Hormone APM Flashcards
Which glands along HPATG axis are solely endocrine function?
Pituitary, Thyroid, and Adrenal
Which glands along HPATG axis are mixed function?
Hypothalamus, Ovaries and Testes
How does thyroid affect progesterone?
Thyroid hormones stimulate FSH mediated LH/hcg receptors to stimulate granulosa cells to produce progesterone. If progesterone is low, then can get menstrual problems.
How does IR affect androgens?
Insulin Resistance causes increased androgen production which increases more insulin and decreases SHBG which allow more androgen to be free and creates this cycle. Disrupts LH signaling.
How is thermoregulatory zone affected in menopause?
Decrease in estrogen causes increase in norepinephrine and serotonin which narrows hypothalamic thermoneutral zone so body thinks its too hot/cold and causes hot flashes/sweats to cool body down.
Where in cell are the steroid hormones produced?
MItochondria
What is acronym STAINS stand for?
In regards to hormone imblance causes: Stressors, Toxins, Antigens-allergens-adverse food reactions, Infections, Nutrition, Sleep.
What is mechanism/effects of IR in PCOS?
Genetics, endocrine disruptors or diet/lifestyle causes IR which leads to hyperinsulinemia which causes the liver to make less SHBG and decreased IGFBP-1 which increases androgens; increased insulin increases pituitary LH which cause ovaries to make more androgens from theca cells. Increased androgens then increases FFA and VAT. More androgens make more insulin making it a vicious cycle.
How is the mental, emotional and spiritual part of matrix affected by hormones?
Sex hormones have neuro-steroid metabolites that affect mood. Depression is associated with elevated TSH(20% or higher vs upper limit), hypothyroidism, anti-TPO ab, estrogen level fluctuations, low levels of testosterone(high testosterone associated with depression and mania).
What mitigates effects of stress on hormones: cortisol, growth hormone, testosterone
Meditation
How is defense and repair mode of matrix affected by stress?
1) Cortisol can suppress NK cell cytotoxicity. Acute stress can be beneficial as it upregulates natural immunity. Brief naturalistic stress can suppress cellular immunity but preserve humoral immunity. However, chronic stress suppresses both cellular and humoral immunity which is not beneficial.
2) Prolonged cortisol can downregulate cortisol receptors which leads to reduced response to anti-inflammatory signaling which leads to nonspecific inflammation which increases disease risk. Elevated cortisol slows wound healing.
3) Maternal elevated cortisol levels influences intrauterine programming of HPA Axis.
How do hormones affect Energy mode of matrix?
Thyroid hormones, epinephrine, norepinephrine, cortisol, estrogens, testosterone affect ATP production and fatigue thru various mechanisms. Thyroid and steroid hormones target mitochondrial genes for transcription and biosynthesis of respiratory enzymes.
Which estrogen metabolites are protective of cancer risks?
2-OH-E1
Which estrogen metabolites increase cancer risks?
Quinones from 4-OH-E1, 16alpha-OH-E1
Which SNPs affect the metabolism of estrogen?
COMT, GST
What are some effects of elevated DHT?
Alopecia, BPH
How is transport mode affected by hormones?
High urinary cortisol predicts CVD mortality across 6 years.
Suboptimal thyroid function associated with dyslipidemia, atherogenesis, MetSyn, obesity and cardiovascular dysfunction. Low testosterone associated with arterial stiffness. Estradiol but not CEE improves arterial stiffness.
How is Communication node affected by hormones?
1) Hyperactivity of HPA axis leads to prolonged and excessive cortisol exposure, Cushing like effects, increased VAT, increased intramyocellular lipids, increased IR and increased MetSyn risk.
2) Hypothyroidism associated with MetSyn, IR, CV risk.
3) Prolonged cortisol exposure downregulates cortisol receptors.
How do hormones affect bone health(structural integrity mode)?
HRT reduces PM osteoporotic fractures of hip, spine, non-spine even in women without osteoporosis; low doses effective in maintaining or improving BMD.
How does intestinal permeability affect ovaries?
Causes inflammation of ovaries and impairs progesterone synthesis.
How does assimilation affect estrogen?
Microbiome impacts 2-/4- estrogen ratios.
What are steroid hormones derived from?
Cholesterol
Where are steroid hormones made?
Mitochondria and/or endoplasmic reticulum, so mitochondrial health important.
What are 5 takeaways in regards to hormones in general?
- Steroids are derived from cholesterol so low calorie/low fat diet, statin use can affect production.
