madman
Super Moderator
Long vs short-acting testosterone treatments: A look at the risks (2022)
Aaron A. Gurayah, Alexandra Dullea, Alexander Weber, John M. Masterson, Kajal Khodamoradi, Arslan I. Mohamed, Ranjith Ramasamy
Abstract
Prescriptions for testosterone therapy (TT) to treat testosterone deficiency have increased in recent years. The purpose of this review was to evaluate the risks of several treatment modalities to better counsel patients. Both short-acting and long-acting TT has been shown to restore normal serum testosterone levels and improve symptoms of testosterone deficiency. Short-acting pharmacology mimics normal physiology more closely than long-acting TT but requires multiple doses per day, while long-acting TT has a higher rate of patient adherence but is more likely to create supraphysiologic serum testosterone and pathologic sequelae.
Introduction
Testosterone therapy (TT) can be used for physiological reasons or be abused. In the former case, testosterone (T) replacement is prescribed for pathologic androgen deficiency, including disorders affecting the hypothalamic-pituitary-testicular (HPT) axis where luteinizing hormone or testosterone secretion is reduced. The objective is to restore the physiologic pattern of circulating T levels1,2. In the latter case, the supraphysiologic dosing of testosterone exploits the androgenic effects on muscle, bone, and other tissues in men, especially in eugonadal patients1
However, the misuse of androgens without a valid clinical indication has become prevalent over the previous decades due to the combination of marketing drive, single-issue clinics, and poor regulatory standards in responding to off-label usage1-3. For instance, Canada had a four-fold increase in per capita testosterone prescribing due to internet pharmacies physically based in the country which are not subjected to national prohibitions of import/export controls of androgens4. Androgen misuse has taken the form of prescriptions for male infertility, anti-aging, and body sculpting, which has led to a 100-fold increase in expenditure on prescription T products over the three decades leading to 20102. However, coinciding with an FDA communication about potential cardiovascular events following testosterone therapy, there was a decrease of 3.2% use of testosterone in men in 2013 to 1.67% in 2016, with new users decreasing from 1.26% to 0.48%5. Nonetheless, we are now seeing the rise of online direct-to-consumer clinics that provide questionnaires to patients who self-report symptoms of erectile dysfunction or premature ejaculation. These questionnaires are reviewed by physicians but do not require a physical exam, a laboratory workup, or counseling about the risks. This may be a future route for testosterone delivery and may potentially contribute to androgen misuse6
Due to challenges in the diagnosis and treatment of male testosterone deficiency, different societies have established guidelines for diagnosing T deficiency7. The American Urologic Association (AUA) states that a patient must have two total morning T measurements on separate occasions that are below 300 ng/dL and present with symptoms of testosterone deficiency (e.g., erectile dysfunction, low sex drive, lack of energy, and decreased strength)7. Meanwhile, the European Association of Urology (EAU), British Society for Sexual Medicine (BSSM), Endocrine Society (ES), International Society for Sexual Medicine (ISSM), and International Society for the Study of the Aging Male (ISSAM) have different cutoffs; the ISSAM and EAU use an early morning measurement of <350 ng/dL to diagnose a patient with T deficiency 8-10, the ES uses a measurement of <264 ng/dL11, and both the ISSM and BSSM use values <8 nmol/L (230 ng/dL) for definite treatment and values between 8 nmol/L and 12 nmol/L (346 ng/dL) for potential treatment12. Additionally, these societies suggest that free testosterone can be used if there is a low-normal total T measurement and/or sex hormone binding globulin (SHBG) levels are abnormal13.
The purpose of TT is to restore and maintain hormone levels at the physiologic serum concentration in order to alleviate symptoms of testosterone deficiency without causing significant side effects or safety concerns7. The benefits of TT have been well demonstrated by the Testosterone Trials by Snyder et al., which highlight its benefits in sexual desire and erectile function, distance walked, improved mood and depressive symptoms, and increased volumetric bone mineral density14. Available in multiple delivery methods, several different types of T therapies exist including intranasal gels, oral pills, intramuscular (IM) injections, transdermal gels and patches, and subcutaneous (SQ) pellets7,15. These treatments can be classified into short-acting and long-acting modalities. Short-acting therapies consist of intranasal gels, oral testosterone capsules, and transdermal gels and patches, while long-acting therapies include IM injections and SQ pellets. These modalities have distinct influences on male reproductive function and patient medication adherence.
