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Study of Leptin for the Treatment of Hypothalamic Amenorrhea

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ClinicalTrials.gov Identifier: NCT00130117
Recruitment Status : Completed
First Posted : August 15, 2005
Results First Posted : May 17, 2017
Last Update Posted : May 17, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of this study is to determine whether administration of an investigational medication called leptin (r-metHuLeptin) in replacement doses can improve bone health, reproductive function, hormone levels, immune function, and overall sense of well-being in women with hypothalamic (exercise-induced) amenorrhea (HA) who are being treated with oral contraceptive pills (OCPs), compared to placebo. Women with hypothalamic amenorrhea have low leptin levels. This study is based on the hypothesis that the relative leptin deficiency in women with hypothalamic (exercise-induced) amenorrhea may be the reason for the lack of menstrual cycles, hormone abnormalities, and bone loss associated with this condition.

Condition or disease Intervention/treatment Phase
Amenorrhea Drug: r-metHuLeptin Drug: Oral Contraceptive Pills (OCPs) Other: Placebo Phase 2

Detailed Description:

Leptin is a hormone secreted by fat cells under normal conditions and acts in the brain to regulate energy usage and hormone levels. Women with HA who do not have regular periods have low leptin levels and may also have other hormone abnormalities as well as loss of bone density (osteopenia or osteoporosis). This study will evaluate how leptin (a fat cell hormone that normally circulates in the blood) affects bone density, menstrual periods, hormone levels, bone metabolism (how bone forms and turns over), immune function (how well the body can fight infection), metabolic rate (how many calories are used at rest), and overall sense of well-being and appetite in women with HA (i.e. no regular menstrual periods due to low levels of pituitary hormones that regulate estrogen production from the ovary). It will also investigate whether leptin replacement can be used as an adjunct to the current standard of care for HA patients, i.e. OCPs.

Part A is a Randomized, placebo-controlled 36-week study. Part B is an Optional open-label 52-week study. There will also be an optional Reward Sub-study, including healthy controls, designed to investigate leptin's relation to reward processing by collecting participants' brain and behavioral responses to images (e.g., pictures of food vs. non-food). Brain responses will be collected and will also be assessed via functional Magnetic Resonance Imaging (fMRI).

Comparison: Part A = leptin-treated group to placebo-treated group and Part B optional sub study = leptin-treated group to health controls

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Randomized, Double-blind, Placebo-controlled Trial of Human Recombinant Leptin (r-metHuLeptin) for the Treatment of Hypothalamic (Exercise-Induced) Amenorrhea
Study Start Date : April 2010
Primary Completion Date : August 2011
Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Metreleptin
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: r-metHuLeptin
r-metHuLeptin administered subcutaneously.
Drug: r-metHuLeptin
Starting dose: 0.08mg/kg once daily Subcutaneous injection.
Other Name: metreleptin
Drug: Oral Contraceptive Pills (OCPs)
Sprintec taken orally once daily.
Other Name: OCPs
Placebo Comparator: Oral Contraceptive Pills (OCPs)
Drug: Oral Contraceptive Pills (OCPs)
Sprintec taken orally once daily.
Other Name: OCPs
Other: Placebo
placebo (no active medication)

Outcome Measures

Primary Outcome Measures :
  1. the Difference Between the Placebo and Leptin Treated Groups in the Change in Bone Mineral Content(BMC) at the Anteroposterior (AP) Spine From Baseline to 36 Weeks [ Time Frame: 36 weeks ]

Secondary Outcome Measures :
  1. Bone Markers - Ctx and Sclerostin [ Time Frame: 36 weeks ]
  2. Body Composition BMI [ Time Frame: 36 weeks ]
  3. Total Body BMD [ Time Frame: 36 weeks ]
  4. Body Fat [ Time Frame: 36 weeks ]
  5. Total Body BMD [ Time Frame: 9 months ]
  6. Lumbar BMD [ Time Frame: 9 months ]
  7. Radial BMD [ Time Frame: 9 months ]
  8. Hip BMD [ Time Frame: 9months ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

