Androgens and Anabolic Steroids PDF

Androgens and Anabolic Steroids Aikseng Ooi, Ph.D. Skaggs, Room 132 [email protected] slide-1 Chapter 40 Basic & Clinical Pharmacology; 13th edition; B.G. Katzung, S.B. Masters, and A.J. Trevor. slide-2 Learning objectives 1. Steroidal sex hormones – Estrogen, progesterone, testosterone, DHT....

Androgens and Anabolic Steroids Aikseng Ooi, Ph.D. Skaggs, Room 132 [email protected] slide-1 Chapter 40 Basic & Clinical Pharmacology; 13th edition; B.G. Katzung, S.B. Masters, and A.J. Trevor. slide-2 Learning objectives 1. Steroidal sex hormones – Estrogen, progesterone, testosterone, DHT. 2. Systemic regulation. 3. Biosynthesis. 4. Mechanism of action. 5. Systemic function. slide-3 Steroids Cholesterol slide-4 Steroids Cholesterol slide-5 Main sex steroid hormones are produced at different ratio in men and in women Estradiol (E2) levels Women (18 year old) Women (post menopause) Men (18 + year old) data*) : 17-200 pg/mL : 7-40 pg/mL : 10-60 pg/mL (18 – 40 year old, nonobese, 2017 Progesterone levels Women (pre-ovulation or post menopause): < 1 ng/mL or 3.18 nmol/L Women (mid-cycle): 5 to 20 ng/mL or 15.90 to 63.60 nmol/L Pregnancy 1st trimester: 11.2 to 90.0 ng/mL or 35.62 to 286.20 nmol/L Pregnancy 2nd trimester: 25.6 to 89.4 ng/mL or 81.41 to 284.29 nmol/L Men (adult) : < 1 ng/mL or 3.18 nmol/L Testosterone (T) levels Women (18 + year old) : 8-60 ng/dL Men (18 – 40 year old, nonobese, 2017 data*) : 204 – 904 ng/dL slide-6 Androgens § Androgens are steroid hormones. § 1. Testosterone 2. Dihydrotestosterone 3. Androstenedione 4. Androstenediol 5. Dehydroepiandrosterone (DHEA) § Produced primarily in the testicles (Leydig cells) and ovaries of women. § They are also synthesized in the adrenals. § Levels in healthy men >> women. slide-7 From: A Population-Level Decline in Serum Testosterone Levels in American Men J Clin Endocrinol Metab. 2007;92(1):196-202. doi:10.1210/jc.2006-1375 J Clin Endocrinol Metab | Copyright © 2007 by The Endocrine Society slide-8 Systemic regulation of sex steroid hormones slide-9 Timing of male and female human sexual differentiation slide-10 Lifetime plasma testosterone levels slide-11 The hypothalamic-pituitarygonadal (HPG) axis Hypothalamic gonadotropin-releasing hormone (GnRH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) slide-12 ©2007 by National Academy of Sciences J. Larry Jameson PNAS 2007;104:17247-17248 GnRH)is)the)principal)molecule)that)regulates) Hypothalamus contains the reproduc-ve)func-on)in)all)vertebrates,) including)humans.) GnRH neurons ) GnRH is the principal molecule that regulates reproductive GnRH)is)a)decapep-de)(10)amino)acids)) function in all vertebrates, including humans. synthesized)in)a)small)number)of)neurons) (~1000))in)the)hypothalamus)of)humans)and) GnRH is a decapeptide (10 amino acids) synthesized in a small number of neurons (~1000) in the hypothalamus of humans and other)primates.) other primates. slide-13 The)pa_ern)of)GnRH)release)is)pulsa-le,)occurring) at)approximately)1C2)hour)intervals)in)all)mammals) GnRH is released in pulses ) 80 60 GnRH (pg/ml) 40 20 6 0 4 2 0 1 2 LH (ng/ml) 0 3 4 Time (hours) Modified from IJ Clarke (1993) Endocrinology 133:1624-1632 slide-14 LH and FSH synergistically regulate the reproductive system LH - luteinizing hormone - responsible for ovulation in females, and spermatogenesis & steroidogenesis in males. FSH – follicle stimulating hormone - responsible for follicular development in females, and Spermatogenesis in males. slide-15 Gonads produce sex steroid hormones Sex steroids hormones include estrogens, progestins, and androgens. Both male and female produce estrogens, progestins, and androgens. But the levels differ between the sexes, body mass index, physical activity, and diet. slide-16 Biosynthesis slide-17 Biosynthesis slide-18 Biosynthesis slide-19 Systemic function of androgens slide-20 Testosterone activates androgen recepter slide-21 Endocrinology of the Testis and Male Reproduction pp 1-22 Testosterone in energy metabolism Review Obesity OBESITY BIOLOGY AND INTEGRATED PHYSIOLOGY slide-22 Obesity (Silver Spring). 