Hypothalamic Amenorrhea and Leptin
© 2005 Prime Health Consultants, Inc.
The authors assessed the effects of leptin treatment in 8 patients with hypothalamic amenorrhea, compared with 6 patients who were not treated. All 14 patients had secondary amenorrhea for 6 months or longer, coincident with increased exercise or low body weight and were otherwise healthy without acne, hirsutism or LH/FSH, TSH, and prolactin alterations. Basal and follow-up assessments in a clinical research center included comprehensive endocrine, body composition, metabolic rate analyses, bone densitometry and pelvic ultrasonography. The patients treated with leptin (r-metHuLeptin) received 0.08 mg/kg/day subcutaneously for 2 to 3 months, with 40% of the dose given at 8:00 AM and 60% given at 8:00 PM. If patients ovulated the study was terminated at 2 months. If no ovulation occurred the dose was increase to 0.2 mg/kg/day for a third month. Leptin treatment increased mean LH levels and LH pulse frequency after 2 weeks of treatment and increased maximal follicular diameter, the number of dominant follicles, ovarian volume and estradiol levels over the study period. Three patients had ovulatory menstrual cycles; 2 had preovulatory follicular development and withdrawal bleeding during treatment. Leptin treatment significantly increased levels of free T3, free T4, IGF-I, IGFBP-3, bone alkaline phosphatase and osteocalcin but not cortisol, corticotropin, nor urinary N-telopeptide. Untreated control patients did not have any significant changes in any of these variables. Body weight did not change in the control patients; however it decreased slightly among the treated ones, owing to a small decrease in body fat without changes in lean body mass. No significant changes in metabolic rates or food intake occurred. The authors concluded that the relative leptin deficiency in women with hypothalamic amenorrhea is improved with leptin treatment. This results in improved reproductive, thyroid, growth hormone axis and markers of bone formation, suggesting that leptin is required for normal reproductive and neuroendocrine function.
Editor’s Comment: Hypothalamic amenorrhea, also called functional amenorrhea, is frequently seen in women who are athletic, underweight and/or stressed. It is usually preceded by irregular menses, weight loss or increase in physical activity and it is considered to be the result of energy deficiency. In non-athletic women of normal weight it may be associated with psychosocial stress also related to subtle deficits in calorie and macronutrient intake. The central energy-related hormone, leptin, is the common factor underlying the pathogenesis of this entity. The study by Welt et al adds data substantiating the importance of leptin in mediating the neuroendocrine abnormalities of hypothalamic amenorrhea, a leptin deficiency condition. They demonstrated an improvement with leptin treatment, without other medications to induce menstruation, while the patients maintained their usual dietary intake, exercise habits and lifestyle. However, let’s not tread into new expensive treatments without correction of nutrient deficiencies or without first attempting to modify the dietary intake to meet all the energy and nutrient needs of the patient. The accompanying editorial by Ahima1 addresses the distinguishing features of this condition from anorexia nervosa, as well as an erudite explanation of the pathophysiology of the disease as it relates to body fat, leptin and hypothalamic amenorrhea.
Fima Lifshitz, MD
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