Chapter 13: Hormones and Affective Disorders Flashcards
Anabolic Steroids
Most are used for muscle gain.
Most act via androgen receptors.
Became illegal in 1991 (DEA schedule 2).
Very effective, very risky.
Chris Benoit “the Canadian Crippler”
Lyle Alzado
Lyle Alzado
Lyle Martin Alzado (1949–1992) was a professional American football player in the NFL, famous for his intense, intimidating style of play.
Alzado was one of the first major US sports figures to admit to using anabolic steroids.
In the last year of his life, as he battled the brain tumor that eventually caused his death, Alzado asserted that his steroid abuse directly led to his fatal illness.
Alzado recounted his steroid abuse:
“I started taking anabolic steroids in 1969 and never stopped. It was addicting, mentally addicting. Now I’m sick, and I’m scared. 90% of the athletes I know are on the stuff….. But all the time I was taking steroids, I knew they were making me play better. I became very violent on the field and off it. I did things only crazy people do. Once a guy sideswiped my car and I beat the hell out of him. Now look at me. My hair’s gone, I wobble when I walk and have to hold on to someone for support, and I have trouble remembering things…”
The role that anabolic steroids may have played in Alzado’s death has been the subject of controversy.
Lyle Alzado died on May 14, 1992 at age 43 after a battle with brain cancer.
Christopher “Chris” Benoit
Christopher “Chris” Benoit
(1967–2007)
Canadian professional wrestler.
Had a 22-year career, was a 2-time world champion. Held 22 wrestling titles.
He was booked to win a third world championship at a WWE event on the night of his death.
Benoit murdered his wife and son on June 22, 2007, and subsequently hanged himself on June 24, 2007.
Research suggests depression and brain damage accrued from numerous concussions are likely contributing factors leading to Benoit’s crime.
The officers discovered the bodies of Benoit, his wife Nancy, and their 7-year-old son Daniel. Over a 3-day period, Benoit had killed his wife and son before hanging himself. His wife was bound before the killing. Benoit’s son was drugged and likely unconscious before Benoit strangled him. Benoit then committed suicide with a weight machine.
Benoit was found to have Xanax, hydrocodone, and an elevated level of testosterone, caused by a synthetic form of the hormone, in his system. The chief medical examiner attributed the testosterone level to Benoit possibly being treated for a deficiency caused by previous steroid abuse or testicular insufficiency.
Prior to the murder–suicide, Benoit had been given illegal steroids not in compliance with WWE in 2006. Benoit received nandrolone & anastrozole.
Years of trauma to his brain may have led to his actions. Tests were conducted on Benoit’s brain, and results showed that “Benoit’s brain was so severely damaged it resembled the brain of an 85-year-old Alzheimer’s patient.”
He was reported to have had an advanced form of dementia, similar to the brains of 4 retired NFL players who had suffered multiple concussions, sank into depression, and harmed themselves or others.
Bailes and his colleagues concluded that repeated concussions can lead to dementia, which can contribute to severe behavioral problems.
Common Steroids
Anadrol Oxandrin Dianabol Winstrol Durabolin Deca-Durabolin Depo-Testoserone Equipoise
Anabolic Steroids:
Illegal Use
Banned substances in professional sports, but use in high school and in amateur body-building often goes unchecked
Estimated over a million high school students use per year
Seen as less risky than other “hard drugs”
Anabolic Steroids:
Health Consequences
Widespread health consequences of chronic steroid use
Substantial risk for heart attack, suicide, cancer—immunosuppression
Euphoria, irritability, anger, mood instability
“Roids rage”
Activational effects
Men Experience:
Baldness, Headaches, Breast Gro
wth, Enlarged Prostate, Reduced Sperm Count, Shrinkage of Testicles
Women Experience:
Increase in facial & body hair, Deepened voice, Reduced breast size, Menstrual Problems, Enlarged clitorus.
Both Men & Women Experience:
Nausea, Bloating, Aggression, Mood Swings, Severe Acne, Liver disease, High Blood pressure, Heart disease, Urinary & Bowel problems, Strokes, Blood Clots.
