Hormones Nuts and Bolts Ron Rothenberg MD
Power Point Slides All slides from my presentation will be available to you. They will be posted to website next week CaliforniaHealthspan.com
Hormone Bio-Identical Symptoms Delivery method Dose Can vary Lab test Can help 80% clinical Safety Side effects Follow-up Clinical, lab Dose adjustment Controversy Medical, legal, philosophical
Hormone: Testosterone Delivery method T cream compounded T cream commercial T patches T buccal T pellets T cypionate compounded T cypionate/t propionate compounded T cypionate commercial T undecanoate commercial HCG HCG + T
Testosterone Cypionate IM or SC Weekly dose - 100 mg Can divide in 2 doses less E2 Physiologic stable levels Easy self injection Less DHT than transdermal Potentially more E2
Transdermal Commercial brands 1% transdermal gel Commercially available 50, 75 or 100 mg packages Compounding pharmacies Can custom produce transdermal gel Less expensive than commercial Can titrate to serum levels by varying percentage 1-10, and dose Preferred to commercial in most men
T Dose Men Cream 50-200 mg/day Cypionate 50-150 mg IM or SQ/ week Undecanoate 750 mg IM q 10 weeks Pellets 75 mg x 5-10 q 3 months HCG 2000-5000 units per week Possible dosing: 250-500 units per day 1000-2500 units twice a week T cypionate 100 mg IM on day 1 HCG 250-500 units SC weekly
Estradiol - Aromatase - DHT 5-alpha Reductase Sperm Sertoli cell Leydig cell
HCG If FSH and LH already relatively high, probably will not work Avoids the TRT side effects of loss of testicle volume and decreased sperm count More aromatization?
Testosterone Lab Testing Test Sex Reference Optimal Total ng/dl Male 350-1030 790-1100 Free* ng/dl (Equilibrium dialysis) Female 10-55 50-80 Male 8-30 20-35 Female 1.1-6.3 3-8 Bioavailable Male 120-600 400-640 pg/ml Female 2-20 10-25 * Free testosterone results vary with methodology direct analog (RIA) in pg/ml same ref range
TOTAL TESTOSTERONE T T T T T T T. T. T.......... ALBUMIN T T T T T T SEX HORMONE BINDING GLOBULIN
FREE TESTOSTERONE T T T T T T T T T T T SEX HORMONE BINDING GLOBULIN T T T T............... ALBUMIN
BIOAVAILABLE TESTOSTERONE T T T T T T T T T T............ ALBUMIN T T T T T T SEX HORMONE BINDING GLOBULIN
SHBG binds T > E 20-60 nmol/l male 40-120 nmol/l female Low SHBG associated with Insulin Resistance in men and women
Increases SHBG Thyroid Estrogens Progesterone Aging Low Insulin Coffee (not decaf). Green tea, soy Decreases SHBG Testosterone DHEA Glucocorticoids GH High Insulin
Low calculated Free Test - symptoms Low cft, even in the presence of normal TT, is associated with androgen deficiencyrelated symptoms. Lab free testosterone inaccurate. Even the best available measurement procedures have technical and fundamental limitations Antonio L et al. Low Free Testosterone is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone. J Clin Endocrinol Metab. 2016 Feb 24
Free Free T calculator http://www.issam.ch/freetesto.htm
T side effects Decreased sperm count Decreased testicle size No roid rage Possibly more assertive or aggressive More libido Possible increase H and H Possible fluid retention Possible gynecomastia
Lab Testing Prostate cancer screen PSA < 4.0 PSA similar to baseline if prior values known DRE no suspicious findings of PC Current PSA Controversy NEJM, JAMA H and H baseline Keep Hg < 17.5 by donating or discarding blood 1-4 times a year if needed
T Metabolites E2, E1 DHT Measure or not? To control or not to control?
T Metabolites E2 increases with increasing T Do not let E2 get to low Should you lower E2 with asymptomatic patient? What is optimal E2? NEJM Finkelstein study 2013 Need E2 for fat control, libido and erectile function Aromatase Inhibition Chrysin 250 mg BID PO 50 mg/gm Topical Zinc 50 mg per day Progesterone 5-10 mg transdermal
Anastrozole Anastrozole 0.5 mg 1-3 x per week Can precisely control E2 Do not let levels fall too low E2 is necessary for brain, heart, bone, fat loss, sex Use only with clinical symptoms?
