Sex Hormone Supplementation for Rotator Cuff Repair

Overseen By Peter Chalmers

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of Utah

Must not be taking: Testosterone

Disqualifiers: Infection, Prostate cancer, Liver disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

58 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether boosting sex hormone levels can improve healing after shoulder tendon repair surgery. Men with low sex hormone levels will receive either hormone therapy (such as Clomiphene Citrate or Testosterone Therapy) or placebo pills to determine if it aids recovery and reduces pain. The trial specifically seeks men planning to undergo rotator cuff surgery with a full-thickness tear wider than 1 cm. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are already taking testosterone supplements.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that clomiphene citrate, a medication commonly used to assist women with fertility issues, has also been studied for other purposes, such as treating low testosterone in men. Some studies suggest that clomiphene might be more effective than testosterone therapy for certain men with low testosterone. It has also been associated with a lower risk of death and fewer health problems in these patients.

Clomiphene is usually well-tolerated in terms of safety. Most people experience only mild side effects, if any. Common side effects include mood swings, headaches, and nausea, but these are generally not serious.

This trial is in Phase 2, indicating that clomiphene has already demonstrated some safety in earlier studies. While more research is needed to confirm its safety for shoulder tendon repair, current evidence suggests that clomiphene is a relatively safe option for eligible participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard surgical and physical therapy treatments for rotator cuff injuries, this trial explores the use of clomiphene citrate, a sex hormone modulator, as a unique adjunct therapy. Researchers are excited because clomiphene citrate may enhance the healing process by modulating hormone levels, potentially improving surgical outcomes and speeding up recovery times. This approach is different because it targets hormonal pathways, offering a novel mechanism of action that current treatments do not address.

What evidence suggests that this trial's treatments could be effective for rotator cuff repair?

In this trial, participants will join different treatment arms to evaluate the effects of clomiphene citrate on tendon healing after rotator cuff surgery. Research has shown that clomiphene citrate, a hormone therapy, might enhance tendon healing post-surgery. Studies have found that clomiphene can raise hormone levels, potentially aiding recovery. Evidence suggests this treatment could reduce pain and improve shoulder movement. Clomiphene might also strengthen bones, which could support more effective tendon healing. While more data is still being collected, these early results are promising for individuals with tendon injuries. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for men planning to undergo primary rotator cuff repair surgery, specifically those with a tear width greater than 1 cm and full-thickness tears in the supraspinatus or infraspinatus tendons. It's aimed at men who have low sex hormone levels.

Inclusion Criteria

I am scheduled for a primary repair of my rotator cuff.

I am male.

I have a tear larger than 1 cm in my shoulder's tendon.

Exclusion Criteria

I am taking testosterone before surgery.

Prisoner

My prostate cancer has not been treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-surgery Treatment

Participants start clomiphene or placebo treatment one month before surgery

4 weeks

1 visit (in-person)

Surgery

Participants undergo rotator cuff repair surgery

1 day

1 visit (in-person)

Post-surgery Treatment

Participants continue clomiphene or placebo treatment for six months after surgery

6 months

Regular follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Clomiphene Citrate
• Rotator Cuff Repair

Trial Overview The study is testing if taking sex hormone therapy (Clomiphene Citrate) after shoulder tendon repair surgery can improve healing and reduce pain compared to a placebo. Participants will be randomly assigned to either receive the hormone therapy or a placebo.

How Is the Trial Designed?

Group I: Clomiphene Experimental Treatment 2 Interventions

All patients will receive non-labeled pills identical in appearance from our pharmacy, to be taking once every other day. In the study group, these will contain 50 mg of clomiphene citrate. These will be taken every other day for seven months beginning four week prior to surgery and extending for six months after surgery.

Group II: Control Placebo Group 1 Intervention

All patients will receive non-labeled pills identical in appearance from our pharmacy, to be taking once every other day. In the control group, these will be placebo. These will be taken every other day for seven months beginning four week prior to surgery and extending for six months after surgery.

Rotator Cuff Repair is already approved in United States, European Union for the following indications:

Approved in United States as Testosterone Therapy for:

• Hypogonadism
• Gender Dysphoria
• Osteoporosis

Approved in United States as Estrogen Therapy for:

• Menopause Symptoms
• Osteoporosis
• Vaginal Atrophy

Approved in European Union as Testosterone Therapy for:

• Hypogonadism
• Gender Dysphoria

Approved in European Union as Estrogen Therapy for:

• Menopause Symptoms
• Osteoporosis

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Published Research Related to This Trial

A survey of 382 men undergoing testosterone replacement therapy (TRT) revealed that 70% were satisfied with their treatment, with satisfaction rates being similar across different methods: injections (73%), gels (68%), and pellets (70%).

