CE ARTICLE

Androgen deficiency syndrome in older people Yaelim Lee, RN, MSN (PhD Student) School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania

Keywords Aging men; androgen deficiency syndrome; testosterone deficiency; testosterone treatment. Correspondence Yaelim Lee, School of Nursing, University of Pennsylvania, Claire M. Fagin Hall, Philadelphia, PA 19104–4217. Tel: (215) 407 3004; E-mail: [email protected] Received: July 2013; accepted: October 2013 doi: 10.1002/2327-6924.12114 To obtain CE credit for this activity, go to www.aanp.org and click on the CE Center. Locate the listing for this article and complete the post-test. Follow the instructions to print your CE certificate. Disclosure The authors report no competing interests.

Abstract Purpose: To support nurse practitioners in their encounters with aging male patients with signs and symptoms related to the decline of male sex hormones. Data sources: An electronic search was conducted on studies from 2006 to 2013 from the following databases: PubMed, CINAHL, Scopus, and related health resources websites. The search terms used included male menopause, andropause, androgen deficiency, testosterone deficiency, late-onset hypogonadism, and testosterone replacement therapy. Relevant studies in English were selected for an integrative review. Conclusions: Androgen deficiency syndrome has been overlooked in clinical settings. However, there has been an increase in health needs related to low testosterone levels. A diagnosis should be made carefully, considering other possible causes of the problems as well as the decision to initiate testosterone treatment (TT) and monitoring. In this article, the current awareness of androgen deficiency syndrome, pathophysiology of aging men’s sex organ, clinical presentation, differential diagnoses, diagnostic strategy, clinical management, monitoring, and referral plans are discussed. Implications for practice: The rapidly growing aged population in our society makes androgen deficiency syndrome a growing issue that needs to be understood, adequately diagnosed, and carefully managed by nurse practitioners.

Introduction Unlike the general understanding of the relationship between the decline of female hormone production and the female aging process, the understanding of male hormonal decline associated with aging is unclear and has not been adequately discussed. Many healthcare providers tend to make light of what aging men experience, saying that it is part of the natural aging process (Bassil & Morley, 2010). Moreover, compared to women who have a specific term for their hormone-related phenomenon (i.e., menopause), because men’s reproductive function still remains to some extent, the term for their declining hormone levels is not yet a matter of consensus (Tsitouras, 2011). It is sometimes called partial androgen deficiency in the aging male (PADAM), androgen deficiency in aging males (ADAM), male climacteric, viropause, relative hypogonadism, hypoandrogenemia, manopause, andropause, male menopause, or late-onset hypogonadism (Tsitouras, 2011). Because the decline of male hormone production not only lowers sexual pleasure, but also causes mul-

tiple symptoms that interfere with health and quality of life, the recognition of this problem is gradually increasing in both patients and healthcare providers (Allan, Strauss, Forbes, Paul, & McLachlan, 2011). In recent years, there have been several studies pointing to this issue. A large number of men have been actively searching for a solution (Lindau et al., 2007). Fourteen percent of men reported having tried prescribed or nonprescribed medication for impaired sexual function, while only 1% of women sought such solutions (Lindau et al., 2007). Thirty-eight percent of men discussed sexual issues with their physician after turning 50 as compared to 22% of women (Lindau et al., 2007). Moreover, a study from Australia showed that prescriptions for testosterone increased 2.5- to 4.5-fold between 1992 and 2010 (Handelsman, 2012). A study done in 2007 suggested that 5.6% of men between 30 and 79 years old are experiencing symptomatic androgen deficiency (Araujo et al., 2007). Furthermore, a study done in Canada reported that 92.6% of physicians agreed that aging men are experiencing these symptoms (Pommerville & Zakus, 2006).

C 2014 The Author(s) Journal of the American Association of Nurse Practitioners 26 (2014) 179–186 