T Metabolites l DHT can increase with increasing T, especially with transdermal T l DHT does not aromatize to E2 l Is DHT evil twin of T or good androgen? l DHT needed for erectile function and anabolic effects l Not associated with Prostate CA in serum levels l Possibly associated with BPH and hair loss
5-alpha reductase inhibition Saw palmetto 320 mg/day Progesterone transdermal 5-10 mg/day Don t let DHT go to zero Finasteride? no Dutasteride? no
Follow up PSA, PSA velocity, PSA controversy DRE Follow H and H Follow E2
Prostate cancer Active Treated Controversies BPH Heart disease Roid rage Testicular atrophy Sperm count
European Study T and PCa 1023 patients up to 17 years with TRT Cohort 1 261 Pca 54.4/10,000 pt years Cohort 2 340 Pca 30.7/10,000 pt years Cohort 3 422 Pca 0/10,000 pt years Background prevalence 96.6/10,000 pt yrs Conclusion- Testosterone therapy in hypogonadal men does not increase the risk of prostate cancer. Ahmad Haider et al. Incidence of Prostate Cancer in Hypogonadal Men Receiving Testosterone Therapy: Observations from Five Year-median Follow-up of Three Registries. The Journal of Urology, Volume 193/Issue 1 (January 2015)
History of T causes PC myth 1941: Huggins and Hodges reported that marked reductions in T by castration or estrogen treatment caused metastatic PC to regress Administration of exogenous T caused PC to grow. This was based on only one patient Based on increased acid phosphatase Multiple subsequent reports revealed no PC progression with T administration Some men even experienced subjective improvement, such as resolution of bone pain Morgantaler A. Testosterone and Prostate Cancer: An Historical Perspective on a Modern Myth. Eur Urol. 2006 Jul 26
Recent data have shown no apparent increase in PC rates in clinical trials of T supplementation in normal men or men at increased risk for PC No relationship of PC risk with serum T levels in multiple longitudinal studies No reduced risk of PC with low T. The paradox in which castration causes PC to regress yet higher T fails to cause PC to grow Resolved by a saturation model, in which maximal stimulation of PC is reached at relatively low levels of T
Morgentaler conclusion There is not now-nor has there ever been a scientific basis for the belief that T causes PC to grow
<100 200 1000
Deficiency Symptoms - Women Low libido Low sense of well-being Inability to maintain muscle Decreased motivation for change Fatigue Forgetfulness-Memory loss Abdominal fat, weight gain
T in women Preparation Compounded cream 1% = 10 mg/gm 0.5% = 5 mg/gm Dose 1.25-10 mg per day q AM T cypionate injections 2.5-10 mg/week
Testosterone is the most abundant biologically active hormone in women Glaser RL, Dimitrakakis C. Testosterone therapy in women: myths and misconceptions. Maturitas. 2013 Mar;74(3):230-4
T women side effects Decrease dose early in sequence so you do not go beyond skin Sequence: Oily skin Acne Increased facial hair Too much libido, aggressiveness Clitoral enlargement Deepening of voice
Follow up Clinical Lab Decrease dose if side effects present Increase dose if benefits not seen up to dose of 20 mg Women are complex and sometimes still do not have libido even when T is high
Controversies Androgenic side effects? Should you treat a woman with low libido who has youthful range lab tests? Does T always work to restore libido? My dog ate my Testosterone
DHEA decline in aging - Adrenopause Produced in adrenal cortex and brain Most abundant steroid hormone Precursor to androgens and estrogens No known receptor found to date Pleomorphic effects on immune system May improve fertility in women E A D H
DHEA No unique symptoms of deficiency but Low levels associated with All cause mortality, Cardiovascular mortality Obesity, Type 2 diabetes Immune dysfunction Autoimmune disease Cancer Hypertension Cardiovascular disease Depression and loss of well-being Low libido, Erectile dysfunction Osteoporosis Ohlsson C et al. Low Serum Levels of Dehydroepiandrosterone Sulfate Predict All-Cause and Cardiovascular Mortality in Elderly Swedish Men. J Clin Endocrinol Metab. 2010 Jul 7.