While both short-acting and long-acting T has been shown to restore normal T levels, there are significant differences between the two modalities. Patients have the option of using transdermal gels or patches that can be applied directly to the axilla or thigh, but these delivery methods increase the risk of transference7. Overall, short-acting T has less impact on the male hypothalamus-pituitary-gonadal (HPG) and has the potential to better preserve fertility7,15. Meanwhile, long-acting injectables, specifically testosterone undecanoate, require a decreased frequency of administration, with some manufacturers recommending dosing only at weeks 0 and 4 and then every 10 weeks thereafter16. In addition, there are potential risks associated with the use of any exogenous T with patients who have a history of prostate cancer or who have a susceptibility to CVD and stroke17,18. Currently, the AUA states that there is insufficient evidence linking testosterone therapy to the development of prostate cancer or showing an increased risk of recurrence of prostate cancer in treated men7. Thus, the benefits and risks of these modalities influence the shared decision-making between physicians and patients when selecting an appropriate TT.
*Given the recent surge of TT usage due to increased consumer advertising, relaxation of the indications for T prescriptions, and the establishment of clinical care centers devoted to men's health, an evidence-based method for selecting the appropriate type of TT is critical 7,19. The purpose of this review was to document the risks of short-acting and long-acting TT [Table 1].
The findings shown here will better enable clinicians to make appropriate decisions for men with testosterone deficiency interested in receiving TT.
Short-acting TT
Short-acting T therapy consists of administering one or more doses a day of T with a shorter half-life throughout the day. This allows patients to maintain homeostasis that closely reflects the body’s normal levels, with minimal impairment of spermatogenesis20
The currently available modalities for short-acting exogenous TT are intranasal testosterone: Natesto®, 2% transdermal testosterone gels: Fortesta®, AndroGel®, and Testim®, transdermal testosterone patches: Androderm® and oral testosterone capsules: Jatenzo® and Tlando® 21,22
Short-acting TT Risks
Generally, the use of short-acting TT causes several side effects including polycythemia, gynecomastia, suppression of spermatogenesis, and impaired fertility, though these are also side effects of long-acting TT21,22. However, it is difficult to interpret the impact of short-acting TT on sperm parameters, as the misuse of TT for male infertility, anti-aging, and body sculpting purposes confounds study results. Most of the other side effects noted in clinical trials of short-acting TT have been minor and directly related to the area of treatment application (i.e., site irritation, and nasal discomfort). Importantly, TT is absolutely contraindicated in older men with a history of heart failure, patients with a hematocrit > 50%, men with metastatic prostate cancer, and men desiring fatherhood23. Relative contraindications include severe lower urinary tract symptoms and severe untreated obstructive sleep apnea23. Formulation-specific risks are outlined below.
*Intranasal Testosterone
*Transdermal Testosterone Gels
*Transdermal Testosterone Patches
*Oral Testosterone Pills
Long-acting TT
The currently available modalities for long-acting exogenous TT are intramuscular (IM) or subcutaneous (SQ) injections of testosterone cypionate (TC) – marketed under the brand name Depo-Tesosterone®, testosterone enanthate (TE) – marketed under the brand name Delatestryl® or Xyosted®, testosterone undecanoate (TU) – marketed under the brand names Aveed® (750 mg/3 mL vial) and Nebido® (1000 mg/4 mL vial), and subcutaneous T pellets, marketed under the brand name Testopel®. The major difference between these medications and other T formulations is that patients are typically injected with TC or TE every one to two weeks, and TU approximately four times per year, while Testopel® pellets are typically replaced every three to four months7.