 C 2014 American Association of Nurse Practitioners

179

Androgen deficiency syndrome

There is rising interest in the treatment of androgen deficiency syndrome (ADS) and addressing its effects on health. In 2009, a study of 3014 men showed a significant relationship between low serum testosterone, estradiol levels, and high mortality (Tivesten et al., 2009). Low testosterone levels increase the risk for atherosclerosis and falls, as well as increase fat mass while decreasing muscle mass and bone mineral density (BMD) that consequently increases the risk for fracture (Tivesten et al., 2009). In addition, a prospective study showed that low testosterone levels are closely related to the risks of metabolic syndromes and type 2 diabetes mellitus (Bassil & Morley, 2010). However, recognition of and information about what aging men are experiencing with regard to declining hormone levels have been ignored compared to the experiences of women (Bassil & Morley, 2010). A review article on public health information resources for ADS concluded that even though there are some online resources for the general public to access, little high-quality or evidence-based information is available, causing the public to misunderstand ADS (Harrison, 2011). The purpose of this article is (a) to summarize the current evidence-based knowledge on ADS, (b) to support nurse practitioners so that they will be able to adequately assess and manage patients with ADS, and (c) to suggest guidance for future nursing studies and practice on ADS. An electronic search was conducted on studies from 2006 to 2013 from the following databases: PubMed, CINAHL, Scopus, and related health resources websites. The search terms used included male menopause, andropause, androgen deficiency, testosterone deficiency, late-onset hypogonadism, and testosterone replacement therapy. An initial search yielded 406 publications. Of these, 128 articles were published in English, provided full-length access, and had information related to the objectives of this article. These articles were therefore selected for review.

Y. Lee

One of the most accepted theories of change in hormonal levels with aging is the reproductive cell-cycle theory (Atwood & Bowen, 2011). According to this theory, the hypothalamic-pituitary-gonadal (HPG) axis has control over human aging, regulating chemical reactions in cell growth, development, and death (Atwood & Bowen, 2011). As men grow older, the HPG axis becomes unbalanced and unable to adequately regulate cells, which will cause a decline in Leydig cells (Atwood & Bowen, 2011). These cells produce testosterone and respond to pituitary regulation hormones such as luteinizing hormone (LH; Atwood & Bowen, 2011). Only 2% of testosterone is shown to be biologically free and active in cells, whereas 98% of testosterone is tied to sex hormone-binding globulin (SHBG; Harvey & Berry, 2009). The problem is that this SHBG level increases with normal aging; this can be tested in a laboratory to diagnose ADS (Harvey & Berry, 2009). In addition, obesity; alcohol and tobacco use; the use of medication, including anticonvulsants and steroids; and chronic illnesses, including metabolic, renal, hepatic, and thyroid problems, are known to cause changes in male sex hormones (Bhasin et al., 2010; Harvey & Berry, 2009).

Clinical presentation History The symptoms that highly suggest ADS are impaired sexual drive and activity, erectile dysfunction, breast discomfort, hot flashes, sweats, and the axillary and pubic hair loss (Bhasin et al., 2010). Symptoms that are less specific but may indicate ADS are irritability; depressed mood; sleep disturbance; and decreased vitality, motivation, initiative, self-confidence, memory, concentration, performance, and sense of well-being (Bassil & Morley, 2010; Bhasin et al., 2010; Travison et al., 2008).

Physical examination

Pathophysiology Testosterone has multiple effects on men, including maintaining reproductive tissues, body hair, and bone mass; stimulating sperm production, sexual function, and erythropoiesis; and increasing body weight, lean body mass, and nitrogen retention (Dandona & Rosenberg, 2010). The decline in testosterone levels occurs with normal aging at varying rates, depending on illnesses, medication use, and lifestyle, causing multiple problems (Dandona & Rosenberg, 2010). Male testosterone is known to decline by about 1% each year after the age of 40 (Gupta & Agarwal, 2010).

180

The signs that highly indicate ADS are shrinking testes, low sperm count, loss of height, low trauma fracture, low BMD, and gynecomastia (Bhasin et al., 2010). Less specific signs that may indicate ADS are mild normochromic, normocytic anemia within the female range, reduced muscle mass and strength, and increased body fat and body mass index (Bassil & Morley, 2010; Bhasin et al., 2010; Travison et al., 2008).

Differential diagnoses The differential diagnoses of ADS include “depression, personality disorders, mild cognitive impairment,

Androgen deficiency syndrome

Y. Lee

hypothyroidism, fibromyalgia” (Harvey & Berry, 2009, p. 209), and “chronic alcoholism” (Bassil & Morley, 2010, p. 198). In particular, men with obesity, hypertension, dyslipidemia, impaired glucose regulation, urinary obstruction, or peripheral vascular disease may present with erectile dysfunction and diminished libido, which are common symptoms of ADS (Wang et al., 2008). Being on certain medications including antihypertensives, steroids, digoxin, opioids, antidepressant, and antifungal drugs may present signs and symptoms similar to ADS (Bassil & Morley, 2010; Harvey & Berry, 2009).

