Male Hormone Replacement Therapy Punita Dhindsa D.O PGY 2
Physiology of Testosterone & Causes of Hypogonadism in Males The use of testosterone therapy is very common in the US, with an estimated 2.3 million American men receiving therapy in 2013. Most of these men are middle aged and older men who are being treated for age-related declines in testosterone.
Physiology of Testosterone & Causes of Hypogonadism in Males Testosterone is the primary male sex hormone and anabolic steroid. In male humans, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate. It also promotes secondary sexual characteristics such as increased muscle and bone mass and the growth of body hair. In addition, testosterone is involved in health and well-being and the prevention of osteoporosis.
Physiology of Testosterone & Causes of Hypogonadism in Males Testosterone is necessary for normal sperm development. It activates genes in the Sertoli Cells, which then promote differentiation of spermatogonia. Testosterone is produced by the Leydig cells in the testes, in response to the Luteinizing hormone, which is produced by the pituitary gland. Decreased production of testosterone by the testes in men is categorized as Hypogonadism. This can then further be classified as Primary, Secondary or Mixed.
TESTOSTERONE EFFECTS IN THE NORMAL MALE Target Male Sex Organs Behavior Bone Fat tissue Muscle Liver Kidney Heart Blood Bone Marrow Hair Effects Growth, development, maintenance of secondary sex characteristics, sperm production, erections and prostatic function Improved libido, mood, memory and energy Linear growth, closure of the epiophyses, increases bone mineral density Body and abdominal fat reduction Anabolic; increases muscle mass and strength Stimulates production of serum proteins Stimulates erythropoietin production which increases blood counts Dilates blood vessels in the heart Suppression of clotting factors (II, V, VII), low HDL-cholesterol Stimulates stem cell production Influences body hair growth, especially facial hair
Physiology of Testosterone & Causes of Hypogonadism in Males Hypogonadism is the failure of the testes to produce: Physiologic levels of testosterone Normal number of spermatozoa Primary Hypogonadism: Is also known as primary testicular failure The failure of the testes to produce sufficient testosterone Secondary Hypogonadism: This type of hypogonadism indicates a problem in the hypothalamus or the pituitary gland parts of the brain that signal the testicles to produce testosterone. The hypothalamus produces gonadotropin-releasing hormone, which signals the pituitary gland to make follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Luteinizing hormone then signals the testes to produce testosterone Carnegie C. Diagnosis of Hypogonadism Clinical assessment and laboratory Tests. Rev Urol. 2004;6(suppl 6):S3-S8.
Physiology of Testosterone & Causes of Hypogonadism in Males Testosterone levels normally begin to decline around 40 years of age. By 80 years of age, more than 50% of men will have testosterone levels in the low range (using a reference range defined by non obese, healthy men, younger than 40). Several common medical conditions such as (Obesity, DM Type 2, COPD, CKD, HIV) along with Opioid dependence have also been associated with low testosterone levels. Carnegie C. Diagnosis of Hypogonadism Clinical assessment and laboratory Tests. Rev Urol. 2004;6(suppl 6):S3-S8.
The ADAM Questionnaire 1. Do you have a decrease in libido (sex drive)? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased "enjoyment of life?" 6. Are you sad and/or grumpy? 7. Are your erections less strong? 8. Have you noticed a recent deterioration in your ability to play sports? 9. Are you falling asleep after dinner? 10. Has there been a recent deterioration in your work performance? If you answered YES to questions 1 or 7 or any 3 other questions, you may have low testosterone. **Adapted from Morley JE, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49(9):1239-1242.
Diagnosis of Male Hypogonadism According to guidelines from the Endocrine Society, male hypogonadism should be diagnosed only if there are signs or symptoms of hypogonadism and total serum testosterone levels are low on at least 2 occasions. Bhasin S, Cunningham GR, Hayes FJ, et al.; Task Force, Endocrine Society. Testosterone Therapy in men with androgen deficiency Syndromes: an Endocrine Society clinical practice Guideline. J Clin Endocrinol Metab, 2010;95(6):2536-2559.