Injectable T, particularly TC and TE, is available in both IM and SQ forms. However, based on previous studies, IM formulations tend to be favored as IM T achieves higher peak T, faster time-to-peak levels, and a shorter half-life (i.e., 173 hours) when compared to SQ T37 In general, smaller IM doses at more frequent intervals (e.g., 100mg weekly) are preferred over higher-dose, less frequent administrations (e.g., 200mg biweekly) subcutaneously38. The best time to obtain monitoring blood tests for IM testosterone has not been defined. Given the half-life of approximately seven days, it is reasonable to obtain testosterone levels four weeks after starting therapy. Other reports have found value in assessing peak level (18-36 hours after injection) as the adverse events may be related to the peak level.7
Patients rarely reported pain while using the SQ TE auto-injector. In one study, 9 out of 1519 injections were reported as painful, rated at a scale of 1 or 2 out of 1039, while another demonstrated 1 patient with mild pain out of a total of 954 injections40. However, formulations such as TC can be taught to patients to be self-administered subcutaneously, which is thought to result in a lower risk of erythrocytosis and less variability in T levels35,41,42
Long-acting TT Risks
Commonly reported side effects of long-acting TT—of which all patients should be aware—are similar to those of short-acting TT and include nausea, vomiting, headache, skin color changes, changes in libido, oily skin, hair loss, and acne43,44. Many of these effects are considered mild and typically do not necessitate discontinuation of therapy. The potential adverse events or risks associated with long-acting TT that may require interruption of treatment or other intervention are also like those associated with short-acting TT.
Polycythemia, defined as a hematocrit of >52%, is a known side effect of T supplementation for which patients should be monitored and, if severe, may require therapeutic phlebotomy if T dose reduction is ineffective7,45,46. The increased risk of CVD and prostate cancer related to TT is somewhat controversial. Newer research shows that physiologic T in testosterone-deficient men may actually provide CVD benefits and may provide important symptomatic relief in patients with treated prostate cancer or low-risk prostate cancer on active surveillance without increasing cancer risk47,48. The official stance of the AUA is that there is insufficient evidence linking T supplementation to an increased risk of cardiovascular mortality or to an increased risk of prostate cancer7. All patients should be counseled regarding these points prior to initiation of T supplementation of any kind.
Patients should be counseled that normalization of semen parameters can take six to 12 months following discontinuation of T therapy49. In the case of long-acting T formulations, this could mean 9 to 15 months following the last dose. In a 2009 study by Gu et al. of approximately 1000 fertile Chinese men, over 90% achieved azoospermia within 6 months of initiation of TU50. In long-term follow-up, spermatogenesis returned to the normal fertile reference range in all but two participants at an average of 16 months50. Similarly, in a multicenter study of 271 men receiving 200 mg TE weekly by IM injection to assess the contraceptive efficacy of hormonally-induced azoospermia, 65% of men became azoospermic at 6 months 51. The mean time to become azoospermic was 120 days (SD 40 days), while the estimated median time from azoospermia to recovery (sperm concentration > 20 million/ml) was 3.7 months (range: 3.6-3.9) after stopping the T injections51
*Testosterone Cypionate and Testosterone Enanthate
*Testosterone Undecanoate
*Testosterone Pellets
Limitations & Future Directions
Limitations of this review include the heterogeneity of study designs and subject populations across studies, which made it challenging to compare T formulations directly and so indirect comparisons were necessary. Additionally, there is still a research need for more long-term data examining the risks and benefits of TT and its alternative treatment options in males61. Controversy still exists surrounding the use of testosterone in functional testosterone deficiency in middle-aged men due to the thought that optimization of PDE-5 inhibitors and lifestyle modifications may improve sexual function and reduce the need for TT62. For example, comorbidities such as untreated obstructive sleep apnea may negatively influence testosterone levels and be a risk factor for secondary polycythemia in this patient population 63. Thus, physicians must weigh these benefits against the risks of worsening symptoms of hyperviscosity and erythrocytosis that accompany the use of TT29,64
Conclusion
There is a growing need for exogenous T treatment, and prescriptions have increased1. There are, however, a variety of T formulations and the differences between these formulations must be understood before prescribing medication. Short-acting T has less impact on fertility but requires more frequent dosing. Long-acting T results in improved patient compliance, but sperm parameters are often impaired in patients while taking the medication. Additionally, there are a variety of treatment modalities to treat testosterone deficiency without exogenous T. Continued research is necessary to fully understand the long-term impacts of these medications.