- All the action occurs in the mitochondria and/or endoplasmic reticulum; therefore, mitochondrial health can be a cause of hormone dysfunction.
- All steroid hormones need water soluble carrier proteins - like SHBG to travel into the hydrophilic environment. Binding matter. \
- Steroid hormones are transformed from one to another via enzymatic modification. (eg: aromatase, COMT, Cytochrome P450)
- ATMs(chronic stress, toxins, nutrient insufficiencies, etc) modulate these enzymes(upregulate or downregulate). Therefore, modulating ATMs can lead to changes in hormones without giving hormone replacement.
What is the rate limiting step in hormone synthesis?
Getting cholesterol to the inner membrane of the mitochondria
What does cholesterol get broken down into and by what enzyme in the Steroidogenic Pathway?
to Pregnenolone via P450cc enzyme on the inner membrane of the mitochondria
Once Pregnenolone is formed what 2 pathways does it go down to?
1) To form DHEA via delta 5 pathway(17-OH-Pregnenolone)
2) To form Progesterone via Delta 4 pathway and enzyme 3 BHSD(beta hydroxysteroid dehydrogenase, isomerase)
What happens to progesterone once it is formed?
It is hydroxylated to form 17-hydroxyprogesterone the immediate precursors to 19 C androgens and ultimately the 18 C estrogens.
Which hormones do androstenedione form into?
Testosterone(17 BHSD) and E1 (aromatase)
What form of estrogen is made from testosterone
E2 via aromatase
What is the 2 immediate precursors to cortisol in the Steroidogenic Pathway?
17-OH-progesterone to 11-deoxycortisol to cortisol
What is the stress response/stress cascade?
Stressor induced activation of the HPA axis and SNS results in a series of neural and endocrine adaptations. Associated with changes in glucocorticoirds and catecholamines, etc. Met by 2 systems - HPA axis and SNS(sympathetic nervous system - fight or flight)
What is the stress response/stress cascade?
Perception of stress leads to release of Epi from adrenal medulla in acute response. Chronic stress results in release of cortisol from adrenal cortex. Cortisol can cause PNMT induction that crosses over to acute response and more adrenaline is released.
Ventral stress response involves which autonomic NS?
Sympathetic in Chest area
What is freeze response?
When there is too much PS stimulation.
What are some functions of cortisol?
Stimulates liver to convert amino acids to glucose
Stimulates increased glycogen in the liver
Mobilizes fatty acids into the blood
Increases coagulation
Suppresses parts of the inflammatory response
Prevents sodium loss in urine
Maintains resistance to stress
Maintains mood and emotional stability
What are some clinical sympathetic responses?
Dilated pupils, decreased saliva, tears, constriction blood vessels, relaxes airways, increased heart rate, stimulates glucose production and release, inhibits digestion, increase epi and norepi from adrenal medulla, affects large intestine, relaxes urinary bladder, stimulates orgasm. Predominantly Nepi neurons.
What are some clinical sympathetic responses?
Dilated pupils, Senses sharpen, sweating, increased heart rate and BP, digestion stops, empty bowels and bladder, increased coagulation, blood flow to muscles increases, breathe more rapidly, airways relax
What are effects of chronic stimulation with catecholamines?
Brain fog, anxiety, depression, increased visceral fat, increases CV risk factors - HTN, myocardial dysfunction
What are effects of chronic stimulation with cortisol?
Stimulation of fat deposits, suppression of immune system, increases in BP, Memory loss(hippocampus), Increase in protein breakdown, Depression, Demineralization of bone, increases in blood sugar
What part of the adrenals does Norepi and Epi get secreted from?
Medulla
What part of the adrenals does cortisol get secreted from?
Cortex
What is POMC
Proopiomelanocortin protein. It is a precursor to other hormones such as ACTH and Beta lipotrophin and Endorphin.
What happens in the acute response to stress on the immune function?
minutes to hours - enhanced dendritic, neutrophil, macrophage, lymphocyte trafficking and maturation, cytokine production
What happens in the chronic response to stress on the immune function?
alteration of Type 1 and 2 cytokine balance, low grade chronic inflammation, suppressingimmune cell numbers and trafficking.
What happens in the chronic response to stress on the immune function?
alteration of Type 1 and 2 cytokine balance, low grade chronic inflammation, suppressing immune cell numbers and trafficking.
How does chronic stress affect the Prefrontal Cortex?
It reduces the size and lose decision making capacity.
What is eustress?
Manageable levels of stress.
What is allostasis?
