The efficacy, safety, and outcomes of testosterone use among transgender men patients

[madman]

The efficacy, safety, and outcomes of testosterone use among transgendermen patients: A review of the literature (2022)
Rimel N. Mwamba | Adaora Ekwonu | Paulo V. B. Guimaraes | Omer A. Raheem


Abstract

Introduction: Gender dysphoria is the discrepancy between biological sex and gender identity. This can be debilitating for transgender populations, including transgender men (TM), individuals who were assigned female at birth but who identify as men, that can benefit from hormonal therapy with testosterone products to address gender dysphoria.

Methods: We aim to summarize the efficacy, safety profile, and outcomes of the different testosterone replacement treatments (TRT) in the TM population. A search of the published literature regarding the various FDA‐approved TRT was performed in PubMed, Web of Science, and Cochrane Library from 2007 to date.

Results: We complied two groups of TRT based on the route of administration including the conventional testosterone therapies (intramuscular and subcutaneous injectables, and transdermal gels) and newer testosterone therapies (oral, buccal, and nasal gels). For the conventional testosterone therapies, we identified nine studies that discussed conventional TRT in the TM population including one randomized trial, four prospective studies, one retrospective study, and three reviews. For newer testosterone therapies, we identified three studies discussing newer TRT in the TM population including one prospective study and two reviews. Articles were then compiled and analyzed. Albeit the majority of TRT data stemming from conventional TRT, there appears to be an overwhelming safety and efficacy profile in the TM population translated with increased free testosterone levels comparable to a male range, menses cessation, anxiety/depression decline, and improved quality of life.

Conclusion: Testosterone therapy can be impactful for the TM population with improved safety, efficiency, quality of life, and function. With the rise of the newer FDA‐approved TRT, randomized studies are warranted to determine its safety and efficacity in this TM population.




1 | INTRODUCTION

Approximately 0.5% of the world population experiences gender dysphoria, a discrepancy between one's biological sex and gender identity.1 For this group, gender dysphoria can be debilitating, leading to increased risks of affective, adjustment, and anxiety disorders.2,3 Traditionally, transgender patients utilize cross‐sex hormone therapy to address the impact of gender dysphoria.4 These therapies have led to improved anxiety and depression among transgender populations after hormonal treatments.2,5,6 Among transgender men (TM), individuals who were assigned female at birth but who identify as men, testosterone is conventionally used before definite gender‐affirming surgeries. Testosterone suppresses female secondary sex characteristics and induces masculinization.7 Features of the therapy include deepening of the voice, increased body hair, and the cessation of menses.2,8

The standard administration of testosterone for TM is intramuscular or subcutaneous testosterone, short‐term release injection, commonly with testosterone cypionate or testosterone enanthate.9,10 These injectable esters are administered 7–21 days in doses of 100–250 mg and have shown great results in the process of masculinization.11 Following these injectable esters is testosterone undecanoate, a long‐lasting injectable therapy, which has also shown promise in maintaining stable levels of testosterone, estradiol, and dihydrotestosterone.12,13 Transdermal testosterone gels, the second most conventional form of therapy, have also been more widely used among the transgender population.10 Although injectables and gels currently dominate the testosterone market, newer formulations and methods of administration have emerged in recent years. Oral, buccal, and nasal delivery systems have begun to be used for testosterone therapies among TM, but there is a paucity of data on the safety and efficacy of these innovative delivery mechanisms. Figure 1 summarizes up‐to‐date FDA‐approved testosterone therapies for adult‐onset hypogonadism.

In this review, we aim to provide up‐to‐date information regarding the efficacy, safety, and outcomes of conventional and newer testosterone treatments for the TM population. Although testosterone therapy has been well documented, its use in transgender patients is limited in the published literature. Furthermore, we hope to provide evidence that can lead to more informed decision‐making for health practitioners encountering this at‐risk TM population.