Diagnosis of Male Hypogonadism Due to circadian variations in testosterone levels, serum testosterone measurement should occur in the morning, or within 2 hours of awakening. In men with borderline total testosterone levels, measurement of free testosterone and SHBG levels should be considered, especially in the presence of conditions that affect sex hormone binding globulin levels (age, obesity and diabetes).
Diagnosis of Male Hypogonadism If low testosterone is confirmed, Luteinizing hormone and Follicle-Stimulating hormone levels should be measured to categorize the deficiency as primary vs. secondary. A prolactin measurement should be considered to rule out a pituitary adenoma, especially if the LH & FSH levels are low. Bhasin S, Cunningham GR, Hayes FJ, et al.; Task Force, Endocrine Society. Testosterone Therapy in men with androgen deficiency Syndromes: an Endocrine Society clinical practice Guideline. J Clin Endocrinol Metab, 2010;95(6):2536-2559.
Conditions with a High Prevalence of Low Testosterone (Screening Suggested) Sellar mass, radiation to sella, other sellar disease On meds that affect testosterone production or metabolism HIV Glucocorticoids, ketoconazole, opioids ESRD and maintenance hemodialysis Moderate to severe COPD Osteoporosis or low trauma fracture (especially if young) Type 2 diabetes mellitus Infertility
Relevant Medical History when Evaluating Hypogonadism Puberty and sexual development Past/present major illnesses Past/present nutritional deficiency All prescription & nonprescription drugs Relationship problems Sexual problems Major life events Related family history Recent changes in body (breasts) Testicle problems
Forms of testosterone in the body. SHBG-bound testosterone is hormonally inactive. T=Testosterone.
Benefits of Testosterone Replacement Therapy : Libido & Erectile Dysfunction A common indication for testosterone therapy is treatment of decreased sexual desire or erectile dysfunction. Although evidence regarding erectile dysfunction is mixed, young men with hypogonadism and erectile dysfunction appear to benefit from testosterone therapy. Numerous studies showed that the effect of testosterone has been smaller than the effect traditionally reported with phosphodiesterase-5 inhibitors, suggesting that testosterone should not be first line treatment for erectile dysfunction. As a part of the Choosing Wisely campaign, the American Urological Association stated that physicians shouldn t prescribe testosterone therapy for men with erectile dysfunction and normal testosterone levels. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction; A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proc. 2007;82(1):20-28.
Who should be treated with Testosterone Men with low testosterone & signs/symptoms of androgen deficiency Men with low testosterone & low libido Men with low testosterone & erectile dysfunction After evaluation of underlying causes of ED And consideration of other treatment for ED Men with low testosterone, HIV infection & weight loss Short-term treatment For weight-maintenance, lean body mass, & muscle strength Men with low testosterone & taking high dose glucocorticoids Short-term treatment For lean body mass and bone mineral density
National guidelines suggest that a testosterone level below 300 ng/dl is suspicious for being low, but obviously this will vary among men. Evidence of a prior testosterone level that is much higher than a current level might warrant treatment even if the current level is > 300ng/dL. Presently, measuring testosterone byproducts such as dihydrotestosterone (DHT), estradiol and dihydroandrosteindione (DHEA) is not that useful in making the diagnosis.
Benefits of Testosterone Replacement Therapy : Bone Density, Body Composition & Muscle Strength Low testosterone levels (less than 200ng/dL) are associated with decreased bone density and unfavorable body composition changes. Testosterone therapy increases bone density at the lumbar spine, but not at the hips in middle aged men with testosterone deficiency. In older men, testosterone therapy increases bone density in the spine and hips. Testosterone therapy has shown to increase lean mass and decrease fat mass, however the effect sizes are small and studies have generally failed to demonstrate improvement in strength or physical function. Fink HA, Ewing SK, Ensured KE, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men, J Clinc ENdocrinol Metal. 2006;91(10):3908-3915.
Testosterone and Cardiovascular Health In a 2015 advisory, the U.S Food and Drug Administration warned that testosterone use is possibly associated with increased cardiovascular risk and advised physicians to discuss this risk with patients before initiating testosterone therapy. This warning came after 2 observational studies and a meta-analysis of randomized controlled trials showed an increased cardiovascular risk. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non fatal myocardial infarction following testosterone therapy prescription in men Pos One, 2014;310(17):1829-1836.