Maintaining homeostasis/stability thru physiological and biological change. It is positive and necessary to life. It is different from homeostasis in that it supports homeostasis. It supports physiological parameters essential for life as environments and/or life history stages change. It allows for a change in the set points of the various physiological systems so that the body can respond adequately to environmental changes.
What is allostasis?
Maintaining homeostasis/stability thru physiological and biological change; the ability to maintain homeostasis in response to stresses
How does multitasking affect brain?
It causes mental fog as multitasking increases cortisol and adrenaline which overstimulates the brain. Attention gets easily hijacked. It leads to dopamine-addiction feedback loop, rewarding the brain for losing focus and seeking external stimulation. Also decreases prefrontal cortex which is responsible for task management.
STAINS stands for
Stressors, Toxins, Antigens/allergens/adverse food reactions, Inflammation/Infections, Nutrition and Sleep (Acronym of what can affect hormone imbalance)
What is the HPATGIG axis?
Hypothalamic-Pituitary-Adrenal-Thyroid-Gut-Immune-Gonadal axis(Its your psycho-neuro-immuno-gastro-endocrine system.
What type of stress has capacity to elevate and maintain the stress response chronically causing disease consequences?
Psychological(opposed to physiological) but there are plenty of ATMs of chronic stress.
How do major life stressors impact you?
Increases in cortisol and DHEA after undesirable life events is predictive of major depression. High Cortisol low DHEA is predictive of persistence of major depression. Stress related cortisol secretion is associated with endocrine metabolic abnormalities and abdominal obesity.
How do toxins affect adrenals?
PCBs and dioxins accumulate in adrenal glands. Interferes with steroidogenic pathways(androgen, cortisol and aldosterone biosynthesis), Interferes with ACTH receptor sensitization, Associated with increased diabetes and cardiovascular risk among highly exposed people. Iatrogenic - etomindate causes adrenal suppression for example.
What is the hazard ratio between celiac and adrenal insufficiency?
11.4
The prevalence of celiac disease in patients with ___________ is significantly increased when compared with general population.
Autoimmune thyroid disease. In some cases, gluten withdrawal may single handedly reverse autoimmune thyroid abnormalities.
How does inflammation affect Adrenals?
It alters the adrenal response, results in the HPA stress response causing inappropriately low cortisol secretion in relation to ACTH secretion(ex RA) and lowers DHEA sulfate as shown in patients with chronic inflammatory disease.
How does vitamin C affect adrenals?
Is needed in organs that make catecholamines(Epi, Norepi and dopamine) such as in the brain and adrenal glands.
Is EFA deficiency associated with high or low plasma cortisol?
Low
When adrenaline goes up after a period of stress, zinc levels go _____.
Down
What nutritional insufficiencies affect adrenals?
Vitamin C, zinc, EFA, Pantothenic acid, magnesium
How does pantothenic acid insufficiency affect adrenal?
Causes impaired adrenocortical function and abnormal stress response.
How does magnesium deficiency affect adrenals?
Causes elevated HPA set point(increases CRH and ACTH). Stress increases requirement for magnesium.
Which type of diet helps lower levels of HPA axis disturbance?
Mediterranean Diet
What type of fat distribution is a disturbed HPA axis associated with?
Abdominal fat distribution, higher content of fat and saturated fatty acids in diet
Define disturbed HPA axis
Lower morning cortisol and post prandial cortisol secretion with low diurnal variability of cortisol
Is abdominal fat or peripheral fat associated with increased urinary cortisol?And why?
Abdominal Fat which may be result of increased CRF or ACTH, secondary to a state of functional cortisol resistance. Stress/inflammation leads to increased CRH/ACTH which leads to functional cortisol resistance which leads to abdominal obesity and to more stress and inflammation.
Does meal timing play a role in diurnal pattern of cortisol?
Yes, mid-day meal is seen to have a synchronizing role for normal plasma cortisol fluctuations
Which amino acid is likely to cause elevations in cortisol?
Tryptophan. All can but particularly tryptophan. Only with naso gastric feeds, not IV, therefore amino acid stimulation of adrenal glands is via gut mucosa and not due to increased serum levels of amino acids.
How soon after sleep deprivation can you see a reduced cortisol?
Next day
What are the effects of sleep deprivation over 1 day and 8 days?
After 1 day, no effect. After 8 days, decreased ACTH response to stress
What happens with sleep debt?
Decreased Glucose tolerance
Decreased Thyrotropin
Increased Evening cortisol
Increased Sympathetic nervous system activity
Effects are similiar to those seen in aging
Sleep can help restore adrenals
How can you help restore adrenals?
