Clinical ScienceLong-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women
Introduction
Chronic energy deficiency and the resulting hypoleptinemia are closely linked to hypothalamic amenorrhea, a condition encompassing a clinical spectrum ranging from hormonal abnormalities in strenuously exercising women athletes to anorexia nervosa [1], [2], [3], [4], [5]. Hypothalamic amenorrhea is caused by suppressed gonadotropin-releasing hormone pulsatility, and endocrine evaluation of these patients often reveals not only suppression of the midcycle gonadotropin surge with decreased downstream gonadal sex steroid production but also decreased serum leptin because of low adipose tissue mass [1], [2], [3], [4], [6]. An imbalance between energy intake and exercise-induced energy expenditure results in the female athletic triad of decreased energy availability, amenorrhea with anovulatory infertility, and decreased bone mineral density (BMD) that increases risk for osteoporosis and stress fractures.
Women with hypothalamic amenorrhea have low BMD and bone mineral content (BMC) and may not attain optimal peak bone mass [6], [7], [8], [9], [10]. Many of the therapies designed to improve the hormonal abnormalities associated with this condition (estrogen, insulin-like growth factor 1 [IGF-1], and dehydroepiandrosterone), isolated or in combination [11], have no consistent or only mild favorable effects on BMD [12], [13]. Thus, the search remains for a treatment that resolves both the reproductive dysfunction and the increased risk of osteoporosis in these women, possibly involving a molecule upstream of all neuroendocrine abnormalities.
Low body weight and adipose tissue mass in strenuously exercising women with hypothalamic amenorrhea raise the possibility that the relative lack of molecules normally secreted from adipose tissue could be responsible, at least in part, for the endocrine- and bone-related abnormalities associated with this condition. Leptin, a pleiotropic, adipocyte-secreted hormone, the circulating levels of which reflect the amount of energy stored in adipose tissue, has recently emerged as a key player in the complex system that regulates bone metabolism [14], [15], [16], [17]. Low leptin concentrations (hypoleptinemia) are frequently observed in young women with hypothalamic amenorrhea, the female athlete triad, and/or anorexia nervosa [1], [2], [3], [4]. We have previously shown that increasing leptin concentrations in women with hypothalamic amenorrhea by administering exogenous recombinant methionyl human leptin (metreleptin) leads to resumption of ovulatory menses and improves many of the underlying metabolic and neuroendocrine abnormalities [18], [19]. In addition, we found that metreleptin treatment significantly increases circulating levels of bone formation markers and/or decreases circulating levels of bone resorption markers [18], [19]. The duration of metreleptin treatment in our previous studies was probably too short to allow for changes in BMD to manifest [18], [19]. In this proof-of-concept, pilot study, we examined the effects of metreleptin treatment for 2 years on BMD, BMC, hormonal profile, and circulating markers of bone metabolism in lean, hypoleptinemic women with hypothalamic amenorrhea.
Section snippets
Subjects
Eligible subjects were strenuously exercising lean women between the ages of 18 and 35 years, with hypothalamic amenorrhea for at least 6 months and hypoleptinemia (fasting morning leptin concentrations <5 ng/mL at screening), recruited through advertisements in the community. At the time of screening, all subjects' body weights had been stable for at least 6 months before and were within 15% of their ideal body weight. Participants were free of any significant coexisting medical conditions,
Body weight and composition
During the first 9 months of the study, metreleptin treatment tended to reduce body weight and significantly decreased fat mass (Fig. 2, left panels). For the subjects who participated in both phases of the study (intention-to-treat: n = 6, Fig. 2, middle panels; on-treatment: n = 4, Fig. 2, right panels), body weight and fat mass appeared to decrease during the first 6 months of metreleptin treatment, stabilize between months 6 and 9 (possibly because of adjustment of metreleptin dosing),
Discussion
We found that increasing leptin concentrations in strenuously exercising, hypoleptinemic lean young women with hypothalamic amenorrhea through metreleptin administration for a prolonged period (2 years) increases lumbar spine BMC and BMD by 4% to 6% but does not significantly affect total body BMC and BMD, or BMC and BMD of the hip and forearm. The increase in lumbar BMD and BMC manifested slowly over the first year of treatment and became more evident after 18 to 24 months. Accordingly, we
Funding
The Mantzoros group is supported by National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929, and 81913 and AG032030. Funding was also received from the National Institutes of Health–National Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National
Conflict of Interest
There are no conflicts of interest associated with this manuscript.
Acknowledgment
We would like to thank Jean Chan, MD, for contributions during initial phases of the study and Holly Kilim, MD, and Florencia Ziemke, MD, for their help in the performance of the study.
References (54)
- et al.
A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms
Mol Cell Endocrinol
(2009) Convergence between bone and energy homeostases: leptin regulation of bone mass
Cell Metab
(2006)- et al.
Reciprocal regulation of bone and energy metabolism
Trends Endocrinol Metab
(2008) - et al.
Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa
Lancet
(2005) - et al.
Leptin regulates bone formation via the sympathetic nervous system
Cell
(2002) - et al.
Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass
Cell
(2000) - et al.
Leptin is a potent stimulator of bone growth in ob/ob mice
Regul Pept
(2000) - et al.
Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases
Bone
(2010) - et al.
Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study
Contraception
(2005) - et al.
Bone mass and architecture determination: state of the art
Best Pract Res Clin Endocrinol Metab
(2008)
Acquisition of optimal bone mass in childhood and adolescence
Trends Endocrinol Metab
Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study
Clin Endocrinol (Oxf)
Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea
J Clin Endocrinol Metab
Relationships among injury and disordered eating, menstrual dysfunction, and low bone mineral density in high school athletes: a prospective study
J Athl Train
Plasma leptin in female athletes: relationship with body fat, reproductive, nutritional, and endocrine factors
J Appl Physiol
Role of leptin in reproduction
Ann N Y Acad Sci
Clinical practice. Functional hypothalamic amenorrhea
N Engl J Med
Cross-sectional evidence of suppressed bone mineral accrual among female adolescent runners
J Bone Miner Res
Decreased spinal mineral content in amenorrheic women
JAMA
Bone mineral content of amenorrheic and eumenorrheic athletes
N Engl J Med
Bone metabolism in adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects
Pediatrics
Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa
J Clin Endocrinol Metab
Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature
Osteoporos Int
Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review
Br J Sports Med
Endocrine manifestations of eating disorders
J Clin Endocrinol Metab
Recombinant human leptin in women with hypothalamic amenorrhea
N Engl J Med
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Clinical trial registration: clinicaltrials.gov, registration no. NCT00130117.
Author contributions: ES and FM contributed to data collection and analysis, data interpretation, and manuscript writing. KNA contributed to data analysis and data interpretation. MB and JPC contributed to data collection and analysis. SC, KMA, and CG contributed to the design and conduct of the study. AK contributed to manuscript writing. CSM contributed to the conduct of the study, data collection and analysis, data interpretation, and manuscript writing.