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439 – Biopsychosocial Impact of Hormone Imbalances
– Review the sex hormones and their functions
– Review the impact of sex hormones in the HPA-Axis
– Review causes and consequences of imbalances in
– Estrogen
– Progesterone
– Testosterone

– Multiple forms
– Estradiol is predominant prior to menopause
– Estrone is the primary form postmenopausally
– Synthesized by fatty tissue
– Estrogen works synergistically with many biological systems to promote physical, cognitive and affective function
– Estrogens can modulate neuronal excitability, through serotonin, norepinephrine, dopamine, and endorphin regulation
– Estrogen supplementation can decreased both systolic and diastolic blood pressures and reduced norepinephrine levels

– Estrogen modulates mood via the serotonergic system
– Estrogen also contributes to the
– Downregulation of 5-HT-2 (stimulating) receptors and monoamine oxidase (think MAOIs)
– Downregulation of 5HT1A receptors presynaptically
– Upregulation of postsynaptic serotonin 5-HT1A (calming) receptors
– In one study, 80% of women given estradiol reported significantly decreased mood symptoms after three or six weeks, compared to only 22% of women on placebo
– Similarly, estradiol resulted in improved mood in 68% of peri-menopausal women with depressive disorders, whereas only 20% of women on placebo experienced similar benefit

– Estrogen also regulates glucose metabolism and energy production
– Declines in these processes are characteristic of neurodegenerative diseases
– Estrogens exert neuroprotective actions to maintain cerebrovasculature health including prevention glutamate-induced excitotoxicity and hippocampal shrinkage
– Estrogens exert some anti-inflammatory effects
– Naturally occurring higher levels of estrone were associated with poorer cognition, specifically working memory performance
– Estradiol acts in part through nitric oxide (arginine)to increase extracellular dopamine levels.

The Sex Hormones
– Estrogen
– Premenopausal females have a better response than males to serotonergic antidepressants, indicating female hormones may improve the efficacy of SSRIs
– Depressed postmenopausal females on supplemental estrogen plus SSRIs showed improved response compared with depressed postmenopausal females without estrogen
– Estrogen alone did not relieve depression
– Largest clinical trials of HT ever conducted revealed an increased risk of cancer, dementia and cognitive decline with prolonged administration of conjugated equine estrogen (CEE)

Estrogen and the HPA-Axis
– Higher levels of Estradiol produced a stronger HPA axis response during non-threatening situations and during and after stressors
– Under conditions of anxiety and stress, women attend to threat differently depending on endogenous estradiol levels, being avoidant when estradiol is lower, and vigilant when estradiol is higher
– Estradiol increases the activation of Corticotropin Releasing Hormone and base levels of ACTH
– Chronic stress produces a hyporesponsive HPA axis that is hypersensitive to the modulating effects of estrogen
– Changes in 5-HT1A receptor binding in the hippocampus and hypothalamus are restored by estrogen replacement.
Estrogen and the HPA-Axis
– Treatment with estradiol could inhibit the negative feedback effects of cortisol increasing cortisol levels
– Estradiol treatment has been shown to increase corticosteroid binding globulin (CBG ) which inactivates cortisol in males
– Crosstalk between the hypothalamic–pituitary–gonadal (HPG) and HPA axes could lead to abnormalities of stress responses, and as a result exacerbate peripheral pathologies i.e.:
– Low estrogen –> blunted HPA-Axis response (depression)
– High estrogen – exacerbated HPA-Axis response and sustained higher levels of ACTH – anxiety, inflammation, autoimmune…
Estrogen and Cognition
– Estrogen
– HT administered at or around the time of menopause may improve cognition, but HT initiated five years or more after menopause shows no cognitive benefit but may produce cognitive decline
– Shorter time between menopause and initiation of HT was associated with larger hippocampal volume
– HT utilizing Estradiol more effectively recalibrates the estradiol/estrone ratio to approximate pre-menopausal levels.
Estrogen and Allergy
– Estrogen
– Estrogen's actions skew immune responses toward allergy and autoimmune responses
– Not only do endogenous estrogens appear to play a role, but environmental estrogens have also been implicated including bisphenol A (BPA) and phthalates enhance allergic sensitization and may enhance asthma in humans.
– Increased estrogen induced by exposure to essential oils of geranium and rose compared to control odor.
– Progestins regulate cognitive functions as well as social behavior and mood
– Some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system
– Synthesized by the ovaries and adrenal glands, it has widely distributed receptors and is antagonistic to estrogen.
– The progestogenic component in combined hormone therapy was found to potentially counteract the beneficial influence of estrogens on mood and to even induce negative mood symptoms
– Women with higher average progesterone levels across their cycles reported higher levels of anxiety
– Progesterone has also been shown to decrease gastric emptying, which has the potential to modify an antidepressant's pharmacokinetics
– Use of combined HT in the previous month was associated with worse depression and anxiety among 6000 peri- and postmenopausal women

