SUMMARY and OBJECTIVES LOW T- I m half the man I used to be A discussion of male hypogonadism David Doriguzzi, PA-C Valley Endocrine & Diabetes Consultants Definition Prevalence Causes Signs & Symptoms Lab Diagnosis Treatment Options Benefits vs. Risks of Treatment Monitoring Treatment Definition of Hypogonadism Male hypogonadism refers to a decrease in either of the two major functions of the testes: Sperm Production Testosterone Production Prevalence of Low-T 13.8 Million men in the US Prevalence of Low T in All Enrolled Patients (%, 95% CI) 60 50 40 30 20 10 0 45 to 54 55 to 64 T = testosterone. Mulligan T, et al. Int J Clin Pract. 2006;60(7):762-769. 65 to 74 75 to 84 Patient Age Range >85 1
Prevalence of Low-T in other clinical conditions Prevalence (%) 80 70 60 50 40 30 20 10 0 74 Chronic Opioid Use 52 50 50 Obesity Diabetes 42 40 Conditions HIV = 30%. ED = erectile dysfunction. Bodie J, et al. J Urol. 2003;169:2262 2264; Daniell HW. J Pain. 2002;3:377-384; Dobs AS. Baillière s Clin Endocrinol Metab. 1998;12:379-390; Grinspoon S, et al. Ann Intern Med. 1998;129:18-26; Mulligan T, et al. Int J Clin Pract. 2006;60:762 769. AIDS Hypertension Hyperlipidemia 19 ED Decline in Serum T Concentration with Increasing Age Total and free T concentrations fell with time regardless of age entered the study From Baltimore Longitudinal Study of Aging Causes of Primary Hypogonadism Congenital Abnormalities Acquired Causes Causes of Secondary Hypogonadism Congenital Klinefelter syndrome Other chromosomal abnormalities Mutation in the FSH receptor gene Cryptorchidism Varicocele Disorders of androgen synthesis Myotonic dystrophy Infections, especially mumps Radiation Alkylating agents Suramin Ketoconazole Glucocorticoids Environmental toxins Trauma Testicular torsion Autoimmune damage Chronic systemic illnesses Hepatic cirrhosis Chronic renal failure AIDS Isolated gonadotropin deficiency Kallmann's syndrome DAX 1 mutation GPR54 mutation Leptin or leptin receptor mutation Prader Willi Gonadotropin subunit mutation Idiopathic Deficiencies of multiple pituitary hormones Pituicyte differentiation gene mutations Idiopathic 2
Causes of Secondary Hypogonadism Acquired Suppression of Gonadotropins Hyperprolactinemia Gonadal steroid administration Glucocorticoid treatment Critical illness Chronic systemic illness Opiates Diabetes mellitus Idopathic GnRH analogs Damage to gonadotroph cells Benign tumors and cysts Malignant tumors Infiltrative diseases Infections Pituitary apoplexy Trauma Surgery in the sellar region Radiation to the sellar region Serum testosterone and gonadotropin concentrations fall in acute MI Changes in the serum T, LH, and FSH throughout hospitalization in a representative 43-year-old man with an acute MI. All three hormones decreased acutely and then returned to baseline levels during recovery. Skin Hair growth, balding, sebum production Liver Synthesis of serum proteins Bone Accelerated linear growth, closure of epiphyses Effects of Testosterone Brain Libido, mood Muscle Increase in strength and volume Kidney Stimulation of erythropoietin production Effects of testosterone deficiency by age at onset First trimester in utero Incomplete virilization of external genitalia Incomplete development of Wolffian ducts to form male internal genitalia Third trimester in utero Micropenis Prepuberty Incomplete pubertal maturation Eunuchoidal body habitus Poor muscle development and reduced peak bone mass Male Sexual Organs Penile growth, spermatogenesis, prostate growth and function Bone Marrow Stimulation of stem cells Postpuberty Decrease in energy, mood, and libido Decrease in body hair, hematocrit, muscle mass and strength, and bone mineral density AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8:439-456; Morley JE, et al. Metabolism. 2000;49:1239-1242 3
Low Testosterone and Body Composition Associated with Increase in body fat Osteoporosis and Hypogonadism MicroMRI of Tibia Control Hypogonadal man Decrease in lean body mass (muscle) Decrease in bone mineral density (BMD) Well connected, predominantly platelike trabecular network of the control More disconnected, predominantly rod-like architecture of the hypogonadal man Benito M et al. J Clin Endocrinol Metab. 2003;88:1497-1502; Isidori AM, et al. Clin Endocrinol. 2005;63:280-293 Increased Fracture Risk in Men After Bilateral Orchiectomy Aging Males with Low-T and Mortality Patients with fracture (%) 60 50 40 30 20 N=429 10 Expected 19% (Population controls) 0 0 5 10 15 Follow-up (years) Observed 40% (Postorchiectomy) Cumulative Survival 1.0 0.9 0.8 0.7 0.6 0.5 Men With a Normal T-Level (n = 452) Men With a Low T-Level (n = 166) Survival 79.9% Survival 65.1% 0 2 4 6 8 10 Survival (y) Melton LJ III, et al. J Urol. 2003;169:1747-1750 Melton LJ III, et al. J Urol. 2003;169:1747-1750 4