Diagnostics Questionnaires There are several questionnaires available to help assess symptoms related to aging men’s hormonal changes, such as the androgen deficiency in aging males (ADAM) and aging male symptoms (AMS) scales (Bassil & Morley, 2010). Both scales have relatively high sensitivities (ADAM, 97%; AMS, 83%) and low specificities (ADAM, 30%; AMS, 39%; Bassil & Morley, 2010). Similarly, a study done in Chile and Europe on ADAM showed high sensitivities over 80% and low specificities around 20% (Blumel et al., 2009). These questionnaires are not rec¨ ommended for screening for ADS, but may be helpful in diagnosis (Bassil & Morley, 2010).

Diagnostic tests Whom to test. A diagnosis is only made when a patient without any acute or subacute disease status complains of symptoms that relate to low serum testosterone levels (Bhasin et al., 2010). The current guidelines of the Endocrine Society recommend performing diagnostic tests for ADS only on men with the consistent symptoms listed earlier (Bhasin et al., 2010). What to test. The testing of the serum testosterone level is the primary test for diagnosing ADS (Bassil & Morley, 2010). Patients with total serum testosterone levels greater than 500 ng/dL do not require treatment, while those with levels less than 300 ng/dL may benefit from testosterone replacement treatment (Bassil & Morley, 2010). If the total serum testosterone level is within 300–500 ng/dL, repeating the total testosterone level test with SHBG levels to calculate the free testosterone levels or directly measuring the free testosterone levels are recommended (Bassil & Morley, 2010). Free testosterone levels below 10 ng/dL and bioavailable testosterone levels below 70 ng/dL are supportive evidence for ADS (Harvey & Berry, 2009). Testosterone levels measured from the saliva have shown to be reli-

able; however, as the testing methods and ranges are not standardized, current guidelines do not recommend this method (Wang et al., 2008). There are several conditions other than ADS that can increase or decrease SHBG levels (Bhasin et al., 2010; Dandona & Rosenberg, 2010). Possible factors leading to increased SHBG levels include hepatic cirrhosis, hepatitis, hyperthyroidism, human immunodeficiency virus (HIV), catabolic conditions such as malnutrition or malabsorption, and the use of anticonvulsants or estrogens (Bhasin et al., 2010; Dandona & Rosenberg, 2010). Conditions that can decrease SHBG levels are nephrotic syndrome; hypothyroidism, acromegaly; diabetes mellitus (especially type II); moderate obesity (especially that caused by a metabolic syndrome); and the use of medications, including glucocorticoids, progestins, and androgenic steroids (Bhasin et al., 2010; Dandona & Rosenberg, 2010). Serum LH, follicle stimulating hormone (FSH), and prolactin levels can be tested to discern whether a patient has primary or secondary hypogonadism, with further evaluation of their hypothalamic-pituitary function via magnetic resonance imaging or computerized tomography (Bassil & Morley, 2010; Bhasin et al., 2010). When to test. A study showed that measuring serum testosterone levels in a single morning was the most reliable method in nonobese men over 55 years old who were experiencing testosterone deficiency symptoms without severe depression, chronic illness, or the excessive use of alcohol (Allan et al., 2011). In addition, to reduce intrasubject variability for the diagnostic criteria for testosterone deficiency, taking the average of two measured testosterone levels was recommended (Allan et al., 2011). The guidelines also support repeating this test for the confirmation of diagnosis (Bhasin et al., 2010). However, as testosterone levels vary throughout the day, measuring the level at the same time is preferred, although this variation is mostly true in younger adults (Tsitouras, 2011).

Clinical management Nonpharmacological treatment There are relatively few studies or recommendations on nonpharmacological treatments for ADS. General health management skills include getting enough rest, having a well-balanced diet, avoiding alcohol consumption and smoking, avoiding emotional stress when possible, engaging in regular and moderate exercise, going to counseling, rediscovering interest in life, receiving treatment for underlying problems, and enhancing spirituality (Tharu & Shroff, 2011).