Removal and rebalance the triggers and mediators within modifiable LS factors - sleep, exercise/movement, nutrition, stress and relationships.
What is the physiological effect of Cortisol Steal?
Stress leads to increased cortisol formation. Stress and inflammation and simple carbs etc inhibits sex steroid hormone production directly and indirectly. (i.e. 17,20 lyase). Stress can increase cholesterol as endocrine system signals brain we need to make more cortisol.
When cortisol is increased, what downstream consequences are there?
Decreased progesterone, estrogens, DHEA, and testosterone. This is referred to as Cortisol Steal.
What are the functions of DHEA?
- Precursor for testosterone and estrogen
- Reverses immune suppression caused by excess cortisol levels
- Stimulate bone deposition and remodeling
- Lowers total cholesterol and LDL
- Increases muscle mass
- Improves body composition
- Involved in conversion of T4 to T3Accelerates recovery from acute stress
- Reverses many of the unfavorable effects of excess cortisol.
How does cortisol steal lead to other issues?
Have less progesterone an initially and estrogen dominant state. More cortisol production and stimulation of aromatase which leads to estrogen dominant conditions(breast cancer, fibroids, endometriosis). Long term decreased formation of androgens and estrogens(inhibition of DHEA pathway to form androgens and estrogens) - explains stress and hot flashes, stress and decreased libido.
How does cortisol steal lead to other issues?
Have less progesterone an initially an estrogen dominant state. More cortisol production and stimulation of aromatase which leads to estrogen dominant conditions(breast cancer, fibroids, endometriosis). Long term decreased formation of androgens and estrogens(inhibition of DHEA pathway to form androgens and estrogens) - explains stress and hot flashes, stress and decreased libido.
What happens in Stage 1 of Selye’s General Adaptation Syndrome?
Both cortisol and DHEA increase with episodic stress, but recovery occurs to baseline. Asymptomatic, stimulated. Rapid increases in catecholamines and slower corticosteroid increase.
What happens in Stage 2 of Selye’s General Adaptation Syndrome?
Cortisol chronically elevated, but DHEA declines. Alarm molecules elevated. Consequent alterations long term in glucose tolerance, blood pressure, thyroid and sex hormone metabolism. Stressed, anxiety attacks, mood swings, depression
What happens in Stage 3 of Selye’s General Adaptation Syndrome?
Adrenal insufficiency - low cortisol and DHEA, Depression and Fatigue.
What happens in Stage 3 of Selye’s General Adaptation Syndrome?
Degenerative disease characterized by adverse influence of corticosteroids and alarm molecules. Low cortisol and DHEA, Depression and Fatigue.
From a laboratory standpoint what changes do we see in Stage 1 Selye’s Adaptation Syndrome?
Elevated Cortisol, elevated sum cortisol or normal depending on where on continuum patient is
Elevated cortisol/DHEA ratio
Elevated cortisol at one time point
Elevated cortisol sum over the day
Normal DHEA or low DHEA(occasionally elevated DHEA)
What are symptoms of elevated cortisol (Stage 1)?
Irritability/anxiety Fatigue/low energy Night sweats/muscular tremors Insomnia Poor sleep/sleep disturbance/hot flashes Increased susceptibility to infection(cortisol effect on immune suppresion) Shakiness between meals/sugar cravings(cortisol and blood sugar) Weight gain - around the middle
What are possible exam findings with elevated cortisol?
Postural hypotension Pupil contraction Sergant's white lines Positive Rogoff's sign Chloasma(Melasma) Swollen ankles
What is pupil contraction?
Iris cannot hold contraction when light is shone into eye
True or False: Higher urinary cortisol in persons with depression is associated with lower bone density.
True. It is also significantly associated with incident fractures. (Higher baseline UFC is an independent predictor of future fracture)
How does chronic stress affect the immune system?
It impairs the response to antiinflammatory signals: The capapcit tot suppress production of proinflammatory cytokines IL-6 was diminished.
From a laboratory standpoint what changes do we see in Stage 3 Selye’s Adaptation Syndrome?
Diminution of corticosteroids over time and continued advance of many degenerative diseases.
Depressed cortisol over 2-4 time points.
Depressed cortisol sum.
Depressed DHEA
Generally, the cortisol/DHEA ratio is no longer useful
What are signs of depressed cortisol (Stage 3)?