Signs and Symptoms of Hypogonadism Nonspecific Similar to those that accompany aging Signs and Symptoms Suggesting Androgen Defficiency Incomplete sexual development, eunuchoidism, aspermia Reduced sexual desire (libido) and activity Decreased spontaneous erections Breast discomfort, gynecomastia Loss of body (axillary and pubic) hair, reduced shaving Very small or shrinking testes (especially <5 ml) Inability to father children, low or zero sperm counts Height loss, low trauma fracture, low bone mineral density (BMD) Reduced muscle bulk and strength Hot flushes, sweats Less Specific (yet more common) Signs and Symptoms of Hypogonadism Diagnosis of Low-T Decreased energy, motivation, initiative, aggressiveness, self-confidence Feeling sad, or blue, depressed mood, dysthymia Poor concentration and memory Diminished physical or work performance Sleep disturbance, increased sleepiness Mild anemia (normochromic, normocytic, in the female range) Increased body fat, BMI Lab Measurement is complicated by: Circadian variability in testosterone level Episodic secretion of testosterone Serum levels drawn at intervals of a few minutes can vary 20-30% Variance in serum level of SHBG that bind testosterone in the blood Assay specificity and assay variability Lack of rigorous identification of normal lab ranges for normal men 5
Laboratory Diagnosis Diurnal Pattern of Testosterone Secretion Serum testosterone peak in the early morning (7am- 10am) and have their nadir in the late afternoon and evening Time of day is shifted in men who work at night Diurnal variation is dampened in aging men Important to repeat the test using early morning sample at least once 30% of men found to have a low serum T on initial measurement will have normal values on repeat testing Regulation of Testosterone SHBG-Bound T 60% FT 2% Albumin-Bound T 38% Measurement of Total, Free, and Bioavailable T Levels Serum Total T = T bound to SHBG, portion bound to albumin, and portion that is free Bioavailable T = 50-60% of T bound to albumin, and 1-3% that is free Only 2% is FT; 98% is bound Certain conditions that increase SHBG resulting in normal T level, but low bioavailable and free T FT = free testosterone; SHBG = sex-hormone binding globulin. Adapted from Braunstein GD. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:422-452. Other conditions that lowers SHBG resulting in low T level yet bioavailable and free T remain normal 6
Conditions Affecting Serum SHBG Male Hormonal Status Changes with Age as SHBG Increases Conditions Increasing SHBG Aging men Hepatic Cirrhosis Hyperthyroidism HIV Anticonvulsants Estrogen Conditions Decreasing SHBG Moderate or Severe Obesity Nephrotic Syndrome Hypothyroidism Glucocorticoids Progestins Androgenic Steroids nmol/l 80 70 60 50 40 30 20 10 0 <34 35-44 45-54 55-64 65-74 >75 Age (y) F T Testosterone SHBG Gray A, et al. J Clin Endocrinol Metab. 1991;73:1016-1025. Serum Testosterone Concentrations in Obesity Obesity is characterized by a reduction in total T level (left) but normal free T level (right) Monitoring Free Testosterone Checking is worthwhile only when it is suspected that an abnormality in T binding to SHBG coexists with hypogonadism Should be performed by equilibrium dialysis and only in laboratories specializing in endo testing. When measured by an analog method, (commonly offered by hospital and commercial labs), does not correlate with the results of equilibrium dialysis. Usually gives misleading info and should be avoided. 7