Inclusion criteria for HA subjects

  • Hypothalamic amenorrhea of at least 6 months duration with low or normal LH and FSH, e.g. due to strenuous exercise (running >20 miles per week or equivalent) or low weight
  • Can be secondary HA OR primary HA with some pubertal development and normal screening labs
  • Age 18-35 years old
  • Body weight within +/- 15% of ideal body weight and stable for 6 months (no change > 5 lbs)
  • Baseline leptin <5 ng/mL (except for the Cognitive Sub-Study Baseline visit where baseline leptin will be greater than 5ng/mL)

Inclusion criteria for eumenorrheic controls for Reward Sub-study

  • Normal menstrual cycles (between 25 and 35 days)
  • Age 18-35
  • Body weight within +/- 15% of ideal body weight and stable 6 months (no change > 5 lbs)
  • Baseline leptin >5 ng/mL

Exclusion criteria:

  • We will exclude subjects with:
  • Significant medical history that may affect the concentrations of the hormones to studied or ability to participate in the study
  • renal or hepatic disease (creatinine > 1.4, AST/ALT > 2x upper limit of normal)
  • diagnosed diabetes mellitus
  • myocardial ischemia
  • malignancy (other than basal cell carcinoma of the skin or in situ carcinoma of the cervix)
  • malabsorption
  • alcoholism, drug abuse, or smoking
  • active eating disorder
  • depression or other psychiatric disease
  • anemia (Hb10 gm/dL on 2 occasions)
  • Conditions that are contraindicated for oral contraceptive use:
  • Thrombophlebitis or thromboembolic disorders
  • A past history of deep vein thrombophlebitis or thromboembolic disorders
  • Cerebral vascular or coronary artery disease
  • Known or suspected carcinoma of the breast
  • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
  • Undiagnosed abnormal genital bleeding
  • Hepatic adenomas or carcinomas
  • Cholestatic jaundice of pregnancy or jaundice with prior OCP use
  • Other endocrine causes of amenorrhea, e.g.
  • hyperprolactinemia
  • hypothyroidism or hyperthyroidism
  • Cushing's syndrome
  • congenital adrenal hyperplasia (elevated 17 OH progesterone)
  • polycystic ovarian syndrome (elevated androgens or LH/FSH ratio >1.5)
  • primary ovarian failure (elevated FSH)
  • On medications known to affect the hormones to be measured such as
  • glucocorticoids
  • anti seizure medications
  • thyroid hormones
  • estrogen (must be off at least 3 months prior to participating in the study)
  • A known history of anaphylaxis or anaphylactoid-like reactions, or a known hypersensitivity to E. Coli derived proteins
  • Breast feeding, pregnant, or wanting to become pregnant during the next 6 months.
  • We will screen for these conditions through a detailed history and systems review, physical examination, laboratory evaluation (as described above in Screening Methods), and EKG.
  • In the Reward Sub-study subjects will be asked to fill out a standard BIDMC MRI safety screening form prior to entering the magnet.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00130117

United States, Massachusetts
Beth Israel Deaconess Medical Center General Clinical Research Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Center for Research Resources (NCRR)
Principal Investigator: Christos S Mantzoros, MD, ScD Beth Israel Deaconess Medical Center, Harvard Medical School
More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT00130117     History of Changes
Other Study ID Numbers: 2004P000123
1R34HD048526-01 ( U.S. NIH Grant/Contract )
5M01RR001032-32 ( U.S. NIH Grant/Contract )
First Posted: August 15, 2005    Key Record Dates
Results First Posted: May 17, 2017
Last Update Posted: May 17, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Christos Mantzoros, Beth Israel Deaconess Medical Center:
hypothalamic amenorrhea
exercise-induced amenorrhea
neuroendocrine function
bone metabolism

Additional relevant MeSH terms:
Menstruation Disturbances
Pathologic Processes
Contraceptive Agents
Contraceptives, Oral
Contraceptives, Oral, Combined
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptive Agents, Female