Clinical Policy Bulletin: Androgens and Anabolic Steroids
Note: Most policies specifically exclude coverage of steroids for performance enhancement. For plans without this exclusion, androgens and anabolic steroids as well as other medical interventions for performance enhancement are not covered because performance enhancement of non-diseased individuals is not considered treatment of disease or injury. Please check benefit plan descriptions for details.
Aetna considers anabolic steroids medically necessary for any of the following indications:
AIDS wasting syndrome; or
Anemia accompanying renal failure; or
Bone marrow failure anemias; or
Breast cancer; or
Conditions associated with decreased fibrinolytic activity due to anti-thrombin III deficiency or fibrinogen excess (including cutaneous vasculitis, scleroderma of Raynaud's disease, vasculitis of Behcet's disease, complications of deep vein thrombosis such as venous lipodermatosclerosis, other vascular disorders associated with these forms of reduced fibrinolytic activity, and prevention of recurrent venous thrombosis associated with anti-thrombin III deficiency); or
Constitutional delay in growth (androgenic anabolic steroids); or
Delayed male puberty (androgenic anabolic steroids); or
Growth failure in children with growth hormone deficiency (treatment adjunct); or
Hereditary angioedema; or
Hypospadias (testosterone injection as pre-surgical adjuvant hormonal therapy); or
Klinefelter's syndrome with hypogonadism (androgenic anabolic steroids) (see appendix); or
Microphallus (androgenic anabolic steroids); or
Refractory red cell production anemias (including aplastic anemia, myelofibrosis, myelosclerosis, agnogenic myeloid metaplasia, hypoplastic anemias caused by malignancy or myelotoxic drugs); or
Severe burn injury; or
Symptomatic* androgen deficiency in men (androgenic anabolic steroids) (androgen deficiency is indicated by either two consecutive low total fasting serum testosterone levels (below the testing laboratory's reference range or below 300 ng/dL if reference ranges are not available), or for persons with low normal total testosterone levels (above 300 ng/dL but below 400 ng/dL), two consecutive low free or bioavailable fasting serum testosterone levels (below the testing laboratory's reference range or less than 225 picomoles per liter (pmol/L) (6 ng/dL) if reference ranges are not available)** (see appendix)); or
Weight loss from cancer chemotherapy.
* Testosterone replacement for androgen deficiency in men is considered medically necessary only for persons with one or more of the symptoms and signs listed in table 1A (see appendix).
** Two morning samples drawn between 7:00 a.m. and 10:00 a.m. obtained on different days are required (see appendix).
Injectable androgens are considered experimental and investigational for treatment of female menopause because of insufficient evidence in the peer-reviewed literature.
Aetna considers androgen therapy experimental and investigational to improve live birth outcome in poor responders undergoing in-vitro fertilization/intra-cytoplasmic sperm injection treatment because of insufficient evidence.
Aetna considers androgens and anabolic steroids experimental and investigational as a treatment for chronic obstructive pulmonary disease, chronic pressure ulcers and for other indications because of insufficient evidence in the peer-reviewed literature.
Aetna considers testosterone injections experimental and investigational for the treatment of amyotrophic lateral sclerosis, female sexual dysfunction/hypoactive sexual desire disorder, and heart failure because of insufficient evidence in the peer-reviewed literature.
Depot forms of testosterone include testosterone cypionate and testosterone undecanoate.
Testosterone is FDA-approved as replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism (FDA, 2015). However, the FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and safety of this use have not been established (FDA, 2015).
The FDA advises that health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests (FDA, 2015). Health care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy. Patients using testosterone should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, or slurred speech.
The FDA is requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications (FDA, 2015). The FDA is also requiring these manufacturers to add information to the labeling about a possible increased risk of heart attacks and strokes in patients taking testosterone. The FDA cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone (FDA, 2015).
Based on the available evidence from studies and expert input from an FDA Advisory Committee meeting, the FDA has concluded that there is a possible increased cardiovascular risk associated with testosterone use (FDA, 2015). These studies included aging men treated with testosterone. Some studies reported an increased risk of heart attack, stroke, or death associated with testosterone treatment, while others did not (FDA, 2015).
