Stress and Sex

1. Stress and Sex • Endocrine review • Stress • Physiology • PTSD • Psychoneuroimmunology • Sex • Sexual development and development pathologies • Sexual preference

2. Stress and Sex • Stress, and sexual development and function are largely endocrine functions, so first a quick review of the endocrine (= secrete into) system.

3. Pineal gland • (Pineal gland – circadian behaviors) • Pituitary - “master” control gland • Thyroid –growth and metabolism • Parathyroid – calcium regulation • Thymus - immune system (children) • Pancreas - blood sugar control • Adrenal – stress, many functions • Gonads (ovaries or testes) – reproduction

4. Endocrine System • Pituitary (hangs beneath hypothalamus) • Anterior pituitary (“Master” gland) • Creates and releases 6 hormones: • FSH = Follicle Stimulating Hormone • LH = Luteinizing Hormone • PRL = Prolactin • TSH = Thyroid Stimulating Hormone • GH = Growth Hormone • ACTH = Adrenocorticotropic Hormone • Gonadotropic (FSH, LH) hormone output is cyclic (28 days) in females, but roughly constant in males. • Controlled by the hypothalamus with GnRH

5. Endocrine System • Pituitary • Posterior pituitary • Releases 2 hormones created in the hypothalamus: • ADH = AntiDiuretic Hormone (aka vasopressin) – blood volume control. • Oxytocin = stimulates uterine contractions and lactation. • Adrenal (on top of kidney) glands • Androgens (tetracyclic steroids) • Glucocorticoids, Cortisol • E (adrenaline), NE

6. Stress

7. Stress • The physiological reaction of the body to perceived aversive or threatening situations. • Often called the “Fight or Flight” response. • Mediated by the sympathetic nervous system. • Controlled by adrenal hormones under the control of the hypothalamus/pituitary. • Also important in many psychopathologies as an important trigger.

8. Stress Response • Pupils dilate • Attention and alertness are enhanced • Energy stores are mobilized for quick availability • Heart rate and blood pressure increase • Non-essential functions are suppressed • Appetite , digestion, libido • In other words, the stress response prepares the body to fight or flee.

9. Stress Response • Corticotropin Releasing Factor (CRF) is released throughout the brain, especially in emotional areas, and serves as a neurotransmitter and neuromodulator. • Amygdala (fear center) projects directly to the paraventricular nucleus (PVN) of the hypothalamus, which secretes CRF. • CRF causes the anterior pituitary to release adrenocorticotropic hormone (ACTH).

10. Stress Response • Both ACTH and direct sympathetic innervation from the brainstem cause the adrenal medulla to secrete epinephrine (E), norepinephrine (NE) and cortisol. • Epinephrine and cortisol act to increase glucose availability and metabolism, increasing the cellular fuel supply. • Epinephrine acts directly on the heart to increase pulse rate and contractility. • NE vasoconstricts to raise blood pressure.

11. Stress Response • Cortisol also helps break down proteins for increased energy availability. • Glucocorticoids seem to be promote post-stress survival: • Animals with adrenalectomy die more often from severe stress. • Humans with adrenalectomy must be given additional glucocorticoids.

12. Long-term Effects • While short-term stress responses are beneficial, long-term effects are harmful. • Victims of prolonged stressful situations (concentration camp survivors, soldiers, accident victims, etc.) have poorer health than the general public. • ATC controllers have greater incidence of hypertension, ulcers and diabetes. • Jensen, Genefke and Hyldebrandt (1982) found brain degeneration in torture victims.

13. Long-term Effects • Long-term effects include: • Chronic hypertension • Steroid diabetes • Inhibition of growth, tissue damage • Suppression of the immune system • Amygdala and hippocampus size decrease • CA1 damage (from excess Ca++) causes memory problems • GABA receptor changes

14. Developmental Effects • Prenatal stress inhibits androgenization of the fetus leaving male offspring less masculinized than normal. • Offspring of prenatally-stressed mothers seem show increased sensitivity to and increased release of glucocorticoids. • Offspring of stressed mothers with adrenalectomies do not show these effects.