2015 Apr;23(4):713-9. Figure 1 Proposed mechanism of androgen action via AR in males. In males, androgens promote glucose and energy homeostasis via actions on AR in skeletal muscle, liver, pancreatic b-cells, and metabolic centers in the hypothalamus. Androgen actions on adipose tissue could be indirectly mediated via AR actions in muscle. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Testosterone in energy metabolism slide-23 Nature Reviews Endocrinology 9, 479-493 (August 2013) Testosterone in brain function and aging - Antidepressant, improves mood and sex drive. - Low testosterone à Depression - Supports spatial memory. - Declines in circulating testosterone levels, correlates well with decline in hippocampal neurogenesis and hippocampal function. - Exercise therapy may mediate mental health benefits through androgen maintenance. - Testosterone promotes cellular DNA repair capacity. - Promotes hematopoiesis. slide-24 Testosterone: secondary sex features Development of male reproductive organs Development of male secondary sex features : Facial hair, deepening of voice, enhance muscle tone and vascularity, increase sebum secretion, decrease fat deposition. Androgenic alopecia (in some men with high scalp 5-alphareductase expression) slide-25 How exercise affects androgen levels slide-26 Types of exercise Androgen (Standard different from means) Aerobic 0.891 Resistance 1.061 Power-based 0.509 Sports Med (2015) 45:713–726 Androgen deficiencies slide-27 Causes of androgen deficiencies Aging – Andropause Hypogonadism Surgery / trauma Obesity Endocrine disruptors Cancer treatment Cancer Autoimmune Fatherhood slide-28 Androgen deficiencies – symptoms Decreased metabolic rate and metabolic diseases including type 2 diabetes Increased fat to muscle ratio Gynecomastia Osteoporosis and other bone problems Diminished masculinization Mood swing, irritable Decreased sex drive Decrease muscle mass and strength Fat accumulation at specific fat depots (gluteal and chest) Symptoms of menopause Obesity related symptoms Lack of energy slide-29 Androgens decrease with age 1. All androgens decrease with age 2. The rate of decrease depends on: A. Physical activities B. BMI C. Diet 3. Unlike menopause, andropause is usually not treated slide-30 slide-31 Oh yeah, don’t forget the Lipitor and metformin Hypogonadism “A clinical syndrome that results from failure of the testes to produce physiological levels of testosterone due to disruption of one or more levels of Hypothalamicpituitary-testicular axis” – Endocrine Society Clinical Practice Guideline slide-32 Male Hypogonadism – Symptoms Fetal development – Female genitals Puberty – Delay puberty, excessive long arms and legs in relation to body, gynecomastia Adulthood – Depression, erectile dysfunction, low sex drive, difficulty concentrating, hot flashes, fatigue, decrease muscle mass, pot belly or weight gain, gynecomastia, decrease body hair, osteoporosis slide-33 Primary Hypogonadism - causes 1. Klinefelter syndrome 2. Undescended testicles 3. Mumps orchitis 4. Hemochromatosis 5. Trauma 6. Cancer treatment slide-34 Secondary Hypogonadism - causes 1. Kallmann Syndrome A X-linked recessive developmental disorder. Diverse manifestation – Cleft lips/palate, color blindness, under developed sexual organs. ~ 1 in 30,000 men, ~ 1 in 120,000 women ANOS1, CHD7, FGFR1, FGF8, PROK2, PROKR2 genes. Failure of GnRH release 2. Pituitary disorder 3. Inflammation disease 4. HIV/AIDS 5. Medications and endocrine disruptors 6. Obesity 7. Aging slide-35 Testosterone as drugs slide-36 Different forms and properties T-propionoate T-cypionoate T-decanoate Half-life Days Indicated for: Male hypogonadism, cancer cachexia, anemia, HIV/AIDS, prostate cancer (supraphysiologic dose in clinical trial) Administration route: intramuscular injection slide-37 Side effects of testosterone in men High estrogen – Due to aromatization. (symptom: gynecomastia) Could be prevented by co-administration with an aromatase inhibitor. Acne – In some men. Due to potentiation to DHT. Could be prevented by topical