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Psy 137 Behavioral Endocrinology Lecture 9
Sexual Differentiation
Website http//mentor.lscf.ucsb.edu/course/summer
/psyc137/
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Overview

• Genetic determinants of sex
• Development of primary sex organs
• Development of secondary sex organs
• Sex differences in nervous system

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Sexual Differentiation

• In sexually-reproductive species, there is
  typically two sexes male and female this is
  true of all mammals but there are other
  strategies in nature.
• Sexual differentiation of genitalia and
  secondary sex characteristics is visibly
  apparent. Sexual differentiation also occurs in
  primary sex organs and nervous system.

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Mammalian sexual differentiation (simple model)
Genetic Sex
Gonad (primary sex organ) Sex
Phenotypic Sex

• Key developmental neuroendocrine concept
• Organization versus activational effects of
  hormones

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Dyanamic Model for Sexual Differentiation
Sexual differentiation is a process that is
cumulative throughout life.
From McEwen 1994 Ann N Y Acad Sci. 1994 Nov
147431-16
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Sex differences in behavior

• Sex differences in behavior even with equal
  hormone stimulation indicates that there are sex
  differences in the brain (as well as obvious
  physical sex differences.)...
• These differences reflect organizational
  effects of hormones.

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Sex chromosomes and determination of genetic sex

• Of the 23 pairs of chromosomes only a pair is sex
  specific.
• Presence of Y chromosome determines (genetic) sex.

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Genetic determinants of sex inheritance.

• Genetic sex is determined by paternal
  contribution (its Dads fault).
• Presence of Y chromosome determines male or
  female.

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Primary sex organ determination

• Primary sex organs are ovaries in women and
  testis in men.

• Testis formation is due to a single gene loci
  sex-determining region of the Y chromosome
  (SRY).
• Formerly testis-determining factor

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Overview

• Genetic determinants of sex
• Development of primary sex organs
• Development of secondary sex organs
• Sex differences in nervous system

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Primary Sex Organs Development

• Primary sex organ testis or ovaries.
• Presence of SRY on Y chromosome causes
  development of testis.
• No SRY results in default of ovaies.

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Male Sex Organs Genitalia

• Testis are primary sex organ (produces sperm and
  sex steroids).
• Rest facilitates union of sperm with ova.
• Secondary sex organs epididymis, bulbourethral
  gland, prostate, seminal vesicles, vas deferens,
  ejaculatory duct.
• Genitalia head and shaft of the penis, scrotum.

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Female Sex Organs Genitalia

• Ovaries are primary sex organ (produces ova and
  sex steroids).
• Rest facilitates union of ova with sperm.
• Secondary sex organs uterine tube, uterus,
  cervix, vagina
• Genitalia clitoris, clitoral hood, labia, vagina

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Accessory Sex Organs

• Accessory organs development involves two
  factors
• Masculinization versus demasculinization.
• Feminization versus defeminization.

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Accessory Sex Organ Development

• Development of Mullerian and Wolfian duct
  systems.
• Males Wolfian ducts are maintained
• Females Mullerian ducts are maintained.

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Development of Male and Female Genitalia

• Male and female genitalia develop from common
  tissue under control of primary sex organs.

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Hormonal Control of the Development of Male and
Female Genitalia

• Testosterone and its metabolites

Cholesterol
Progesterone
Aromatase
5-alpha-reductase
Testosterone
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Androgens in Genital Development

• Adrogen (Testosterone or DHT) treatment will
  masculinize female genitalia.
• Treatment with estrogen does not masculinize
  genitalia.
• Male rodents treated with anti-androgen blocks
  masculinization of genitalia.
• Therefore stimulation of androgen receptor
  mediates masculinization of genitalia.

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Male Sexual Development

• SRY determines testis formation
• Sertoli cells in developing testis produce
  Mullerian-inhibiting hormone (aka MIS).
• Leydig cells in developing testis produce
  testosterone.
• MIS results in defeminization of accessory sex
  organs.
• Testosterone/DHT results in masculinization of
  genitalia.

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Female Sexual Development

• Lack of SRY results in formation of ovaries.
• No MIS allows Mullerian ducts to develop.
• No Testosterone results in Wolfian duct
  regression.
• Feminization and demasculinization
• Default or Pre-Programmed Pathways

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Summary of Genitalia Development

• Y chromosome results in testis formation.
• Testis production of
• androgens which produces masculinization of
  genitalia by androgen receptor stimulation.
• MIS which produces defeminization of genitalia.
• Absence of Y chromosome results in ovary
  development.
• Females have low gonadal steroids and no MIS
  during development producing feminization and
  demasculinization of genitalia.

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Overview

• Genetic determinants of sex
• Development of primary sex organs
• Development of secondary sex organs
• Sex differences in nervous system

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Secondary Sexual Characteristics

• At point of sexual maturation (aka puberty),
  large amounts of gonadal steriods are released
  resulting in development of physical sex specific
  characteristics.
• Masculinization
• feminization

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Gonadal Hormones and Puberty
Two stage model of sexual behavior development.
Puberty finishing school for
development. Initiation of puberty is unknown
leptin, Kisspeptins???
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Disorders of Human Sexual Development

• Congenital Adrenal Hyperplasia (CAH)
• Genetic female with ovaries
• Excessive adrenal activity results in excess
  production of testosterone.
• Masculinization of genitalia.
• Ovaries and fallopian tubes.

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Androgen Insensitivity Syndrome (AIS).

• Also called testicular feminization mutation.
• Genetic male with testis.
• Nonfunctional androgen receptor.
• Testis development and testosterone production.
• Feminization of genitalia.
• Secondary sex characteristics develop at puberty
  due to estrogen receptors low circulating
  estrogen but zero androgen receptor function.

