Hormones Nuts and Bolts. Ron Rothenberg MD

Size: px

Start display at page:

Download "Hormones Nuts and Bolts. Ron Rothenberg MD"

Stanley Williams
6 years ago
Views:

1 Hormones Nuts and Bolts Ron Rothenberg MD

3 Power Point Slides All slides from my presentation will be available to you. They will be posted to website next week CaliforniaHealthspan.com

4 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

5 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

6 Testosterone Cypionate IM or SC Weekly dose mg Can divide in 2 doses less E2 Physiologic stable levels Easy self injection Less DHT than transdermal Potentially more E2

7 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

8 T Dose Men Cream mg/day Cypionate mg IM or SQ/ week Undecanoate 750 mg IM q 10 weeks Pellets 75 mg x 5-10 q 3 months HCG units per week Possible dosing: units per day units twice a week T cypionate 100 mg IM on day 1 HCG units SC weekly

9 Estradiol - Aromatase - DHT 5-alpha Reductase Sperm Sertoli cell Leydig cell

10 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?

11 Testosterone Lab Testing Test Sex Reference Optimal Total ng/dl Male Free* ng/dl (Equilibrium dialysis) Female Male Female Bioavailable Male pg/ml Female * Free testosterone results vary with methodology direct analog (RIA) in pg/ml same ref range

12 TOTAL TESTOSTERONE T T T T T T T. T. T ALBUMIN T T T T T T SEX HORMONE BINDING GLOBULIN

13 FREE TESTOSTERONE T T T T T T T T T T T SEX HORMONE BINDING GLOBULIN T T T T ALBUMIN

14 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

15 SHBG binds T > E nmol/l male nmol/l female Low SHBG associated with Insulin Resistance in men and women

16 Increases SHBG Thyroid Estrogens Progesterone Aging Low Insulin Coffee (not decaf). Green tea, soy Decreases SHBG Testosterone DHEA Glucocorticoids GH High Insulin

17 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 Feb 24

18 Free Free T calculator

19 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

20 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

21 T Metabolites E2, E1 DHT Measure or not? To control or not to control?

22 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

23 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?

24 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

25 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

26 Follow up PSA, PSA velocity, PSA controversy DRE Follow H and H Follow E2

27 Prostate cancer Active Treated Controversies BPH Heart disease Roid rage Testicular atrophy Sperm count

28 European Study T and PCa 1023 patients up to 17 years with TRT Cohort Pca 54.4/10,000 pt years Cohort Pca 30.7/10,000 pt years Cohort 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)

29 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 Jul 26

30 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

31 Morgentaler conclusion There is not now-nor has there ever been a scientific basis for the belief that T causes PC to grow

34 <

39 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

40 T in women Preparation Compounded cream 1% = 10 mg/gm 0.5% = 5 mg/gm Dose mg per day q AM T cypionate injections mg/week

41 Testosterone is the most abundant biologically active hormone in women Glaser RL, Dimitrakakis C. Testosterone therapy in women: myths and misconceptions. Maturitas Mar;74(3):230-4

42 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

43 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

44 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

46 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

47 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 Jul 7.

48 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 July; 56(7):

49 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) Oct 18;:1-11

50 Lab tests DHEAS not DHEA Serum optimal Men micrograms/dl Women micrograms/dl DHEA Saliva optimal Men 250 pg/ml Women 200 pg/ml

51 Dose Men mg Women mg 7-keto DHEA No downstream metabolites Probably the same benefits More thermogenesis and weight loss Men and women mg

52 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 May 24

53 7-Keto DHEA Decline contributes to fat gain Weight loss without side effects (kalman) Improves Immune function Improves lipids Improves memory in rats Dose: mg in AM Can use alone or combine with DHEA

54 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 Mar;60(3):

55 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?

58 Thyroid Lab tests - Optimal Free T3 in upper 1/3 of reference range ng/dl T4 is a pro hormone TSH < 1.5 Reverse T3 lower ½ reference range

59 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

60 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?

61 Thyroid math Short half-life of T3 Consider BID or Extended Release for T3/T4 combinations

62 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)

64 Bio-Identical Hormone Replacement in Women Balance Estrogens, Progesterone and Testosterone Every woman needs a unique balance Progesterone protects against breast cancer

65 Female Hormones Estrogens Progesterone Testosterone Delicate balance between E and P both antagonistic and complimentary Thierry Hertoghe MD

67 Progesterone

68 Serum Progesterone Lab tests Day ng/ml optimal Saliva results can be hard to interpret Day 21 premenopausal 300 pg/ml menopausal pg/ml? Usefulness for monitoring treated patients? E/P Ratio 1:10 or 1:20

69 Progesterone (P4) Is usually the first hormone to become deficient in perimenopause.

70 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

71 Dose Oral mg HS 5-allo-pregnenolone metabolite is sedating Transdermal less sedating and less CNS 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?

72 Controversy MPA is dangerous, why is progesterone safe and beneficial? Does she still need progesterone with no uterus?

73 Results from the E3N cohort study- Fournier ,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 Feb 27

75 Estrogens

76 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

77 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 Oct;22(10): Samaras N et al Hormones in anti-aging medicine. Clinical Interventions in Aging. 2014:

78 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

79 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

80 Estradiol Lab tests Serum Day 21 optimal ng/ml

81 Dose BiEst = E3 + E2 default 80/ mg per gram Once per day or BID 1 gram 80/20 BiEst 2.5 mg/gm = 2.0 mg E mg E2 Pellets, IM E2 E2 patches

82 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?

83 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 Jan-Feb 17(1)

84 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 Jul-Aug;60(3-4):

85 Transdermal E2 + Oral Progesterone L'Hermite M. HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric Aug;16

87 Cortisol Deficiency Fatigue Anxious, nervous Poor stress tolerance Hypersensitivity to environment Absent-minded, Forgetful Feeling spacey, confused Depression Paranoid feelings Irritable / hostile Concentration problems

88 Lab test AM cortisol only one data point Salivary cortisol draws curve 24 hour urine includes metabolites Can be high Usually low adrenal fatigue

90 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 mg as tolerated Adaptagens- rhodiola, ginseng, licorice in daytime, ashwaganda at night Adrenal extract 2-3 times a day Phosphatidyl Serine 400 mg DHEA 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

91 Treatment High Lifestyle Eliminate stress Meditation Low Adrenal support Vitamins, Glandulars Bio-identical cortisol Compounded cortisol 5-20 mg per day divided BID

92 Controversies What? You are treating a patient with corticosteroids. Do precursors work? How useful are lab tests?

93 Growth Hormone

94 Symptoms of AGHD Decreased quality of life Sarcopenia Loss of exercise capacity Osteopenia Loss of strength Increased total and intra-abdominal fat

95 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

96 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

97 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 :

98 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 &

99 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) Feb;64(2):

100 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

101 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)

102 Follow up 4 possible side effects PAGE Paresthesias Arthralgias Glucose and insulin getting worse instead of better Edema

103 Controversies Cancer? Side effects too prevalent? Diabetes? Dosage schedule?

104 Secretagogue/Peptides?

105

106

107

108

109

110

Professor TTUHSC Dept of Family and Community Medicine

Stephen G. Dalton D.O. Adjunct Clinical Assistant Stephen G. Dalton D.O. Adjunct Clinical Assistant Professor TTUHSC Dept of Family and Community Medicine 1-The first hormone to become deficient in perimenopauseis