Amenorrhea
Conditions
Keywords
leptin, hypothalamic amenorrhea, exercise-induced amenorrhea, neuroendocrine function, bone metabolism
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.
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
Interventions
DRUGr-metHuLeptin
Starting dose: 0.08mg/kg once daily Subcutaneous injection.
DRUGOral Contraceptive Pills (OCPs)
Sprintec taken orally once daily.
OTHERPlacebo
placebo (no active medication)
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Center for Research Resources (NCRR)
Amgen
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | 36 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Body Composition BMI | 36 weeks |
| Total Body BMD | 36 weeks |
| Body Fat | 36 weeks |
| Bone Markers - Ctx and Sclerostin | 36 weeks |
| Radial BMD | 9 months |
| Hip BMD | 9months |
| Lumbar BMD | 9 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| r-metHuLeptin r-metHuLeptin administered subcutaneously.
r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection.
Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. | 11 |
| Placebo placebo
Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.
Placebo: placebo (no active medication) | 9 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo | r-metHuLeptin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 11 Participants | 20 Participants |
| Age, Continuous | 25.4 years STANDARD_DEVIATION 1.2 | 26.6 years STANDARD_DEVIATION 1.4 | 26 years STANDARD_DEVIATION 1.3 |
| Region of Enrollment United States | 9 participants | 11 participants | 20 participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 11 | 0 / 6 |
| serious Total, serious adverse events | 0 / 11 | 0 / 6 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| r-metHuLeptin | 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 | 51.0 g |
| Placebo | 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 | 58.2 g |
p-value: 0.024ANOVA
p-value: 0.049ANOVA
Secondary
Body Composition BMI
Time frame: 36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-metHuLeptin | Body Composition BMI | 20.8 BMI-kg/m^2 | Standard Error 0.6 |
| Placebo | Body Composition BMI | 21.1 BMI-kg/m^2 | Standard Error 0.6 |
Secondary
Body Fat
Time frame: 36 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| r-metHuLeptin | Body Fat | 23.9 fat % | Standard Error 1.4 |
| Placebo | Body Fat | 20.8 fat % | Standard Error 1.3 |
Secondary
Bone Markers - Ctx and Sclerostin
Time frame: 36 weeks
Population: Only for subjects participating in both phase A and phase B (n=4), bone markers were assessed to see the change over 24 month period. All these patient got metreleptin treatment
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| r-metHuLeptin | Bone Markers - Ctx and Sclerostin | CTX | 0.60 ng/mL |
| r-metHuLeptin | Bone Markers - Ctx and Sclerostin | Sclerostin | 0.08 ng/mL |
p-value: 0.02ANOVA
Secondary
Hip BMD
Time frame: 9months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| r-metHuLeptin | Hip BMD | 0.89 g/cm2 |
| Placebo | Hip BMD | 0.88 g/cm2 |
Secondary
Lumbar BMD
Time frame: 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| r-metHuLeptin | Lumbar BMD | 0.92 g/cm2 |
| Placebo | Lumbar BMD | 0.97 g/cm2 |
Secondary
Radial BMD
Time frame: 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| r-metHuLeptin | Radial BMD | 0.54 g/cm2 |
| Placebo | Radial BMD | 0.54 g/cm2 |
Secondary
Total Body BMD
Time frame: 36 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| r-metHuLeptin | Total Body BMD | 1.07 g/cm^2 |
| Placebo | Total Body BMD | 1.13 g/cm^2 |
Secondary
Total Body BMD
Time frame: 9 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| r-metHuLeptin | Total Body BMD | 1.09 g/cm2 |
| Placebo | Total Body BMD | 1.13 g/cm2 |