Continuing Education Article Age-Related Androgen Deficiency and Type 2 Diabetes Journal of Pharmacy Practice 24(3) 316-322 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190010397719 http://jpp.sagepub.com Gina J. Ryan, PharmD, BCPS, CD1 and Lynetta J. Jobe, DVM, PhD2 Abstract There is a higher prevalence of low testosterone levels in males with type 2 diabetes compared to those without. Additionally, there is evidence that low testosterone levels may predict the development of type 2 diabetes. Symptoms of hypogonadism include decreased libido, decreased bone mineral density (BMD), and decreased lean muscle mass. The majority of the published cases in men with diabetes were attributed to age-related idiopathic hypogonadotropic hypogonadism. This paper reviews the link between type 2 diabetes and age-related hypogonadism and the treatment options for hypogonadism. Pharmacists who provide care for males with diabetes should be aware of the increased incidence of hypogonadism, know how to screen for it, and be able to recommend appropriate therapy. Keywords diabetes, hypogonadism, testosterone, men’s health, andropause Learning Objectives After completing this continuing education program, the pharmacist should be able to: 1. 2. 3. 4. 5. 6. List the symptoms of hypogonadism. Describe the normal physiology of testosterone production. Describe the link between diabetes and hypogonadism. List the optimal therapy for hypogonadism. Describe the goals of therapy for hypogonadism List the advantages, disadvantages, and patient education points for the various testosterone preparations that are available in the United States. Background In males, hypogonadism may present with low testosterone levels, infertility, and/or other symptoms, depending upon the age at disease onset. The condition is rarely recognized before puberty. In adult males, symptoms of hypogonadism may include decreased muscle strength, altered libido, erectile dysfunction, the inability to concentrate, and occasionally menopausal-type hot flushes. In addition to decreased muscle bulk, signs of hypogonadism can include a loss of body hair, gonadal atrophy, low sperm counts, and decreased bone mass (Table 1).1 The normal range for total testosterone levels is approximately 300 to 1000 ng/dL (10.5 to 35 nmol/L) although the actual limits vary between laboratories. Typically, after the age of 40, levels decline at a rate of 1% to 2% per year,2 and almost half of all men in their eighties have hypotestosteronemia, compared with only 12% of those under 50. The term ‘‘clinical hypogonadism’’ refers to cases in which low serum testosterone is associated with symptoms. In one study, the incidence of clinical hypogonadism is 4.1% among men 40 to 49 years old, and the rate doubles (9.4%) among those 60 to 70 years old.3 This physiological age-related decrease in testosterone levels is known as ‘‘age-related androgen deficiency,’’ also called andropause.1 Type 2 diabetes is also strongly associated with aging, as observational studies have shown that 15% to 34% of patients with this disease also have hypotestosteronemia.4-8 This article will review the link between these 2 diseases and the treatment options for hypogonadism. The Pathophysiology of Male Hypogonadism The hypothalamus secretes pulses of gonadotropin-releasing hormone, which stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary. 1 Department of Pharmacy, Mercer University, Atlanta, GA, USA University of Maryland Eastern Shore, School of Pharmacy and Health Professions, Hazel Hall, Princess Anne, MD, USA 2 Corresponding Author: Gina J. Ryan, Department of Pharmacy, Mercer University, Atlanta, GA, 30341, USA Email: [email protected] Ryan and Jobe 317 Table 1. Symptoms of Clinical Hypogonadism1,23 Erectile dysfunction Oligospermia Azoospermia Menopausal-type hot flushes Decreased muscle mass Decreased libido Decreased concentration the assay used to measure the unbound hormone levels.10-12 Non-SHBG-bound testosterone levels can be estimated by using SHBG-bound and total testosterone levels, but the accuracy of this method is questionable.10,11 The Link between Diabetes and Low Testosterone Levels Luteinizing hormome stimulates testicular production and secretion of testosterone, and FSH promotes spermatogenesis and increases inhibin B production by Sertoli cells. Inhibin B and testosterone close the negative feedback loop by inhibiting further secretion of FSH and LH, respectively (Figure 1). Primary hypogonadism (ie, testicular failure) is characterized by low plasma testosterone levels and elevated gonadotropin levels. Technically, secondary forms are caused by low pituitary production of LH and FSH whereas decreased hypothalamic production of gonadotropin-releasing hormone is known as tertiary hypogonadism. In clinical settings, however, the term ‘‘secondary hypogonadism’’ is also commonly applied to cases related to hypothalamic or pituitary dysfunction. ‘‘Androgen deficiency in the aging male’’ is typically related to changes at both the testicular and hypothalamic levels. Testosterone secretion follows a diurnal rhythm with peak levels normally observed in the