Sexual Differentiation in Mammals

Role of Sex Chromosomes

§ Genetic sex (XX or XY) is determined by the type of sperm (X-bearing or Y-bearing) that fertilizes the egg.

§ Early gonads have potential to be either ovaries and testes for ~6 weeks

§ Sex-determining region of the Y chromosome (SRY) is a gene producing a protein which causes the middle of the neuter gonads to become testes.

§ If testes develop, they begin to produce androgens like testosterone.

§ If this gene is not present, the outside of the neuter gonads turn into ovaries.

Evidence

§ Removal of SRY gene from Yà XY mouse develops as a female

§ Add SRY gene to X à XX mouse develops as a male

§After Gonad Development, the remainder of sexual development depends on hormone environment.

§Normal sources of sex hormones:

l Testes and ovaries

l Adrenal cortex

Organizational Effects of Hormones

§ We all begin with ducts, genitals and brains which can go either way (male or female)

§ Differentiation of male ducts, genitals, & brain depends on action of androgens (testosterone & dihydrotestosterone (DHT)).

§ Female differentiation requires no hormones.

§ In fact, in males, development of female ducts must be actively inhibited by release of another hormone: Mullerian inhibiting hormone (MIH), usually in 2^nd & 3rd month of gestation.

Timecourse of Differentiation

§ Differentiation of gonads, genitals, ducts, and brain occurs at different (but overlapping) time periods during gestation.

§ Example: newly formed testes begin producing androgens about week 7-8 beginning the masculinization of genitals but penis may not be visibly distinct until 3rd or 4th month & not complete until ~5th month.

Differentiation of the Brain

§ Androgens also have defeminizing and masculizing effects on developing brain.

§ Example: Exposure to androgens “program” the hypothalamus for the fairly constant sex hormone secretions seen in males vs the cyclic hormone secretion of females

§ There is some evidence that masculinization of brain occurs later than masculinization of body.

Sexually Dimorphic Nucleus (SDN) of Preoptic Region of Hypothalamus

Structural Differences in the Brain

§ Rats - part of medial preoptic hypothalamus shows testosterone-related size differences; ventromedial hypothalamus important in females

§ “Sexually dimorphic nucleus” is larger in males and testosterone-treated females and smaller in females and castrated males.

§ Simon LeVay- 3rd interstitial nucleus of the anterior hypothalamus (INAH3) in humans is larger in heterosexual males and smaller in females and gay males

§ Many other regions show sex differences – e.g. females have more neurons in Wernicke’s area and more axons in corpus callosum

Sex-Typical Behaviors

Another of Mother Nature’s Jokes

§ In rats testosterone entering the brain is turned into estradiol by the process of “aromatization” and estradiol, in turn, triggers the “masculinization” of the brain (e.g. SDN and medial preoptic hypothalamus).

§ Maternal estrogens present during pregnancy do not masculinize the brain because they bind to alpha-fetoprotein and can’t get past the BBB.

§ However, if excess estrogens are present, some do get into brain and do bias behavior in a male direction.

Other Species

§ Decreased perinatal testosterone in males or testosterone treatment of females has induced same sex preferences and changes in sex-typical patterns of sexual behavior in a wide range in species (rats, hamsters, ferrets, pigs, finches, dogs, sheep etc.).

§ There is correlational data from both men and women suggesting that early hormone environment may also affect sexual orientation in humans.

Other Evidence for a Biological Basis of Sex Orientation

§ Brothers both homosexual?

l identical twins - 52% of time

l fraternal twins - 22% of time

l adopted brothers - 11% of time

§ Sisters both lesbian?

l Identical twins - 48%

l fraternal twins - 16%

l adopted sisters - 6%

Special Cases

§ XY baby whose body can’t respond to androgens due to lack of androgen receptors: “androgen-insensitivity” - baby has female genitalia, feels female

§ XX baby exposed to more androgens than usual - body & brain masculinized; “androgenization of females”, e.g. congenital adrenal hyperplasia or adrenogenital syndrome

§ Lack of DHT – female genitalia until puberty, then penis & scrotum develops. Assumes male identity despite 10+ years of “female experience”

§ Homosexuality also may be due to unusual prenatal hormone exposure (decreased masculinization of brain), as may cases of gender identity disorder

§ Estimated that 1 out of 100 has some degree of genital ambiguity.

Role of Environment?

§ The Case of John/Joan – unsuccessful rearing as female

§ DHT deficiency – despite years as a female, easy switch to male identity at puberty.

§ In both cases brain would be masculinized by early testosterone.

Summary

§ Early in life hormones have an organizational effect on body and brain.

§ The amount and timing of hormones will have a life-long effect on physiology and behavior.

§ Alterations in hormones during critical sensitive periods of prenatal development are the likely cause of variations in sex preference.

Puberty and Beyond

§ At puberty both males & females need hormones to develop secondary sexual characteristics.

§ From that point on, hormones have an activational rather than organizational effect, influencing sexual motivation rather than sex preference.

§ Sex drive in females seems more closely related to androstendione than to estrogen- ovariectomy does not decrease drive

Hormonal Drugs

§ Because of the feedback mechanisms (body-> brain), taking hormone supplements commonly leads to decreased production of natural hormones.

§ E.g.:Taking testosterone like drugs (anabolic steroids) can cause atrophy of testes and breast development due to conversion to estrogen