3 | RESULTS: EVIDENCE SYNTHESIS FOR THIS REVIEW

3.1 | Conventional testosterone therapies: Intramuscular, subcutaneous, and gel testosterone

3.2 | Efficacy of conventional testosterone therapies

3.3 | Safety of conventional testosterone therapies

3.4 | Outcomes of conventional testosterone therapies




3.5 | Newer testosterone therapies: Oral, buccal, and intranasal testosterone

In recent years, innovations have been made in testosterone administration for transgender patients. These masculinizing treatments have included buccal, intranasal, and oral routes of administration (Figure 1). Buccal administration of testosterone was first introduced in 2003 and requires the application of tablets to the gums of the mouth.14 Through buccal administration, there is increased bioavailability due to the bypassing of the liver.14 Advantages of buccal administration include the fact that it is self‐administered, and has a quick reversal. Disadvantages of these tablets include possible skin irritation and the need for multiple administrations daily.14 Buccal testosterone has also been noted for altered taste and poor adhesion to the buccal mucosa, making it a less recommended form of administration.21

Nasal testosterone was first approved by the FDA in 2014. This is a non-invasive method of administration that has lower dose levels because of efficient absorption.14,28 Advantages of nasal testosterone also include the fact that it is self‐administered and has quick reversal.14 Disadvantages of this method include multiple administrations, nostril irritation, and contraindications for patients with nasal diseases.14

Oral testosterone, the most innovative testosterone administration to date, was approved by the FDA in 2020. Advantages of oral testosterone include convenience, modifiable dosage, and quick reversal.14 Disadvantages include multiple administrations, short half-life, unpredictable absorption, fluctuating T serum levels, and the fact that is taken with fatty food.14,21,29 Owing to recent FDA approval for the use of these newer TRT products, there has been little contemporary data detailing their efficacy, safety, or outcomes in the TM population and underpinning the unmet need for research studies on their use.16 Table 4 summarizes newer testosterone therapies, applications, advantages, and disadvantages.




4 | DISCUSSION

Across all studies, conventional testosterone treatment has been found to be safe for long-term use with minimal risk for life‐threatening side effects.30,31 Comorbidities can be monitored and managed through regular blood pressure screenings, metabolic panels, and complete blood count tests.9 The Endocrine Society Clinical Practice Guideline for transgender patients recommends that clinicians measure patient hormone levels at regular intervals to ensure that their free testosterone levels remain within a normal male physiological range and that estradiol levels are sufficiently suppressed.32 Moreover, those at‐risk TM patients that could be worsened by the depletion of endogenous hormones or influx of androgens should be addressed and managed with the patient's general physician before beginning testosterone treatment.32 Hematocrit and hemoglobin levels should be measured every three months for the first year, and then twice a year to monitor the risk of polycythemia.33

Standard of care recommendations also includes mental health screenings as part of the routine follow-up for all transgender patients.9 Patients who do not elect for mastectomy, hysterectomy/oophorectomy, or sexual reassignment surgery should continue with regular mammograms, breast exams, and cervical cancer screenings as recommended and work with their health care provider to determine if and when the time is right for surgical transition.16,32

This comprehensive review highlights that the majority of TRT data in the TM population were stemming from conventional TRT use and there appears to be an overwhelming safety and efficacy profile in the TM population clinically proven and translated with increased free testosterone levels comparable to a male range, menses cessation, anxiety/depression decline and improved quality of life. Notwithstanding, testosterone therapy can be impactful for the TM population with improved safety, efficiency, quality of life, and function. With the rise of the newer FDA‐approved TRT, randomized studies are warranted to determine its safety and efficacity in this TM population.




5 | CONCLUSION

The use of testosterone to induce masculinization among TM has shown great promise in recent years. More conventional therapies, including intramuscular injections, subcutaneous injections, and transdermal gels, have been extensively studied and show promising efficacy and outcomes with limited safety concerns.

The newer therapies, including oral, buccal, and nasal testosterone formulations, have not yet been extensively studied. As newcomers to the market, increased research is needed to determine the efficacy, safety profile, and outcomes of these formulations among the TM population.

 

[madman]

FIGURE 1 List of up‐to‐date FDA‐approved testosterone therapies for adult‐onset hypogonadism.

 

[madman]

TABLE 1 The efficacy of conventional testosterone therapies

 

[madman]

The safety profile of conventional testosterone therapies

 

[madman]

TABLE 3 The outcomes of conventional testosterone therapies

 

[madman]

TABLE 4 Newer testosterone therapies, applications, advantages, and disadvantages

 

[Nelson Vergel]

FIGURE 1 List of up‐to‐date FDA‐approved testosterone therapies for adult‐onset hypogonadism.
View attachment 26839

Finally! An updated chart of TRT products approved in the US by 2022.

