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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.
Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with
hypothalamic amenorrhea. N Engl J Med 2004;351:987-97.
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
Reference - (linked to  )
- Ahima RS. N Engl J Med 2004;351:10:959-62.
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Current GGH - Vol. 24 No. 1
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