15. Post-traumatic Stress Disorder • Develops right after exposure to severe trauma • Symptoms include: • Recurrent dreams, recollections & flashbacks • Intense psychological distress • Memory problems • To avoid these, sufferers develop: • Feelings of fear, hopelessness and detachment • Decreased interest in social activities • Suppressed emotions

16. PTSD • Specific psychological symptoms include: • Hypervigilance (acetylcholinesterase) • Difficulty falling or staying asleep • Recall and learning problems • Irritability • Outbursts of anger • In kids: • Loss of recently acquired toilet or language skills • Somatic complaints

17. PTSD • Many factors influence susceptibility to PTSD • Personality traits & genetics affect susceptibility. • Other psychiatric disorders often comorbid. • National Vietnam Veterans Readjustment Study found 4 factors which increase susceptibility: • Being raised in a household with financial difficulties • A history of drug abuse or dependency • A history of affective disorders • A history of childhood behavior problems

18. PTSD • Physical changes • Bremner et al. 1995/Gurvits et al. 1996 found 10-20% deterioration of hippocampus in MRIs in veterans with PTSD, proportional to exposure. • The hippocampus is very sensitive to stress, and is largely responsible for the associated memory deficits. • Shin et al. 1997 used PET to find increased activity in the anterior cingulate gyrus and right amygdala when imagining combat scenes. • Decreased orbitofrontal activation seems to provide less inhibition to emotional areas.

19. Psychoneuroimmunology • Immune system is one of the most complex of all bodily systems. • Purpose is to protect us from infection. • Depression of the immune system can lead to increased infectious disease. • A widow(er) often dies of infection closely following the loss of a spouse. • Glasser et al. (1987) report increased acute infections in medical students at finals time.

20. Psychoneuroimmunology • 5 types of lymphocytes are derived in the bone marrow from white blood cells (WBC). • Lymphocytes are “trained” in the thymus to distinguish “self” from foreign items by recognizing cellular surface proteins. • When a lymphocyte detects a foreign invader, it releases cytokines to tell other WBCs to proliferate and attack the invader.

21. Psychoneuroimmunology • Glucocorticoids, heavily released under stress (real or imagined), inhibit the immune system by interfering with cytokines, preventing the “call to arms.” • Shavitt, et al. (1984, 1986) found that endogenous opioids suppress the production of and action by natural killer cells. • Bone marrow, the thymus and lymph nodes are all innervated, possibly allowing direct neural control of the immune system.

22. Sexual Development & Behaviors

23. Sexual Development • Until about 6 weeks, all fetuses have a common set of primordial gonads and both sets of ducts.

24. Sexual Development Milestones • At 6-7 weeks, genetic males (TDF gene on the Yp chromosome) start producing H-Y antigen. • H-Y antigen causes the medulla to form the testes. • Absence of H-Y antigen causes ovary formation from cortex at around 10-11 weeks. • A male (XY) fetus injected with anti-H-Y-antigen at 6 weeks develops ovaries. • A female (XX) fetus injected with H-Y antigen at 6 weeks develops testes.

25. Sexual Development Milestones • At about 3 months, the testes will produce Müllerian-inhibiting substance & androgens. • Müllerian-inhibiting substance causes the female tubes to degenerate. • Androgens cause the male organs to develop. • Testes descend at about 7 months. • In any fetus not exposed to androgens at 3 months, Müllerian tubes will form fallopian tubes, cervix and uterus. • So, female is the default sex.

26. Sexual Development Milestones • Androgens act throughout the brain • Directly bind to and modulate enzymes, channels and receptors. • Cross cell wall and indirectly affect transcription of DNA. • Testosterone effects are actually due to estradiol! • Injections of estradiol masculinize a brain. • Dihydrotestosterone (non-aromatizable) will not masculinize a brain. • Anti-aromatizing drugs block masculinization.