Risks of Testosterone Therapy & Contraindications: Prostate CA Because prostate cancer can be stimulated by testosterone, testosterone therapy is contraindicated in patient with known or suspected prostate CA. There has been concern that testosterone therapy may increase the risk of developing prostate cancer and increase symptoms of benign prostatic hyperplasia. Use of testosterone therapy in men with hypogonadism and previously treated (and presumed cured) prostate cancer is controversial, with little data to guide treatment decisions in this group. Gray H, Seltzer J, Talbert RL. Recurrence of prostate cancer in patients receiving testosterone supplementation for Hypogonadism. AM J Health Syst Pharm. 2-15;72(7):536-541.
Risks of Testosterone Therapy & Contraindications: Hematologic Conditions Testosterone stimulates erythropoiesis and testosterone therapy (particularly the intramuscular esters) are associated with an increased risk of polycythemia. Preexisting polycythemia (Hct of more than 54%) is an absolute contraindication to starting testosterone therapy. Developing polycythemia during treatment should lead to cessation of therapy, lowering of the dose, or switching to a lower-risk formulation to avoid increased risk of Myocardial Infarction, Stroke or VTE. Testosterone therapy has been shown to increase hemoglobin levels and correct anemia in a significant portion of older men with anemia of otherwise unknown etiology. Calof OM, Singh AB, Lee ML, et al. Adverse events Associated with testosterone replacement in middle Aged and older men. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451-1457.
Testosterone Replacement for Male Hypogonadism: FDA Indicated Uses As a part of its 2015 advisory of cardiovascular risk, the FDA also issued a statement clarifying that testosterone therapy is approved specifically for men with low testosterone levels caused by disorders of the testicles, pituitary gland or brain that cause hypogonadism (genetic disorders, damage from chemotherapy/infection, or pituitary tumors) and not for men with age-related low testosterone. Physicians should be aware that prescribing testosterone for low testosterone levels due to aging constitutes off-label use. U.S Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone. March 3, 2015.
Testosterone Replacement for Male Hypogonadism: Formulations & Precautions Many testosterone formulations are available and no formulation has superior clinical effects. The selection of formulation requires discussion about administration route, adverse effects and cost. Testosterone preparations are FDA Schedule III controlled substances that are subject to diversion and misuse. Completion of a controlled substance contract should be considered before prescribing.
Monitoring of Men on Testosterone Therapy Baseline Testosterone level DRE PSA Hematocrit Follow-up : 3 months then annually Assess improvement/side effects Testosterone level DRE PSA age appropriate interval Hematocrit If osteoporosis - DXA at 1-2 years
Monitoring of Men on Testosterone Therapy Men receiving testosterone therapy should be monitored regularly for adverse effects and to ensure normalizing of serum testosterone levels. Before initiation of testosterone therapy, testing should include a CBC (measure HCT) and a PSA along with a DRE to detect preexisting prostate CA. Patients should be reevaluated for therapeutic response and adverse effects 3-6 months after initiation of treatment, including a repeat testosterone measurement. If laboratory results are stable, reevaluation may be performed annually. Bhasin S, Cunningham GR, Hayes FJ, et al.; Task Force, Endocrine Society. Testosterone Therapy in men with androgen deficiency Syndromes: an Endocrine Society clinical practice Guideline. J Clin Endocrinol Metab, 2010;95(6):2536-2559.
The goal serum testosterone level should be in the mid normal range (400-700 ng/dl). Values outside of this range will require a dose adjustment. Monitoring of Men on Testosterone Therapy An increase in HCT to greater than 54% should lead to cessation of treatment, lowering the dose, or change to a lower-risk formulation. An increase in PSA of greater than 1.4 ng per ml over 12 months or an abnormal digital rectal examination should get a prompt referral to a urologist. *There is no consensus on the necessity and timing of a repeated PSA testing and DRE for men on testosterone therapy. The Endocrine Society recommends annual PSAs & DRE in men of 40 years and older, however the USPSTF recommends against routine PSA screening and doesn t specify its recommendations on DREs. Therefore physicians and patients should engage in shared decision making, weighing the risks and benefits in screening.