antibiotic or increased skin hygiene. Androgenic alopecia – In some men. Due to potentiation to DHT. Testicular atrophy – Due to HPG axis shut down. Decrease fertility – Due to decreased T level in the testes (reversible). Testosterone withdrawal – Due to testosterone deficiency cause by treatment cessation or improper dosing. Erythrocytosis – In most men. Due to increased red blood cell production. Water retention – Due to aromatization of testosterone to estrogen. Cardiovascular problems – Due to aromatization of testosterone to estrogen. slide-38 Side effects of testosterone in women High estrogen – Due to aromatization. Acne – In some women. Due to potentiation to DHT. Could be prevented by topical antibiotic or increased skin hygiene. Androgenic alopecia – In some women. Due to potentiation to DHT. Decrease fertility – Due suppression of menstrual cycle (reversible). Testosterone withdrawal – Due to testosterone deficiency cause by treatment cessation or improper dosing. Erythrocytosis –Due to increased red blood cell production. Water retention – Due to aromatization of testosterone to estrogen. Cardiovascular problems – Due to aromatization of testosterone to estrogen. Deepening of voice – Androgenic effect of testosterone (permanent). Facial hair - Androgenic effect of testosterone. slide-39 Testosterone withdrawal Testosterone withdrawal is caused by testosterone deficiency due to treatment cessation or improper dosing. Mostly because testosterone level become too low. 1. Mood swing and aggression 2. Irritability 3. Depression 4. Hot flashes 5. Decrease sex drive 6. Fatigue slide-40 7. Insomnia Anabolic steroids slide-41 Anabolic steroids: Anabolic activity of testosterone with low androgenic properties To minimize unwanted androgenic effects when use on female patients Anabolic : Androgenic ratio Use to treat anemia, trauma, cachexia, HIV/AIDS patients Some have less side effects than testosterone itself. slide-42 Anabolic steroids Universal side effect : erythrocytosis Winstrol (Stanazolol) A form of DHT Oral anabolic steroid for treatment of Lipodermatosclerosis. Does not aromatize Anabolic:androgenic = 30 Side effects : low E2 Oxandrin, Anavar (Oxandrolone) DHT analog Testosterone analog for burn and trauma patients. HIV/AIDS patients Less androgenic Does not aromatize Does not reduced Anabolic:androgenic = 10 Side effects : low E2 slide-43 Anabolic steroids Deca-durabolin (Nandrolone) Testosterone analog for Anorexia and cachexia patients Reduce to a weaker metabolite Less propensity to aromatize Anabolic:androgenic = 10-15 Side effects : Low E2, erectile dysfunction Anadrol-50 (Oxymetholone) Oral tablet 50-100mg once a day For some anemia and Fanconi anemia Anabolic:androgenic = 9 Side effects : Low E2, erectile dysfunction, liver damage and liver tumors slide-44 Testosterone alternatives slide-45 Testosterone alternatives for hypogonadism Human Chorionic Gonadotropin (hCG) For hypogonadal men desiring fertility Shares same receptor as LH May be combined with FSH (rhFSH) Success rate depends on testicular volumes Risks – testicular enlargement slide-46 Testosterone alternatives for hypogonadism Clomiphene A SERM class of compound Increases GnRH release slide-47 Selective Androgen Receptor Modulator (SARMs) slide-48 SARMs class of compounds are in clinical trial SARMs are compounds that can bind and activate androgen receptor in certain tissue types, while have low to no activity in others. Two SARMs are currently in clinical trials for various indication: Enobosarm a.k.a. MK-2866 a.k.a. ostarine Ligandrol a.k.a. LGD-4033 Administration : Oral Potency For the same concentration: Note: DHT = 10X Testosterone Enobosarm < testosterone < LGD-4033 < DHT HPG suppression: Enobosarm (low), LGD-4033 (high) Others in phase I trial : RAD140, LGD-2226 slide-49 Androgen and anabolic steroids use in sports slide-50 Androgen and anabolic steroids are used at supraphysiologic levels for performance enhancement Typically used at very high dose to achieve performance enhancement. Increase muscle mass, hematocrit, joint and connective tissues