A few mistakes: Androgel was approved before Testim (I am almost sure). Andriol was never a generic in the US. Delatestryl and Depo Test were approved before the 70's (almost sure).

 

[tareload]

Nandrolone for Mood | Feeling much Better..

Also, I haven't read the mouse study, but it occurs to me that in the early days of Low Carb, there was an attempt to show that (I think) olive oil was toxic using FMD as a measure. However I believe Volek subsequently showed that it was a short-term affect which disappeared after several weeks...

www.excelmale.com

Conclusions​

Ours is the first study to examine the androgen effects on endothelial function in TGM. We demonstrated that the hyperandrogenic milieu in TGM is a primary factor associated with endothelial dysfunction, independent of lipids, blood pressure and BMI. Our present study supports earlier studies from our laboratory demonstrating that poor NO responsiveness is a key causative link in natal females exposed to chronic endogenous and/or high levels of exogenous androgens leading to endothelial dysfunction and ultimately cardiovascular disease. Future studies should address how changes in other hormones such as estrogen, or other substances, such as inflammatory cytokines, may impact changes in vascular function during HT. As described earlier, endothelial dysfunction in these TGM occurred independent of differences in lipids, BMI or blood pressure indicating a separate etiology. Understanding the mechanisms by which exogenous androgens mediate endothelial dysfunction in TGM may allow for early interventions to mitigate the potential long-term cardiovascular risk.

 

[tareload]

Pathophysiological effects of androgens on the female vascular system - Biology of Sex Differences

Sex hormones and their respective receptors affect vascular function differently in men and women, so it is reasonable to assume they play a role in the sex differences in cardiovascular disease states. This review focuses on how the effects of testosterone on arterial vessels impact the female...

link.springer.com

Conclusions​

Our data and others support an association between hyperandrogenism and mild elevations in blood pressure, endothelial dysfunction, and dyslipidemia in trans men and women with AE-PCOS. Despite the evidence that androgen exposure during gender-affirming hormone therapy is associated with mild hypertension, endothelial dysfunction, and dyslipidemia in trans men, the lack of long-term studies and infrequent follow-up measures for existing studies has led to uncertainty about the effects of HT on cardiovascular outcomes [80]. Cardiovascular markers are not always treated in trans men or AE-PCOS, leaving these cohorts at greater risk for cardiovascular events and future CAD, and even mild hypertension can be detrimental to the cardiovascular system when chronic. AE-PCOS is often diagnosed in the early teenage years, and gender transition often occurs at a young age. In both cases, androgen exposure will last for many years. Long-term and follow-up research are needed to develop guidelines for cardiovascular outcomes during HT and support health and longevity in trans men.

Perspectives and significance​

Despite the work presented in this review, the long-term health risks of testosterone exposure on the female vascular system and the impact of testosterone in women with AE-PCOS, and in trans men receiving androgens, remain underappreciated. In particular, attention to cardiovascular and metabolic risk factors should be integral to the care of these cohorts. The high, chronic androgen therapy environment in trans men provides a unique opportunity to study the impact of long-term androgen exposure on the female vascular system. This is especially important because the elevated androgens in trans men remain throughout their lifetime, continuing into older age when CAD risk develops independent of hormone exposure.

 

[tareload]

Testosterone administration increases leukocyte-endothelium interactions and inflammation in transgender men

To evaluate the effect of testosterone treatment on metabolic and inflammation parameters and leukocyte-endothelium interactions in transgender men (T…

www.sciencedirect.com

Subjects​

Our study population was composed of 157 TGM receiving medical attention at the Department of Endocrinology and Nutrition at the University Hospital Dr. Peset, Valencia, Spain. The following criteria were applied: having been assigned 12-week treatment with testosterone undecanoate (intramuscular) at a dose of 1,000 mg; no treatment that could have interfered with the physiological function of the gonadal-pituitary-hypothalamic axis in the previous 6 months; no infectious, inflammatory, malignant, hematological, or organic disease; and absence of history of heart disease, stroke, thromboembolism, hyperlipidemia, hypertension, PCOS, or diabetes mellitus. Transgender men were evaluated and managed according to Diagnostic and Statistical Manual of Mental Disorders V criteria. Eligibility of the subjects for gender-affirming hormone treatment was determined following the guidelines of the World Professional Association for Transgender Health and those of the Endocrine Society. All the subjects were naive to hormonal treatment and eugonadal, which were confirmed by medical history, physical examination, and biochemical criteria before initiating treatment. Oophorectomy was not performed in any of these patients.All participants were informed about all the methods and procedures of the study and gave their written consent. The study was conducted in accordance with the Helsinki Declaration and approved by the Ethics Committee of University Hospital Dr. Peset (ID: 98/19).

