Male Hypogonadism -- Definition - Low T, Low Testosterone Hypogonadism -...a clinical syndrome that results from failure of the testes to produce physiological concentrations of testosterone due to pathology at one or more concentrations of the hypothalamic-pituitary-testicular axis. (Endocrine Society Guidelines, 2018) Kelli Virgin, D.O., M.P.H. Endocrinology Fellow McLaren Health System Mt. Clemens, MI Objectives - Confidently recognize symptoms of male hypogonadism Epidemiology Affects up to 4 million adult men in the U.S. Prevalence up to 38.7% in men age 45 and older - Assess etiology of both primary and secondary hypogonadism Testosterone begins to decline starting at age 30. - Utilize and understand the biochemical evaluation of hypogonadism - Select appropriate therapeutic treatment plan for male hypogonad patients. Men with Hypogonadism HYPOGONADISM 5% treated 95% untreated CNS = Central Nervous System GnRH = Gonadotropin Releasing Hormone FSH = Follicle Stimulating Hormone LH = Luteinizing Hormone 1
PRIMARY HYPOGONADISM Normal Hypothalamic & Pituitary Function Testicular Dysfunction High LH & FSH Low testosterone Impaired sperm production SECONDARY HYPOGONADISM Normal Testicular Function Hypothalamic/Pituitary Dysfunction Low / Inappropriately normal LH/ FSH Low Testosterone CNS = Central Nervous System GnRH = Gonadotropin Releasing Hormone FSH = Follicle Stimulating Hormone LH = Luteinizing Hormone CNS = Central Nervous System GnRH = Gonadotropin Releasing Hormone FSH = Follicle Stimulating Hormone LH = Luteinizing Hormone MIXED Hypogonadism HYPOGONADISM Testicular AND Hypothalamic or Pituitary Dysfunction Low / Inappropriately normal LH/FSH Low testosterone Impaired sperm production PRIMARY - From testes - Generally irreversible - Fertility not commonly regained SECONDARY - From other non-testicular etiology - Evaluate for other hormone deficiencies - Fertility can be regained PRIMARY HYPOGONADISM CLASSIFICATION Organic: Klinefelter s (XXY) Syndrome Cryptorchidism Some Malignancies Chemotherapy / Irradiation Orchidectomy Mumps Orchitis Testicular Trauma Advanced Age Functional: Medications End Stage Renal Disease Endocrine Society Guidelines, 2018, Adapted from Bhasin et al. SECONDARY hypogonadism Classification Organic: Functional: Hyperprolactinemia Hypothalamic/Pituitary Tumor Medications: Opioids Iron Overload Syndromes Anabolic steroids Glucocorticoids Infiltrative/Destructive Alcohol and Marijuana Disease Organ Failure Kallmann Syndrome Malnutrition & Obesity Idiopathic Severe comorbid illness 2
Screening? - NO CRITERIA FOR GENERAL SCREENING - No proven mortality benefit - No trials proving cost-effectiveness or efficacy - Do NOT screen for unrelated care Signs & Symptoms of Hypogonadism - Decreased libido - Erectile dysfunction - Breast discomfort/gynecomastia - Infertility - Hair loss* - Decreased muscle mass - Shrinking / small testes* - Decreased energy and vitality - Depressed mood - Low bone mineral density or fracture - Delayed sexual development* * Specific signs / symptoms Signs & Symptoms of Hypogonadism ADAM Questionnaire European Male Aging Study --- syndromic association with low testosterone Sexual Symptoms poor morning erections decreased libido erectile dysfunction Hypogonadism History - Puberty and sexual development - History of chronic illness - All prescription/nonprescription agents - Sexual history - Dissatisfaction - Relationship difficulties - Family History - Testicle/Breast changes This Photo by Unknown Author is licensed under CC BY-SA 3