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Disorders of Human Sexual Development

• 5a-reductase deficiency
• Absence of enzyme to convert testosterone to DHT
• Feminization of genitalia
• At puberty high testosterone produces partial
  masculinization.
• Individuals undergo gender identity switch to
  males

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Overview

• Genetic determinants of sex
• Development of primary sex organs
• Development of secondary sex organs
• Sex differences in nervous system

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Somatic and autonomic innervation of sex organs.

• Pattern of innervation of human sex organs is
  identical in males and females.
• But

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Sex differences in spinal nucleus

• Males have more motor neurons in the spinal
  nucleus of bulbocavernosous that are dedicated to
  innervation of the sex organs.
• Based on general rule of size of target area.
• No differences in sensitivity.

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SBN dimorphism is due to muscle degeneration.

• Female has Bulbocavernosus (BC) muscle until PD7
• Give T or DHT (but not E2) at birth can maintain
  BC and SNB neurons.
• Due to BC production of ciliary neurotrophic
  factor (CNTF) which maintains SBN neurons.

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Sex Dimorphism in Rat Brain

• Hypothalamic differences in brain structure.
• Sexually-dimorphic nucleus of the preoptic area
  (SDN-POA).

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Testosterone control of SDN-POA

• Perinatal Testosterone controls sexually
  dimorphisms in rat hypothalamus.
• Can increase size with testosterone.
• Can decrease size with castration.

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SDN-POA control by Estrogen Receptor Stimulation

• Perinatal treatment of female with either
  testosterone or estrogen can produce
  masculinization of SDN.
• Conversely, application of aromatase inhibitors
  blocks masculinization.

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Testosterone SDN-POA

• Testosterone influence neuron survival during
  development
• Females have low steriod hormones
• Males have high testosterone
• Effects of testosterone are mediated through
  estrogen receptor
• Aromatase.
• Estrogen receptor
• Estrogen receptor activation alters gene
  expression to inhibit programmed cell death
  apoptosis.
• Role in primates is less clear

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Protection against SDN-POA Masculinization in
females.

• Females are exposed to high estrogens during
  development.
• Alpha-feto-protein binds circulating estrogens in
  rodents.
• Primate AFP does not bind estrogen perhaps other
  proteins???
• Role of aromatization in primates is unclear.

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Role of Steroids in Maintenance of Sexual
Dimorphisms in the Brain

• The SDN of the hypothalamus
• Larger in males
• Unaltered by adult castration
• The Medial amygdala posterior dorsal
• nucleus is larger in males
• sensitive to castration.
• There are multiple mechanisms involved in
  different brain dimorphisms.

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Summary of Mechanisms Underlying Sexual
Dimorophisms in the Nervous System.

• Spinal nucleus of bulbocavernosous (SBN) produced
  indirectly by masculinization of genitalia
  (requires androgen receptor stimulation) during
  perinatal development.
• Sexually-dimorphic nucleus of the preoptic area
  (SDN-POA) produced by estrogen-receptor
  mediated reduction of apoptosis during perinatal
  development.
• Medial amygdala posterior dorsal (MeApd)
  produce by estrogen-receptor stimulation that
  must be maintained throughout life.

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Human SDN and Aging.

• SDN is larger in adult males than in adult
  females because females loose neurons in SDN
  prior to puberty (i.e. postnatal apoptosis).

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Sex differences in human brain

• These differences are corrected for differences
  in overall brain size (male brain is bigger than
  women proportional to body size).

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Hypothalamus Sexual Orientation

• Neural correlate of sexual orientation

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Further Studies of the Neural Correlates of
Sexual Orientation

• LeVay- INAH-3 of hypothalamus smaller in
  homosexuals.
• Gorski Anterior commissure larger in
  homosexuals.
• Swaab Suprachiasmatic nucleus is larger in
  homosexuals.
• All failed to mutually-replicate dimorphisms
  between sexual orientiations
• But generally consistent for sex differences.

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Hypothalamic Sexual Dimorphism and Homosexuality
in Non-human Primates.

• Japanese Macques exhibit life-long pair-bonding
  between females (i.e. same-sex dyads).
• Males are solitary or in same-sex troops.
• Females exhibit extensive homosexual sexual
  behavior, mutual care of offspring, distress
  during partners absence, etc.
• Vasey Pfaus (2005) asked what about sexually
  dimorphic brain structures

SDN-POA (INAH-3) occurs in J. Macques same as
other Macques where same-sex pair bonds do not
exist.
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Genetic Studies of Homosexuality

• One of the most frequently cited studies of
  homosexuality was that of Kallmann (1952) in J
  Nerv Ment Dis
• He reported 100 concordance in identical twins
  for homosexuality, 12 in fraternal twins
• Subsequent studies have failed to repeat
  Kallman's findings. Kallman later himself
  postulated that this impressive concordance was
  an artifact due to the fact his sample was
  largely drawn from mentally ill patients.
• The largest twin study This study included
• 56 pairs of identical twins, 54 pairs of
  fraternal twins, 142 non-twin brothers of twins
  and 57 pairs of adoptive brothers.
• They found that the concordance rate of
  homosexuality for
• genetically unrelated adoptive brothers was 11
• for non-twin biologic brothers about 9
• the rate for fraternal twins was 22
• and for identical twins it was 52

Rem this reflects variability accounted by
genetics Note would also reflect common
environmental factors during development e.g.
epigenetics
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Chromosomal Determination of Sexual Orientation.

• Male twins that are concordant for homosexuality
  share a portion of the X chromosome.
• Genetic determinant of sexual orientation
• Has been replicated in one of two additional
  populations by the same group of investigators.

• Point to ponder If homosexuality is a gene, how
  could the gene survive? Surely it would have
  disappeared due to homosexuals fathering less
  children?