Patients preferred injectable testosterone mainly due to lower costs, while pellet users valued convenience and ease of use; additionally, improvements in mood and concentration were more pronounced in satisfied patients, highlighting the importance of these factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. Kovac, JR., Rajanahally, S., Smith, RP., et al.[2022]

Testosterone replacement therapy (TRT) is effective in treating men with symptomatic hypogonadism, leading to improvements in libido, energy levels, bone density, muscle strength, and potential heart health benefits.

However, TRT is not safe for men with untreated prostate or breast cancer, and those undergoing TRT need regular monitoring for side effects like increased red blood cell count, swelling, and possible heart or liver issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks of testosterone replacement therapy in men. Osterberg, EC., Bernie, AM., Ramasamy, R.[2021]

In an ovariectomized rat model, which simulates an estrogen-deficient state, tendon-to-bone healing after rotator cuff repair was significantly impaired, showing lower bone mineral density and biomechanical properties compared to control rats.

The study suggests that postmenopausal women, who experience similar estrogen deficiency, may benefit from treatments that enhance bone metabolism to improve healing outcomes after rotator cuff surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Estrogen-Deficient State on Rotator Cuff Healing. Tanaka, K., Kanazawa, T., Gotoh, M., et al.[2020]

Testosterone replacement therapy (TRT) significantly increased serum testosterone levels in aging men with low testosterone, but did not significantly alter prostate tissue levels of testosterone or dihydrotestosterone after 6 months.

No significant changes were observed in prostate histology, biomarkers, or cancer incidence, suggesting that TRT may be safe for prostate health in older men, although further studies are needed to confirm long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. Marks, LS., Mazer, NA., Mostaghel, E., et al.[2016]

Testosterone replacement therapy (TRT) can significantly improve erectile function and libido in men diagnosed with hypogonadism (total testosterone levels below 12 nM), based on a systematic review of randomized controlled trials and observational studies.

When properly diagnosed and managed, TRT does not pose cardiovascular risks or increase the likelihood of venous thromboembolism or prostate issues, but its effects on other health outcomes like metabolism and mood remain unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testosterone Therapy: What We Have Learned From Trials. Corona, G., Torres, LO., Maggi, M.[2020]

Testosterone replacement therapy (TRT) can effectively alleviate symptoms of testosterone deficiency, such as low libido and muscle loss, by increasing serum testosterone levels, but its long-term safety, especially in older men with heart conditions, remains uncertain due to limited clinical trial data.

Different TRT delivery methods (like buccal, transdermal, and intramuscular) have their own advantages and disadvantages, and clinicians should tailor treatment based on individual patient needs and closely monitor for potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testosterone replacement therapy. Barbonetti, A., D'Andrea, S., Francavilla, S.[2021]

Recent studies indicate that testosterone replacement therapy (TRT) may be associated with an increased risk of cardiovascular events in men, contrasting earlier findings that showed no such risk.

Due to these potential risks, physicians are advised to exercise caution when prescribing TRT, ensuring that patients are informed about the risks and that regular monitoring is conducted to minimize side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State-of-the-Art: a Review of Cardiovascular Effects of Testosterone Replacement Therapy in Adult Males. Elsherbiny, A., Tricomi, M., Bhatt, D., et al.[2018]

In a study of 50 hypogonadal men, the first transdermal testosterone therapy in the UK (Andropatch) showed comparable testosterone levels to depot replacement but had low patient acceptability, with only 22% choosing to continue after experiencing high rates of adverse effects, primarily dermatological issues.

Despite its pharmacokinetic advantages, the transdermal therapy was deemed uncomfortable and visually obtrusive, leading most participants to prefer returning to depot therapy, indicating that patient comfort and satisfaction are critical factors in the success of testosterone replacement options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with transdermal testosterone replacement therapy for hypogonadal men. Parker, S., Armitage, M.[2019]

Patients prescribed testosterone replacement therapy (TRT) had a 3.6 times greater risk of sustaining rotator cuff tears (RCTs) compared to a control group, indicating a significant association between TRT and RCT incidence.

The TRT group also showed a 1.6 times higher rate of rotator cuff repairs (RCRs) and a staggering 26.7 times greater risk of needing a subsequent RCR within one year, highlighting potential musculoskeletal risks associated with testosterone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Relationship Between Testosterone Therapy and Rotator Cuff Tears, Repairs, and Revision Repairs. Testa, EJ., Albright, JA., Hartnett, D., et al.[2023]

In a study involving 72 male mice, both estrogen and testosterone supplementation after rotator cuff repair improved the histological structure of the tendon healing site, suggesting potential benefits for tendon recovery.

