Nuts and Bolts of Hormone Optimization Ron Rothenberg MD Relevant financial relationships in the past twelve months by presenter or spouse/partner: NA Equipment: NA Speakers Bureau: NA Stock Shareholder: NA Grant/Research Support: NA Consultant: NA Status of FDA devices used for the material being presented NA Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation NA
Hormones Nuts and Bolts Ron Rothenberg MD
Hormone Symptoms Lab test Safety Side effects Follow-up Controversy Bio-Identical Delivery method Dose Can vary Can help 80% clinical Clinical, lab Dose adjustment Medical, legal, philosophical
Hormone: Testosterone Delivery method T cream compounded T cream commercial T patches T buccal T pellets T cypionate 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 1000-5000 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
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
SHBG binds T > E 20-60 nmol/l male 40-120 nmol/l female
Increases SHBG Thyroid Estrogens Progesterone Aging Low Insulin Decreases SHBG Testosterone DHEA Glucocorticoids GH High Insulin
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
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? Can use dosage of 250 500 IU daily 2500 5000 IU weekly 250 500 IU once weekly with T cypionate to modify side effects
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 Topical 50 mg/gm 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 DHT can increase with increasing T, especially with transdermal T DHT does not aromatize to E2 Is DHT evil twin of T or good androgen? DHT needed for erectile function and anabolic effects Not associated with Prostate CA in serum levels 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
TRT MEN PSA < 4.0 No PSA accel>1.0/yr DRE neg No hx Prostate/Breast CA NO
TRT MEN-2 Consider combination of testosterone IM and HCG 250-500 IU SQ weekly
E2 very high, symptomatic
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
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 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?
Prostate Breast CA 400-600 No 50-200 mg/day Repeat DHEAS 7- keto Titrate Optimal Follow and Estradiol change NO optimal?? YES CA MENto "Contraindications" micrograms/dl May not or Probably Testosterone, Optimize 50-200 show be or anti-cancer may no estrogen up mg
Breast Reproductive But anti-cancer 150-300 7keto 25-100 mg/day May No or DHEAS Optimal? Is Testosterone too Titrate Dose Avoid Effects Acne, Hirsutism YES NO CA 5-15 Estrogen WOMEN metabolism may high? not be testca "Contraindications" Androgenic Side
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)
THYROID YES NO ALGORITHM Thyroid? Cold Dry Constipation Resistance Rxollow Consider Rxwith Titrate T3n Rare Treat NTX Get T3Free T4everse T3TSH, Optimize T4eplacement No Warmer T3ptimal? T3sot mproved s f mprovement n ab ower antibodies bymiting ange atigue uboptimal ducate nd bout xcess tc. xercise etter f rain) rains/day ose esiccated orcine eroxidase -2 /2 months Reverse upper concerned lower PM tests EKG Free Skin of symptoms reverse grains thyroid Intolerance the 1/2 osteoporosis weight Thyroid tiredness range urine half or hands signs 1/2 every low patient energy of equiv document inresistant of loss Weight and and of range along Free with feet loss sinus 5-8 with rhythm the
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
Oral 50-200 mg HS Dose 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?
Progesterone Replacement 50 HS Start 100 gm cyclical If control consider Agitation Anxiety Water Swollen, Bloating Mood Joints Breakthrough Heavy etc. Estrogen are day ub Disturbances? YES Monitor symptoms Progesterone deficiency/ excess NO Are?Sleep unable 3 optimal -200 topically 21 months, mg/gm, there Progesterone Swings disturbances saches symptoms Retention Menstrual for testing Excess tender continuous of signs Estrogen oral 1/2 Deficiency/ at and/or - levels breasts 1BleedingEstrogen Excess
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
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?
YES NO ESTROGEN REPLACEMENT Moderate/severe daily Mild Biest gm need if sxabsent Signs/Symptoms excess? progesterone Estrogen Hot Night Foggy Forgetfulness Fatigue Palpitations Depression Vaginal Escessive Decreased etc. Estradiol 21 does clinical deficiency? If persistent months testing. Monitor of Progesterone 5mg/gm, 2.5 daytime level estrogen continuous. Sub daily flashes mg/gm symptoms- patient topically, Sweats Day Thinking optimal presentation Dryness consider for 1/2 topically, sleepiness very after -Deficiency/Progesterone libido energy signs/ 1/2 have - excess 1 replacement cyclical May mild. or 3gm Start cyclical 1not with Excess
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
Treatment High Lifestyle Eliminate stress Meditation Low Adrenal support Vitamins, Glandulars Bio-identical cortisol Compounded cortisol 5-20 mg per day divided BID
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 Phospytidyl 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, Numbe 2 2009
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
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 Unique legal status of GH Cancer? Side effects too prevalent? Diabetes? Dosage schedule?
Adult Growth Hormone Deficiency NO < 40 and Suspect organic pituitary disorder or > 40
ose ormones, alanced nti-aging ssess efer H ecrease /C o OES de festyle ab owly g/day eared fects? estyle, cgnificant orkup solved? mp art eatment reens ologist, 0.4 GH Controversial effects to GH for 0.1 by negative? program 0.2 cancer dose Hormones 3 Oncologist Consult? weeks mg/day dult Growth Hormone Deficiency -2-
dose olerated GF ncrease oo itrate nouthful ide 2 months lucose ecrease OES 500 250 3 weeks? Low months effects to 0.6 0.2 Insulin mg 1st 6 t oo.4 eep verage ange months 0.4 mg high year dose mg 0.1-0.7 0.4 0.6 2nd female mg year Adult Growth Hormone Deficiency -3-
Adult Growth Hormone Deficiency -4- Side Effects? Edema Arthralgia Low diuretics after Continue antiinflammatories D/C Consider dose month Resolved? Decrease Anti-inflammatory YES NO diuretics GH dose after 1 month inc lower dose 1 dose dose
OS Hcrease stosterone vere? nt ld? dose if ycemic dects? gh onth stosterone ucose rict eat rbs creased sulin? ercise:resistance n tient wer dex resthesias estyle nsider solved? perglycemia? C ld tressed ek contraindication young Aerobic GH dose after 1-2 men diet dose Intolerance 1 change increase lower restart months dose limiting serum 1with range for free if dult Growth Hormone Deficiency -5-