morning. Total testosterone levels comprise free (1%-2% of the total) and bound forms of the hormone. Approximately 20% to 30% of total testosterone is bound to albumin, and 40% to 50% is bound to the sex hormone-binding globulin (SHBG).9 The effect of SHBG on levels of total and free testosterone is not completely understood. Low circulating levels of SHBG can be expected to cause increases in the unbound fraction. However, conflicting reports have been published on the relationship between free testosterone and SHBG levels, and data vary depending upon Hypothalamus Anterior pituitary FSH LH Testosterone Interstitial cells TESTIS Stimulates Inhibits Sertoli cells Figure 1. Hypothalamic-pituitary-testis access. Inhibin The precise causes of hypogonadism and type 2 diabetes have yet to be defined, but it is clear that the 2 diseases are correlated. A systematic review and meta-analysis of 43 prospective and cross-sectional studies containing a total of 6427 men examined the relationship between testosterone and diabetes risk and revealed that elevated levels of the hormone reduced the risk for type 2 diabetes by 42% (relative risk ratio: 0.58; 95% confidence interval (CI): 0.39 to 0.87). In this study, males with type 2 diabetes had on average a 76.6 ng/dL lower testosterone level than men without diabetes.13 Statistical models adjusting for age, race, and adiposity found that low free testosterone was 4 times more common in men (N ¼ 1413) with type 2 diabetes than compared to those without (odds ratio [OR] 4.12 [95% CI 1.25-13.55]), and that low androgen levels may be a risk factor for development of type 2 diabetes.14 In an 8-year observational study, the risk of developing type 2 diabetes was 2.7 times higher in men (N ¼ 294) with low testosterone levels at baseline (95% CI: 1.1-6.6). These findings suggest that the onset of type 2 diabetes may be preceded by hypotestosteronemia.15 Androgen levels are shown to be correlated with obesity, insulin resistance, and other alterations associated with the metabolic syndrome. Decreased levels of free testosterone have been found in patients with body-mass indices (BMI) over 35 kg/m2, but this parameter was not altered in those with lower BMIs.16 In a cross-sectional study of 355 males over 30 years old with type 2 diabetes, BMI (r ¼ .210; P<.001) and waist circumference (r ¼ .148; P < .006) were negatively correlated with free testosterone.8 In the same study, SHBG correlated with BMI (r ¼ .309; P < .001) and waist circumference (r ¼ .277; P < .001). Obesity can lead to hypogonadism by increasing aromatization of testosterone to estradiol (much of which occurs in adipose tissue) and/or derangements in the hypothalamic-pituitary-adrenal-testicular axis.17 Hyperinsulinemia and obesity also seem to be associated with decreased SHBG production,16,18-20 and patients with type 2 diabetes have been found to have lower levels of this globulin than age- and BMI-matched controls.21 Until more is known about the relationships between SHBG, free testosterone, and total testosterone levels,10-12 it will be difficult to determine the significance of the effects of diabetes-induced reductions in SHBG. Low LH and testosterone levels are shown to be associated with metabolic syndrome.15,19,22 The results from a observational cross-sectional study showed that there was an inverse relationship between total testosterone (OR ¼ 0.43; 95% CI 0.32-0.59), SHBG (OR ¼ 0.46, 95% CI 0.33-0.64), and metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP), in 400 men between the age of 40 and 80 years.15,19,22 Chen et al, conducted an 8- 318 Journal of Pharmacy Practice 24(3) Table 2. Risk Factors for Low Testosterone Type 2 diabetes Sellar mass HIV-associated weight loss End-stage renal disease Infertility Osteoporosis or low-trauma fracture Moderate or Severe Chronic Obstructive Lung Disease 1,23 Use of medications that affect testosterone levels: glucocorticoids ketoconazole opioids year observational trial of 195 men, average age 76.2 years, found that subjects with metabolic syndrome had a higher total testosterone level compared to normal subjects (348 mg/dL vs 409 mg/dL, P ¼ .03).15,19,22 Dhindsa et al reported that the low androgen levels observed in 103 men with type 2 diabetes are secondary to reduced levels of FSH and LH.5 In addition, the LH pulses in obese males are characterized by normal frequency but lower amplitude.16 Collectively, these findings indicate that the hypotestosteronemia associated with type 2 diabetes is not caused exclusively by testicular failure. Diagnosing Hypogonadism The diagnosis of adult male hypogonadism can be difficult because the symptoms are often vague and can overlap those related to normal aging. The American Association of Endocrinologists (AACE) and the Endocrine Society, however, both recommend that diagnosis of age-related hypogonadism be based on the presence of symptoms coupled with low morning levels of total testosterone.1,23 The Endocrine Society recommends not routinely using a screening questionnaire in the general population, but only those patients at high risk (Table 2). Measurement of testosterone levels should