Study of Leptin for the Treatment of Hypothalamic Amenorrhea

• hormone levels and bone markers [ Time Frame: 36 weeks ] [ Designated as safety issue: Yes ]
• immune function [ Time Frame: 36 weeks ] [ Designated as safety issue: Yes ]
• body composition (weight and body fat) [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
• total, radial, hip bone density [ Time Frame: 36 weeks ] [ Designated as safety issue: Yes ]
• resting metabolic rate [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
• overall sense of well-being, appetite and food intake [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]

• evidence of ovulation basied on menstrual bleeding and progesterone levels
• hormone levels and bone markers
• immune function
• body composition (weight and body fat)
• total, radial, hip bone density
• resting metabolic rate
• overall sense of well-being, appetite and food intake

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.

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

• Drug: r-metHuLeptin
  Starting dose: 0.08mg/kg once daily Subcutaneous injection.
• Drug: Oral Contraceptive Pills (OCPs)
  Sprintec taken orally once daily.

• Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, Arampatzi KM, Gao C, Koniaris A, Mantzoros CS. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism. 2011 Sep;60(9):1211-21. Epub 2011 Jul 7.
• Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, Mantzoros CS. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6585-90. Epub 2011 Apr 4.
• Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004 Sep 2;351(10):987-97.
• Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab. 2011 Oct;301(4):E567-84. Epub 2011 Jul 26. Review.
• Matarese G, La Rocca C, Moon HS, Huh JY, Brinkoetter MT, Chou S, Perna F, Greco D, Kilim HP, Gao C, Arampatzi K, Wang Z, Mantzoros CS. Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):E818-27. doi: 10.1073/pnas.1214554110. Epub 2013 Feb 4.
• Aronis KN, Diakopoulos KN, Fiorenza CG, Chamberland JP, Mantzoros CS. Leptin administered in physiological or pharmacological doses does not regulate circulating angiogenesis factors in humans. Diabetologia. 2011 Sep;54(9):2358-67. Epub 2011 Jun 10.
• Alonso-Alonso M, Ziemke F, Magkos F, Barrios FA, Brinkoetter M, Boyd I, Rifkin-Graboi A, Yannakoulia M, Rojas R, Pascual-Leone A, Mantzoros CS. Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding. Am J Clin Nutr. 2011 Aug;94(2):377-84. Epub 2011 May 18.

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.

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Research Resources (NCRR)
• Amgen