Subcutaneous Kisspeptin for Hypogonadotropic Hypogonadism

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stephanie B. Seminara, MD

Must not be taking: Hormonal replacements

Disqualifiers: Excessive alcohol, Illicit drugs, Pregnancy, 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: 12

Duration: 2 weeks

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether kisspeptin, a natural hormone, can trigger the release of other key reproductive hormones in individuals with idiopathic hypogonadotropic hypogonadism (IHH), a condition characterized by insufficient hormone production. Researchers are also examining if kisspeptin can aid in egg release from the ovaries in women. Participants will receive kisspeptin through a small pump for two weeks and undergo regular monitoring to assess their body's response. This trial may suit those with a confirmed IHH diagnosis, normal blood pressure, and no current use of medications affecting reproductive hormones. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant findings.

Will I have to stop taking my current medications?

If you are using hormonal replacement or medications that affect reproductive hormones, you may need to stop them for a certain period before joining the trial. This period without medication is called a 'washout period.'

Is there any evidence suggesting that kisspeptin is likely to be safe for humans?

Research has shown that kisspeptin is generally safe and well-tolerated. Animal studies, such as those with dogs, found that even at high doses, kisspeptin did not cause major side effects. In human studies, kisspeptin has been used without serious issues. For instance, it safely increased certain hormones in men, aiding reproductive health.

In this trial, researchers will administer kisspeptin in a specific way to help individuals with idiopathic hypogonadotropic hypogonadism (IHH). The body's response will be carefully monitored. While trying new treatments always carries some risk, evidence so far suggests that kisspeptin is safe to use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for hypogonadotropic hypogonadism rely on hormone replacement therapies like GnRH or testosterone to stimulate the body’s hormone production. However, kisspeptin 112-121 offers a fresh approach by targeting the body’s natural hormone signaling pathways directly. This treatment is unique because it uses a specific segment of the kisspeptin protein, which is administered subcutaneously through a pump, allowing for pulsatile delivery every 60-240 minutes. Researchers are particularly excited about this because it could provide a more natural and potentially safer way to restore fertility and hormonal balance without the side effects often associated with traditional hormone replacements.

What evidence suggests that kisspeptin might be an effective treatment for hypogonadotropic hypogonadism?

Research has shown that kisspeptin, a natural hormone, can increase the release of reproductive hormones. One study found that a form of kisspeptin, called kisspeptin-10, caused a strong release of luteinizing hormone (LH) and raised testosterone levels in men. This trial will investigate the effects of subcutaneous administration of kisspeptin, specifically Kisspeptin 112-121, on participants with idiopathic hypogonadotropic hypogonadism (IHH). Previous studies suggest that kisspeptin might help treat conditions like IHH, where hormone levels are too low. Other studies have shown that kisspeptins could help restore fertility, especially in women with reproductive issues. These findings support the idea that kisspeptin could be effective in treating IHH by boosting hormone production and possibly aiding egg release in women. ^{5 6 7 8 9}

Who Is on the Research Team?

Stephanie B. Seminara, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for men and women with idiopathic hypogonadotropic hypogonadism (IHH) who have low sex hormones due to low gonadotropins. Participants should not be on hormonal replacement or willing to stop it temporarily, and must have normal blood pressure. Pregnant women, those breastfeeding, or with a history of severe medication reactions cannot join.

Inclusion Criteria

Your blood pressure should be within the range of 140/90 or lower.

I have been diagnosed with congenital IHH based on hormone levels.

No current or recent use of a medication that, in the opinion of a study investigator, can modulate the reproductive axis or willing to complete an appropriate washout for that particular medication and method of administration

Exclusion Criteria

You drink more than 10 alcoholic drinks a week or use illegal drugs.

I use marijuana and understand it may affect my participation in the study.

History of a medication reaction requiring emergency medical care

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Treatment

A single SC injection of leuprolide acetate may be administered approximately six days before kisspeptin administration. A pelvic ultrasound will be performed on women to assess baseline follicular size.

1 week

1 visit (in-person)

Treatment

Participants receive pulsatile SC kisspeptin for two weeks. Frequent blood sampling and pelvic ultrasounds for women are conducted to monitor response.

2 weeks

10 blood sampling sessions, 3 ultrasound sessions for women

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Kisspeptin 112-121

Trial Overview The study tests if kisspeptin can trigger reproductive hormone release in IHH patients and help women ovulate. It involves subcutaneous injections of kisspeptin for two weeks and GnRH for about six days, along with ultrasound monitoring in women and frequent blood sampling to measure the body's response.

How Is the Trial Designed?

