Kisspeptin for Low Testosterone

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stephanie B. Seminara, MD

Must be taking: Reproductive condition treatments

Must not be taking: Reproductive endocrine drugs

Disqualifiers: Illicit drugs, Excessive alcohol, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 2

Duration: 52 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks new treatments for individuals with hypogonadotropic hypogonadism (HH), a condition that causes low testosterone levels. Researchers are testing a treatment called kisspeptin to determine if it can boost hormone levels. Participants will receive kisspeptin and another treatment, GnRH (a hormone therapy), through an IV. This trial may suit those with long-term low testosterone who have not recently used medications affecting reproductive hormones. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking any prescription medications known to affect reproductive endocrine function for at least 2 months or for 5 half-lives of the drug, whichever is shorter, unless they are used to treat your reproductive condition.

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

Research has shown that kisspeptin, a natural hormone, is generally safe for people. Studies have found that kisspeptin can raise hormone levels such as LH (luteinizing hormone) and sometimes testosterone, suggesting it functions safely in the body and may aid reproductive health.

For GnRH (gonadotropin-releasing hormone), research indicates it is safe when used in treatments. It is often employed to test and treat hormone-related issues. Some studies suggest it can lead to changes in body weight and composition, but these effects are typically manageable.

Overall, both kisspeptin and GnRH have been studied for their safety and are considered well-tolerated in people. However, individual responses to treatments can vary. It is important to consult a doctor for personalized advice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about kisspeptin 112-121 for low testosterone because it introduces a novel approach to hormone regulation. Unlike traditional testosterone replacement therapies, which directly supplement testosterone, kisspeptin works by stimulating the body's natural hormone pathways. This treatment targets the release of Gonadotropin-releasing hormone (GnRH), which can help boost testosterone levels more naturally and potentially reduce the risk of side effects associated with direct hormone replacement. Additionally, its intravenous administration over a short period offers a unique dosing strategy that could lead to quick and effective results.

What evidence suggests that this trial's treatments could be effective for hypogonadotropic hypogonadism?

Research has shown that kisspeptin, a natural hormone, can increase the release of luteinizing hormone (LH) in men, which then boosts testosterone levels. One study found that a form of kisspeptin, called kisspeptin-10, increased both the frequency and amount of LH release, leading to higher testosterone levels. In this trial, participants will receive kisspeptin 112-121 as part of the treatment. Additionally, the trial includes the administration of GnRH, which other studies have shown to increase testosterone levels in most patients over time, with about 93% of men reaching normal levels. These treatments hold promise for improving testosterone levels in conditions like hypogonadotropic hypogonadism (HH). ^{6 7 8 9 10}

Who Is on the Research Team?

Stephanie B. Seminara, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults diagnosed with hypogonadotropic hypogonadism (HH) can join this trial if their condition is stable and they're not on meds affecting reproductive hormones, except for HH treatment. Women must not be pregnant or breastfeeding, and all participants need normal blood tests, hormone levels within certain ranges, no drug allergies needing emergency care, and no excessive alcohol use.

Inclusion Criteria

Women need to have a negative pregnancy test before starting the study.

I have been diagnosed with hypogonadotropic hypogonadism and have low testosterone or estradiol levels.

I have been diagnosed with HH and never had a severe reaction to medication.

Exclusion Criteria

No illicit drug use

You drink less than 10 alcoholic drinks per week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive kisspeptin intravenous boluses and undergo blood sampling

52 hours

Inpatient stay with continuous monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• GnRH
• kisspeptin 112-121

Trial Overview

The study is testing the effectiveness of kisspeptin 112-121 in treating low testosterone due to HH. It aims to develop new treatments by administering kisspeptin externally. Participants will receive either GnRH or kisspeptin as part of the trial interventions.

How Is the Trial Designed?

Group I: Experimental: kisspeptin, GnRH Experimental Treatment 2 Interventions

• Intravenous administration of kisspeptin 112-121; 20 boluses in a 40-hour period. Intravenous administration of GnRH; one bolus.

Who Is Running the Clinical Trial?

Stephanie B. Seminara, MD

Lead Sponsor

Trials

10

Recruited

840+

Published Research Related to This Trial

Kisspeptin plays a crucial role in regulating reproductive functions by controlling the release of GnRH, but its therapeutic use is limited due to its susceptibility to degradation.

Investigational kisspeptin analogs have shown promise in clinical studies, causing initial increases in gonadotropin and testosterone levels, although these effects diminish over time, indicating a need for further research on their long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects and therapeutic potentials of kisspeptin analogs: regulation of the hypothalamic-pituitary-gonadal axis. Matsui, H., Asami, T.[2022]

In a study measuring plasma kisspeptin levels in 11 males (4 with hypogonadism and 7 normal controls), it was found that kisspeptin levels varied significantly, with elevated levels in cases of Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism, suggesting a link between kisspeptin and the regulation of male reproductive function.

