Download Lecture 6 Sex and Stress

Stress and Sex
• Endocrine review
• Stress
– Physiology
– PTSD
– Psychoneuroimmunology
• Sex
– Sexual development and development pathologies
– Sexual preference
Stress and Sex
• Stress, and sexual development and function
are largely endocrine functions, so first a
quick review of the endocrine (= secrete
into) system.
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
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
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
Stress
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.
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.
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).
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.
Stress Response
• Cortisol also helps break down proteins for
increased energy availability.
• Glucocorticoids seem to be promote poststress survival:
– Animals with adrenalectomy die more often
from severe stress.
– Humans with adrenalectomy must be given
additional glucocorticoids.
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.
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
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.
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
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
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
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.
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.
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.
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.
Sexual Development & Behaviors
Sexual
Development
• Until about 6
weeks, all
fetuses have a
common set of
primordial
gonads and both
sets of ducts.
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-Yantigen at 6 weeks develops ovaries.
• A female (XX) fetus injected with H-Y
antigen at 6 weeks develops testes.
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.
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 (nonaromatizable) will not
masculinize a brain.
• Anti-aromatizing drugs block
masculinization.
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
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.
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pineal Gland
Pineal
Hypothalamus
GnRH
Pituitary
FSH
LH
Maturing follicles
Estrogen
Oxytocin
Ovary
Ovulation
Scents
Corpus luteum
Fertilized?
Prostaglandin
menstruation
Progesterone
Retain lining
Uterus
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.
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%.
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 (antiH-Y) adaptation.
• Anti-H-Y given prenatally to rats induces
homophilia in adulthood.
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
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
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.