Conclusion​

Although gender-affirming hormones are considered medically necessary, the present research demonstrates that testosterone can induce an increase in leukocyte-endothelium interactions, adhesion molecules, and proinflammatory cytokines in TGM. Future research concerning endothelial impairment and inflammation may determine the physiological mechanism involved in this effect, an effect that should be taken into account to monitor cardiovascular risk in these individuals.

 

[madman]

Finally! An updated chart of TRT products approved in the US by 2022.

A few mistakes: Androgel was approved before Testim (I am almost sure). Andriol was never a generic in the US. Delatestryl and Depo Test were approved before the 70's (almost sure).

Yes.

Androgel holds that title among the transdermal T-gels.

Delatestryl was approved in 1953 and Depo-T in 1979.

Methyltestosterone was the first oral to hit the market in the early 70s and although it is still being manufactured in the US it is rarely prescribed due to its high potential for liver toxicity.

Jatenzo was the first non-c17 alpha alkylated oral on the US market.

Clarus Therapeutics Receives U.S. FDA Approval of JATENZO® (Testosterone Undecanoate Capsules for Oral Use) (CIII) for Testosterone Replacement Therapy in Certain Adult Men

JATENZO is a first-in-class proprietary softgel oral formulation of testosterone undecanoate for testosterone replacement therapy in certain adult men, and...

www.globenewswire.com

*JATENZO is a first-in-class proprietary softgel oral formulation, and the first oral testosterone medicine approved in more than 60 years

Dr. Newmark provides updates on FDA-approved oral testosterone undecanoate

In a recent study presented at the 2021 SMSNA Fall Scientific Meeting, Jay Newmark, MD, MBA, and co-authors report promising findings on the first experiences of patients using JATENZO in the real world.

www.urologytimes.com

*JATENZO is the first oral testosterone replacement therapy that's been approved by the FDA in over 40 years. The previous product, methyl testosterone, was known to cause hepatotoxicity and therefore is almost never used today. JATENZO is formulated as a self-emulsifying drug delivery system and avoids the first pass effect through the liver




Androgel 1% -2000
Testim 1% - 2002
Andriol - never approved in the US
Delatestryl - 1953
Depo-Testosterone - 1979





B. FDA Approval of Depo-Testosterone

In 1953, the Food and Drug Administration approved a new drug, Delatestryl, as a testosterone replacement injection. Its original purpose, according to the new drug application filed on its behalf, was to treat men whose bodies did not produce enough testosterone naturally. This NDA came before many of today’s regulatory requirements, though Delatestryl later passed effectiveness screening in the 1960s as required under the then-new Drug Efficacy Study Implementation program.

In 1979, the FDA approved the Upjohn Company’s abbreviated new drug application (ANDA) for Depo-Testosterone, a testosterone injection similar to Delatestryl. Depo-T, as the product is still called, produced safety and effectiveness results equivalent to those of Delatestryl. Under the drug approval process at the time, similar results sufficed for streamlined ANDA approval. But because of a slight difference in its physical composition that made it not quite the same as Delatestryl, after the 1984 statutory changes were implemented, Depo-T became the reference listed drug (RLD) for its precise kind of testosterone injection. This meant that any drugs seeking to follow in Depo-T’s footsteps had to demonstrate bioequivalence to (i.e., that they were the same as) Depo-T to qualify for the streamlined approval process of an abbreviated new drug application. See above at 4; see also 21 U.S.C. § 355(j)(2)(A)(iv); 21 C.F.R. § 314.3(b). When these lawsuits were filed, defendant Pfizer had taken over the production and marketing of Depo-T, and the drug remained the reference listed drug. More than half a dozen other testosterone drugs have followed Depo-T’s lead since its approval in 1979.