Treatment of Hypogonadism: Current and Future Therapies

Introduction

The Endocrine Society Clinical Practice Guideline defines male hypogonadism as “a clinical syndrome that results from failure of the testes to produce physiological levels of testosterone due to disruption of one or more levels of the hypothalamic-pituitary-testicular axis”¹. Given that testosterone concentrations decline with age^2,3 and the increasing awareness of the signs and symptoms of hypogonadism, prescriptions for testosterone therapy have increased significantly in the last several years⁴.

In this review, we will briefly summarize the risks and benefits of testosterone replacement therapy. In addition, we will describe the existing options for testosterone therapy, including several newer formulations of testosterone under development. Lastly, we will discuss the data available on alternative therapies occasionally used for the treatment of male hypogonadism.

Risks and benefits of testosterone therapy

For men with symptomatic hypogonadism, there are a number of potential clinical benefits with testosterone replacement therapy, including improvements in libido, erectile function, muscle strength and body composition (including decreased fat mass, increased lean mass, and improved bone mineral density), mood, and cognition¹. The potential clinical benefits of testosterone therapy must be carefully weighed against potential risks. Potential adverse effects of testosterone replacement include erythrocytosis, increases in prostate-specific antigen (PSA) and worsening of prostate disorders (including benign prostatic hyperplasia [BPH]), dermatologic effects, including acne and skin irritation, and worsening of existing obstructive sleep apnea¹. In addition, exogenous testosterone administration leads to the suppression of luteinizing hormone (LH), decreased intra-testicular testosterone concentrations, and reduced spermatogenesis⁵. Thus, testosterone replacement therapy is not appropriate for hypogonadal men desiring fertility.

Notably, the US Food and Drug Administration (FDA) has recently added important warnings to testosterone products. The first is a warning added to all testosterone preparations highlighting a potential increased risk of cardiovascular disease (including myocardial infarction and stroke) in patients taking testosterone, although additional studies are needed to guide clinicians in better understanding these potential risks, as the magnitude of these risks are unknown. However, until additional information becomes available, the current recommendation is that clinicians in practice should discuss these potential risks with all patients when starting or continuing testosterone replacement therapy^6,7.

In October 2016, the FDA added additional warnings to the labeling of testosterone products to alert prescribers to the potential for abuse of testosterone and other anabolic androgenic steroids. The FDA statement outlined potential adverse effects of abuse of anabolic androgenic steroids, including myocardial infarction, heart failure, stroke, liver injury, male infertility, and mood changes including depression, aggression, and hostility. They also raised concerns that abuse of high doses of testosterone was reported to be associated with potential withdrawal symptoms including depression, irritability, fatigue, insomnia, and decreased libido. The potential for abuse of testosterone and other androgens should be considered in both adult and adolescent populations.

Testosterone replacement therapy

There are a variety of testosterone preparations currently on the market in the US (Table 1) and additional formulations available abroad and in development (see below). In choosing the testosterone formulation for an individual patient, clinicians must consider the individual values and preferences of the patient as well as other factors including cost, convenience, and availability. Owing to their ease of use and relatively low cost, injectable and transdermal testosterone preparations are currently the most widely used in the US.

Injectable formulations

Two intermediate-acting injectable testosterone formulations are currently available in the US market: testosterone enanthate and testosterone cypionate^8,9. These are usually dosed every 1–2 weeks. In contrast, a newer long-acting testosterone ester, testosterone undecanoate (“Nebido” in Europe and “Aveed” in the US), can be dosed every 6–12 weeks. All of these formulations are administered as intramuscular injections. The majority of patients are able to administer injections independently at home with the help of a partner. Intramuscular testosterone formulations are highly effective in improving symptoms of hypogonadism. Additional benefits of long-acting injectable preparations include low cost of therapy (as compared to other preparations) and they more reliably achieve therapeutic serum concentrations of testosterone (as compared to transdermal preparations), thus reducing the need for routine monitoring of serum testosterone concentrations during therapy. With testosterone enanthate and testosterone cypionate, testosterone concentration and clinical effects peak 1–2 days after the injection and wane over the subsequent 2 weeks¹⁰. For some patients, the fluctuations in serum testosterone concentrations can lead to adverse impacts on mood, energy, and sexual function, which can be bothersome or disruptive. In these cases, alternate dosing using half the usual dose administered weekly (instead of full dose every 2 weeks) or use of an alternate testosterone preparation may be preferred.

In contrast, testosterone undecanoate achieves relatively stable testosterone concentrations. Unfortunately, the relative large volume of testosterone undecanoate injections can be associated with the risk of pulmonary oil microembolism and anaphylaxis, albeit rarely. As a result, testosterone undecanoate is available only through a Risk Evaluation and Mitigation Strategy (REMS) program and must be administered by a trained, registered care provider in an office or hospital setting – it cannot be self-administered at home by the patient.

Transdermal formulations

Transdermal testosterone gels are widely available and popular among both patients and clinicians. There are multiple transdermal gel formulations currently available in the US including AndroGel, Testim, Fortesta, and Axiron (Table 1). They are supplied in sachets, tubes, or metered-dose pumps and are applied by hand to the skin of the arms, torso, or thighs. Newer concentrated testosterone preparations offer the advantage of applying a smaller volume of gel at each dose. Benefits of transdermal gels include high efficacy for the management of symptoms of hypogonadism, ease of home administration, and minimizing fluctuations in testosterone concentration from day to day. As a result, these formulations may be preferable for patients who struggle with peak and trough effects associated with the use of intermediate-term intramuscular injections. Risks of transdermal gels include mild skin irritation and potential for skin-to-skin transfer to others. All patients using gels should be instructed on careful hand washing after gel application and avoiding skin-to-skin contact with others (particularly female partners or children) on the gel-treated areas¹¹. In contrast to injectable testosterone preparations, absorption of transdermal testosterone gel can be quite variable. If a patient using a transdermal formulation of testosterone has no improvement in symptoms, it is reasonable to measure the serum testosterone concentration and adjust the dose as needed to achieve adequate circulating testosterone concentrations.