be reserved for symptomatic patients since treatment offers few benefits for asymptomatic forms of hypotestosteronemia. Therapy should not be given to asymptomatic patients.23 According to the AACE guidelines, testosterone replacement for hypogonadism should be considered when total testosterone levels drop below 200 ng/dL (7 nmol/L) and symptoms (Table 1) are present.1,23 Since the reference range of testosterone varies between different laboratories, the Endocrine Society recommends using the lower limit of the range of the reference laboratory as the diagnostic criteria.1,23 The 10-item Androgen Deficiency in Aging Males (ADAM) questionnaire,24 8-item the Massachusetts Male Aging Study Questionnaire,25 and the 17-item Aging Males’ Symptoms Scale26 are 3 questionnaires that have been developed to screen Table 3. Contraindications to Testosterone Replacement Therapy1,23 Absolute: Prostate cancer Breast cancer Relative: Hematocrit > 50% Severe benign prostatic hypertrophy (BPH) Severe congestive heart failure (Class III or IV) Sleep apnea Table 4. Benefits and Risks of Testosterone Replacement Therapy1,23,41 Benefits Risks Increased: Libido Muscle mass Hemoglobin Bone mineral density Energy Sense of well-being Cognition BPH Stimulates prostate cancer Erythrocytosis Acne and oily skin Decreased Sperm production Decreased Fertility patients for age-related hypogonadism. The most recent AACE guidelines recommend against using them because; there are no case-detection trials of these instruments; it is not known whether they are more cost-effective than measurement of serum testosterone; and their specificity is low.1,23 Treatment The AACE and the Endocrine Society both recommend testosterone replacement therapy for symptomatic andropause.1,23 The contraindications for testosterone therapy are summarized in Table 3, and the risks and benefits are listed in Table 4. Despite the suggested link between low testosterone, metabolic syndrome, and diabetes, it is unclear whether testosterone therapy affects insulin sensitivity. Studies examining testosterone influence on insulin sensitivity have conflicting results. In a 20-week study, Singh et al examined the effects of testosterone on insulin sensitivity and plasma lipid levels. Sixty-one healthy eugonadal men 18 to 35 years old received intramuscular testosterone (25 mg, 50 mg, 125 mg, 300 mg, or 600 mg) following suppression of endogenous testosterone production with a gonadotropin antagonist. At the end of the study, there were no significant changes in insulin sensitivity, compared with baseline findings, and the only significant effect on lipid profiles was a decrease in high-density lipoprotein levels among men treated with the 600 mg dose.27 In another trial, a one-time injection of 500 mg of testosterone ethanate caused glucose tolerance to decrease in 6 men. However, a single 250 mg injection of testosterone ethanate increased glucose tolerance in 8 men. In the same study, 11 men were given daily 40 mg of testosterone undecanoate for 6 weeks and glucose tolerance also increased in 8 men after 250 mg per day of topical testosterone gel for 3 months.28 Conflicting data have been reported regarding the effects of testosterone replacement on blood glucose in men with type 2 diabetes. In a non-randomized, open-label trial of 10 men with type 2 diabetes, low testosterone, and symptoms of hypogonadism, Corrales et al found that 150 mg every 14 days of intramuscular injections of testosterone enanthate had no significant effect on glycemic control.29 Similar results emerged from a more recent nonrandomized, uncontrolled, open-label trial in which 11 men with type 2 diabetes were treated with 100 mg of intramuscular testosterone every 3 weeks for 3 months.30 Additionally, testosterone 200 mg every 15 days for 3 months failed to significantly affect insulin resistance, glycosylated hemoglobin, Ryan and Jobe 319 Table 5. Testosterone Preparations Available in the United Statesa,23 Preparations Dose Oral Methyltestosterone 10 -50 mg po (Testred1, Viridaily lon1, Android1) Buccal, mucoadhesive, 30 mg buccal 30 mg (Striant1) twice daily Injectable Testosterone 50-400 mg IM, enanthate, every 2-4 200 mg/ml, weeks (Delastryl1) Testosterone cypio50-400 mg IM, nate, 100 mg/ml or every 2-4 200 mg/ml (Depo weeks Testosterone1) Testopel (sq testos150-450 mg terone pellets) SC, every 3-6 months Transdermal Testosterone gel 1%, 5-10 gm of gel (Androgel1, (50-100 mg testosterTestim1) one) daily 1 or 2 patches Testosterone patch change (Androderm), 2.5 daily mg/24 h, 5 mg/24 h a Advantages Disadvantages Easy administration Hepatotoxicity " lipid levels Low bioavailability 9.2% rate of gum irritation42, Not injectable, May Accidental detachment from provide " levels, gum Avoids skin irritation Inexpensive if selfadministered, Very flexible dosing Inexpensive if selfadministered, Very flexible dosing Facilitates compliance Mimics diurnal rhythm, Flexible dosing, Easy to use, Minimal skin irritation <5% Easy to use, Mimics diurnal rhythm Patient Education Place the rounded side against the upper gums and hold finger over lip for 30 seconds; system should stay in