– Testosterone is essential for maintaining virilization and muscle mass and may also affect libido, mood regulation, bone health and cardiac disease
– Hypogonadal men exhibit a significantly higher prevalence of anxiety disorders and major depressive disorder
– Certain chemotherapies can reduce testosterone and increase anxiety
– testosterone can enhance dopamine and serotonin release in the mesolimbic system
– Testosterone can enhance GABA
– Gonadal dysfunction appears to impair dopamine release but not synthesis (important esp for transgender individuals)
– Testosterone acting in the hippocampus has a number of anxiolytic, antidepressant, and protective cellular actions
– Testosterone can influence the degree of amygdala activation in relation to fear, with a positive correlation observed between testosterone levels and amygdala activation in men and a negative correlation in women

– Gonadal steroids impact HPA axis reactivity differentially.
– Testosterone replacement blunts the CORT and ACTH response to stress.
– Estradiol treatment increases the reactivity of the HPA axis
– To maintain homeostasis, the neuroendocrine system continuously monitors the levels of gonadal steroids using estrogen and androgen receptors in the hypothalamus.
– Dysregulation of either or both of these axes can result in compromised responses to stressful life events.
– Testosterone is suppressed with long term opioid use
– Testosterone treatment in hypogonadal men has beneficial effects on depressed mood.
– The highest prevalence for maternal depression was typically during the first 3 postpartum months; whereas paternal depression seemed to peak somewhat later, between 3 and 6 months postpartum
– 30% lower testosterone levels in the postpartum period. Interaction with the infant lowers Testosterone levels even more.
– Testosterone levels increase in a reproductive context (i.e., mating) and decrease in long-term bonds and paternal care settings
HPA Axis
– Chronic activation of the HPA-Axis, has an inhibitory effect upon estrogen and testosterone secretion
– Stress in adulthood continues to mediate HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine (NE) into the ovary, which produces a non-cyclic anovulatory ovary that develops cysts. (PCOS)
– Chronic social stress in females may lead to low estradiol and a hypersensitivity in Estradiol-replacement
– The ability to modulate the HPA-Axis is significantly reduced in ovariectomized females suggesting a hyporesponsive HPA phenotype resembling that observed in several human psychopathologies, including post-traumatic stress disorder.

– Depression and anxiety commonly associated with dysregulation of the mesolimbic system, the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamic areas, hippocampus, and medial prefrontal cortex
– Dysfunction in hormone synthesis, release or reuptake can disrupt the hormone balance and impact the HPA axis via the HPG axis
– Variance in body fat, hormone levels, and liver metabolism between sexes have been shown to affect the pharmacokinetics of antidepressants and oral hormone replacement.

Biopsychosocial Impact
– Physical
– HPA-Axis Activation
– Autoimmune disorders
– Blood pressure dysregulation
– Insomnia
– Fatigue
– Hypervigilance
– Altered libido
– Psychological
– Irritability
– Anxiety
– Depression
– Increased risk for addiction
– Social
– Social withdrawal (depression/anxiety/fatigue)
– Impaired relationships due to irritability
– Work impairment

Potential “Hidden” Culprits
– Triclosan (antibacterial agent) disrupts estrogen, testosterone and thyroid hormones according to the Natural Resources Defense Council.
– Estrogen Increasers
– BPA and Pthyalates (water bottles, PVC, food wraps, canned foods and plastics)
– PFAS/PFOAs (Teflon)
– Certain essential oils
– Phytoestrogens (plant estrogens)
– Testosterone Lowering
– Opioids
– Cimetidine (Tagamet for GERD)
– Antidepressants
– Statins (lower cholesterol)
– Diabetes
– Child birth

– To treat depression or anxiety by increasing serotonin, norepinephrine and/or dopamine is overly simplistic.
– Mood and physical symptoms may result from impaired reuptake of one or more of the monoamines or sex hormones.
– It should be noted that when sex hormones or monoamines are artificially replaced, it impacts the balance of the whole system.
– Estrogen and testosterone have neuroprotective effects, but excess can also cause problems with monoamine balance
– Too much testosterone: Mood swings, irritability, anxiety, impaired judgment
– Too much estrogen: Anxiety, insomnia, fatigue, cognitive decline, mood swings, weight gain
– Too little estrogen: Mood swings, hot flashes, depression, fatigue, difficulty concentrating
– Too little testosterone: depression, cognitive decline, fatigue, weakness