Low BP
FM
Dizziness on standing or bending
Easy bruising/slow healing of cuts
What are symptoms of depressed cortisol (Stage 3)?
Fatigue, apathy, unmotivated
Absent minded/poor concentration
Increased excessive sleep but poor quality
Increased susceptibility to inflammation and allergies(not infections)
Depression, worse in evening
Early onset perimenopause or menopause
Muscle pains
Craving salty foods, pickles, etc
Inability to handle even slight stresses
Low blood sugar symptoms(dizzy, irritable, symptoms relieved by food)
Unstable body temperatures
What conditions are associated with depressed HPA axis and depressed cortisol?
Atypical depression Seasonal affective disorder Postpartum depression Panic attacks/generalized anxiety disorder Bipolar II disorder PTSD CFIDS(Chronic fatigue immune dysfunction syndrome) FM
What are problems with measuring plasma cortisol?
Hard to measure free cortisol as most is bound by plasma protein corticosteroid binding globulin(CBG). CBG levels are affected by estrogen, progesterone, aldosterone, exogenous steroids, stress and other factors. Levels also fluctuate rapidly. Blood draw itself elevates cortisol. Can be artificially elevated by factors including drugs, pregnancy and congenital alterations.
What are issues with measuring urinary cortisol?
Represents urinary free cortisol over last 24 hours, no diurnal measurement, not well researched(but may be available now), inconvenient
What are advantages of measuring salivary cortisol?
Avoids issues that come with plasma cortisol and it still reflects the instant cortisol secretion, easy to collect, noninvasive and thus can do multiple sampling. Multiple sampling allow for diurnal variations to be plotted.
Should you measure DHEA or DHEA-S in blood?
DHEA-S as most is found in its sulfated form which has levels 100-1000 times higher than those of free DHEA. DHEA-S shows little diurnal variations whereas free DHEA does. DHEA-S does not fluctuate in short term in blood. Salivary DHEA-S is related to serum levels but dependant on PH of saliva and flow rate so levels may fluctuate. Overall the literature seems to suggest saliva is useful and reliable indicator for DHEA. DHEA fluctuates daily and is affected by factors that affect HPA axis. Baseline levels change over lifetime. DHEA-S levels change slowly and are a readout of overall balance in the system. They also change with age, peaking in mid 20’s and declining thereafter. Serum DHEA-S and salivary DHEA correlate well. However, the use of Cortisol/DHEA ratio can be useful and best done thru saliva. In summary - order salivary cortisol and DHEA to assess HPA axis. If pt cannot afford saliva testing or if testing other hormones thru blood, then get serum DHEA-S.
What time should you measure morning cortisol?
Within 30 minutes of wakening.
What is a big picture approach to fixing hormones?
Removal of triggers and mediators, lifestyle modification, diet modification(Elimination diet, CM diet), supplements, botanicals, hormone replacement.
Long term overexposure to stress hormones accounts for ____% of all primary care visits in the US.
75-90%.
What is the number 1 reason why people eat poorly, quit healthy lifestyle programs and practice substance abuse?
Long term over exposure to stress hormones.
What are some Lifestyle tools to address stress?
1)CBT(relaxation training, progressive muscle relaxation)
2)Primary Care interventions:
Teach relaxation techniques(mindfulness, breathing,
meditation)
Promote self awareness with compassion
Promote connectedness with family and friends
Promote movement/exercise to tolerance
3)Biofeedback-based intervention
4)Dial UP the self care one step at a time
What are key aspects of dietary approach to Hormonal balance?
1) Glucose and insulin balance(avoid skipping meals and include protein at every meal)
2) Low glycemic load(CM or Elimination food plans)
3) Unrefined carbohydrates(increase veggies/low glycemic index fruits) with good -quality protein and fats(nuts, seeds) at all meals.
4) Avoid stimulants- caffeine, refined CHO’s(sugar, flour, bread, fruit juice and chocolate)
5) Consider if any part of the SAD is contributing to allostatic load by adding to inflammation, metabolic burdens(eg. high glycemic load).
What are nutritional supplements that can help with stress?
High quality multivitamin with special attention to:
1) B Complex(co-factors in hormone production)
a) B5- pantothetic acid(100-150 mg)
b) B6 - pyridoxine (50-100 mg)
c) Biotin (1000 mcg)
d) Folate (400-800 mcg)
2) Vitamin C (1-2 grams) and antioxidant blend
3) Magnesium (400-600 mg)
4) Phosphatidylserine (600-800 mg) - give 30 minutes before bed if cortisol is high at night.