Testosterone supplementation specifically restored activity levels in the mice without negatively affecting the biomechanical strength of the repaired tendon, indicating a promising avenue for enhancing recovery in future human studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen and testosterone supplementation improves tendon healing and functional recovery after rotator cuff repair. Tashjian, RZ., Zitnay, J., Kazmers, NH., et al.[2023]

In a study involving 33 male mice, the addition of the estrogen-like compound diethylstilbestrol (DES) to rotator cuff repairs significantly improved the quality of tendon healing compared to standard repair methods.

The use of DES led to increased expression of important genes related to bone and tendon healing, as well as enhanced protein expression at the tendon attachment site, suggesting a beneficial role in tendon repair mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of estrogen-like compound on rotator cuff tendon healing in a murine model. Tashjian, RZ., Kazmers, NH., Epperson, RT., et al.[2023]

Exogenous testosterone for transgender men and estrogen with anti-androgens for transgender women are effective in inducing desired physical changes and improving psychological well-being during the transition process.

Long-term hormone therapy requires careful monitoring of bone and cardiovascular health, as well as metabolic indices, to ensure the safety of transgender patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormone therapy for transgender patients. Unger, CA.[2020]

Testosterone replacement therapy (TRT) is considered safe for men with testosterone deficiency who have low-risk prostate cancer after treatment, challenging the historical view that testosterone fuels prostate cancer.

Bipolar androgen therapy (BAT) shows potential for treating castration-resistant prostate cancer, but further research is needed before it can be widely implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of androgen therapy in prostate cancer: from testosterone replacement therapy to bipolar androgen therapy. Xie, T., Song, XL., Wang, C., et al.[2022]

In a study analyzing data from a large insurance database, it was found that women with estrogen deficiency had a 48% higher likelihood of needing rotator cuff repair (RCR) compared to those without deficiency.

Similarly, men with testosterone deficiency had an 89% higher chance of requiring RCR, indicating a strong association between sex hormone deficiencies and the need for this surgical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Sex Hormone Deficiency on the Incidence of Rotator Cuff Repair: Analysis of a Large Insurance Database. Smith, KM., Hotaling, JM., Presson, AP., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04944836

Sex Hormone Supplementation and Rotator Cuff Repair: A ... Sex hormone therapy increases sex hormone levels, and the investigators will test whether these increased sex hormone levels show promise in improving tendon ...

2. trial.medpath.com trial.medpath.com/clinical-trial/6122c1c1421bda63/nct04944836-sex-hormone-supplementation-rotator-cuff-repair

Sex Hormone Supplementation and Rotator Cuff Repair: A ... The purpose of this study is to determine whether clomiphene treatment decreases pain and improves function, increases tendon healing, and improves bone quality ...

3. reporter.nih.gov reporter.nih.gov/search/o4otDrTCJ0eYiA_brAlEoA/project-details/11000262

RePORT RePORTER - National Institutes of Health (NIH) | Prospective randomized and controlled studies have demonstrated that rotator cuff repair (RCR) is indicated for small- and medium-sized tears. Over 500,000 RCRs ...

4. ctv.veeva.com ctv.veeva.com/study/sex-hormone-supplementation-and-rotator-cuff-repair-a-preliminary-randomized-trial

Sex Hormone Supplementation and Rotator Cuff Repair: A ... In the study group, these will contain 50 mg of clomiphene citrate. These will be taken every other day for seven months beginning four week prior to surgery ...

5. withpower.com withpower.com/trial/phase-3-rotator-cuff-injuries-2-2022-38191

Sex Hormone Supplementation for Rotator Cuff Repair Trial Overview The study is testing if taking sex hormone therapy (Clomiphene Citrate) after shoulder tendon repair surgery can improve healing and reduce pain ...

6. dailymail.co.uk dailymail.co.uk/health/article-10436899/Female-fertility-drug-fix-mens-shoulders.html

Female fertility drug to fix men's shoulders 'We believe that clomiphene treatment will reduce pain and improve functioning, enhance tendon healing and increase bone quality with rotator ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8266119/

Safety and Efficacy of Clomiphene Citrate in the Treatment ... The study showed that clomiphene is more effective than testosterone to treat secondary hypogonadism. We also found decreased overall mortality and incidence ...

8. auajournals.org auajournals.org/doi/10.1016/j.juro.2018.03.115

Evaluation and Management of Testosterone Deficiency Patients using anastrozole, clomiphene citrate, or hCG should be tested no earlier than four weeks. The Panel recommends that patients on ...

9. tau.amegroups.org tau.amegroups.org/article/view/11490/html

Off label therapies for testosterone replacement - DiGiorgio There is a paucity of reliable data on whether testosterone restoration is as effective as testosterone replacement in the resolution of hypogonadal symptoms.