position until removed. To remove, push system down toward the tooth. Do not chew/swallow. Review IM injection techniques if product will Injection site pain, May require be self-administered. Review side effects. office visit for injections, Peak and trough drug levels may be uncomfortable Injection site pain, May require office visit for injections, Peak and trough drug levels may be uncomfortable Requires minor surgery for insertion, Pellets may be expelled Potential transfer to others via direct contact Apply to clean dry skin on abdomen, upper arms, or thighs. Gel can be transferred to others via direct contact Skin irritation in 37%35 Do not place over bony prominences or scrotum. Allow at least 7 days between applications to the same site. Irritation may occur. All preparations are schedule III controlled substances. and fasting blood glucose in a double-blind, placebo-controlled, crossover study in 22 men with type 2 diabetes.31 However, in a randomized, open-label, no-treatment controlled trial, 3 months of treatment with 120 mg/day of oral testosterone undecanoate reduced glycosylated hemoglobin levels from 10.4% to 8.5% (P < .05) in 24 subjects with type 2 diabetes.32 In a randomized, double-blind, placebo-controlled, crossover study, 24 men with hypogonadism and type 2 diabetes received 200 mg of intramuscular testosterone injections every 2 weeks for 3 months.33 During testosterone supplementation, glycosylated hemoglobin decreased by 0.37% (P ¼ .03), and insulin sensitivity improved (P ¼ .02). Another group of investigators found that abrupt withdrawal of sex steroid increased insulin resistance in healthy men with idiopathic hypogonadotropic hypogonadism.34 Larger randomized, controlled, and blinded studies are needed to define the effect of testosterone replacement on glycemic control in patients with type 2 diabetes. Testosterone Preparations Table 5 shows the main characteristics of the testosterone preparations currently marketed in the United States. The most recent guidelines from the Endocrine Society recommend that methyltestosterone not be used because of its potential hepatoxicity.1,23 It can also causes an increase in low-density lipoprotein and a decrease in high-density lipoprotein.1,23 The other oral form, undecanoate testosterone, is not available in the United States. A buccal system has been developed that adheres to the gum and provides sustained release of testosterone, which is absorbed via the buccal mucosa. This route of administration eliminates the need for injections and provides adequate serum levels, but it can cause local gum irritation and has to be administered twice a day.1,23 Testosterone cypionate and testosterone enanthate are longacting parenteral preparations. The optimal initial regimen is intramuscular injection of 50 to 100 mg every 7 to 10 days, but slightly larger, less frequent doses (ie, 100-150 mg every 2 weeks) can be used to reduce the number of injections.1 The latter approach carries a higher risk of immediate side effects, and symptoms of hypogonadism are more likely to reappear prior to the next dose. Once the optimal parenteral dose of testosterone has been established, long-term fixed-dose replacement can be achieved with subcutaneous testosterone pellets. Insertion of these pellets requires a minor surgical procedure.1,23 320 Testosterone can also be administered via transdermal patches. The scrotal patch, Testoderm1, was removed from the market in 2005. The currently available patches are applied to the back, abdomen, upper arms, or thighs and replaced every 24 hours. The primary advantage with the transdermal preparation is it mimicks diurnal variation. The disadvantage is skin irritation is a common adverse effect. Another topical option is testosterone gel (1%). This is the testosterone product most commonly prescribed because it allows flexible dosing and causes considerably less irritation than injections or patches. The primary disadvantage is the gel can be transferred to others via direct contact with the application site. This risk can be reduced, however, by instructing the patient to cover the application site with clothing after the gel has dried. The hands should also be carefully washed with soap and water after each application.35 Goals of Therapy According to the AACE and Endocrine Society, the goals of testosterone replacement therapy include improvement of clinical symptoms, restoration of normal testosterone levels, and reduction of the risk of adverse events. Testosterone levels and symptoms should be monitored every 3 to 4 months during the first year of therapy. Patients should have a prostate exam with measurement of prostate-specific antigen levels prior to treatment and every 6 to 12 months, and lipid profiles and hematocrit levels should also be monitored on a regular basis.1,23 Adverse Events and Drug Interactions The most common adverse effects of testosterone replacement include erythrocytosis, acne, prostate cancer, decreased sperm counts, and infertility.23 Gynecomastia, male-pattern balding, breast cancer, benign prostatic hypertrophy symptoms, mood liability, aggressive behavior, and worsening