Hypogonadism Signs on Physical Exam - Body Hair: decreased/ sparse - Breast Exam: development or tenderness - Genital Exam: - Testicular exam: - Shape - Consistency - position - Penile exam - Size - Other abnormalities - Muscle development TESTOSTERONE Laboratory Analysis - Total testosterone (280-850 ng/dl*) - bound to albumin and SHBG - Free testosterone (52-280 pg/ml*) - Bioavailable testosterone (70-320 ng/dl*) - Free & albumin bound Free T SHBG-Bound T Albumin-Bound T Need 2 assessments before diagnosing hypogonadism *Range may vary depending on laboratory that is used SEX HORMONE BINDING GLOBULIN TESTOSTERONE LEVEL VARIATION SHBG Lowered by: - Obesity - Nephrotic syndrome - Hypothyroidism - Steroids - Progestins - Androgenic steroids SHBG Increased by: - Age - Cirrhosis - Hyperthyroidism - Anti-convulsants - Estrogens - HIV SHBG = Sex Hormone Binding Globulin CHANGES IN TOTAL TESTOSTERONE WITH OBESITY Obesity is associated with decreased SHBG levels, and decreased total testosterone. 1 Free and bioavailable testosterone levels are low in severely obese men. 1 When Class III obese men undergo significant weight reduction, SHBG levels, as well as total, free, and bioavailable testosterone levels increase. 2-4 THEORETIC ASSOCIATION BETWEEEN HYPOGONADISM, OBESITY, AND INSULIN RESISTANCE Adipose tissue Increased number of adipocytes in obese and type-2 diabetic men Greater aromatase activity Increased metabolism of testosterone to estradiol Low testosterone Pituitary and hypothalamus Reduction in LH pulse amplitude Leydig cells Increased insulin resistance affects cells SHBG = sex hormone-binding globulin. 1. Vermeulen A, et al. J Clin Endocrinol Metab. 1993;76:1140-1146. 2. Strain GW, et al. J Clin Endocrinol Metab. 1988;66:1019-1023. 3. Mingrone G, et al. Atherosclerosis. 2002;161:455-462. 4. Kaukua J, et al. Obes Res. 2003;11:689-694. FSH = follicle stimulating hormone; LH = luteinizing hormone. Kapoor D, et al. Clin Endocrinol (Oxf). 2005;63(3):239-250. Pitteloud N, et al. JCEM 2005;90(5):2636-2641. 4
HYPOGONADISM TREATMENT - Make patient feel better + help patient live longer - Therapeutic Goals: - Improved sexual symptomatology - Increase in lean mass / decrease in fat mass - Improvement in energy, mood, and overall sense of well-being - Increased bone mineral density - Improvement or maintenance of secondary sex characteristics TESTOSTERONE REPLACEMENT CONSIDERATIONS - Topical gel therapies may allow for secondary exposure - virilization - Azoospermia and testicular atrophy - Acne - BPH - Gynecomastia - Precipitation or worsening of obstructive sleep apnea TESTOSTERONE REPLACEMENT CONTRAINDICATIONS TESTOSTERONE PREPARATIONS - Prostate or Breast cancer* - Pregnant/Breast-feeding women* - Known or suspected sensitivity to ingredients* - DRE prostate abnormality - PSA >3 without urologic evaluation - Severe BPH - Erythrocytosis (>50-54%) - Hyperviscosity - Untreated OSA - Severe Heart Failure (Class III/IV) - MI or CVA in the last 6 months - Severe lower UTI symptoms - Thrombophilia *Endocrine society recommendations IM Testosterone - T. enanthate, T. cypionate Topical Testosterone - T Axillary solution - Axiron - Transdermal Gel Androgel - Transdermal Patch Androderm Buccal Tablets - Striant Testosterone Pellets - Testopel Injectable long-acting Testosterone T. undecanoate - Aveed Nasal T gel - Natesto IM Testosterone Testosterone cypionate or Testosterone enanthate -- 100-200 mg/ml 150-200 mg q 2 weeks, or 75-100 mg q week Testosterone undecanoate 750 mg IM q4 10 weeks Therapeutic Targets: - Peak mid-normal - Trough avoid <200, no consensus Mood and libido can fluctuate Topical Testosterone Androderm - 2-4 mg patch (up to 6 mg daily) Start with 2 mg patch daily, to thigh/back/upper arm Androgel / Testim 50-100 mg 1% gel 20-80 mg 1.62% gel 40-70 mg 2% gel **Avoid contact with children and women! Do not wash for 4-6 hours 5
Axillary Solution 60 mg applied to axilla Nasal Gel 11 mg BID - TID Buccal tablets 30 mg twice daily Topical Testosterone Testosterone Pellets 4-6 200 mg pellets subcutaneous Testosterone peaks at 1 month. Typical duration 4-6 months Requires surgical procedure for placement Spontaneous Extrusion Increased risk of infection MONITORING Thank You 6