The primary aims of testosterone replacement treatment for PADAM is to restore eugonadal levels of testosterone and ameliorate symptoms and signs of low testosterone, while minimizing the potential for side effects of these treatments. Four major types of hormone replacement are available in the United States: oral, injectable, transdermal, and buccal mucosal systems (Table 45–5). The most popular formulations are the transdermal gels, injectables, and transdermal patches, in that order. Oral testosterone replacement is associated with an unacceptably high rate of liver toxicity and should no longer be used. More than 95% of prescribed testosterone medication is administered through a transdermal or injectable route. Risks of specific testosterone formulations are summarized in Table 45–5, while general risks are summarized in the next section.
Table 45–5. Types of Testosterone Replacement Therapy Available in the United States. |Favorite Table|Download (.pdf)
Table 45–5. Types of Testosterone Replacement Therapy Available in the United States.
100–400 mg IM every 2–3 weeks
Deep IM injection. Gives supraphysiologic peaks and low trough hormone levels; mood fluctuations
Scrotal patch: requires daily shaving, variable absorption
Nonscrotal patch: high incidence of skin welts at placement site
2.5 g, 60 patches $320
5 g, 30 patches $340
Testopel (pellets inserted subQ through 5 mm incision in abdomen with local anesthesia)
(Available as 75 mg/pellet; initial placement is 8–10 pellets q 3–4 months)
Local site infections, extravasation, mood swings, elevated hematocrit
AndroGel, Testim (applied to clean, dry skin of arm, back, thigh)
Transference of hormone to partner or children. Musky odor (Testim)
Testim 1%, 30 tubes (5 g/tube) $330
Androgel, 30 tubes (5 g/tube) $325
120 pumps (1.25 g/pump) $325
Cardiovascular disease: A relationship between cardiovascular disease (CAD) and elevated testosterone levels was proposed on the basis of a higher incidence of cardiovascular events among men compared with women; however, several studies have demonstrated that this relationship is not causal. In fact, several studies have demonstrated that higher testosterone levels may decrease the risk of CAD. Furthermore, studies of testosterone replacement for hypogonadal men have not revealed an increased risk of CAD. Despite these reassuring findings, the long-term effects of testosterone replacement on cardiovascular functioning are yet to be determined.
Lipid profiles: Although supraphysiologic doses of testosterone, particularly oral nonaromatizable androgenic steroids, appear to lower HDL levels, numerous studies have demonstrated that physiologic doses of testosterone do not have a significant effect on HDL, total cholesterol, and LDL levels. Testosterone formulation does not appear to alter these relationships.
Polycythemia: Evidence suggests that testosterone levels are associated with erythropoiesis. Pubertal boys experience a 15–20% increase in hemoglobin levels in conjunction with increasing testosterone levels. Hypogonadal men often have mild anemia that is improved with testosterone therapy, and testosterone replacement therapy in men with normal hemoglobin levels can result in supraphysiologic hemoglobin levels. The utilization of testosterone injections is most often associated with this side effect.
Spermatogenesis and infertility: Exogenous testosterone of any type generally leads to spermatogenic arrest through negative feedback inhibition of both pituitary LH and FSH secretion. Azoospermia occurs in >90% of patients within 10 weeks. With cessation, sperm levels rebound usually within 18 months, but some patients may remain azoospermic. Patients receiving hormone replacement therapy should be informed that fertility will be impaired on this treatment.
Hepatotoxicity: Liver toxicity has been reported with oral administration of methyl testosterone and fluoxymesterone; however, it is only rarely observed with parenteral, transdermal, and transbuccal formulations. Testosterone undecanoate is an oral testosterone formulation that does not appear to increase hepatic toxicity, but it is not available in the United States.
Prostate cancer: Since Huggins first described the relationship between suppression of testosterone levels and regression of prostate cancers in the 1940s, treatments designed to reduce testosterone levels have been used to treat advanced prostate cancer. For many years, the question of increasing the risk of prostate cancer with testosterone supplementation has been unanswered. Early case reports suggested that testosterone therapy unmasked occult prostate cancers. Larger, prospective studies, however, have failed to confirm these anecdotal observations. In fact, the preponderance of evidence would suggest that testosterone replacement therapy is not associated with an increased risk of prostate cancer. Despite these reassuring data, proper monitoring with digital rectal examinations and serum prostate specific antigen (PSA) levels are important to diagnose any occult prostate cancers that may occur after initiating testosterone replacement therapy.