DHEA And Well-Ness Study Cognitive, life satisfaction and sexual function evaluated Healthy, normal cognitive Double blind placebo controlled with 50 mg daily of DHEA Increased testosterone (60%) and estrogen (40%) in women, not in men No significant difference from placebo No adverse effects Kritz-Silverstein, D et al. Effects of DHEA supplementation on cognitive Function and Quality of Life: The DHEA and Well- Ness (DAWN) Study. J Am Geriatric Soc. 2008 July; 56(7): 1292-1298
DHEA and Memory 150 mg DHEA BID x 7 days healthy young men Placebo double blind crossover Reduction in evening salivary cortisol Improved mood and memory Hippocampal activation on Low-resolution brain electromagnetic tomography (LORETA) Alhaj HA et al. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a doubleblind, placebo-controlled study. Psychopharmacology (Berl). 2005 Oct 18;:1-11
Lab tests DHEAS not DHEA Serum optimal Men 350-400 micrograms/dl Women 150-200 micrograms/dl DHEA Saliva optimal Men 250 pg/ml Women 200 pg/ml
Dose Men 25-100 mg Women 12.5-25 mg 7-keto DHEA No downstream metabolites Probably the same benefits More thermogenesis and weight loss Men and women 25-100 mg
7-oxo DHEA=7-keto DHEA 3-acetyl-7-oxo-dehydroepiandrosterone Does not bio transform to androgenic and estrogenic metabolites Associated with thermogenesis and weight loss Hanpl et al. Steroids and thermogenesis. Physiol Res. 2005 May 24
7-Keto DHEA Decline contributes to fat gain Weight loss without side effects (kalman) Improves Immune function Improves lipids Improves memory in rats Dose: 50-200 mg in AM Can use alone or combine with DHEA
Ergogenic=Thermogenic Steroid Increase heat production in mitochondria Body temp does not rise significantly Thermoregulation increases heat disposal in the periphery 7-oxo 4 times more thermogenic than DHEA Uncoupling proteins synthesized Useful in Raynauds? Ihler G et al. 7-oxo-DHEA and Raynaud's phenomenon. Med Hypotheses. 2003 Mar;60(3): 391-7.
Controversies Use in Autoimmune disease Should every patient on corticosteroids be on DHEA? Since DHEA downstream metabolizes, can you treat all sex steroid deficiencies with DHEA? Is 7 keto DHEA bioidentical?
Thyroid Lab tests - Optimal Free T3 in upper 1/3 of reference range 3.5-4.2 ng/dl T4 is a pro hormone TSH < 1.5 Reverse T3 lower ½ reference range
The Drug Thyroid Combination of T3 and T4 Desiccated Thyroid extract = 38 mcg T4 + 9 mcg T3 per grain = 60 mg Can have compounded equivalent Short half life of T3 makes it difficult to use just T3 Dose 1-4 grains Follow symptoms and Free T3
Controversies Is T3 plus T4 better than T4 alone Atrial Fib Osteoporosis Just look at the TSH, you do not need other testing Why test at all, just treat clinically no matter what the results Type 2 Hypothyroidism? How do you decrease reverse T3? Do you need T4 for brain?
Thyroid math Short half-life of T3 Consider BID or Extended Release for T3/T4 combinations
Thyroid Math approximate Clinical results come first To convert T4 to combined T3/T4 T4/2 = new T4 New T4 /4 = new T3 Converted thyroid treatment: new T4 + new T3 To convert above to DTE consider 1 grain = 60 mg DTE contains 38 micrograms T4 + 9 micrograms T3 or 100 micrograms T4 = 90 mg DTE= 1 ½ grains DTE (this one comes out with a little more)
Bio-Identical Hormone Replacement in Women Balance Estrogens, Progesterone and Testosterone Every woman needs a unique balance Progesterone protects against breast cancer
Female Hormones Estrogens Progesterone Testosterone Delicate balance between E and P both antagonistic and complimentary Thierry Hertoghe MD
Progesterone
Serum Progesterone Lab tests Day 21 4-23 ng/ml optimal Saliva results can be hard to interpret Day 21 premenopausal 300 pg/ml menopausal 400-1500 pg/ml? Usefulness for monitoring treated patients? E/P Ratio 1:10 or 1:20
Progesterone (P4) Is usually the first hormone to become deficient in perimenopause.