What supplement lowers cortisol?
Phosphatidyl Serine has been shown to attenuate the serum cortisol response to acute exercise stress, increase performance, improve mood and lower feelings of stress.
What are adaptogens?
Are botanicals that are non-toxic, produce a non-specific response in the body, and have a normalizing influence on physiology, regardless of the direction of change from normal caused by the stressor. In general, they work on the whole body rather than a specific organ system.
How do adaptogens affect HPA axis?
Overall, they have a balancing effect on HPA axis by:
1) Appropriate stimulation of adrenocortico-tropic hormone(ACTH) in the pituitary gland during times of acute stress
2) Improving cortisol sensitivity by increasing HPA sensitivity to glucocorticoids.
3) Possibly by promoting diffusion of corticosteroids across cell membranes in the hypothalamus
What are some adaptogenic herbs for hyper-adrenal states?
Rhodiola rosea(Russian Golden Root) Hypericum perforatum (St John's Wort)
How does Rhodiola rosea help with hyper-adrenal states?
Has an anti-fatigue effect that increases mental performance, particularly the ability to concentrate, and decreases cortisol response to awakening stress in burnout patients with fatigue syndrome. Some stress chemicals like cortisol, act as excitotoxins and damage cells via cell membrane effects. Salidroside, a constituent in Rhodiola rosea, has been shown to prevent excessive calcium channel activity induced by KCL and glutamate.
What happens to HPA axis in depression?
Patients with major depression tend to have an excessive activation of the HPA axis manifested as hypersecretion of ACTH and cortisol.
How does St John’s wort(Hypericum Perforatum) help for depression?
SJW and hypericin have effects on the expression of genes that are involved in the regulation of the HPA axis. Individual flavonoids from SJW reduced plasma ACTH and Corticosterone after 2 weeks.
What are some adaptogens for the exhausted hypo-adrenal state?
Panax quinquefolius(Panax Ginseng) Glycyrrhiza glabra(Licorice)
True or False: Several human trials have shown Panax Ginseng to have anti anxiety effects without any adverse side effects reported.
True.
How does Panax Ginseng help adrenal glands recover from chronic stress?
Improves corticoid response and the corticotropin feedback loops with the HPA axis(upregulates). Animal studies have shown Panax administration to enhance energy metabolism during exercise.
What happened when mice undergoing stress were treated with Panax ginseng and Withania somniferum?
Corticosterone levels were higher in all the herb supplemented groups. Physical endurance of swimming mice also increased in all the groups receiving Panax.
How does Glycyrrhiza glabra spare cortisol?
It inhibits 11-beta hydroxysteroid DH which blocks conversion of cortisol into cortisone.
What are side effects of glycyrrhizin?
Can cause pseudoaldosteronism leading to increased BP and alterned potassium levels. Licorice should not be used long term and interact s with multiple drugs.
What are the functions of DHEA?
1) Precursor to estrogen and testosterone
2) Reverses immune suppresion caused by excess cortisol
3) Stimulates bone deposition and remodeling
4) Lowers total cholesterol and LDL levels
5) Increases muscle mass
6) Improves body composition
7) Involved in conversion T4 to T3
8) Accelerates recovery from acute stress
9) Reverses many of the unfavorable effects of excess cortisol
What have clinical trials suggested in regards to dosage of DHEA for young adults with primary and secondary adrenal insufficiency?
Dosages of 50 mg oral DHEA but not <30 mg can increase serum androgen levels to within the physiologic range for young adults with primary and secondary adrenal insufficiency, possibly improve sexual function, improve mood and self-esteem(depression) and decrease fatigue.
What are dosages for DHEA in men and women and what consideration, side effects should you consider?
Females 5-25 mg bid
Males 10-50 mg bid
Side effects can include acne, facial hair in women and aggressiveness/irritability in men
Positive safety record up to 1 year at these dosages. But always test, don’t guess.
What are side effects of DHEA?
Acne, facial hair - women
Irritability, aggressiveness - men
Positive safety record up to 1 year at safe doses.
How does childhood trauma lead to an average decrease in life expectancy of 20 years?
Chronic stress increases glucocorticoid receptor resistance which results in failure to downregulate the inflammatory response which leads to increased risk of CVD.
How is depression and cortisol related?
Patients with acute depression had 25% more cortisol than controls. However, within 60 minutes of wakening, the cortisol levels were same as controls. Thus, depressed patients tend to have increased early morning cortisol secretion but the demonstration of this effect requires control for time of waking.