When the risk of skin-to-skin transfer of testosterone is of concern, the use of a transdermal patch may be appropriate. There is currently one transdermal testosterone patch preparation (Androderm) available in the US. Use of the patch has been limited by relatively high rates of skin irritation, with up to one-third of men who use the patch experiencing significant skin irritation. Similar to other transdermal testosterone preparations, monitoring of circulating serum testosterone concentration and appropriate dose adjustment are reasonable with transdermal patches, since testosterone absorption can be variable.

Other testosterone formulations

A subcutaneous testosterone pellet (Testopel) is available for the treatment of hypogonadism¹². Testopel is placed in the subcutaneous fat of the buttock, lower abdomen, or thigh every 3–6 months. Pellets are placed using sterile technique in an office or hospital setting and cannot be injected by the patient at home. Risks with subcutaneous testosterone pellets include infection, fibrosis, and pellet extrusion. Benefits include eliminating risk of skin-to-skin transfer, infrequent dosing, and relatively stable serum testosterone concentrations.

Nasal and buccal testosterone preparations are also available for the treatment of hypogonadism and may be useful in limited clinical settings where other testosterone preparations are not effective or appropriate. Use of nasal and buccal preparations is limited because of the potential for nasal/sinus and gingival irritation, limited published data on use of the nasal preparation, and animal studies suggesting possible increases in central nervous system testosterone levels above that expected with other formulations^13,14.

Oral testosterone undecanoate (Andriol) is available in many countries outside the US; however, serum testosterone concentrations achieved with this formulation can be low and administration must occur with a fat-containing meal. New self-emulsifying drug formulations of testosterone undecanoate are under development and may reach the market in the next 1–2 years¹⁵. However, high post-dose serum peaks and a relatively large degree of inter-individual variability in achieved drug concentrations are issues for these formulations. In response, the companies developing these newer formulations of testosterone undecanoate are developing dosing algorithms to ensure patients receive the appropriate dose to achieve therapeutic concentrations of testosterone. Other oral preparations, especially those alkylated at the 17-carbon position, such as methyltestosterone, are associated with hepatotoxicity and are not recommended for use.

Some newer testosterone formulations have recently come to the global market. These include both transdermal and injectable formulations. One of the transdermal formulations includes a hydro-alcoholic 2.5% testosterone gel (Testocur) that is approved for use in Germany. This drug was studied after application both transdermally and transscrotally, and compared with Androderm 2.5% patches applied transdermally in an open-label, parallel group, randomized controlled fashion in previously treated hypogonadal men for 24 weeks¹⁶. While the scrotal gel and patches achieved equivalent serum androgen (testosterone and dihydrotestosterone [DHT]) concentrations, the transdermal gel actually achieved higher concentrations. The transdermal gel was also better tolerated than the patches whilst proving equivalent in safety outcomes such as hematocrit, serum PSA, and prostate volumes. Another formulation that is currently approved for use in Australia is an alcohol-free testosterone cream (AndroForte 5, 50 mg/mL or 5%, Lawley Pharmaceuticals)¹⁷. This was studied in an open-label, randomized crossover study, comparing it with 1% testosterone gel in hypogonadal men with a treatment period of 30 days. Pharmacokinetic end points of both were comparable and there were no differences in serum hormone concentrations.

Alternative therapies for treatment of male hypogonadism

Given the concerns surrounding the safety and benefits of testosterone therapy in men, other agents have also been used for the treatment of male hypogonadism. In particular, in younger men who are interested in fertility, testosterone replacement therapy is not recommended.

Challenges for alternative testosterone therapies for hypogonadism

While alternatives to testosterone therapy have appeal, particularly for men wishing to avoid suppression of spermatogenesis by testosterone, there is greater uncertainly regarding their risks and benefits, as they have been less well studied. In addition, FDA approval for these therapies has been difficult to obtain, as the FDA has indicated that raising testosterone is not acceptable as a primary endpoint for non-testosterone therapies. Instead, the FDA requires data on improvement of the signs and symptoms of hypogonadism⁴⁶. Such studies will likely require larger samples and better outcome measures, work that is somewhat hampered by the paucity of validated patient-reported outcome measures in the field.

Conclusions

Treatment of male hypogonadism remains an area that requires in-depth discussion of the risks and benefits of therapy with the patient before proceeding. With the numerous testosterone formulations that exist and are being developed, patients have a variety of options to choose from, depending on their preferences. Additionally, there are a number of non-testosterone alternative therapies too that can be considered, particularly in men desiring fertility or wishing to avoid specific side effects of testosterone therapy. Still newer therapies, currently in the stages of early clinical trials (selective androgen receptor modulators), may indeed be the future of androgen replacement therapy and hint at the promise of more benefits than harm, which would simplify these patient discussions and decisions.

Abbreviations

BPH, benign prostatic hyperplasia; DHT, dihydrotestosterone; E2, estradiol; FDA, US Food and Drug Administration; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; LH, luteinizing hormone; LUTS, lower urinary tract symptoms; PSA, prostate-specific antigen; REMS, Risk Evaluation and Mitigation Strategy; rhFSH, recombinant human follicle-stimulating hormone; SARMs, selective androgen receptor modulators.