Progesterone deficiency symptoms Bloating Swollen, tender breasts Spotting or breakthrough bleeding Mood swings-agitation, Irritability, Aggressiveness, Anxiety, Anger Poor sleep, insomnia Water retention Achy joints, Headache Weight Gain Excessive bleeding, menorrhagia Endometriosis Fibrocystic breasts
Dose Oral 50-200 mg HS 5-allo-pregnenolone metabolite is sedating Transdermal less sedating and less CNS 50-100 mg Premenopausal usually cycle days 14-start of menses Can use 2 or more steps i.e. 50 mg days 1-13 Can use daily if needed for mood stabilization Menopausal continuous (static) or cycle?
Controversy MPA is dangerous, why is progesterone safe and beneficial? Does she still need progesterone with no uterus?
Results from the E3N cohort study- Fournier 2007 80,377 postmenopausal women No increase or decrease in breast cancer in women on E2 and Progesterone. RR 1.0 E2 plus MPA had RR of 1.69 or 69% increase in risk of breast cancer. Progestins are not Progesterone Fournier A. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2007 Feb 27
Estrogens
Estrogens E1=Estrone Not needed in menopause Get some anyway through conversion of E2 Normally 10% of estrogens, in menopause increases to 80% E2=Estradiol CV, bone, CNS, sex benefits, catechol and methoxy metabolites are protective Normally 10% of estrogens, in menopause decreases to trace levels E3=Estriol Cancer protective, weak Normally 80% of estrogens, in menopause decreases to much lower levels
Advantages of Estriol (E3) E3 can bind preferentially to ER beta and inhibits ER alpha ER beta is protective of brain and cardiovascular function Low E3 levels associated with increased BC Schmidt JW et al. Hormone replacement therapy in menopausal women: Past problems and future possibilities. Gynecol Endocrinol. 2006 Oct;22(10):564-77 Samaras N et al Hormones in anti-aging medicine. Clinical Interventions in Aging. 2014:9. 1175-1186
Estrogen deficiency Hot flashes, Night sweats Vaginal Dryness, Decreased libido Poor memory, Foggy thinking, Decreased concentration, Dementia Fatigue, Low energy, Depressed mood Stress incontinence and UTI s Osteoporosis, Cardiovascular disease
Excess Estrogen and Side effects Swollen or tender breasts Mood swings, Agitated, Anxiety, Feeling snappy Weight gain Water retention, bloating Headaches, Achy joints Spotting, breakthrough or excessive bleeding Poor sleep
Estradiol Lab tests Serum Day 21 optimal 50-200 ng/ml
Dose BiEst = E3 + E2 default 80/20 1.25-5.0 mg per gram Once per day or BID 1 gram 80/20 BiEst 2.5 mg/gm = 2.0 mg E3 + 0.5 mg E2 Pellets, IM E2 E2 patches
Controversies Does Bio-identical E increase rates of breast cancer and cardiovascular disease? Lab tests vs. clinical picture to treat initially. Does transdermal cream work on all women? Why not use bio-identical oral E?
CHOIICE study: BHRT Cardiovascular biomarkers- CRP, Fibrinogen + other clotting factors, fasting glucose, triglycerides, BP and health outcomes were favorably impacted Transdermal Biest, Progesterone, Testosterone and DHEA Stephensen, K et al. The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors, cardiovascular biomarkers, quality of-life measures; and health outcomes in postmenopausal women. Int J Pharm.Compd. 2013 Jan-Feb 17(1) 74-85.