181

Androgen deficiency syndrome

Pharmacological treatment Although the extent of the testosterone treatment (TT) effect is still controversial, the aim of TT is to reduce the symptoms caused by ADS (Emmelot-Vonk et al., 2008). For older men, in general, there is strong evidence suggesting that this treatment can improve their sense of quality of life and decrease fat mass while increasing lean body mass (Bhasin et al., 2010). Although there is insufficient evidence of testosterone replacement improving muscle strength, strong evidence has been found regarding its improvement of men’s sexual function, grip strength, and sense of well-being (Bhasin et al., 2010; Emmelot-Vonk et al., 2008). There is some weak evidence that the treatment will improve BMD, sexual satisfaction, depression, and cognition (Bhasin et al., 2010). However, TT is contraindicated in patients with breast or prostate cancer (Bhasin et al., 2010). Men with palpable prostate nodules or prostate-specific antigen (PSA) levels greater than 4 ng/mL, as well as men with levels greater than 3 ng/mL with a high risk for prostate cancer (e.g., African Americans or those with a family history of prostate cancer in first-degree relatives) require additional tests to be cleared of the risk for prostate cancer (Bhasin et al., 2010). Also, patients with hematocrit levels greater than 50%; uncontrolled comorbid conditions, such as obstructive sleep apnea, lower urinary tract symptoms, and heart failure; or those planning to have a baby should not receive the treatment (Bhasin et al., 2010). Generally, TT is not recommended for older men unless they have serious clinical symptoms or the treatment benefits outweigh the risks (Bhasin et al., 2010). The treatment comes in various delivery systems, including oral, transdermal patch, gel, intramuscular, subcutaneous implant, and nasal spray (Bassil & Morley, 2010; Bhasin et al., 2010). The dosage, frequency, administration, and cautions differ with the medication, as listed in Table 1 (Bassil & Morley, 2010; Bhasin et al., 2010).

Potential risks Common potential risks for TT in older men include stimulating the growth of the prostate, aggravating benign prostatic hypertrophy (BPH), and breast cancer (Bassil & Morley, 2010; Bhasin et al., 2010). However, there is no clear evidence that TT increases the risk factors for prostate cancer or BPH (Bassil & Morley, 2010; Bhasin et al., 2010). Also, because liver cancer and hepatotoxicity in TT have been reported, the careful administration of TT to older men or those with liver

182

Y. Lee

problems is necessary (Bassil & Morley, 2010; Bhasin et al., 2010). Because testosterone stimulates erythropoiesis, the development of polycythemia should be considered, especially in terms of the risks accompanied by the increased viscosity of the blood, including vascular diseases (Bassil & Morley, 2010). Hematocrit levels above 54% indicate erythrocytosis, and it is recommended that the treatment be stopped until such levels become normal again (Bassil & Morley, 2010). The treatment should be restarted at a lower dose, monitoring for hypoxia and sleep apnea (Bassil & Morley, 2010; Bhasin et al., 2010). In addition, less commonly, gynecomastia is possible because testosterone is aromatized into estradiol in the tissues; testicular atrophy can appear with a downward readjustment of gonadotropins; an exacerbation of sleep apnea is presented, affecting central control; skin irritations are reported with transdermal TT; and the worsening of edema is observed because testosterone can cause some electrode and water retention (Bassil & Morley, 2010; Bhasin et al., 2010). A systematic review and meta-analysis of the adverse effects of TT between 2003 and 2008 stressed that the adverse effects of TT should be clearly addressed, and ´ that it should be administered with caution (FernandezBalsells et al., 2010). The results showed no significant effects with regard to increasing PSA levels; deteriorating urological outcomes; and increasing cardiovascular risk factors, including glucose, low-density lipoprotein, triglyceride, and blood pressure, but they did show a significant, though small, lowering of high-density lipopro´ tein and a high incidence of erythrocytosis (FernandezBalsells et al., 2010).

Monitoring Baseline assessment Before the initiation of TT, the following tests are needed to check for baseline levels: BMD, PSA, hemoglobin, hematocrit, lipids, and liver function tests (LFTs; Bassil & Morley, 2010; Bhasin et al., 2010; Harvey & Berry, 2009). During the treatment, the patient should be monitored for any of the side effects listed earlier (Bassil & Morley, 2010; Bhasin et al., 2010; Harvey & Berry, 2009). After the first 3, 6, and 12 months of TT, a followup assessment of patients’ responses to the treatment and the development of side effects is recommended (Bhasin et al., 2010; Harvey & Berry, 2009). Laboratory tests of hemoglobin, hematocrit, lipids, LFTs, and testosterone should be repeated on each 3, 6, and

Androgen deficiency syndrome

Y. Lee

Table 1 Testosterone treatments Route Oral

Patch

Gel IM

SC Intranasal

Medication

Dosage

Administration

Caution

Bioadhesive buccal testosterone tablet Oral testosterone undecnoate (unavailable in the United States)

30 mg

Apply to buccal mucosa every 12 h

Alteration in taste, inner mouth irritation

40–80 mg

Twice or three times daily with meals

Liver toxicity, development of benign and malignant neoplasm, unfavorable effect on cholesterol levels

17-Alpha-methyl testosterone Transdermal testosterone patch Testosterone-inadhesive matrix patch 1% Testosterone Testosterone enanthate or cypionate