Where and what points of leverage do you need to address with Cortisol/DHEA imbalances?
1) Production/synthesis and secretion of hormones - supply hormone precursors and co-factors to increase/decrease stimulation as needed.
2) Transport/conversion/distribution/interaction with other hormones
3) Sensitivity at the cellular level to the hormone signal - glucocorticoid receptor insensitivity
4) Detoxification/metabolism/excretion of the hormone - slow conversion of cortisol to cortisone
What is normal diurnal cortisol response?
Cortisol quickly peaks 30-45 minutes post awakening(about 50% increase). Gradual decline thru the day. The act of awakening causes cortisol response.
What are some facts about CAR?
1) It is one component of the circadian cortisol rhythm. It describes a salivary increase in cortisol within the first hour of awakening that is separate from the cortisol increase during the second half of the night.
2) Current evidence indicates that the CAR is independently regulated as it is mediated by an extra pituitary pathway to the adrenal from the supra-chiasmatic nucleus.
3) Can be influenced by stress anticipation as it serves to prepare to deal with demands of the day, therefore, the CAR is highly dynamic and reflects capacity to cope with an acute stressor.
4) In research setting, abnormalities of CAR have been associated with a number of health conditions including depression, T2DM, metabolic syndrome and central obesity.
How does thyroid supplementation affect the HPATG axis?
It increases the sensitivity of CRH to release ACTH, so patients who are initially put on thyroid supplementation get a hit to the adrenals and tend to feel good. Both hypothyroidism and subclinical hyperthyroidism tx with suppressive doses do this.
How does Cortisol affect the Thyroid?
It suppresses TSH conversion of T4 to RT3 and T3.
How does estrogen affect the Thyroid?
It increases TSH production.
What is the effect of synthetic estrogen/progestins on the defense and repair node?
It increases proinflammatory cytokines. Premarin - increases by 125%, Prempro - increases 150%
How is assimilation node affected in prenatal moms under stress?
It changes the infants microbiome.
How do antibiotics affect the metabolism of hormones?
They affect the metabolome and increase steroid metabolites from C21 pathway in the feces after abx tx
How does assimilation node affect the ovaries?
Metabolic endotoxins cross leaky gut into circulation, causing inflammation specifically in the ovaries, thus, decreasing progesterone production which causes luteal phase deficiency. So can affect fertility optimization and estrogen dominance as need progesterone to correct them.
What is the affect of phthalates on thyroid in children?
Early phthlate exposure reduces thyroid hormones and can cause cognitive dysfunction. There is an inverse relationship between phthlate metabolites measured in children age 3 and thyroid function in preschool children.
How does social support affect menopause?
It reduces symptoms
What is allostasis
It is how you cope with stresses to maintain homeostasis. The ability of an organism to maintain homestasis in response to stressors.
What is allostatic load?
All the stressors that affect you
How does stress affect immune function?
Increases susceptibility to infection
Increases severity of infection
Diminishes the strength of response to vaccines
Reactivates herpes virus
Delays wound healing
Increases release of proinflammatory cytokines that cause disease.
How does stress affect the steriodogenic pathway?
It directly stimulate the pituitary to increase release of ACTH to make more cortisol
It indirectly slows the anabolism of 17,20 lyase so doesn’t go thru Test/Est pathway. It also stimulates aromatase to make more estrogen.
How does inflammation affect the steriodogenic pathway?
It inhibits 17,20 lyase and stimulates aromatase; It also increases 5 alpha reductase activity leading to increased DHT and hair loss. Insulin can also do this.
What is the rate limiting step in steroid synthesis?
Getting LDL cholesterol to the mitochondrial membrane
What types of sex steroids do ovaries produce?
Progestogens, estrogens and androgens
What enzyme does ovary lack and so what can’t it produce?
21 hydroxylase, 11B hydroxylase, glucocorticoids, mineralcorticoids
How does steroid synthesis get cholesterol?
All steroid hormone producing cells can make it from acetate, but can’t meet demand, thus, is required to get it from diet. Thus, think about hormone deficiency in undernourished or over athletic pts or those with too low cholesterol
What enzyme and where is it bound to transform cholesterol into prenenolone?
P450cc, mitochondria
What stimulates P450cc in the mitochondria of ovary?
FSH, LH
What stimulates P450cc in the mitochondria of the adrenals?
ACTH
What 2 substances does pregnenolone make?
DHEA(via 17OH pregnenolone with 17 a-hydroxylase)(delta 5 pathway)
Progesterone(directly)(delta 4 pathway)
Once progesterone is formed, what is it hydroxylated to and by which enzyme?