Testosterone 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 serum testosterone concentration (Snyder, 2013). In comparison, increasing the serum testosterone concentration in a man who has symptoms suggestive of hypogonadism but whose testosterone concentration is already normal will not relieve those symptoms. The principal goal of testosterone therapy is to restore the serum testosterone concentration to the normal range. The role of testosterone replacement to treat the decline in serum testosterone concentration that occurs with increasing frequency above age 60 in the absence of identifiable pituitary or hypothalamic disease is uncertain.
Measurement of the serum testosterone concentration is usually the most important single diagnostic test for male hypogonadism because a low value usually indicates hypogonadism. Measurement of the serum total (free plus protein-bound) testosterone concentration is usually an accurate reflection of testosterone secretion. Interpretation of serum testosterone measurements should take into consideration its diurnal fluctuation, which reaches a maximum at about 8 AM and a minimum, approximately 70 percent of the maximum, at about 8 PM. It is easier to distinguish subnormal from normal when normal is higher, so the measurements should always be made at 8 AM. If a single 8 AM value is well within the normal range, testosterone production can be assumed to be normal. If a single 8 AM value is low or borderline low or does not fit with the clinical findings, the measurement should be repeated once or twice before making the diagnosis of hypogonadism.
Testing during acute illness or during a time of decompensation of chronic illness is not advised since testosterone levels may be temporarily depressed during such times (Hayes, 2015). Relevant chronic illnesses include coronary artery disease, heart failure, and diabetes. The recommended target of testosterone therapy is the middle of a normal range for healthy young men. Food, especially glucose ingestion, also decreases the serum testosterone concentration, so the blood should also be drawn fasting (Snyder, 2013).
Guidelines recommend that free or bioavailable testosterone be measured when total testosterone levels are close to the lower limit of the normal range (less than 400 ng/dL) and when altered SHBG levels are suspected, as may be the case in older men and men with obesity, diabetes mellitus, cachexia, malnutrition, advanced cirrhosis, acromegaly, hypothyroidism, or nephrotic syndrome (Hayes, 2015; ASRM, 2006).
Following a determination of abnormally low serum testosterone, best practice requires measurement of serum LH and FSH levels to distinguish between primary (testicular) and secondary (pituitaryhypothalamic)hypogonadism, as well as other tests for possible causes of primary or secondary hypogonadism (Hayes, 2015). Additional laboratory tests and/or imaging are recommended for cases of secondary hypogonadism in order to evaluate etiology and exclude diagnoses such as pituitary neoplasia, hyperprolactinemia, hemochromatosis, obstructive sleep apnea, and genetic disorders. A karyotype is recommended for cases of primary hypogonadism of unknown etiology to rule out Klinefelter's syndrome.
In symptomatic men, regardless of age, testosterone levels are assessed by comparing them with the normal range for young men, based on the known gradual decline of testosterone levels with aging, starting at approximately age 30 years (Hayes, 2015). The lower limit of normal for healthy young men is 280 to 300 ng/dL (9.7 to 10.4 nmol/L). The panel assembled for the current Endocrine Society guidelines was divided between 2 options for symptomatic older men (Bhasin et al., 2010; Hayes, 2015):
Treat only when levels of total testosterone are < 300 ng/dL (10.4 nmol/L) because of the association between testosterone at those levels and typical symptoms of androgen deficiency.
Treatment only when levels of total testosterone are < 200 ng/dL (6.9 nmol/L) because randomized trials have suggested that testosterone therapy is ineffective in men with pretreatment values of 300 ng/dL.
Free and bioavailable testosterone can be calculated by various formulas on the basis of total testosterone and SHBG assays (Hayes, 2015). There is no consensus regarding cutoff values for free or bioavailable testosterone, but a level of > 225 picomoles per liter (pmol/L) (6 ng/dL) is generally considered normal.
Measurement of salivary testosterone has been proposed as an alternative to serum testosterone, but measurement of salivary testosterone is not a standard practice (Hayes, 2015).