Benign prostatic hyperplasia: It is known that prostatic enlargement is an androgen-dependent process. Chemical or surgical castration causes a clear decrease in the volume of prostate tissue. Testosterone replacement therapy has been associated with an increase in prostate volume to a level similar to that of eugonadal men. Despite these findings, no changes in urinary flow rate, lower urinary tract symptoms, or postvoid residuals have been noted with testosterone treatment. Furthermore, a higher rate of urinary retention has not been noted with this treatment. However, it is prudent to monitor voiding symptoms as a standard part of routine monitoring.
Exacerbation of sleep apnea: Testosterone therapy can worsen preexisting sleep apnea. Although not a cause of sleep apnea, testosterone can exacerbate the problem in patients predisposed to the condition (ie, elderly men, obese men, and patients with chronic obstructive pulmonary disease). All potential patients should be questioned for sleep-related breathing disorders before androgen replacement is considered. This side effect appears to be dose related. A centrally mediated mechanism has been postulated, as no upper airway changes have been noted in men taking testosterone therapy who develop worsening sleep apnea.
Fluid and electrolyte disturbances: Water retention is known to occur with androgen therapy. In aging men, it can lead to hypertension, peripheral edema, or exacerbation of congestive heart failure. Moreover, retention of sodium, chloride, potassium, calcium, and inorganic phosphates can occur. Weight and blood pressure monitoring are important for at-risk patients.
Gynecomastia or breast tenderness: Painful breast enlargement due to elevated levels of estrogen (a metabolite of testosterone) frequently develops, and may occasionally persist, in patients on testosterone therapy. Estrogen receptor blockers can be used to treat this side effect.
Miscellaneous: Local skin irritation is commonly reported with the use of the testosterone patch. Acne, headaches, emotional lability, insomnia, and hot flushes have been reported with testosterone therapy. The transfer of testosterone to significant others after gel application is minimized by washing the skin site 10 minutes after application. A component of Testim gel, pentadecalactone, has a musky odor that some men find unappealing. Transbuccal formulations (Striant) may cause gingivitis, stinging of the lips, toothache, and has a bitter taste. Despite these side effects, 60% of men when given the option preferred to continue with a transbuccal treatment approach.
Contraindications and Precautions
Testosterone replacement therapy should not be given to men with prostate cancer, breast cancer, and/or untreated melanoma, as this treatment may increase the growth of these tumors. For men with bladder outlet obstruction related to severe benign prostatic hypertrophy and severe sleep apnea, testosterone replacement therapy should be administered with caution as these symptoms may be exacerbated with this treatment.
At present, there is insufficient evidence to justify the use of testosterone supplementation (not replacement) in men of any age with low-normal but not truly “androgen-deficient” testosterone levels. The IOM consensus statement from 2003 concluded that there was insufficient evidence to justify the use of testosterone therapy for widespread, generalized use for preventing age-related disease or to enhance strength or mood in otherwise healthy older men.
Testosterone replacement for PADAM is normally a lifelong treatment. Monitoring of the patient with PADAM should be performed at baseline, at 1–2 months after initiating treatment, at intervals of 3–6 months during the first year, and annually thereafter. A digital rectal examination, serum PSA and hematocrit/hemoglobin determination, assessment of voiding function, and sleep apnea are mandatory at the baseline evaluation (Table 45–6). Within a month or two after treatment is started, the efficacy of treatment and serum testosterone levels should be assessed. As testosterone levels can fluctuate, particularly after intramuscular (IM) administration, clinical indicators may be a better guide for adjusting the dose of testosterone. During the first year of therapy, patients should be followed every 3–6 months to assess clinical and biochemical response, with serial digital rectal examinations and PSA levels if they are older than 40 years. The history and physical examination at these time points should evaluate the presence of gynecomastia, urinary side effects, and changes in degree of sleep apnea. After the first year, patients who remain stable may subsequently be followed annually. Annual evaluations should include testosterone, hemoglobin, liver function tests, lipid profile, and PSA measurements. Bone density and psychological evaluations should be performed depending on the initial indications for androgen supplementation.
Table 45–6. Patient Monitoring before and during Testosterone Treatment. |Favorite Table|Download (.pdf)
Table 45–6. Patient Monitoring before and during Testosterone Treatment.
Hgb, HCT, and PSA level
Digital rectal exam
Ascertain symptoms of voiding dysfunction and sleep apnea
Consider DEXA scan for bone mineral density
1–2 months of treatment
Assess treatment efficacy: testosterone level and symptom relief. Consider adjusting dose for either variable
3–6 month intervals during first year
Assess symptomatic response to treatment, voiding symptoms and sleep apnea
Perform physical exam with DRE and obtain testosterone, LFTs, lipid profile, PSA, and Hgb levels
Annually after first year
Assess symptomatic response to treatment, voiding symptoms, and sleep apnea
Perform physical exam with DRE and obtain testosterone, LFTs, lipid profile, PSA, and Hgb levels