27. Sexual Development Pathologies • Androgen Insensitivity Syndrome • Defect on X produces no androgen receptors. • External male organs do not develop fully or at all. • H-Y antigen still produced. • Primordial gonads differentiate into testes. • Anti-Müllerian hormone is still produced. • Female tubes still degenerates. • Outwardly female, with no internal sex organs. • Sterile

28. Sexual Development Pathologies • Persistent Müllerian duct syndrome (46XY) • Failure to produce anti-Müllerian hormone or failure to produce its receptors. • Testes develop, but do not descend (cryptorchidism). External genitals are male. • Müllerian tubes do not decay, so fallopian tubes, cervix and uterus develop. • Dual sexual organ systems interfere.

29. Sexual Development Pathologies • Sex is not a nominal variable! • Normal females are XX, normal males are XY. • Intersex individuals • XX with transplanted Y segments (hermaphrodite). • Non-standard number of chromosomes (not 46) • Turner’s (X0) and Klinefelter’s (XXY) • Non-standard chromosome arrangements: • XY: XXY, XXYY, etc. • Sometimes multiple chromosome arrangements (mosaicism ), i.e. XXY + XXYY + XXYYY

30. Sexual Development Pathologies • 45 Chromosomes • X0 (Turner’s Syndrome) • About 40% have a portion of a Y chromosome. • Ovaries are either missing or incompletely formed, but all other internal and external female organs are formed. • XX individuals can have a defective X. • 0Y is generally incompatible with life. • 47 Chromosomes • XXY (Klinefelter’s syndrome) – overly feminine males (eg. have penis and breasts), always sterile • XXX – generally normal females, XXX not usually passed • XYY – generally tall, aggressive, fertile males

31. Puberty • At puberty, there is a surge in the release of growth hormone (GH) and the gonadotropins from the anterior pituitary. • Males: • Causes release of androgens from testes. • Masculinizes the body: hair, voice, muscles, etc. • Females: • Causes release of estrogen from ovaries. • Femininizes the body: fat distribution, hair.

32. Brain Differences by Sex • Brain development differences • Gender differences in thalamus & hypothalamus. • Male • Brains about 15% larger. • Higher metabolic activity in temporal lobe and limbic system. • Females • Larger corpus callosum and possibly anterior commissure. • Higher metabolic activity in the cingulate gyrus.

33. Adulthood • Lust • Mediated by testosterone in both sexes. • Attraction • Love is a drug! It affects D, NE and 5-HT areas. • Tolerance develops, and effect wears off. • Attachment • Mediated by oxytocin and vasopressin (ADH). • Oxytocin released during arousal, orgasm and suckling.

34. Adulthood • The hypothalamus and sex • Preoptic area of anterior hypothalamus • Stimulation produces sexual behaviors. • Lesions cause decreased sexual function. • SDN in rats is 5-8 times larger in males • INAH is SDN analog in humans • INAH2 and INAH3 are twice as large in males • Seem to be related to postnatal testosterone release • Hypothalamus sends GnRH to pituitary • Controls release of FSH and LH.

35. Adulthood • Male • Sexual behaviors activated by androgens. • Orchidectomies tend to produce: • Impotence, feminization, and loss of libido. • Theorized to be caused by decreased testosterone. • Testosterone injections restore all of the above. • GnRH release is tightly regulated. • FSH controls sperm production in testes. • Testes produce inhibin - inhibits pituitary FSH production. • LH controls testosterone production.

36. Adulthood • Females • Do not exhibit estrous cycles like most animals. • But there is variation with the cycle. • Some evidence of pheromone communication. • Ovariectomies produce: • Infertility, amenorrhea, lack of lubrication. • Like males, sexual motivation seems to be related to the androgens. • Ovariectomized females with estradiol and progesterone injections come into estrus. • Ovariectomy + adrenalectomy = libido loss.