The findings indicate that measuring kisspeptin levels could provide valuable insights into the mechanisms of male hypogonadism, as elevated levels may reflect decreased negative feedback from gonadal steroids, particularly in conditions where the hypothalamic-pituitary-gonadal axis is affected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma kisspeptin levels in male cases with hypogonadism. Kotani, M., Katagiri, F., Hirai, T., et al.[2018]

Investigational kisspeptin analogues TAK-448 and TAK-683 effectively suppress testosterone levels in male rats, demonstrating a rapid and profound reduction to castrate levels within 3-7 days of continuous administration, which is more effective than traditional GnRH agonists like leuprolide.

Both analogues showed strong receptor-binding affinity and agonistic activity, suggesting they could be promising therapeutic options for managing reproductive functions and hormone-related diseases, such as prostate cancer, as indicated by their ability to reduce plasma prostate specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide. Matsui, H., Masaki, T., Akinaga, Y., et al.[2017]

The study developed stable analogs of the metastin/kisspeptin decapeptide that maintain high receptor affinity and activity, crucial for regulating reproduction and cell migration.

One promising analog, D-Trp(47), demonstrated both high metabolic stability in mouse serum and effective activation of the KISS1R receptor, suggesting potential for improved therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides. Asami, T., Nishizawa, N., Ishibashi, Y., et al.[2017]

In a study measuring plasma kisspeptin levels in 11 males (4 with hypogonadism and 7 normal controls), elevated kisspeptin levels were found in cases of Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism, suggesting a link between these conditions and hypothalamic kisspeptin secretion.

The findings indicate that measuring kisspeptin levels could provide valuable insights into male hypogonadism, as elevated levels may reflect decreased negative feedback from gonadal steroids, particularly in cases where the lesions are downstream of the kisspeptin neurons.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma kisspeptin levels in male cases with hypogonadism. Kotani, M., Katagiri, F., Hirai, T., et al.[2019]

A new nonapeptide analog of metastin, named compound 26, shows improved stability in serum and retains strong binding affinity to the KISS1R receptor, which is important for regulating hormone secretion.

Compound 26 effectively reduces plasma testosterone levels in male rats and represents a promising candidate for treating hormone-dependent diseases, leading to further development of investigational analogs for clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity. Asami, T., Nishizawa, N., Matsui, H., et al.[2017]

A new peptide analogue, Ac-[D-Tyr46,D-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54), demonstrated significantly enhanced testosterone-suppressive activity (10-50 times more potent) compared to earlier versions, indicating its potential for treating hormone-dependent diseases.

This compound showed improved metabolic stability and agonistic activity at the KISS1 receptor, suggesting that controlled release of these short-length agonists could effectively suppress testosterone levels by targeting the hypothalamic-pituitary-gonadal axis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity. Asami, T., Nishizawa, N., Matsui, H., et al.[2017]

Citations

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11927256/

Comparison of outcomes between pulsatile gonadotropin ...

But pulsatile GnRH therapy induced spermatogenesis faster and leaded to better testicular growth. Pre-treatment baseline TTV could predict ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8267282/

Efficacy and safety of pulsatile gonadotropin-releasing ...

This study also showed that patients' testosterone levels did not increase until 30 days after treatment. Thus, during pulsatile GnRH treatment, ...

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academic.oup.com

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Predictors of Outcome of Long-Term GnRH Therapy in Men ...

Ninety-three percent attained normal T levels on GnRH therapy (499 ± 37 ng/dl at 24 months). In contrast, IB increased but stabilized at a level significantly ...

4.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0016648002005324

The effects of long-term testosterone, gonadotropin ...

In conclusion, high doses of GnRHa in combination with T can increase plasma LH levels in juvenile males but do not induce complete testicular maturation.

5.

apm.amegroups.org

apm.amegroups.org/article/view/68515/html

The efficacy of pulsatile gonadotropin-releasing hormone ...

Within the good-response group, 71.4% of patients achieved spermatogenesis within an average of 13 months of treatment. In patients who had poor ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3264425/

Efficacy and safety of gonadotropin-releasing hormone ...

Prospective trials have shown that in the first year of ADT, fat mass and weight can increase by 10% and 2%, respectively, and lean body mass can decrease by 3% ...

7.

sciencedirect.com

sciencedirect.com/science/article/pii/S258893112400213X

Comparative Cardiovascular Safety of Gonadotropin ...

Real-world evidence studies indicate that degarelix, compared with GnRH agonists, is associated with a modest increased risk of MACEs.

8.

uhcprovider.com

uhcprovider.com/content/dam/provider/docs/public/policies/comm-medical-drug/gonadotropin-releasing-hormone-analogs.pdf

Gonadotropin Releasing Hormone Analogs

... GnRH analogs for the treatment of gender dysphoria and transgender individuals is limited and lacks long-term safety data. Statistically robust randomized ...

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atm.amegroups.org

atm.amegroups.org/article/view/72826/html

Efficacy and safety of pulsatile gonadotropin-releasing ...

In conclusion, the Innopump® hormone pump is accurate, effective, and safe in the treatment of CHH. More than 1 month is required to determine the therapeutic ...

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go.drugbank.com/drugs/DB00644

Gonadorelin: Uses, Interactions, Mechanism of Action

Gonadorelin is a synthetic GnRH used to test the function of gonadotropes and the pituitary.