Aaron A. Gurayah, Alexandra Dullea, Alexander Weber, John M. Masterson, Kajal Khodamoradi, Arslan I. Mohamed, Ranjith Ramasamy
Abstract
Prescriptions for testosterone therapy (TT) to treat testosterone deficiency have increased in recent years. The purpose of this review was to evaluate the risks of several treatment modalities to better counsel patients. Both short-acting and long-acting TT has been shown to restore normal serum testosterone levels and improve symptoms of testosterone deficiency. Short-acting pharmacology mimics normal physiology more closely than long-acting TT but requires multiple doses per day, while long-acting TT has a higher rate of patient adherence but is more likely to create supraphysiologic serum testosterone and pathologic sequelae.
Introduction
Testosterone therapy (TT) can be used for physiological reasons or be abused. In the former case, testosterone (T) replacement is prescribed for pathologic androgen deficiency, including disorders affecting the hypothalamic-pituitary-testicular (HPT) axis where luteinizing hormone or testosterone secretion is reduced. The objective is to restore the physiologic pattern of circulating T levels1,2. In the latter case, the supraphysiologic dosing of testosterone exploits the androgenic effects on muscle, bone, and other tissues in men, especially in eugonadal patients1
However, the misuse of androgens without a valid clinical indication has become prevalent over the previous decades due to the combination of marketing drive, single-issue clinics, and poor regulatory standards in responding to off-label usage1-3. For instance, Canada had a four-fold increase in per capita testosterone prescribing due to internet pharmacies physically based in the country which are not subjected to national prohibitions of import/export controls of androgens4. Androgen misuse has taken the form of prescriptions for male infertility, anti-aging, and body sculpting, which has led to a 100-fold increase in expenditure on prescription T products over the three decades leading to 20102. However, coinciding with an FDA communication about potential cardiovascular events following testosterone therapy, there was a decrease of 3.2% use of testosterone in men in 2013 to 1.67% in 2016, with new users decreasing from 1.26% to 0.48%5. Nonetheless, we are now seeing the rise of online direct-to-consumer clinics that provide questionnaires to patients who self-report symptoms of erectile dysfunction or premature ejaculation. These questionnaires are reviewed by physicians but do not require a physical exam, a laboratory workup, or counseling about the risks. This may be a future route for testosterone delivery and may potentially contribute to androgen misuse6
Due to challenges in the diagnosis and treatment of male testosterone deficiency, different societies have established guidelines for diagnosing T deficiency7. The American Urologic Association (AUA) states that a patient must have two total morning T measurements on separate occasions that are below 300 ng/dL and present with symptoms of testosterone deficiency (e.g., erectile dysfunction, low sex drive, lack of energy, and decreased strength)7. Meanwhile, the European Association of Urology (EAU), British Society for Sexual Medicine (BSSM), Endocrine Society (ES), International Society for Sexual Medicine (ISSM), and International Society for the Study of the Aging Male (ISSAM) have different cutoffs; the ISSAM and EAU use an early morning measurement of <350 ng/dL to diagnose a patient with T deficiency 8-10, the ES uses a measurement of <264 ng/dL11, and both the ISSM and BSSM use values <8 nmol/L (230 ng/dL) for definite treatment and values between 8 nmol/L and 12 nmol/L (346 ng/dL) for potential treatment12. Additionally, these societies suggest that free testosterone can be used if there is a low-normal total T measurement and/or sex hormone binding globulin (SHBG) levels are abnormal13.
The purpose of TT is to restore and maintain hormone levels at the physiologic serum concentration in order to alleviate symptoms of testosterone deficiency without causing significant side effects or safety concerns7. The benefits of TT have been well demonstrated by the Testosterone Trials by Snyder et al., which highlight its benefits in sexual desire and erectile function, distance walked, improved mood and depressive symptoms, and increased volumetric bone mineral density14. Available in multiple delivery methods, several different types of T therapies exist including intranasal gels, oral pills, intramuscular (IM) injections, transdermal gels and patches, and subcutaneous (SQ) pellets7,15. These treatments can be classified into short-acting and long-acting modalities. Short-acting therapies consist of intranasal gels, oral testosterone capsules, and transdermal gels and patches, while long-acting therapies include IM injections and SQ pellets. These modalities have distinct influences on male reproductive function and patient medication adherence.