In a prospective, double-blind, placebo-controlled, 16-week study, Sharma et al (2008) examined the benefits of anabolic steroids in patients with severe chronic obstructive pulmonary disease (COPD) who did not participate in a structured rehabilitation program. Biweekly intra-muscular injections of either the drug (nandrolone decanoate) or placebo were administered. A total of 16 patients with severe COPD were randomized to either placebo or nandrolone decanoate. The placebo group weighed 55.32 +/- 11.33 kg at baseline and 54.15 +/- 10.80 kg at 16 weeks; the treatment group weighed 68.80 +/- 6.58 kg at baseline and 67.92 +/- 6.73 kg at 16 weeks. Lean body mass remained unchanged, 71 +/- 6 kg versus 71 +/- 7 kg in placebo group and 67 +/- 7 kg versus 67 +/- 7 kg in treatment group, at baseline and 16 weeks respectively. The distance walked oin 6 mins was unchanged at baseline, 8 weeks, and 16 weeks in placebo (291.17 +/- 134.83 m, 282.42 +/- 115.39 m, 286.00 +/- 82.63 m) and treatment groups (336.13 +/- 127.59 m, 364.83 +/- 146.99 m, 327.00 +/- 173.73 m). No improvement occurred in forced expiratory volume in 1 second, forced vital capacity, maximal inspiratory pressure, maximal expiratory pressure, VO(2) max or 6-min walk distance or health related quality of life. The authors concluded that administration of anabolic steroids (nandrolone decanoate) outside a dedicated rehabilitation program did not lead to either weight gain, improvement in physiological function, or better quality of life in patients with severe COPD.
It is interesting to note that while testosterone treatment improved body composition and sexual function in men with COPD in a 6-month trial, no improvement in pulmonary function was found (Svartberg et al, 2004).
Miller and Btaiche (2009) stated that severe thermal injury is associated with hyper-metabolism and hyper-catabolism, leading to skeletal muscle breakdown, lean body mass loss, weight loss, and negative nitrogen balance. Muscle protein catabolism in patients with severe thermal injury is the result of stress-induced increased release of cytokines and counter-regulatory hormones. Coupled with decreased serum anabolic hormone concentrations such as testosterone and growth hormone along with the presence of insulin resistance, anabolism in patients with severe thermal injury is inefficient or impossible during the acute post-burn period. This causes difficulty in restoring lean body mass and regaining lost body weight, as well as poor healing of the burn wound and delayed patient recovery. Oxandrolone, a synthetic derivative of testosterone, has been used in adult patients with severe thermal injury to enhance lean body mass accretion, restore body weight, and accelerate wound healing. In clinical studies, oxandrolone 10 mg orally twice-daily improved wound healing, restored lean body mass, and accelerated body weight gain. During the rehabilitation period, oxandrolone therapy with adequate nutrition and exercise improved lean body mass, increased muscle strength, and restored body weight. However, most data on oxandrolone use in adult patients with severe thermal injury were derived from single-center studies, many of which enrolled a relatively small number of subjects and some of which had a poor design. The authors stated that multi-center, prospective, randomized studies are needed to better define the optimal oxandrolone dosage and to confirm the safety and effectiveness of this drug in adult patients with severe thermal injury.
Woerdeman and de Ronde (2010) stated that a variety of clinical conditions/diseases are complicated by loss of weight and skeletal muscle, which may contribute to morbidity and mortality. Anabolic androgenic steroids have been demonstrated to increase fat-free mass, muscle mass and strength in healthy men and women without major adverse events and therefore could be beneficial in these conditions. The authors provided an overview of clinical trials with anabolic androgenic steroids in the treatment of chronic diseases including HIV-wasting, chronic renal failure, COPD, muscular disease, alcoholic liver disease, burn injuries and post-operative recovery. Relevant studies were identified in PubMed (years 1950 to 2010), bibliographies of the identified studies and the Cochrane database. Although the beneficial effects of anabolic androgenic steroids in chronic disorders are promising, clinically relevant endpoints such as quality of life, improved physical functioning and survival were mainly missing or not significant, except for burn injuries. The authors concluded that more studies are needed to confirm their long-term safety and effectiveness.
