Organizational a nd Activational Effects of Hormones on Brain Development

1. Organizational and Activational Effects of Hormones on Brain Development 23 April 2012

2. Housekeeping • NO CLASS on Wednesday or Friday • Instructions for your writing assignment will be available on Blackboard • LAB on Wednesday and Thursday • Instructions are in your handout

3. Berthold's Capons Suggests separate organizational and activationaleffects of hormones

4. Human Sexual Development

5. Human Sexual Development XY XX XX XY

6. What’s Y got to do with it? All embryos can become male or female (bipotentiality) Human embryo

7. What’s Y got to do with it? • A single gene on the Y chromosome (Sry) produces testis-determining factor • causes gonads to become testes • Testes release Anti-Müllerian Hormone and Androgens • “Female is nature’s default”

8. Evidence for Embryonic Bipotentiality • Androgen Insensitivity Syndrome (XY) • Androgen receptor function reduced or absent • Gonads develop into Testes (Sry) • Defeminization (Anti-Müllerian hormone) • Masculinization fails; internal sex organs do not develop, external genitalia are female • Incidence for complete AIS is about 1:12,000 births • Male genotype, female phenotype

9. Individuals with androgen-insensitivity syndrome Newborn genetic male (46XY) with complete androgen insensitivity syndrome and female external genitalia Nature Clinical Practice Urology (2004) 1, 38-43

10. Evidence for Embryonic Bipotentiality • Persistent Müllerian Duct Syndrome (XY) • Mutation of AMH receptors • Masculinization succeeds; external genitalia are male • Defeminization fails; BOTH sets of internal sex organs develop • Turner Syndrome • 1:2500 female births • X genotype; no defeminization AND no masculinization • No gonad development

11. Quick Quiz • What’s Y got to do with it? • Organizational effect of hormones • Now we’re going to look at? • Activationaleffect of hormones

12. Hormonal Control of Sexual Behavior • Females • Behavior (in rats) has been poorly studied • Lordosis • “Receptivity” is related to gonadal hormones • In rodents, estradioland progesterone peak just before peak receptivity • Activationaleffect of hormones

13. Hormonal Control of Sexual Behavior Relative incidence of female-initiated sexual activity (heterosexual couples)

14. Hormonal Control of Sexual Behavior GonadectomizedMale Rats

15. Sexual Behavior • Is sexual orientation a biological trait or a behavior? • Money (1972) suggested that individuals have the potential to become male or female within the first two years of life • Bell et al. (1981): study of several hundred male and female homosexuals • Found no predictive childhood environmental factors; suggested a biological basis for sexuality

16. Prenatal Hormone Exposure and Sexuality • Androgen Insensitivity Syndrome • Genetic XY, raised as girls • Display no difference in sex drive, activity and satisfaction compared to general population • No increased incidence of phenotypic homosexuality

17. David Reimer • Video

18. David Reimer • Born as an identical twin to his brother • Penis was destroyed during circumcision • his brother’s circumcision was then cancelled • Parents enlisted the help of John Money • At 22 months, sexual reassignment surgery was performed, and “Bruce” became “Brenda” • Raised as a female

19. David Reimer • Brenda rejected her femininity, preferred to play with trucks instead of dolls, ponies, etc. • At the same time, John Money was publicizing the case as a successful gender reassignment, proof that boys and girls were “interchangable” • Brenda was in a great depression; when she was entering puberty, her father told her everything • Brenda immediately self-reassigned to David, lived as a man, later had surgery to reconstruct a penis • Two recent studies (from Johns Hopkins, ironically) have suggested that an individual’s sense of “gender” may result from prenatal androgen levels

20. Prenatal Hormone Exposure and Sexuality Evidence? Congenital Adrenal Hyperplasia • Occurs 1:15000 live births • Excessive amounts of androgens released from the adrenal glands • Boys develop normally • Girls undergo masculinization • Enlarged clitoris, labia • Increased incidence of “masculinity”

21. 5 year-old boy 5 year-old girl 5 year-old girl with CAH 6 year-old girl

22. Prenatal Hormones and Sexuality • Incidence of homosexuality in CAH females is significantly higher than in the general population (25% to 50%) • Together with findings from individuals with AIS, these observations suggest that: • Prenatal androgen exposure is a significant factor in determining sexual orientation • Sexual attraction to men is the “default” • Changes in prenatal androgen exposure or receptors may lead to homosexuality in both females and males

23. Sexuality and Genetics

24. Sexual Behavior: Summary • Hormones play two roles in sexual development and behavior • Organizational:Prenatal exposure to androgens masculinize sex organs AND brain structures • Activational: Exposure to sex hormones (estradiol, progesterone, testosterone) in adulthood leads to the expression of sexual behavior • Gender, Gender Identity, Sexual Orientation and Sexual Behaviordepend on brain organization