of sleep apnea have been reported with much lower frequency.23 Testosterone may decrease the anticoagulant requirements for patients taking warfarin. Additional monitoring is recommended if either drug is used concomitantly with testosterone.35 In patients receiving diabetes medications, serum glucose levels may also need closer monitoring since testosterone may increase insulin sensitivity.32,33 Patient Education General patient education should include a review of the common adverse effects of testosterone as well as specific instructions for administration (Table 5). Patients receiving injectable preparations should be warned about peak-and-trough effects on mood stability. Counseling is important for men who administer self-injections to avoid soft tissue damage or skin infection. Men using topical agents should be informed that a rash may occur at application site.1,23 Journal of Pharmacy Practice 24(3) Chorionic Gonadotropin Hormones Human chorionic gonadotropin hormone (hCG) is most commonly known as the hormone that is assayed in pregnancy tests. Human chorionic gonadotropin hormone increases after conception and prevents disintegration of the ovary’s corpus luteum and promotes male sexual differentiation in the fetus by stimulating replication Leydig cells and increasing testicular testosterone secretion. The results of one study suggest that, in adult males with oligospermia, high hCG levels stimulate spermatogensis in males.36 In one trial, low doses of hCG increased testosterone levels in all normal subjects (N ¼ 37), who were first made hypogonadal with treatment of a gonadotropin-releasing hormone antagonist.37 In 40 male subjects with partial age-related androgen deficiency (testosterone 441 ng/dL), 250 mcg of subcutaneous hCG was administered twice weekly for 3 months in a double-blind, randomized, placebo-controlled trial.38 Subjects treated with hCG had a 150% increase in total and free testosterone (P < .001). And although muscle mass increased (2 kg P < .001), there was no significant increase in muscle strength. Prostate symptoms and prostate-specific antigen was not significantly increased by hCG. Three men treated with hCG reported nipple tenderness, but no gynecomastia was observed. Meier et al also reported that 3 months of twice-weekly subcutaneous 250 mcg injections of hCG increased osteoblastic collagen sythensis in older males with partial age-related androgen deficiency.39 Although there are no clinical trials evaluating the effects of hCG in male patients with type 2 diabetes, investigators reported that hCG does not alter insulin sensitivity or b-cell function.40 Larger long-term studies of various doses are needed prior to recommending chorionic gonadotropin for treatment of age-related hypogonadism. Additionally, further studies in patients with type 2 diabetes will help determine its effect on hCG’s effects on glycemic control. Therapy with hCG is not recommended by either AACE or the Endocrine Society for the treatment of age-related androgen deficiency.1,23 Conclusion Approximately 15% to 33% of adult males with type 2 diabetes have low testosterone levels, although the frequency of clinical hypogonadism in this population has never been determined. Both the AACE and the Endocrine Society recommend testosterone replacement therapy for patients with symptomatic hypotestosteronemia. Pharmacists working with patients with diabetes should be aware of the symptoms and refer patients for screening as necessary. Once treatment has been initiated, closer monitoring of blood glucose levels may be warranted since testosterone may alter glycemic control. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article. Ryan and Jobe 321 Funding The author(s) received no financial support for the research and/or authorship of this article. 16. 17. References 1. Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients–2002 update. Endocr Pract. 2002;8(6):440-456. 2. Araujo A, O’Donnell A, Brambilla D, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metabol. 2004;89(12):5920-5926. 3. Harman S, Metter E, Tobin J, et al. Longitudinal effects of aging on serum total and free tesosteone levels in healthy men; Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731. 4. Corona G, Mannucci E, Petrone L, et al. Association of hypogonadism and type II diabetes in men attending an outpatient erectile dysfunction clinic. 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Liu PY, Wishart SM, Celermajer DS, et al. Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin. Eur J Endocrinol. 2003; 148(1):55-66. 41. Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc. 2003;51(1):101-115, discussion 15. 42. Striant [package insert]. Covington, NJ: Columbia Laboratories; 2003. Continuing Education Credit The NYSCHP is approved by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.5 contact hours (0.15CEUs) of continuing education. Universal Program Number is 0134-0000-11-067-H01-P. Submission of exam for CE credit expires 06/30/2014. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. There is no charge to NYSCHP members. 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