Not recommended for liver toxicity Avoid pressure areas or genital areas, caution for skin reaction

4.8 mg

Apply nightly over the skin of the back, thigh, or upper arm 2 × 60 cm2 patches

5–10 g 75–100 mg, 150–200 mg

Daily over covered area Weekly, Every 2 weeks

One/two (5–10 mg)

1000 mg Injectable long-acting testosterone undecanoate in oil Testosterone Varies pellets implant Further studies needed in regards to its effect and safety

Initial: 1000 mg At 6 week: 1000 mg every 10–14 week: 1000 mg

Implant intervals of 3–6 months

Skin irritation

Caution for skin-to-skin contact Fluctuations in mood and libido, cough, elevation of Hct. level, excessive erythrocytosis, especially in the older men Cough in a very small number of men

Infection, expulsion of pellet

Note. IM, intramuscular; SC, subcutaneous; Hct., hematocrit. Adapted and modified from “Late-life onset hypogonadism: A review,” by Bassil, N., & Morley, J. E. (2010). Clinics in Geriatric Medicine, 26(2), 197-222, and “Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline,” by Bhasin, S., Cunningham, G. R., Hayes, F. J., Matsumoto, A. M., Snyder, P. J., Swerdloff, R. S., Task Force, E. d. S. (2010) Journal of Clinical Endocrinology and Metabolism, 95(6), 2536–2559.

12 months after initiating TT (Bassil & Morley, 2010; Bhasin et al., 2010). The target serum testosterone level of older men with TT is 400–500 ng/dL. Levels can be increased to 700 ng/dL if the symptoms are still distressing (Bhasin et al., 2010). The target levels of testosterone metabolites and of 5-a-dihydrotestosterone (DHT) and estradiol are 36–573 and 6–46 pg/mL, respectively (Bhasin et al., 2010; Harvey & Berry, 2009). The measuring time of the serum testosterone level differs with the route of TT administration (Bassil & Morley, 2010; Bhasin et al., 2010). Patients receiving injectable TT should be tested between injections, whereas patients with transdermal patches should be tested 3–12 h after applying the patch (Bassil & Morley, 2010). Patients with buccal TT should be tested just before the administration of a new system, while patients using gels can be checked anytime (Bassil & Morley, 2010).

The evaluation of PSA is recommended after 3 months, then according to prostate cancer screening guidelines (Bhasin et al., 2010), men over the age of 40 with baseline PSA levels greater than 0.6 ng/mL are recommended for digital prostate examinations and PSA measurements before continuing the treatment (Bhasin et al., 2010).

Annually After reaching the target testosterone level of midnormal range, yearly evaluation of the level is recommended, as well as annual evaluation of hemoglobin, hematocrit, lipids, and LFTs (Bassil & Morley, 2010; Bhasin et al., 2010). For men with osteoporosis or low trauma fracture, BMD tests are recommended every 1 to 2 years while they are undergoing TT (Bassil & Morley, 2010; Bhasin et al., 2010).

183

Androgen deficiency syndrome

Y. Lee

Clinical presentation More spe cif ic

L e s s sp e c i f i c

History

Reduced sexual drive and activity, erectile dysfunction, breast discomfort, and the loss of axillary and pubic hair

Decreased vitality, motivation, initiative, self-confidence, memory, concentration, performance, and sense of well-being Depressed mood, irritability, and sleep disturbance

Physical examination

Shrinking testes, low sperm count, height loss, low trauma fracture, low BMD, hot flashes, sweats, and gynecomastia

Mild normochromic, normocytic anemia within the female range, reduced muscle bulk and strength, increased body fat and BMI

Differential diagnoses Health conditions

Presenting symptoms often seen in people with ADS

Depression, personality disorders, mild cognitive impairment, hypothyroidism, fibromyalgia, stress, and chronic alcoholism

Presenting erectile dysfunction Obesity, hypertension, dyslipidemia, impaired glucose regulation, insulin resistance, and diminished libido hyperprolactinemia, metabolic syndrome, bladder outlet obstruction, or peripheral vascular disease Medication

Corticosteroids, cimetidine, spironolactone, digoxin, opioid analgesics, antidepressants, antifungal drugs, and antihypertensives

Diagnostic strategy Who to test?

Only on men with the consistent symptoms

What to test?

Serum T

> 500 ng/dL 300~500 ng/dL

Androgen deficiency syndrome in older people.

To support nurse practitioners in their encounters with aging male patients with signs and symptoms related to the decline of male sex hormones...
231KB Sizes 3 Downloads 3 Views