While both short-acting and long-acting T has been shown to restore normal T levels, there are significant differences between the two modalities. Patients have the option of using transdermal gels or patches that can be applied directly to the axilla or thigh, but these delivery methods increase the risk of transference7. Overall, short-acting T has less impact on the male hypothalamus-pituitary-gonadal (HPG) and has the potential to better preserve fertility7,15. Meanwhile, long-acting injectables, specifically testosterone undecanoate, require a decreased frequency of administration, with some manufacturers recommending dosing only at weeks 0 and 4 and then every 10 weeks thereafter16. In addition, there are potential risks associated with the use of any exogenous T with patients who have a history of prostate cancer or who have a susceptibility to CVD and stroke17,18. Currently, the AUA states that there is insufficient evidence linking testosterone therapy to the development of prostate cancer or showing an increased risk of recurrence of prostate cancer in treated men7. Thus, the benefits and risks of these modalities influence the shared decision-making between physicians and patients when selecting an appropriate TT.
*Given the recent surge of TT usage due to increased consumer advertising, relaxation of the indications for T prescriptions, and the establishment of clinical care centers devoted to men's health, an evidence-based method for selecting the appropriate type of TT is critical 7,19. The purpose of this review was to document the risks of short-acting and long-acting TT [Table 1].
The findings shown here will better enable clinicians to make appropriate decisions for men with testosterone deficiency interested in receiving TT.
Short-acting TT
Short-acting T therapy consists of administering one or more doses a day of T with a shorter half-life throughout the day. This allows patients to maintain homeostasis that closely reflects the body’s normal levels, with minimal impairment of spermatogenesis20
The currently available modalities for short-acting exogenous TT are intranasal testosterone: Natesto®, 2% transdermal testosterone gels: Fortesta®, AndroGel®, and Testim®, transdermal testosterone patches: Androderm® and oral testosterone capsules: Jatenzo® and Tlando® 21,22
Short-acting TT Risks
Generally, the use of short-acting TT causes several side effects including polycythemia, gynecomastia, suppression of spermatogenesis, and impaired fertility, though these are also side effects of long-acting TT21,22. However, it is difficult to interpret the impact of short-acting TT on sperm parameters, as the misuse of TT for male infertility, anti-aging, and body sculpting purposes confounds study results. Most of the other side effects noted in clinical trials of short-acting TT have been minor and directly related to the area of treatment application (i.e., site irritation, and nasal discomfort). Importantly, TT is absolutely contraindicated in older men with a history of heart failure, patients with a hematocrit > 50%, men with metastatic prostate cancer, and men desiring fatherhood23. Relative contraindications include severe lower urinary tract symptoms and severe untreated obstructive sleep apnea23. Formulation-specific risks are outlined below.
*Intranasal Testosterone
*Transdermal Testosterone Gels
*Transdermal Testosterone Patches
*Oral Testosterone Pills
Long-acting TT
The currently available modalities for long-acting exogenous TT are intramuscular (IM) or subcutaneous (SQ) injections of testosterone cypionate (TC) – marketed under the brand name Depo-Tesosterone®, testosterone enanthate (TE) – marketed under the brand name Delatestryl® or Xyosted®, testosterone undecanoate (TU) – marketed under the brand names Aveed® (750 mg/3 mL vial) and Nebido® (1000 mg/4 mL vial), and subcutaneous T pellets, marketed under the brand name Testopel®. The major difference between these medications and other T formulations is that patients are typically injected with TC or TE every one to two weeks, and TU approximately four times per year, while Testopel® pellets are typically replaced every three to four months7.
