Prolonged Pulsatile Kisspeptin Administration in Hypogonadotropic Hypogonadism

* Assignment: Each study subject will serve as their own control. The order of kisspeptin doses will be randomized within each set/exposure.
* Delivery of Interventions:

* Prior to the study visit, subjects will undergo a review of their medical history and screening laboratories. Subjects will also wear a gonadotropin releasing hormone (GnRH) pump prior to the inpatient study visit.
* On the day of the inpatient study, the subjects will

* Undergo q10 min blood sampling for 6 hours,
* Receive kisspeptin intravenous (IV) boluses from hour 6 to hour 44 (20 boluses total),
* Undergo q10 min blood samplings for another 6 hours,
* Receive a single GnRH IV bolus at hour 51.

• kisspeptin 112-121 (Drug), also known as metastin 45-54: 20 intravenous doses of kisspeptin 112-121 (4 different doses of kisspeptin (randomized) in 5 sets)
• GnRH (Drug), also known as gonadotropin-releasing hormone: 1 intravenous dose of GnRH

Primary outcomes

• Average Change in Luteinizing Hormone (LH) Pulse Amplitude in Response to Kisspeptin [52 hours]: Change in LH amplitude before, during and after kisspeptin administration

Secondary outcomes

• Average Change in LH Pulse Frequency in Response to Kisspeptin [52 hours]: Change in LH frequency before and after kisspeptin administration

Sex: All, ages: 18 Years to any

Inclusion/exclusion criteria:

* Age 18 years and older,
* Confirmed diagnosis of HH with

  * Low testosterone or estradiol,
  * Low or low-normal gonadotropin levels,
  * Thyroid stimulating hormone (TSH) and prolactin within the reference range,
  * Absence of abnormal pituitary or hypothalamic findings on Magnetic resonance imaging (MRI),
* All other medical conditions stable and well controlled,
* No prescription medications known to affect reproductive endocrine function for at least 2 months or for 5 half-lives of the drug (whichever is shorter) except for medications used to treat the subject's reproductive condition,
* No history of a medication reaction requiring emergency medical care,
* No illicit drug use,
* No excessive alcohol consumption (<10 drinks/week),
* Normal blood pressure (BP), (systolic BP < 140 mm Hg, diastolic < 90 mm Hg),
* White blood cell, platelet counts, and TSH between 90% of the lower limit and 110% of the upper limit of the reference range,
* Prolactin below 110% of the upper limit of the reference range,
* Hemoglobin

  * Women: no less than 0.5 gm/dL below the lower limit of the reference range for normal women,
  * Men: on adequate testosterone replacement therapy: normal male reference range,
* Blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT) not elevated,
* For women,

  * Negative serum human chorionic gonadotropin (hCG) pregnancy test at the time of screening (additional urine pregnancy test will be conducted prior to drug administration),
  * Not breastfeeding and not pregnant.

Participant flow

Outcome results

• Average Change in Luteinizing Hormone (LH) Pulse Amplitude in Response to Kisspeptin (Primary), Mean, IU/L: Experimental: Kisspeptin, GnRH 0.35 +/- 0.43
• Average Change in LH Pulse Frequency in Response to Kisspeptin (Secondary), Mean, # pulses/hour: Experimental: Kisspeptin, GnRH 0.17 +/- 0.27

Adverse events

Time frame: From time of study consent until removal from study participation (approximately 3 months).

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2021-03-12)
• Informed Consent Form (PDF, 2022-04-14)

• Stephanie Seminara, Principal investigator, Massachusetts General Hospital