Oxandrolone, an anabolic steroid used to treat muscle wasting in HIV patients, is associated with decreased loss of lean body mass, improved wound healing compared with placebo, and decreased hospital stay in severe burn injury (Wolf et al, 2006). However, oxandrolone may prolong the need for mechanical ventilation in trauma patients and can elevate serum transaminase levels.
Sunkara and colleagues (2011) noted that many trials have evaluated the use of androgen supplements and androgen-modulating agents to improve outcome of poor responders undergoingin-vitro fertilization (IVF) treatment. These investigators performed a systematic review and meta-analysis of controlled trials of androgen adjuvants (testosterone, dehydroepiandrostereone) and the androgen-modulating agent (letrozole) in poor responders undergoing IVF treatment. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, ISRCTN Register and ISI proceedings. All randomized and non-randomized controlled trials were included. Study selection, quality appraisal and data extraction were performed independently and in duplicate. The main outcome measure was clinical pregnancy rate. The secondary outcome measures were dose and duration of gonadotrophin use, cycles cancelled before oocyte retrieval, oocytes retrieved and ongoing pregnancy rates. A total of 2,481 cycles in women considered as poor responders undergoing IVF/intra-cytoplasmic sperm injection (ICSI) treatment were included in 9 controlled trials. Meta-analyses of these studies did not show any significant difference in the number of oocytes retrieved and ongoing pregnancy/live-birth rates with androgen supplementation or modulation compared with the control groups. The authors concluded that there is currently insufficient evidence from the few randomized controlled trials to support the use of androgen supplementation or modulation to improve live birth outcome in poor responders undergoing IVF/ICSI treatment.
Makinen and Huhtaniemi (2011) stated that normal testicular function is essential for the maintenance of male physical strength and behavior irrespective of age. A new term of late-onset hypogonadism (LOH) has been coined for the condition of decreased testosterone and hypogonadal symptoms in aging men. The most important testicular hormone, testosterone, is responsible for the gender-specific androgenic-anabolic effects in men. Testicular production of testosterone remains stable until around the age of 40 years after which it declines by 1 to 2 % annually. Despite this age-related decline, serum testosterone levels in most older men remain within the reference range of younger men. The decreasing androgen levels are paralleled by well-defined objective biological and non-specific subjective signs and symptoms of aging. Because these symptoms are similar to those observed in young men with documented hypogonadism, androgen replacement therapy (ART) has been considered a logical way to treat them. These researchers conducted a thorough review of the existing literature to evaluate the current concepts and controversies related to aging men and ART. Although it is intuitively logical that the symptoms of LOH are due to the aging-related deficiency of testosterone, and that they can be reversed by ART, the evidence for this is still variable and often weak. In particular, evidence-based information about long-term benefits and risks of ART in aging men is largely missing. The authors concluded that despite widespread use, evidence-based proof for the objective benefits and side effects of ART of elderly men is still scanty, and such treatments should be considered experimental.
Shelton and Rajfer (2012) noted that androgen deficiency in aging men is common, and the potential sequelae are numerous. In addition to low libido, erectile dysfunction, decreased bone density, depressed mood, and decline in cognition, studies suggest strong correlations between low testosterone, obesity, and the metabolic syndrome. Because causation and its directionality remain uncertain, the functional and cardiovascular risks associated with androgen deficiency have led to intense investigation of testosterone replacement therapy in older men. Although promising, evidence for definitive benefit or detriment is not conclusive, and treatment of LOH is complicated.
The British Committee for Standards in Haematology’s guideline on “The diagnosis and management of myelofibrosis” (Reilly et al, 2012) provided the following recommendations:
Danazol should be considered as a therapeutic option to improve the hemoglobin concentration of patients with myelofibrosis and transfusion-dependent anaemia (Evidence level 2, Grade B).
Recommended starting dose is 200 mg daily, with a gradual dose escalation, depending on tolerability and patient weight (to a maximum of 600 mg daily for patients less than80 kg and 800 mg for patients greater than 80 kg) (Evidence level 2, Grade B).