Exogenous vs. Endogenous Testosterone Normally testosterone replacement therapy refers to the treatment of hypogonadism with Exogenous testosterone - testosterone that is manufactured outside of the body. Preliminary research has shown that Clomiphene Citrate (Clomid), a drug generally prescribed to stimulate ovulation in women struggling with infertility, can foster the production of natural testosterone, termed Endogenous testosterone, in men. In a recent prospective study, 30 hypogonadal men took a daily dose of Clomiphene Citrate for at least 3 months. Within 4-6 weeks, all of the men had heightened levels of testosterone and none reported any side effects during the year they were followed. Because Clomid is not approved by the FDA for use in men, little information exists about the long-term effects of taking it (including the risk of developing prostate cancer) or whether it is more effective at boosting testosterone than exogenous formulations.
Alternatives to Testosterone Therapy DIHYDROTESTOSTERONE (DHT) The natural androgen DHT is a metabolite of testosterone. It is a selective androgen because, unlike testosterone, it cannot be converted to estrogens. It is also a potent androgen, binding to receptors more avidly than testosterone. DHT has an effect on several target tissues, including external genitalia, prostate and skin. DHT deficient men have normal muscle mass and are not osteoporotic. In normal men, DHT supplements suppress pituitary FSH and LH secretion, likely causing infertility. As an androgen, DHT is relatively prostate sparing. Because of its potency and potential, significant research is being conducted with DHT supplements for androgen replacement.
Alternatives to Testosterone Therapy DEHYDROEPIANDROSTERONE (DHEA) DHEA is available in over-the-counter formulations in the US. It is a steroid hormone made by the adrenal gland and its level progressively declines beginning the third decade of life and beyond. As a consequence of this, studies have attempted to correlate levels of DHEA and DHEA-sulfate with many health conditions. Clinical trials looking at DHEA for multiple conditions have been inconsistent. Placebo-controlled studies suggest that doses of 30-50mg of oral DHEA may produce physiologic androgen levels. In men with poor adrenal function, 50mg of oral DHEA can increase serum androgen levels to within the physiologic range for young adults, improve sexual function, mood and selfesteem, and decrease fatigue/exhaustion. However, its value in older men is not well established.
Alternatives to Testosterone Therapy GROWTH HORMONE There are decreases in growth hormone and insulin-like growth factor-i with age in both men and women. In addition, treatment of young GHdeficient adults with growth hormone improves body composition, muscle strength, physical function, and bone density, and reduces blood cholesterol and cardiovascular disease risk. Some of these improvements are in health domains similar to those affected by testosterone. However, growth hormone treatment is often accompanied by carpal tunnel syndrome, peripheral swelling, joint pain and swelling, breast tenderness, glucose intolerance, and possibly increased cancer risk. In older individuals, growth hormone treatment improves lean body mass and reduces body fat. However, clinically significant functional benefits, prolongation of youth, and life extension have not been demonstrated. Until more research better defines these risk/benefit relationships, treatment of elderly individuals with growth hormone is not recommended.
Case J.S is a 45 year old male who presented to the outpatient FM clinic for his yearly wellness exam. Patient had been complaining of increased fatigue and decreased energy over the past year and wanted to get some labwork done to evalute these symptoms. Patient is a bus driver and stated that he wanted to ensure he was in good health to allow him to continue with his job. He denied any other symptoms of unintentional weight loss, vision changes or chest pain.
PMH: Gilbert s Disease PSH: None Medications: None Family History: Mother: Alive, 82 y/o with Dementia Father: Alive, 84 y/o with h/o MI Allergies: NKDA Social History: Denies tobacco, alcohol or drug use
Physical Exam General appearance: No evidence of abuse or trauma, well nourished, no acute distress. AAOx3. Head: Atraumatic. Eyes: Pupils equal/reactive to light and accommodation. Extraocular muscles intact. Nose: Mucosa, septum and turbinates normal. Mouth: Posterior pharynx without erythema or exudate. MMM. Neck/Thyroid: Supple, no lymphadenopathy. Cardiovascular: S1, S2, no murmur, gallops or rubs. RRR. Lungs: CTA bilaterally, no wheezes, rales or bronchi. Chest: No visible gynecomastia Abdominal: Soft, nontender, nondistended. NABS. MSK: Normal exam. Neuro: CN II-XII intact. No visual field defect, visual acuity normal. Normal facial muscle function bilaterally, normal facial sensation bilaterally, hearing within functional limits, tongue movements and midline extension normal, shoulder shrug bilaterally normal. Strength equal in upper and lower extremities. Reflexes symmetrical.