Group I: kisspeptin pump Experimental Treatment 2 Interventions

SC administration of kisspeptin for two weeks (pulsatile, every 60-240 minutes); administration of a single shot of leuprolide acetate (previously GnRH was used in this study)

Who Is Running the Clinical Trial?

Stephanie B. Seminara, MD

Lead Sponsor

Trials

10

Recruited

840+

Published Research Related to This Trial

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]

Kisspeptin-54 (KP54) effectively differentiates men with congenital hypogonadotropic hypogonadism (CHH) from healthy men, showing a significant difference in luteinizing hormone (LH) response, which was much lower in CHH patients (0.4 iU/L) compared to healthy men (12.5 iU/L).

KP54 demonstrated superior accuracy in identifying hypothalamic dysfunction compared to gonadotropin-releasing hormone (GnRH), with a perfect area under the curve of 1.0 for KP54, indicating its potential as a specific test for hypothalamic function in CHH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism. Abbara, A., Eng, PC., Phylactou, M., et al.[2022]

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]

A new class of small peptide drugs derived from kisspeptin analogs has been developed, showing potential for treating sex hormone deficiency, particularly by maintaining moderate testosterone levels in male rats.

The pentapeptide analog (19) demonstrated strong agonist activity for the KISS1R receptor and effectively increased luteinizing hormone levels without causing testosterone depletion, unlike previous nonapeptide analogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new class of pentapeptide KISS1 receptor agonists with hypothalamic-pituitary-gonadal axis activation. Nishizawa, N., Asami, T., Nishibori, K., et al.[2020]

Kisspeptin-10 (KP-10) was found to have a favorable safety profile in a study involving dogs, with no signs of toxicity observed at doses up to 1,000 μg/kg administered intravenously for 14 days.

The study indicated that KP-10 effectively stimulated luteinizing hormone (LH) release, peaking at 5 minutes post-dose, suggesting its potential as a therapeutic agent for reproductive disorders without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Evaluation of KP-10 (Metastin 45-54) Following once Daily Intravenous Administration for 14 Days in Dog. Terse, PS., Peggins, J., Seminara, SB.[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]

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]

The study identified a new metastin derivative, TAK-448, which effectively suppresses plasma testosterone levels in male rats at lower doses than the standard treatment leuprolide, indicating its potential as a more efficient therapeutic option.

TAK-448 not only demonstrated superior pharmacological activity but also improved water solubility and stability, avoiding gel formation in solution, which enhances its usability for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility. Nishizawa, N., Takatsu, Y., Kumano, S., 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]

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

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04648969?term%253Dpeptide

Prolonged Pulsatile Kisspeptin Administration in ... The goal of this study is to develop novel treatments for patients with a condition called hypogonadotropic hypogonadism (HH) through the use of exogenous ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5413024/

Mechanistic insights into the more potent effect of KP-54 ... Data suggest that KP-54 and KP-10 are not equally effective at eliciting reproductive hormone secretion after peripheral delivery.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1111184

Inactivating KISS1 Mutation and Hypogonadotropic ... We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12112093/

Kisspeptins Regulating Fertility: Potential Future Therapeutic ... Exogenous administration of kisspeptins appears to hold significant promise in restoring fertility, with ongoing studies in their application in ovarian ...

5. academic.oup.com academic.oup.com/jcem/article/96/8/E1228/2833644

Kisspeptin-10 Is a Potent Stimulator of LH and Increases ... Kisspeptin-10 boluses potently evoke LH secretion in men, and continuous infusion increases testosterone, LH pulse frequency, and pulse size.

6. journals.sagepub.com journals.sagepub.com/doi/abs/10.1177/10915818211023459

Safety Evaluation of KP-10 (Metastin 45–54) Following ... Vaginal cytology results indicated all dogs were in anestrous throughout the dosing period. There were also no KP-10–related findings observed ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34126799/

Safety Evaluation of KP-10 (Metastin 45-54) Following once ... In conclusion, KP-10 demonstrated favorable safety profile in dog where 1,000 μg/kg dose was considered as a no-observed-adverse-effect level ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04648969?term=peptide

Prolonged Pulsatile Kisspeptin Administration in ... The goal of this study is to develop novel treatments for patients with a condition called hypogonadotropic hypogonadism (HH) through the use of exogenous ...

9. e-enm.org e-enm.org/journal/view.php?doi=10.3803/enm.2015.30.2.124

Comprehensive Review on Kisspeptin and Its Role in ... Kisspeptin has recently emerged as a key regulator of the mammalian reproductive axis. It is known that kisspeptin, acting centrally via the ...