DiscoverCounselor Toolbox PodcastBiopsychosocial Impact of Hormone Imbalances and Strategies for Prevention
Biopsychosocial Impact of Hormone Imbalances and Strategies for Prevention

Biopsychosocial Impact of Hormone Imbalances and Strategies for Prevention

Update: 2019-11-09


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









Biopsychosocial Impact of Hormone Imbalances and Strategies for Prevention

Biopsychosocial Impact of Hormone Imbalances and Strategies for Prevention

Charles Snipes