17 a-hydroxyprogesterone by 17 a-hydroxylase
What is 17-OHprogesterone a precursor to?
19C androgens(Androstenedione which goes to testosterone) and from there both can go to 18C estrogens via aromatase. It also is a precursor to cortisol.
What estrogen does testosterone form?
Estradiol
What estrogen does Androstenedione form?
Estrone which then can be converted to estradiol
What substances does progesterone produce?
17-OHprogesterone to cortisol or androgens(event to estrogens)
11 -deoxycorticosterone(eventually aldosterone)
What is cortisol steal?
If body needs cortisol or aldosterone, then less progesterone is circulated because it is shunted away; Also called pregnenolone steal.
What are physiological effects of cortisol steal?
Less progesterone and initially estrogen dominant state
More cortisol production and stimulation of aromatase which leads to estrogen dominant conditions
Longterm decreased formation of androgens/estrogens d/t inhibition of DHEA pathway to form androgens/estrogens which can explain stress, hot flashes and decreased libido
How does stress effect cortisol steal?
It increases cortisol formation which inhibits sex steroid directly and indirectly(17-20 lyase). Inflammation, simple carbs also do this.
What forms from DHEA?
Androstenedione and DHEA sulfate
What enzyme converts testosterone to estradiol?
Aromatase
What enzyme converts Androstenedione to estrone?
Aromatase
What does Androstenedione convert to and by which enzymes?
Testosterone via 17 B-OHsteroid dehydrogenase and estrone via aromatase
Why do you need to be careful in dosing DHEA supplement?
Too much can lead to increased estrogen and risk of breast cancer
What part of the adrenal is cortisol produced?
Cortex
What part of adrenal is adrenaline hormones produced?
Medulla
Why are androgens not produced in adrenal cortex?
No 17,20 lyase activity. Androgens are not produced in areas of cortisol activity.
Where is DHEA produced?
Ovarian theca cells, testicular leydig cells and adrenal reticularis
Where is progesterone made?
Corpus luteum
What decreases SHBG?
Obesity, inflammation, insulin resistance, hypothyroidism, androgens,IGF-1, corticoids, progestins. (Breast cancer risk)
What increases SHBG?
Vegetarian diet(so this can be a treatment in estrogen dominance)
Pregnancy
Hyperthyroidism
HRTs or OCPs
How are androgens formed in the ovary?
LH stimulates theca cell to produce androstenedione and testosterone via cAMP from cholesterol. This can go to granulosa cells via stimulation of FSH and via aromatase make estrone and estradiol.
What stimulates the ovary to make progesterone and in which cell of ovary and at what time?
LH, granulosa, after ovulation
How much of E2 and T are bound to SHBG once made? And where is rest bound to?
69% to SHBG
30% to Albumin
1% is free
What is transcortin?
Corticosteroid binding globulin; carries cortisol and progesterone.
What transport proteins carry progesterone?
Transcortin - 18%
Albumin - 80%
2% is free
What transport proteins carry cortisol?
Transcortin - 75%
Albumin - 15%
10% is free
Where is estriol made and from what?
in periphery, from estradiol(E2) and estrone(E1); Except in pregnancy it is formed by a detoxification. It is NOT made in the ovary.
Which biotransformation phase 2 process is important for excretion of estrogens?
Methylation
What is meant by perhipheral conversion of hormones?
Free circulating androgens from the adrenals are converted to free estrogens in the skin and adipose tissue. Therefore, women with more adipose produce more estrogens which can lead to vaginal bleeding in menopausal women and why estrogen depletion can be noticed in skin by some women.
Where does most of the estrogens come from in Men?
peripheral conversion of androgens
In women, what is the major source of circulating androgens, esp androstenedione?
Adrenal glands
What enzyme is missing in CAH and what is result?
21 hydroxylase, severe decrease in adrenal production of glucocorticoids; this leads to increased ACTH to make more cortisol d/t feedback loop. It also causes increased 17 OH progesterone/androgens so become virilized as 17OH P can’t go down pathway to cortisol so it gets converted to androstenedione.
What is treatment for CAH?
Give cortisone to decrease ACTH stimulation
What hormone is not converted peripherally from steroids and why?
Progesteroneas it comes from ovary, almost nothing comes from adrenals. (Only exception is in pregnancy)
What level of progesterone will you see in CAH?
Higher levels up to 50x normal because of 21 hydroxylase deficiency