BHRT safer HRT in young post-menopausal women safe and effective tool for Counteract climacteric symptoms Prevent long-term degenerative diseases Osteoporotic fractures Cardiovascular disease Diabetes mellitus Cognitive impairment Non oral estrogens: No VTE and better BP Natural Progesterone - positive cognitive effects and no increase in breast cancer TD E2 and Natural P4 significant advantages L'hermite M et al. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008 Jul-Aug;60(3-4):185-201. 2013
Transdermal E2 + Oral Progesterone L'Hermite M. HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric. 2013 Aug;16
Cortisol Deficiency Fatigue Anxious, nervous Poor stress tolerance Hypersensitivity to environment Absent-minded, Forgetful Feeling spacey, confused Depression Paranoid feelings Irritable / hostile Concentration problems
Lab test AM cortisol only one data point Salivary cortisol draws curve 24 hour urine includes metabolites Can be high Usually low adrenal fatigue
Adrenal Support Daily Nutrition Vitamin B complex with 1000 mcg b12, Vitamin C 1000mg, Vitamin D 5000 IU Omega 3 s 2-4 gms Magnesium 100-400 mg as tolerated Adaptagens- rhodiola, ginseng, licorice in daytime, ashwaganda at night Adrenal extract 2-3 times a day Phosphatidyl Serine 400 mg DHEA 25-100 mg Head, K et al. Nutrients and Botanicals for Treatment of Stress: Adrenal Fatigue, Neurotransmitter Imbalance, Anxiety, and Restless Sleep. Alternative Medicine Review Volume 14, Number 2 2009
Treatment High Lifestyle Eliminate stress Meditation Low Adrenal support Vitamins, Glandulars Bio-identical cortisol Compounded cortisol 5-20 mg per day divided BID
Controversies What? You are treating a patient with corticosteroids. Do precursors work? How useful are lab tests?
Growth Hormone
Symptoms of AGHD Decreased quality of life Sarcopenia Loss of exercise capacity Osteopenia Loss of strength Increased total and intra-abdominal fat
Symptoms of AGHD Glucose intolerance Dyslipidemia Increased fragility of skin and blood vessels Decreased skin thickness Decreased muscle tone, increased droopiness Decreased confidence and optimism Decreased immune function
Lab tests Stimulation tests IGF-1 Low values correlated with AGHD Can have normal values and be deficient Typically increases 100 ng/dl with 0.33 mg per day treatment 24 hour urine
Growth Hormone Stimulation GHST Glucagon 1 mg IM Test (GHST) GH measured at baseline, 90, 120, 150, and 180 min Peak level < 3 micrograms/l- severe GH deficiency 3-5 mild GH deficiency >5.1 = normal Lisa A. Kreber et al. Detection of Growth Hormone Deficiency in Adults with Chronic Traumatic Brain Injury. Journal of Neurotrauma. 2016. 33:1607 1613
DX AGHD No Testing Needed In summary, adult GHD can be predicted with 95% accuracy by the presence of either three or four Pituitary Hormone Deficiencies (PHDs) or a serum IGF-I concentration less than 84 micrograms/liter Hartmann, M et al. Which Patients Do Not Require a GH Stimulation Test for the Diagnosis of Adult GH Deficiency? The Journal of Clinical Endocrinology &
Does GH cause cancer? Extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. Jenkins PJ et al. Does growth hormone cause cancer? Clin Endocrinol (Oxf). 2006 Feb;64(2):115-21.
GH decreases Insulin Resistance Low-dose GH treatment combined with dietary restriction resulted not only in a decrease of visceral fat but also in an increase of muscle mass with a consequent improvement of the insulin resistance observed in obese type 2 diabetic patients. Nam SY et al. Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients. Int J Obes Relat Metab Disord 2001 Aug;25(8):1101-7
Dose Ramp up 0.2 mg per day 0.4 mg 0.6 mg Women need more than men Not effective in women taking oral estrogens (transdermal OK)
Follow up 4 possible side effects PAGE Paresthesias Arthralgias Glucose and insulin getting worse instead of better Edema
Controversies Cancer? Side effects too prevalent? Diabetes? Dosage schedule?
Secretagogue/Peptides?