Localizing the Defect Hypothalamic-Pituitary- Testicular Axis Once low serum measurement of T (total, free, or bioavailable) is confirmed, it is pertinent to determine the site of defect Testicular (primary) vs. hypothalamic/pituitary (secondary) abnormalities Serum LH levels elevated in pts with primary testicular disease. Serum LH levels low or inappropriately normal in hypothalamic or pituitary abnormalities. T and inhibin are produced by testes. T has negative feedback on LH production and hypothalamus while Inhibin has negative feedback on FSH production. Localizing the Defect Check Prolactin in secondary hypogonadism Rule out prolactinoma (MRI if suspected) Certain drugs can elevate prolactin and suppress GnRH Check serum iron and ferritin in primary hypogonadism Exclude the diagnosis of hemachromatosis Treatment Options Should first establish whether T deficiency is primary or secondary If secondary hypogonadism is associated with anatomical lesions of the hypothalamus or pituitary, a neurology consult is warranted If future fertility is desired, treatment options are limited 8
Fertility Options for Men with Primary Hypogonadism Referral to urologist with expertise in reproductive endocrinology May be potential candidates for Intracytoplasmic Sperm Injection if some sperm are found in ejaculate or testes Fertility Options for Men with Secondary Hypogonadism Pulsatile GnRH injections Hypothalamic disease Gonadotropin injections Hypothalamic or pituitary disease HCG Used to stimulate testosterone secretion and spermatogenesis Clomiphene citrate Increases endogenous gonadotropins and serum testosterone T Replacement is the treatment of choice in men with NO Desired Fertility Potential Benefits vs. Risks of Testosterone Replacement Benefits Maintenance of sexual hair patterns Improvement of libido and erectile function Improvement of sense of well-being Increase in skeletal muscle mass and strength Decrease in fat mass Increase in BMD and possibly decreased bone fractures Risks Acne Gynecomastia Precipitation of or worsening sleep apnea Potential increase in cardiovascular disease and events Worsening of lower urinary obstructive symptoms Potential for advancement of occult prostate cancer to clinical prostate cancer 9
Lean Body Mass Increases in TRT in Hypogonadal Men Lean Body Mass (kg) 67 66 65 64 63 62 61 60 59 58 Baseline P = 0.0002 90 Days T patch (5 g) T gel* (5 g) T gel* (10 g) *AndroGel Study. Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-2853. Changes in BMD after Testosterone Replacement BMD (% Change) 14 12 10 8 6 4 2 0-2 -4 Changes in Lumbar Spine BMD Mean ± SEM 0 10 20 30 40 Time (mo) Amory JK, et al. J Clin Endocrinol Metab. 2004;89:503-510 T+F P <0.001 General T Replacement Guidelines T should be administered only to a man who is hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a distinctly subnormal T concentration. In comparison, increasing T level in a man who has symptoms suggestive of hypogonadism, but whose T level is already normal will not relieve those symptoms. T can be replaced satisfactorily whether T deficiency is due to primary or secondary hypogonadism. General T Replacement Guidelines The principal goal of testosterone therapy is to restore the serum T concentration to the normal range. It is not yet known if restoring the normal circadian rhythm of T is important The role of T replacement to treat the decline in serum T concentration that occurs with increasing frequency above age 60 in the absence identifiable pituitary or hypothalamic disease is uncertain 10
Methods of Testosterone Replacement Oral tablets Either with fluoxymesterone or methyl testosterone Most Commonly Prescribed Forms of TRT Gels Injectables Oral tablets dissolved in oil (T undecanoate) Bioadherent buccal T tablets IM Testosterone esters (T cypionate & T enanthate) vs T undecanoate Subcutaneous implantation of T pellets Transdermal T patches (Scrotal versus Torso) Testosterone gels (AndroGel, Testim, Axiron) 70% 17% 10% 3% Patches Other Oral Testosterone Pills and Capsules Fluoxymesterone or methyl T pills Has a 30% of liver toxicity replacement dose Not recommended Methyl T marketed as Android, Methitest, and Testred Oral T undecanoate capsule dissolved in oil Requires 40 mg TID vs 80 mg BID Inefficient delivery Buccal Testosterone Tablets Tablet adheres to the gum and enters circulation via the buccal mucosa Tablets are replaced every 24 hours Provides normal range of serum T levels in 66-75% of hypogonadal men Adherence may be hindered by dentures Marketed as Striant 11