37. Conception and Gestation Cycle • Every 28 days, with input from the pineal gland, the hypothalamus sends GnRH (LHRH) to the pituitary, where it causes the release of LH and FSH. • FSH causes a few follicles to start developing. • Developing follicles release estrogen, which causes storage of LH instead of release. • One follicle outgrows the others, and releases lots of estrogen.

38. Conception and Gestation Cycle • Increase in estrogen causes peak sexual receptivity, and causes the release of stored LH. • The LH pulse causes ovulation. • The luteinized egg releases progesterone, which causes the uterus to retain its lining. Also causes nest building behaviors in animals. • If egg is not fertilized, uterus releases prostaglandin, which stops progesterone and causes destruction of the egg and menstruation.

40. Conception and Gestation Cycle • The luteinized egg secretes a chemical signal. • hOR17-4 (& other?) receptors (Ca++ channels) in their tails guide the sperm to the egg. • Fertilized egg continues progesterone production itself.

41. Conception and Gestation Cycle • At the end of the fetus’s maturation, it causes the pituitary to release: • Prolactin, which starts milk production • Prolactin is produced and remains high as long as there is demand for milk (suckling). • Prolactin is responsible for male refractory period. • Oxytocin, which causes contractions of the uterus for birth. • Oxytocin is also responsible for milk let down. • Oxytocin also released during arousal and orgasm, and promotes attachment behaviors.

42. Pineal Pineal Gland Hypothalamus GnRH Pituitary FSH LH Oxytocin Maturing follicles Estrogen Ovary Ovulation Scents Corpus luteum Fertilized? Prostaglandin menstruation Progesterone Retain lining Uterus

43. Sexual Preference • 5-10% prefer mates of the same sex. • Preference was historically thought to be a result of childhood experiences: • Bell, Weinberg and Hammersmith (1981) found no evidence of social causes of homosexual preferences. • Thought to be result of sex steroid levels: • Meyer-Bahlburg (1984) found no correlation between sex steroid levels and homosexuality.

44. Sexual Preference • Raising a child as the opposite gender does not work. John/Joan is a famous case. • Bailey (1991) & Hamer (1993) documented the concordance rates for homosexuality: MZ = 52% , DZ = 22%. • Hamer & Hu (1995), Turner (1995): Xq28 correlated in some homosexual brothers (but not sisters). • Genetics accounts for about 30%.

45. Sexual Preference • Blanchard, et al. (1995-1997): Male homosexuals are consistently more likely to have a late fraternal birth order. • Each older brother increases chance of homosexuality by about 35%. • This implies a maternal immune system (anti-H-Y) adaptation. • Anti-H-Y given prenatally to rats induces homophilia in adulthood.

46. Sexual Preference • 1999 McFadden and Pasanen study on otoacoustic emissions. • Females have higher OAEs than males. • Bi- or homo-sexual females have lower (more masculine) OAEs than heterosexuals. • Females in M-F twin sets have lower OAEs. • Since otoacoustic emissions are completely unrelated to sex, this is further evidence of a biological difference. • 2D:4D ratios also sexually dimorphic

47. Sexual Preference • Miller, et al. (1986) documented cases of brain injury leading to altered sexuality. • Insults to the medial basal frontal or diencephalic areas induced hypersexuality. • Insults to the temporal lobe structures caused changes in sexual preference. • Kranz & Ishai (2006) studied response to faces • Visual cortex, limbic system, prefrontal the same • Thalamus and medial orbitofrontal different • Sexual preference linked to reward circuitry

48. Sexual Preference • M/F mechanisms different. • A likely cause seems to be brain differences caused by differences in prenatal exposure to androgens, e.g. from maternal stress. • Congenital adrenal hyperplasia (CAH) • Produce excess androgens in adrenal glands. • Does not affect males much. • At least 40% of CAH females describe themselves as bi- or homo-sexual.