Kisspeptin in the Evaluation of Delayed Puberty

Overseen By Study Coordinator

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Disqualifiers: Chronic illness, Weight loss, others

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

Compensation: Varies

Number of Visits: 2

Duration: 1-2 weeks

24 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of the drug GnRH and its components?

Research shows that GnRH agonists, which are similar to the natural hormone, are effective in treating conditions like prostate cancer by suppressing hormone release. Additionally, metastin, a component related to GnRH, is involved in reproductive functions, suggesting its potential role in treating related disorders. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

GnRH analogues, including LHRH agonists, have been used safely in the treatment of conditions like prostate cancer, though there may be some cardiovascular risks associated with LHRH agonists. Overall, these treatments are considered safe in clinical settings, but specific safety concerns like initial flare-ups and cardiovascular risks should be discussed with a healthcare provider. ^{2 6 7 8 9}

How does the drug GnRH, kisspeptin 112-121 differ from other treatments?

The drug GnRH, kisspeptin 112-121 is unique because it involves a combination of GnRH and kisspeptin, which are peptides that play a role in regulating hormone release. Unlike standard treatments, this drug may offer a novel approach by potentially modulating hormone levels through different mechanisms, such as inhibiting or stimulating hormone release, which could be beneficial for conditions with no standard treatments. ^{10 11 12 13 14}

What is the purpose of this trial?

This trial tests if certain hormones can predict whether delayed puberty in children will resolve on its own or need treatment. It involves children with delayed puberty. The hormones signal the body to start puberty, helping doctors determine if the delay is temporary or permanent.

Research Team

Stephanie B Seminara, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Inclusion Criteria

This study is not open to teenage boys.

You have not experienced any breast development changes in the past 6 months and are in the early stages of puberty.

The study does not allow participation of teenage girls.

Exclusion Criteria

history or presence of underlying condition that could cause delayed puberty (chronic illness, weight loss, abnormal cranial magnetic resonance imaging (MRI))

history of an allergic drug reaction

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous administration of kisspeptin and GnRH during two hospital admissions

1-2 weeks

2 outpatient visits, 1 overnight admission, 1 day admission

Follow-up

Participants are monitored every 6 months until they reach 18 years of age to determine if their pubertal delay was self-resolved or permanent

Variable, until age 18

Treatment Details

Interventions

• GnRH
• kisspeptin 112-121

Participant Groups

Group I: Kisspeptin, GnRH Experimental Treatment 2 Interventions

Intravenous (IV) administration of kisspeptin 112-121 0.24 nmol/kg and GnRH 75 ng/kg

GnRH is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Gonadorelin for:

• Infertility
• Precocious puberty
• Endometriosis
• Prostate cancer

Approved in European Union as Gonadorelin for:

• Infertility
• Precocious puberty
• Endometriosis
• Prostate cancer
• Breast cancer

Approved in Canada as Gonadorelin for:

• Infertility
• Precocious puberty
• Endometriosis
• Prostate cancer

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

Metastin, a peptide linked to the GPR54 receptor, plays a role in regulating reproductive functions and is found in higher levels in pregnant women, suggesting its importance in reproductive health.

In a patient with isolated hypogonadotropic hypogonadism, high levels of luteinizing hormone releasing hormone (LHRH) were observed, but plasma metastin levels were normal, indicating that peripheral metastin may have different functions compared to its central role in stimulating reproductive hormone release.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment and clinical application of enzyme immunoassays for determination of luteinizing hormone releasing hormone and metastin. Katagiri, F., Tomita, K., Oishi, S., et al.[2011]

The GnRH analogue [(imBz1)-D-His6,Pro9-NEt]GnRH is 200 times more potent than the natural hormone in vitro, leading to significantly increased levels of LH and FSH in single-dose studies in humans.

This analogue not only shows a prolonged duration of activity but also appears to be safe, suggesting potential clinical applications for treating conditions related to hormone regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single dose responses to the gonadotropin-releasing hormone agonist analogue [(imBz 1)-D-His6,Pro9-NEt]GnRH. Doelle, GC., Evans, RM., Alexander, AN., et al.[2013]

In a study of 45,059 men with prostate cancer receiving androgen deprivation therapy, the risk of major adverse cardiovascular events (MACE) was found to be significantly higher for those treated with GnRH antagonists compared to LHRH agonists, with a hazard ratio of 1.62.

Additionally, the risk of all-cause mortality was also greater for patients on GnRH antagonists versus LHRH agonists, indicating that LHRH agonists may be a safer option in terms of cardiovascular health following ADT initiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Risk in Prostate Cancer Patients Using Luteinizing Hormone-Releasing Hormone Agonists or a Gonadotropin-Releasing Hormone Antagonist. Crawford, ED., Hafron, JM., Debruyne, F., et al.[2023]

GnRH analogues are established as safe and effective treatments for hormone-dependent advanced prostate cancer, but their unique mechanism of action complicates the entry of generic versions into the market.

Regulatory requirements for GnRH analogues are stringent due to their comparison with surgical castration, which has a 100% success rate, and they face competition from antagonistic treatments that do not cause flare-up effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacology and regulatory consequences of GnRH analogues in prostate cancer. Eckstein, N., Haas, B.[2022]

GnRH and its agonists play a crucial role in regulating reproductive functions and are used to treat various conditions like prostate cancer, endometriosis, and infertility, highlighting their therapeutic efficacy.

Recent developments in small molecule GnRH antagonists present a promising alternative to peptidic forms, potentially allowing for oral administration and expanding treatment options for conditions currently managed with injections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-peptidic GnRH receptor antagonists. Armer, RE., Smelt, KH.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Establishment and clinical application of enzyme immunoassays for determination of luteinizing hormone releasing hormone and metastin. [2011]

2. United States pubmed.ncbi.nlm.nih.gov

Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Clinical impact of LH rises prior to and during ganirelix treatment started on day 5 or on day 6 of ovarian stimulation. [2021]

4. India pubmed.ncbi.nlm.nih.gov

To Compare the Effect of GnRH Agonist versus Human Chorionic Gonadotropin (HCG) Trigger on Clinical Pregnancy Rate in Intrauterine Insemination Cycle. [2022]

5. France pubmed.ncbi.nlm.nih.gov

[Pharmacokinetics and pharmacodynamics of triptorelin]. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Single dose responses to the gonadotropin-releasing hormone agonist analogue [(imBz 1)-D-His6,Pro9-NEt]GnRH. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular Risk in Prostate Cancer Patients Using Luteinizing Hormone-Releasing Hormone Agonists or a Gonadotropin-Releasing Hormone Antagonist. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Clinical pharmacology and regulatory consequences of GnRH analogues in prostate cancer. [2022]

9. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Non-peptidic GnRH receptor antagonists. [2019]

10. Chile pubmed.ncbi.nlm.nih.gov

[Hypothalamic inhibiting factor of luteinizing hormone secretion: relation to the fragment 1-5 of the LH releasing hormone]. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Identification of the second gonadotropin-releasing hormone in chicken hypothalamus: evidence that gonadotropin secretion is probably controlled by two distinct gonadotropin-releasing hormones in avian species. [2019]

12. Denmark pubmed.ncbi.nlm.nih.gov

Use of a highly specific monoclonal antibody against the central variable amino acid sequence of mammalian gonadotropin releasing hormone to evaluate GnRH-I tissue distribution compared with GnRH-I binding sites in adult male rats. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Gonadotropin-releasing hormone antagonists. [2022]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Structure and biological activity of gonadotropin-releasing hormone isoforms isolated from rat and hamster brains. [2017]