health, and recovery. AAS often combined with testosterone and an aromatase inhibitor. Provide athlete with unfair advantages over slide-51 others. Negative consequences of testosterone and anabolic steroids abuse Increased risks of heart attack and stroke. Become dependent on the anabolic steroid use. Improper dosing led to severe withdrawal symptoms. Permanent androgenic side effects among female athletes. Stunted growth if used during pubescent years. Side effects associated with too high or too low estrogen levels. slide-52 Antiandrogen slide-53 Androgen and cancer treatment slide-54 Antiandrogens 5α-reductase inhibitors: finasteride (proscar) 1. benign prostatic hyperplasia. 2. male pattern baldness (propecia) 3. hirsutism in women. The new england journal Hirsutism of medicine of free testosterone is often eleva tal testosterone level is normal in This reflects the relatively low le mone–binding globulin in such w termines the fraction of plasma te free or bound to albumin.14 The mone–binding globulin are supp perinsulinemia of insulin resistan gen excess itself,12,15 so that the t level may be normal despite excess The level of sex hormone–binding low in persons with hypothyroid congenitally absent.16 A strategies and ev slide-55 B n engl j med 353;24 differential diagnosis Antiandrogens Androgen receptor antagonists: Flutamide, bicalutamide used together with a GnRH analog to treat metastatic en, hirsutism develops without the presence of exprostate cancer. cess androgen (termed idiopathic hirsutism). Figure 2. Varying Degrees of Hirsutism. Panel A demonstrates hirsutism with a Ferriman–Gallwey score of 1 for the lip and 4 for the chin. In Panel B, the score is 3 to 4 for the lip and 3 for the chin. Photographs courtesy of Dr. David Ehrmann. Flutamide can induce hepatotoxicity. Testosterone is the key circulating androgen.6-9 It arises as a by-product of ovarian and adrenal function, either by secretion or by the metabolism of secreted prohormones (mainly androstenedione or dehydroepiandrosterone sulfate) in peripheral tissues, such as fat.3,10 Testosterone levels during the midfollicular phase of the menstrual cycle vary by about 25 percent above and below the mean and are highest in the early morning; levels are slightly lower in the premenstrual phase and slightly higher in midcycle.11 Free testosterone seems to be the main bioactive portion of plasma testosterone.12,13 The level Spironolactone (aldactone): weak AR inhibitor, competitive inhibitor of aldosterone, used as a diuretic or against hypertension. Also used to treat hirsutism in women. Risk: breast cancer in male. 2580 n engl j med 353;24 Hirsutism must be distinguishe chosis — generalized excessive occurs as the result of either here medications such as glucocortico minoxidil, or cyclosporine. Hypert hair is distributed in a generalized tern, is not caused by excess and hyperandrogenism may aggravate Approximately half of wome sutism (i.e., hirsutism with a sco of a maximum of 36, on the Fe scale) have the idiopathic condit the remainder of these women and with more marked hirsutism, an elevated. Hyperandrogenism is m by the polycystic ovary syndrome. in a recent review article,18 this d when there is otherwise unexpla perandrogenism and oligo-ovula tion.19 Documentation of polycys necessary for the diagnosis of pol drome but is a criterion for it if ev lation is lacking.20,21 About half nonclassic — they lack some of th cally associated with the syndrom strual irregularity, polycystic ovarie — and thus the absence of some s hirsute woman does not rule ou Polycystic ovary syndrome is asso tility and insulin resistance (manif mellitus or the metabolic syndro expressed cluster of findings, inclu sity, hypertension, glucose abnorm lipidemia),23 and possibly with an endometrial cancer.18,20 Other causes of androgen ex www.nejm.org december 15 , 2005 The New England Journal of Medicine Downloaded from nejm.org at University of Arizona on April 27, 2016. For personal use only. No other uses with Copyright © 2005 Massachusetts Medical Society. All rights reserved. slide-56