Patients should be treated for a minimum period of 6 months. Responding patients should be maintained for a further 6 months on 400 mg daily before titrating down the dose to the minimum required in order to maintain a response (Evidence level 2, Grade B).
Toma et al (2012) stated that low testosterone is an independent predictor of reduced exercise capacity and poor clinical outcomes in patients with heart failure (HF). These investigators examined if testosterone therapy improves exercise capacity in patients with stable chronic HF. They searched Medline, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (1980 to 2010). Eligible studies included randomized controlled trials (RCTs) reporting the effects of testosterone on exercise capacity in patients with HF. Reviewers determined the methodological quality of studies and collected descriptive, quality, and outcome data. A total of 4 trials (n = 198; men, 84 %; mean age of 67 years) were identified that reported the 6-minute walk test (2 RCTs), incremental shuttle walk test (2 RCTs), or peak oxygen consumption (2 RCTs) to assess exercise capacity after up to 52 weeks of treatment. Testosterone therapy was associated with a significant improvement in exercise capacity compared with placebo. The mean increase in the 6-minute walk test, incremental shuttle walk test, and peak oxygen consumption between the testosterone and placebo groups was 54.0 m (95 % confidence interval [CI]: 43.0 to 65.0 m), 46.7 m (95 % CI: 12.6 to 80.9 m), and 2.70 ml/kg per min (95 % CI: 2.68 to 2.72 mL/kg per min), respectively. Testosterone therapy was associated with a significant increase in exercise capacity as measured by units of pooled SDs (net effect, 0.52 SD; 95 % CI: 0.10 to 0.94 SD). No significant adverse cardiovascular events were noted. The authors concluded that given the unmet clinical needs, testosterone appears to be a promising therapy to improve functional capacity in patients with HF. They stated that adequately powered RCTs are required to assess the benefits of testosterone in this high-risk population with regard to quality of life, clinical events, and safety.
On March 6, 2014, the Food and Drug Administration (FDA) approved testosterone undecanoate injectable (Aveed, Endo Pharmaceuticals) for the treatment of men with hypogonadism. Aveed is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate. It offers a novel dosing schedule, with a single 3-ml (750 mg) intra-muscular injection given once at initiation of therapy, at 4 weeks, and then every 10 weeks thereafter. The approval follows 3 previous rejections of Aveed by the FDA for safety and risk/benefit concerns and comes just a month after the FDA announced that it is investigating cardiovascular safety data for all testosterone preparations. The FDA is requiring that Aveed's label contain a boxed warning regarding the risks of serious pulmonary oil micro-embolism (POME) and anaphylaxis and is making the product available only through a restricted distribution scheme known as a risk evaluation and mitigation strategy (REMS) to ensure that it is used only in men for whom the benefits out-weigh the risks.
According to the Prescribing Information, Aveed (testosterone undecanoate) injection is indicated for testosterone replacement therapy in adult males (18 years and older) for primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). The most common side effects of Aveed include acne, difficulty sleeping, feeling tired, increased estradiol level, increased prostate specific antigen, increased red blood cell count, irritability, low testosterone level, mood swings, and pain at the injection.
Reis and Abdo (2014) evaluated the use of androgens in the treatment of a lack of libido in women, comparing 2 periods, i.e., before and after the advent of the phosphodiesterase type 5 inhibitors. These researchers also analyzed the risks and benefits of androgen administration. They searched the Latin-American and Caribbean Health Sciences Literature, Cochrane Library, Excerpta Medica, Scientific Electronic Library Online, and Medline (PubMed) databases using the search terms disfunção sexual feminina/female sexual dysfunction, desejo sexual hipoativo/female hypoactive sexual desire disorder, testosterona/testosterone, terapia androgênica em mulheres/androgen therapy in women, and sexualidade/sexuality as well as combinations thereof. They selected articles written in English, Portuguese, or Spanish. After the advent of phosphodiesterase type 5 inhibitors, there was a significant increase in the number of studies aimed at evaluating the use of testosterone in women with hypoactive sexual desire disorder. However, the risks and benefits of testosterone administration have yet to be clarified.