Injectable T, particularly TC and TE, is available in both IM and SQ forms. However, based on previous studies, IM formulations tend to be favored as IM T achieves higher peak T, faster time-to-peak levels, and a shorter half-life (i.e., 173 hours) when compared to SQ T37 In general, smaller IM doses at more frequent intervals (e.g., 100mg weekly) are preferred over higher-dose, less frequent administrations (e.g., 200mg biweekly) subcutaneously38. The best time to obtain monitoring blood tests for IM testosterone has not been defined. Given the half-life of approximately seven days, it is reasonable to obtain testosterone levels four weeks after starting therapy. Other reports have found value in assessing peak level (18-36 hours after injection) as the adverse events may be related to the peak level.7
Patients rarely reported pain while using the SQ TE auto-injector. In one study, 9 out of 1519 injections were reported as painful, rated at a scale of 1 or 2 out of 1039, while another demonstrated 1 patient with mild pain out of a total of 954 injections40. However, formulations such as TC can be taught to patients to be self-administered subcutaneously, which is thought to result in a lower risk of erythrocytosis and less variability in T levels35,41,42
Long-acting TT Risks
Commonly reported side effects of long-acting TT—of which all patients should be aware—are similar to those of short-acting TT and include nausea, vomiting, headache, skin color changes, changes in libido, oily skin, hair loss, and acne43,44. Many of these effects are considered mild and typically do not necessitate discontinuation of therapy. The potential adverse events or risks associated with long-acting TT that may require interruption of treatment or other intervention are also like those associated with short-acting TT.
Polycythemia, defined as a hematocrit of >52%, is a known side effect of T supplementation for which patients should be monitored and, if severe, may require therapeutic phlebotomy if T dose reduction is ineffective7,45,46. The increased risk of CVD and prostate cancer related to TT is somewhat controversial. Newer research shows that physiologic T in testosterone-deficient men may actually provide CVD benefits and may provide important symptomatic relief in patients with treated prostate cancer or low-risk prostate cancer on active surveillance without increasing cancer risk47,48. The official stance of the AUA is that there is insufficient evidence linking T supplementation to an increased risk of cardiovascular mortality or to an increased risk of prostate cancer7. All patients should be counseled regarding these points prior to initiation of T supplementation of any kind.
Patients should be counseled that normalization of semen parameters can take six to 12 months following discontinuation of T therapy49. In the case of long-acting T formulations, this could mean 9 to 15 months following the last dose. In a 2009 study by Gu et al. of approximately 1000 fertile Chinese men, over 90% achieved azoospermia within 6 months of initiation of TU50. In long-term follow-up, spermatogenesis returned to the normal fertile reference range in all but two participants at an average of 16 months50. Similarly, in a multicenter study of 271 men receiving 200 mg TE weekly by IM injection to assess the contraceptive efficacy of hormonally-induced azoospermia, 65% of men became azoospermic at 6 months 51. The mean time to become azoospermic was 120 days (SD 40 days), while the estimated median time from azoospermia to recovery (sperm concentration > 20 million/ml) was 3.7 months (range: 3.6-3.9) after stopping the T injections51
*Testosterone Cypionate and Testosterone Enanthate
*Testosterone Undecanoate
*Testosterone Pellets
Limitations & Future Directions
Limitations of this review include the heterogeneity of study designs and subject populations across studies, which made it challenging to compare T formulations directly and so indirect comparisons were necessary. Additionally, there is still a research need for more long-term data examining the risks and benefits of TT and its alternative treatment options in males61. Controversy still exists surrounding the use of testosterone in functional testosterone deficiency in middle-aged men due to the thought that optimization of PDE-5 inhibitors and lifestyle modifications may improve sexual function and reduce the need for TT62. For example, comorbidities such as untreated obstructive sleep apnea may negatively influence testosterone levels and be a risk factor for secondary polycythemia in this patient population 63. Thus, physicians must weigh these benefits against the risks of worsening symptoms of hyperviscosity and erythrocytosis that accompany the use of TT29,64
Conclusion
There is a growing need for exogenous T treatment, and prescriptions have increased1. There are, however, a variety of T formulations and the differences between these formulations must be understood before prescribing medication. Short-acting T has less impact on fertility but requires more frequent dosing. Long-acting T results in improved patient compliance, but sperm parameters are often impaired in patients while taking the medication. Additionally, there are a variety of treatment modalities to treat testosterone deficiency without exogenous T. Continued research is necessary to fully understand the long-term impacts of these medications.