Roids Rage
Roid rage is a term given to people who act in very aggressive or hostile manner after taking large doses, usually on a regular basis, of anabolic steroids, sometimes nicknamed as “roids”.
In recent times, several prominent murders and brutal attacks have been linked to roid rage, which might suggest a person is less responsible for committing a crime.
This is not always an adequate defense given that people who take anabolic steroids tend to do so willingly.
Further, roid rage resulting in violent behavior may be a little more complex than it is generally portrayed in the media.
When people use anabolic steroids, a dangerous practice for many reasons, they are essentially placing extra levels of testosterone in their bodies.
This hormone can at first have positive effects on the psyche, which later turn negative.
Steroid users at first may equate steroid use with feeling well, unconquerable or very happy.
Continued use of steroids may result in much greater mood and behavior change.
People may become more aggressive, more hostile, or they may manifest symptoms of various forms of mental illness, like schizophrenia, mania, and deep depression.
Anabolic steroid use is linked not only to roid rage and sudden mood changes, but also to a higher incidence of suicide than in the general populace.
Affective Disorders
Affective disorders are a set of psychiatric diseases, also called mood disorders.
The main types of affective disorders are depression, bipolar disorder, and anxiety disorder.
Symptoms vary by individual, but they typically affect mood.
Mood disorders:
Major Depressive Disorder
Anxiety Disorders:
PTSD, OCD, Panic Disorder, General Anxiety Disorder
Eating Disorders
Reproductive-related disorders:
Postpartum depression
Premenstrual affective disorders
Premenstrual Syndrome
Depressed mood, anxiety, emotonal lability, anhedonia, mania, disordered sleep
Often physical symptoms too:
bloating, pain, changes in feeding, fatigue, muscle soreness, sleep disturbances
To be diagnosed with Premenstrual Dysphoric Disorder, one must have one physical and one psychological symptom
Otherwise, it’s called premenstrual syndrome
Emotional lability
the tendency to laugh or cry unexpectedly at what might seem the wrong moment.
Emotional lability is often a temporary symptom that reduces over time. It is more common to experience emotional lability if your ability to think and reason have been affected.
anhedonia
inability to feel pleasure.
The Luteal Phase of the Menstrual Cycle
High Progesterone, low Estrogen normally.
**Estrogen is usually anxiolytic and anti-depressive, but so is P!
PMS = ‘withdrawal’ symptoms once P levels decrease at menstruation
Progesterone can act on GABA receptors to increase their action (at benzodiazepine receptor), so loss of Progesterone can induce anxiety.
GnRH also may play a role:
GnRH agonist can help PMS & PMDD by preventing reproductive cycling.
Highly effective at reducing depressive symptoms.
Also leads to reduced progesterone.
The follicle left behind turns into the Corpus Luteum (Latin for “yellow body”)
anxiolytic
a substance inhibits anxiety.
This effect is in contrast to anxiogenic agents, which increase anxiety
PMS = ‘withdrawal’ symptoms once ______ levels decrease at menstruation
PMS = ‘withdrawal’ symptoms once Progesterone levels decrease at menstruation
Progesterone can act on ____ receptors to increase their action (at _______ receptor), so the loss of P can induce anxiety
Progesterone can act on GABA receptors to increase their action (at benzodiazepine receptor), so loss of Progesterone can induce anxiety
The Follicular Phase of Menstruation
Increasing Estrogen
Low Progesterone
Eggs develop inside of follicles.
One egg emerges as dominant and grows alone.
The egg bursting out of the follicle at the moment of Ovulation marks the peak/end of the Follicular Phase, and the beginning of the luteal phase.
There is a hypothesis that PMS is associated with the long term consequences of having ‘too many’ periods versus our ancestors.
10-20 periods in the past when there was continuously breeding, lactating, etc (2-3 years without a period per kid) versus probably about 400 periods now…
Results of chronic exposure to hormone fluctuations:
Seasonique (constant birth control) or SSRIs as treatment
Postpartum Depression
Depression occurs mildly in many new mothers, becomes PPD in about 15-20% of women.