The European Federation of Neurological Societies’ guidelines on the clinical management of amyotrophic lateral sclerosis (Andersen et al, 2012) did not recommend testosterone for the treatment of amyotrophic lateral sclerosis because of insufficient evidence of its effectiveness.
In a parallel-group, placebo-controlled, randomized trial, Bauman et al (2013) examined if oxandrolone increases the percentage of target pressure ulcers (TPUs) that heal compared with placebo and whether healed ulcers remain closed 8 weeks after treatment. A total of 1,900 patients were prescreened, 779 screened, and 212 randomly assigned inpatients with spinal cord injury (SCI) and stage III or IV TPUs. Oxandrolone, 20 mg/d (n = 108), or placebo (n = 104) until the TPU healed or 24 weeks. The primary outcome was healed TPUs. The secondary outcome was the percentage of TPUs that remained healed at 8-week follow-up. A total of 24.1 % (95 % CI: 16.0 % to 32.1 %) of TPUs in oxandrolone recipients and 29.8 % (CI: 21.0 % to 38.6 %) in placebo recipients healed (difference, -5.7 percentage points [CI: -17.5 to 6.8 percentage points]; p = 0.40). At 8-week follow-up, 16.7 % (CI: 9.6 % to 23.7 %) of oxandrolone recipients and 15.4 % (CI: 8.5 % to 22.3 %) of placebo recipients retained a healed TPU (difference, 1.3 percentage points [CI: -8.8 to 11.2 percentage points]; p = 0.70). No serious adverse events were related to oxandrolone. Liver enzyme levels were elevated in 32.4 % (CI: 23.6 % to 41.2 %) of oxandrolone recipients and 2.9 % (CI: 0.0 % to 6.1 %) of placebo recipients (p < 0.001). The authors concluded that oxandrolone showed no benefit over placebo for improving healing or the percentage of TPUs that remained closed after 8 weeks of treatment.
Testosterone replacement for androgen deficiency in men is considered medically necessary only for persons with one or more of the symptoms and signs listed in table 1A (see below). Endocrine Society guidelines recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. The guidelines recommend that clinicians measure serum testosterone level in patients with clinical manifestations shown in Table 1A. They recommend that clinicians also consider measuring serum testosterone level when the less specific symptoms and signs listed in Table 1B occur in conjunction with those listed in Table 1A.
Androgen deficiency is indicated by either two consecutive low total (free plus protein-bound) fasting serum testosterone levels (below the testing laboratory's normal reference range or below 300 ng/dL), or for persons with low normal total fasting serum testosterone levels (above 300 ng/dL but below 400 ng/dL), two consecutive low free or bioavailable fasting serum testosterone levels (below the testing laboratory's normal reference range or less than 225 picomoles per liter (pmol/L) (6 ng/dL) if reference ranges are not available). Two consecutive fasting total serum testosterone levels are required to determine medical necessity of testosterone replacement, or two consecutive free or bioavailable fasting serum testosterone levels if total testosterone is in the low normal range. Two morning samples drawn between 7:00 a.m. and 10:00 a.m. obtained on different days are required. (One fasting total serum testosterone level is sufficient for persons with severe deficiency (less than 150 ng/dL.) Testosterone levels should not be measured during acute or subacute illness.
Note: The Endocrine Society's clinical practice guideline on "Testosterone therapy in adult men with androgen deficiency syndromes" (Bhasin et al, 2010) stated that reference laboratories ranges should be used for reporting testosterone levels. Available at: http://www.endo-society.org/guidelines/final/upload/FINAL-Androgens-in-Men-Standalone.pdf. A laboratory reference range is defined as the set of values 95 percent of the normal population falls within (that is, 95% prediction interval).
Table 1A: Symptoms and Signs Suggestive of Androgen Deficiency in Men
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
Reduced muscle bulk and strength
Hot flushes, sweats
Table 1B: Other Symptoms and Signs of Androgen Deficiency That are Less Specific Than Those in Table 1A
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