Aromatization hypothesis

• In rats and other rodents E is as effective as T
  in masculinizing and defeminizing behavior.
  
• Blocking aromatization is often (but not always)
  as effective as blocking T production.
  
• Why arent females masculinized by their mothers
  (or their own) E?
  
• Alpha-fetoprotein binds E, but not T keeps much
  of it in blood and out of cells
  
• a-FP can be swamped by excess E or T injections
• Therefore, T is a sneaky way to get E to brain.

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Peripheral development

• Development of external genitals and spinal
  nuclei are androgen dependent, though.
  
• Spotted hyenas
• Females are dominant, aggressive, secrete high
  levels of androstenedione.
  
• Female-typical SDN-POA, and do mate and give
  birthbut with difficulty!!

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