IM Testosterone Esthers IM Testosterone Esthers T cypionate and T enanthate Similar pharmacokinetics Serum testosterone levels tend to be supranormal 2-3 days after injection 50-100 mg IM weekly vs 200 mg biweekly T undecanoate Approved in many European countries, but still undergoing clinical trials in the US Adequate serum T levels maintained for 6-12 weeks Requires 3-5 ml injected volume Advantages Provides most adequate levels of serum T when other methods fail Most economical form of testosterone replacement Disadvantages Levels fluctuate depending on dose and frequency of injections Fluctuation in mood or libido Painful at injection site Adds to cost if injected at doctor s office rather than self-injected Subcutaneous implantation of Testosterone Pellets Transdermal T Patches Advantages Maintains normal serum testosterone levels for 3-6 months Disadvantages Requires a small surgical incision, insertion with a trocar, and retention suture 10% incidence of pellet extrusion Small incidence if infection Not widely accepted in the US, despite availability Initially available as scrotal or non-scrotal patches (non-scrotal applied to torso) Scrotal patches are no longer available in the US Marketed as Androderm and available to deliver 2.5 mg and 5 mg QD Recommended to be applied in the evenings after bathing 12
Transdermal T Patches Testosterone Gels Advantages Serum T usually peaks 4-10 hours after application of patch and slowly falls Topical reactions can be reduced with steroid cream at the time of application Steroid cream does not significantly impede absorption of testosterone Disadvantages Causes erythema at application site in 30% of patients May cause blisters More expensive than IM testosterone injections Administered as 1%, 1.62%, or 2% gel, rubbed onto the skin Usual starting dose is 5g Delivers about 5 mg of testosterone Dose is adjusted in 2.5 g increments Marketed as Androgel, Testim, and Axiron. Testosterone Gels Comparison of Preparations Advantages Gels dry quickly after application Absorbed through the skin and into circulation in a predictable manner Serum testosterone levels tend to be relatively stable Serum T can be maintained even if the site is washed 4 or more hours after application Disadvantages Testosterone residue remains on the skin surface Intimate contact can result in significant transfer and testosterone absorption into recipient s circulation More expensive than testosterone injections A) During 14 days following the injection of 200 mg of testosterone enanthate. B) During the 24 hours after application of one or two testosterone patches that deliver approximately 5 mg of testosterone each. C) During the 24 hours after application of a testosterone gel containing 50 or 100 mg of testosterone 13
Monitoring Treatment Monitoring effects on hair pattern, weight, body habitus, stamina, vitality, sexual desire, and erectile function Validate that serum T levels are appropriate (ie. 400-600 ng/dl) regardless of delivery method Usually checked 2-6 weeks after tx initiated Peak levels usually 2-4 hrs after oral ingestion of tablets Sampling done at any time or prior to application of a tablet Serum T level checked midway between injections of T enanthate or cypionate Serum T is typically checked 4-10 hrs after application or T patches Serum T can be measured any time using either of the T gels (may be some variation throughout the day) Baseline Eval and Treatment Monitoring in Men over 50 Serum Testosterone Levels Hematocrit (at 3 months and annually thereafter) Serum PSA (at 3 months and annually thereafter) Digital rectal examination of the prostate BMD scan (baseline and every 18-24 months in those with low BMD) Baseline Eval and Treatment Monitoring in Men over 50 Assessment for symptoms of sleep apnea Assessment of symptoms and signs associated T efficacy Acne (more frequent in younger men) Gynecomastia (more frequent in younger men) Contraindications to TRT Absolute Contraidications Prostate Cancer Breast Cancer Relative Contraidications Hematocrit of 50% or greater Untreated sleep apnea Class III or IV heart failure International Prostate Symptom Score of >19 Known or suspected sensitivity to ingredients used testosterone preparations 14
Summary Low-T in adult men is often underdiagnosed and undertreated T-levels gradually diminish with age, often to hypogonadal levels Signs and symptoms often nonspecific Hypogonadism may cause decreased energy, BMD, libido, ED Need to establish and confirm diagnosis before treatment TRT can increase T-levels to normal ranges, significantly improving symptoms, and is safe with proper monitoring 15