Huge changes in Estrogen, Progesterone, and Oxytocin at parturition, but none has been clearly tied to the disorder
Tom Cruise criticizes Brooke Shields for using Postpartum medication after the birth of her child.
parturition
the action of giving birth to young; childbirth.
Postpartum Depression:
Physiology
Beta endorphin (an endogenous opiod) may play a role. Concentrations rise during pregnancy, peak at parturition, and then plummet. Women with most PPD issues had biggest change (decrease) in B-endorphin after parturition.
HPA axis changes:
Women that end up having PPD have higher CRH levels at mid-gestation.
The PLACENTA is the source of this surge of CRH.
Stress during pregnancy increases incidence of PPD, as does post-partum stress
Corticotropin Releasing Hormone (CRH)
A peptide hormone secreted by the hypothalamus that stimulates the release of ACTH (corticotrophin) by the anterior pituitary gland.
CRH is also called corticotrophin releasing factor (CRF).
ACTH Review
ACTH is made in the pituitary gland in response to the release of Corticotropin-Releasing Hormone (CRH), by the hypothalamus.
In turn, the adrenal glands then make cortisol, which helps your body manage stress.
Cortisol is a hormone that’s needed for life, so its levels in the blood are closely controlled.
When cortisol levels rise, ACTH levels normally fall (negative feedback).
When cortisol levels fall, ACTH levels normally rise.
Major Depressive Disorder
Most MDD patients experience 5–6 episodes during their lifetimes
The risk for major depression increases with age in men, whereas women experience their peak risk in the age range of 35-45.
MDD affects 1 in 5 Americans at some point in their lives
Prior to adolescence, boys & girls are equally likely to experience depression
Major Depressive Disorde
WOMEN
In adults, women are about twice as likely as men to be diagnosed with MDD
Anxiety Disorders even more common in women
Biological difference?
Estrogens can be anti-depressant. Estrogen treatment is effective during menopause, but no clear association between ovarian hormone levels and depression incidence.
In adults, sex difference may be related to fluctuations in female hormones (e.g., PMS, PMDD, postpartum depression, menopause)
Also related to social and cultural factors
Genetics of Depression
Concordance rate between identical twins (monozygotic) is 40% versus 11% for fraternal (dizygotic) twins
Adoption studies support a role for genetics in depression, with a similar rate for twins reared apart
Gene by environment interactions
Gene & Environment Interaction and Depression
Genes —> polymorphisms, epigenetics
Environment –> STRESS, trauma, illness
Many single nucleotide polymorphisms associated with increased risk if environmental risk is present.
Several relate to serotonin, hormones, or stress response.
________ receptor polymorphism interacts with sex and stress (parental divorce) to predict depression risk
.Oxytocin receptor polymorphism interacts with sex and stress (parental divorce) to predict depression risk
Brain Changes in Depression
Structural abnormalities in several brain areas:
Decreased volume of hippocampus and orbitofrontal cortex.
Increased amygdala volume.
Functional changes:
Decreased ACC activation.
Blunted emotions (anhedonia).
Increased blood flow in PFC
and amygdala.
Increased anxiety & fear response.
Incresased stress response.
Emotional Dysregulation in stress
circuit
The stress response in depression
- Much higher baseline cortisol levels
What is the cause? Overactive hypothalamus? Overactive pituitary? Overactive adrenals? More life stress?
- Impaired negative feedback—probably at level of hippocampus
Hippocampal atrophy
Dexamethasone suppression test
Dexamethasone Suppression test
used to assess adrenal gland and/or hippocampus function by measuring how cortisol levels change in response to an injection of dexamethasone.
Typically used to diagnose Cushing’s syndrome. It may also play a role in diagnosing depression.
Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary gland to suppress the secretion of adrenocorticotropic hormone (ACTH).
Specifically, dexamethasone binds to glucocorticoid receptors in the anterior pituitary gland, which lie outside the blood brain barrier, resulting in regulatory modulation.
A low dose of dexamethasone suppresses cortisol in individuals with no pathology in endogenous cortisol production.