Labs Obtained Free Testosterone Total Testosterone CBC CMP Vitamin B12, Folate, Vitamin D
Initial Results Albumin: 4.5 (3.5-5) Free Testosterone (Direct): 3.3 (6.8-21.5 pg/ml) Total Testosterone: 89 (264-916 ng/dl) Vitamin B12, Folate & Vitamin D - Normal
Based upon these laboratory findings, it was evident that patient did have a significantly lowered testosterone level, however the source of his decreased testosterone was yet to be discovered. Instead of just calling the patient and starting him on testosterone (hormone) replacement therapy, I decided to do some further workup to ensure I properly evaluated why his testosterone levels were this low. Patient was brought back to explain why more labs were going to be obtained and a few more questions were asked. He denied any change in his sex drive, along with no trouble with any erectile dysfunction. He also denied any trouble with infertility and had 2 children of his own. He denied any gynecomastia, galactorrhea, testicular atrophy, headaches or mood changes.
Secondary Labs Free Testosterone Total Testosterone SHBG FSH, LH TSH, Free T4 PSA Prolactin
Total Testosterone Measurement of total testosterone in the blood does not distinguish between bound and unbound (bioavailable) testosterone but, as the name implies, determines the overall quantity of testosterone in the blood. In many cases, this is sufficient to evaluate excessive or deficient testosterone production.
Sex Hormone Binding Globulin The sex hormone binding globulin (SHBG) test may be used to help evaluate men for low testosterone and women for excess testosterone production. It may be ordered in conjunction with other tests to evaluate the status of a person's sex hormones. Changes in SHBG levels can affect the amount of hormone that is available to be used by the body's tissues. If a person's SHBG level is not normal, then the total testosterone may not be an accurate representation of the amount of testosterone that is available to the body's tissues. The Endocrine Society professional guidelines recommend measuring total testosterone in the initial screen for testosterone deficiency. If abnormal, the test is repeated on another day.
Sex Hormone Binding Globulin A high SHBG level means that it is likely that less free testosterone is available to the tissues than is indicated by the total testosterone test. A low SHBG level means that more of the total testosterone is bioavailable and not bound to SHBG.
Testosterone Circulates Mostly Bound to Sex Hormone Binding Globulin Increased SHBG levels may be seen in: Liver disease Hyperthyroidism Eating disorders (anorexia nervosa) Corticosteroids or estrogen use (hormone replacement therapy and oral contraceptives) Decreased sex hormone production (hypogonadism) Pregnancy Decreases in SHBG are seen with: Obesity Polycystic ovary syndrome Hypothyroidism Androgen (steroid) use Cushing disease
Sex Hormone Binding Globulin SHBG concentrations are normally high in children of both sexes. After puberty, SHBG levels decrease more rapidly in males than in females. Levels are normally stable in adults and then begin to increase in the elderly male at the same time that the total testosterone begins to decrease. In postmenopausal women, SHBG, testosterone, and estrogen concentrations decrease as hormone production by the ovaries tapers off.
Sex Hormone Binding Globulin If repeat results are low-normal and/or if SHBG is abnormal, one of the following is recommended: Measure bioavailable testosterone (using ammonium sulfate precipitation or SHBG) Calculate free testosterone from total testosterone and SHBG Measure free testosterone (using a method called equilibrium dialysis)
FSH & LH LH and FSH can be used to distinguish between hypogonadotropic and hypergonadotropic hypogonadism and guide further evaluation and management in both males and females. Hypergonadotropic hypogonadism indicates a primary gonadal defect (congenital or acquired), while hypogonadotropic hypogonadism suggests a hypothalamic/pituitary process (congenital or acquired).
