What's New in Testosterone Replacement Therapy

By: Jeffrey Campbell, MD | Posted on: 01 Feb 2021

Similar to most conferences in 2020, the Sexual Medicine Society of North America (SMSNA) converted its Annual Fall Meeting to a virtual platform, which ran from November 9–15, 2020. The meeting was well attended and jam-packed with a week’s worth of innovative talks on novel research. One area of particular interest at this meeting was the discussion of and insight into new regimens of testosterone replacement therapy, identifying at-risk patients for testosterone deficiency and recognizing both basic science and clinical links between hypogonadism and lower urinary tract symptoms (LUTS). A total of 26 abstracts were presented and 6 plenary/podium presentations regarding testosterone replacement therapy were given over the course of the week.

One of the top basic science abstracts presented at the meeting proposed a new targetable pathway for restoring testosterone to physiological levels in patients with both sickle cell disease and hypogonadism, which may prevent stuttering priapism (see figure). Dr. Sezen Karakus and Dr. Arthur Burnett’s group from Johns Hopkins School of Medicine treated sickle cell mice with FGIN-1-27, a drug ligand for TSPO, which is a cytosolic protein involved in cholesterol mobilization. They found that treatment with FGIN-1-27 increased serum testosterone and reversed primary hypogonadism. Interestingly, correcting hypogonadism in sickle cell mice corrected prolonged detumescence, decreased nitric oxide sensitivity and downregulated phosphodiesterase type 5, thus normalizing erectile function and reducing priapic activity. 1 This study further supports Dr. Burnett’s previous work on hypogonadism in sickle cell disease, and additional studies will hopefully confirm this novel treatment pathway that can offer a solution for sickle cell patients suffering from recurrent priapism episodes.

Figure. Proposed pathway for endogenous testosterone production by FGIN-1-27.

There was a theme of screening atypical populations for testosterone deficiency. Dr. Marisa Gray from the University of Virginia won the Sexual Tipping Point® in Mental Health award presented by the MAP Education and Research Foundation. Her prospective study evaluated men presenting with depressive symptoms and screened these patients for hypogonadism using the Androgen Deficiency in Aging Males (ADAM) questionnaire score. Surprisingly, although the majority of patients (91%) presenting with depression met ADAM criteria for screening, only 6% of the participants tested had biochemical testosterone deficiency. 2 Other studies presented during the SMSNA meeting also suggested clinicians should screen other high risk patient populations (those with pancreatic cancer, patients on immunotherapy) for testosterone deficiency in order to optimize patient outcomes and quality of life. Ideally through multicenter prospective trials, a much larger number of patients is needed to truly understand how the SMSNA could develop screening guidelines for at-risk populations. It is clear that there are likely many populations of patients experiencing symptoms of testosterone deficiency but we are not adequately screening these patients and chalking their symptoms up to an alternative diagnosis.

Several new delivery methods for testosterone therapy came to fruition in 2020. Dr. Yafi and his team at the University of California, Irvine discussed the data on the new subcutaneous testosterone enanthate autoinjector Xyosted®. Approved by the U.S. Food and Drug Administration in 2018, this new delivery method offers a lower peak-to-trough ratio compared to the conventional intramuscular testosterone cypionate. In a randomized trial with followup of 12 weeks, subcutaneous testosterone had a 14% greater increase in trough total testosterone level (p=0.027) compared to intramuscular testosterone cypionate. As expected, the subcutaneous testosterone replacement also had a 41% lower post-treatment hematocrit (p <0.001) and 26% lower post-treatment estradiol (p <0.001). Subcutaneous testosterone enanthate autoinjector appears to be safe and a great delivery option for patients requiring testosterone replacement, although long-term studies are needed. 3 Additionally, oral testosterone undecanoate was presented by industry and demonstrated adequate safety and efficacy at 1-year followup, although further multicenter trials are needed for generalizable outcomes.

Finally, Dr. Abdulmaged Traish from Boston University and Dr. Ranjith Ramasamy from the University of Miami provided informative discussions on the role of testosterone replacement therapy for LUTS. Preclinical data on the topic were summarized and drove home the importance of testosterone replacement therapy for smooth muscle function. Testosterone deficiency can alter the smooth muscle-to-collagen ratio, density of elastic fibers and bladder contractility, compliance and capacity. Testosterone replacement therapy can reverse all of these consequences, leading to improved bladder function. In human studies, testosterone replacement therapy has been shown to improve International Prostate Symptom Score (IPSS), reduce post-void residual volumes and improve bladder compliance in men with testosterone deficiency. Although historically a contraindication, these presentations support the use of testosterone replacement therapy in men with LUTS related to benign prostatic hyperplasia, and future clinical studies will help support this paradigm shift.

Although the meeting was held virtually, there were several interactive sessions, debates and workshops. I encourage readers to register and get access to these great talks. I’m looking forward to more innovative discussions, in person, in 2021.

  1. Musicki B, Karakus S, La Favor JD et al: TSPO ligand FGIN-1-27 controls priapism in sickle cell mice via endogenous testosterone production. Presented at 21st Annual Fall Scientific Meeting of SMSNA. November 2020; abstract 106.
  2. Gray M, Congleton JY, Smith J et al: Should men presenting with depression be screened for low testosterone? Presented at 21st Annual Fall Scientific Meeting of SMSNA. November 2020; abstract 006.
  3. Choi E, Xu P, Loeb C et al: Comparison of outcomes for hypogonadal men treated with intramuscular testosterone cypionate versus subcutaneous testosterone enanthate. Presented at 21st Annual Fall Scientific Meeting of SMSNA. November 2020; abstract 027.