A high dose of dexamethasone exerts negative feedback on pituitary ACTH-producing cells, but not on ectopic ACTH-producing cells or adrenal adenoma.
Cortisol and Depression
Two disorders related to adrenal hormones present with depression:
Cushing’s Disease:
TOO MUCH CORTISOL
Addison’s Disease:
TOO LITTLE CORTISOL
Addison’s Disease:
TOO LITTLE CORTISOL
Cushing’s Disease:
TOO MUCH CORTISOL
Depression and Estrogens:
Depressed women have significantly decreased E2.
Women hospitalized with depression show dramatic improvement following E2 treatment (very high doses).
Mood improvements seen most dramatically in post-menopausal women
Depression and Thyroid Hormones:
Depressed people often have low thyroid function
Treatment with TRH can alleviate depressive mood in some
Thyroid hormones can help with PMDD and PMS, too.
Not always high or low in PMDD, but much more variable than in control group.
Autoimmune Thyroidosis is most associated with depression.
Immune system and depression?
Elevated cytokines
Monoamine – Circadian Interaction
Monamines play an essential role in regulation of sleep & wake cycles:
Serotonin, melatonin
Cortisol release by adrenal glands in response to both circadian rhythms and stress-related activity (HPA axis)
Depressed people have disrupted circadian rhythms:
Too much REM, phase delays, high melatonin, low serotonin
Links stress, circadian disruption, and development of depression
Chicken and egg…
Seasonal Affective Disorder (SAD)
Seasonal depression in winter
More common in latitudes far from equator
Remit in spring when long days return
Seasonal Affective Disorder (SAD)
Causes:
Overproduction of melatonin in winter due to less light, dimmer light
Those with SAD have dysregulated melatonin onset
Sleep Phase Delays
Seasonal Affective Disorder (SAD):
Treatments:
SSRIs
Light Treatment
Prevent phase delays with melatonin and light
Avoid exposure to light at bedtime
Posttraumatic Stress Disorder (PTSD)
Recurrent dreams of trauma, flashbacks, hyperarousal and avoidance of stimuli associated with trauma, high levels of vigilance, and an impairment in daily functioning
Automobile accidents, combat, natural disasters, assaults, and abuse are common traumas that result in PTSD
10-30% may experience PTSD
2/3 of patients are female
Poor negative feedback tone of HPA axis
Hyperactive stress response (both HPA and SNS)
PTSD sufferers have bigger ____, responds with more activity to ‘fearful’ stimuli
PTSD sufferers have bigger amygdala, responds with more activity to ‘fearful’ stimuli
PTSD sufferers have decreased inhibition of AMYGDALA by prefrontal cortex
Prefrontal cortex is important for extinction of conditioned fear
Estrogens slow extinction of conditioned fear, and lead to persistent negative associations
Reduced ________ may be a predictor for PTSD risk
Reduced Neuropeptide Y may be a predictor for PTSD risk
It’s associated with stress, emotion, and feeding
Stress or fearful stimuli also increase levels of ______, which might increase response to fear in amygdala
Stress or fearful stimuli also increase levels of ghrelin, which might increase response to fear in amygdala
Anti-ghrelin drugs developed as anti-obesity drugs may be useful as therapeutics
PTSD highly associated with increased obesity
PACAP: Pituitary Adenylate Cyclase Polypeptide
PACAP content in the blood is increased in women with PTSD
Unbiased screen showed polymorphism in PACAP increases PTSD risk in women.
Polymorphism is in an estrogen response element…so is regulated by female-hormone action
Risk allele (CC) associated with higher amygdala activation to fearful stimuli
Polymorphism
Natural variations in a gene, DNA sequence, or chromosome that have no adverse effects on the individual and occur with fairly high frequency in the general population
Polymorphism involves one of two or more variants of a particular DNA sequence. The most common type of polymorphism involves variation at a single base pair.
Polymorphisms can also be much larger in size and involve long stretches of DNA. Called a single nucleotide polymorphism, or SNP (pronounced “snip”), scientists are studying how SNPs in the human genome correlate with disease, drug response, and other phenotypes.