Secondary Labs Free Testosterone (Direct): 3.6 (6.8-21.5 pg/ml) - LOW Total Testosterone: 83 (264-916 ng/dl) - LOW SHBG: 20.4 (16.5-55.9 nmol/l) - NORMAL TSH: 2.66 (0.47-4.68), Free T4: 0.77 (0.78-2.19) - NORMAL/LOW FSH: 2.9 (1.5-12.4), LH: 1.7 (1.7-8.6) - NORMAL PSA: 0.44 (<4.00) - NORMAL Prolactin: 607.8 (4.0-15.2 ng/ml) - HIGH *Calculated Free testosterone: 1.90 ng/dl *Bioavailable Testosterone: 46.6 ng/dl
Based on the results of patient s labwork, it was evident with how significantly elevated his Prolactin level was, that he had an excessive production of Prolactin, and most likely had a Pituitary Adenoma. It was suspected that this patient had Hyperprolactinemia secondary to a Prolactinoma, causing Hypogonadotrophic Hypogonadism. Patient was called and an MRI the brain was obtained, which did confirm the presence of a Prolactinoma. MRI Brain w/wo contrast: Enlarged heterogeneously enhancing pituitary with a rounded masslike area of increased enhancement consistent with a probable adenoma (0.3cmx0.5cm).
Patient was referred to both Neurosurgery & Endocrinology and was evaluated. Neurosurgery: He was evaluated and it was noted that patient s Prolactin level was high while his FSH & LH were within normal limits. On the MRI, it seemed that patient had a sellar and suprasellar mass invading the right cavernous sinus and displacing the normal pituitary gland to the left. There was no compression by the tumor on the optic chiasm or optic nerves. The tumor was found to be hugging the internal carotid artery inside of the cavernous sinus on the right. Patient was started on Destinex (Cabergoline) and the plan was to repeat patient s prolactin levels after 4 weeks, followed by repeat MRI. Today, patient s Prolactin levels have come down from 607 to 353 after about 6 weeks of treatment.
Endocrinology: Patient was referred here to see if he did in fact need steroid replacement therapy and for treatment/evaluation. Patient was found to have severe central hypogonadism with central hypothyroidism (normal TSH, low free T4). Patient was going to have further screening of other co-secretion hormones to check for further pituitary hormone deficiency. IGF-I & DHEAS were found to be normal and Free T4 after equilibrium dialysis was found to be normal. Based on patient s further lab work, he wasn t found to have any further pituitary hormone deficiency other than Gonadotropins. I spoke specifically to the Endocrinologist involved in patient s care and he remarked on the importance of doing a thorough workup, well exhibited in this case because if this patient was given Testosterone replacement after the initial labwork, his true cause of suppression wouldn t have been appropriately treated and more harm would have been done to him.
References 1. Carnegie C. Diagnosis of Hypogonadism Clinical assessment and laboratory Tests. Rev Urol. 2004;6(suppl 6):S3-S8. 2. Bhasin S, Cunningham GR, Hayes FJ, et al.; Task Force, Endocrine Society. Testosterone Therapy in men with androgen deficiency Syndromes: an Endocrine Society clinical practice Guideline. J Clin Endocrinol Metab, 2010;95(6):2536-2559. 3. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction; A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proc. 2007;82(1):20-28. 8. U.S Food and Drug Administration. FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone. March 3, 2015. 9. Bhasin S, Cunningham GR, Hayes FJ, et al.; Task Force, Endocrine Society. Testosterone Therapy in men with androgen deficiency Syndromes: an Endocrine Society clinical practice Guideline. J Clin Endocrinol Metab, 2010;95(6):2536-2559. 10. Turek PJ. Smith s Urology, 17th ed. Edited by EA Tanagho and JC McAninch. Appleton and Lange, Stamford, 2003. Chapter 46. 4 Fink HA, Ewing SK, Ensured KE, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men, J Clinc ENdocrinol Metal. 2006;91(10):3908-3915. 5. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non fatal myocardial infarction following testosterone therapy prescription in men Pos One, 2014;310(17):1829-1836. 6. Gray H, Seltzer J, Talbert RL. Recurrence of prostate cancer in patients receiving testosterone supplementation for Hypogonadism. AM J Health Syst Pharm. 2-15;72(7):536-541. 7. Calof OM, Singh AB, Lee ML, et al. Adverse events Associated with testosterone replacement in middle Aged and older men. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451-1457.