Correspondence

Luteinizing Hormone–Releasing Hormone and Postmenopausal Flushing

N Engl J Med 2009; 361:1218-1219September 17, 2009

Article

To the Editor:

The trigger for postmenopausal flushing is incompletely understood1; therefore, it has been difficult to develop new treatments. Neuroendocrine mechanisms, such as increased activity of luteinizing hormone–releasing hormone (LHRH), might be involved.2 It has been speculated that a functional link exists through LHRH-producing neurons, which are very close to the hypothalamic thermoregulatory centers.3 To test this hypothesis, we treated three women who had severe postmenopausal flushing with cetrorelix, an LHRH receptor antagonist. Each of the women had undergone menopause as a result of oophorectomy, which had been performed several years previously. Severe flushing developed in Patient 1 (who was 65 years of age) after estrogen-replacement therapy was discontinued. Patient 2 (49 years of age) was a survivor of breast cancer who had been treated with anastrozole. Patient 3 (59 years of age) had undergone successful surgery for stage I endometrial carcinoma.

The short-term response to cetrorelix was studied during a 5-day in-hospital suppression test with a dose of 250 μg given subcutaneously once a day at 9 a.m.4 Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured on basal samples just before the cetrorelix was administered. Hot flushes were recorded in a diary. The frequency of flushing decreased by 60 to 80% in Patients 1 and 2, but no effect was observed in Patient 3. Because Patient 3's body-mass index (the weight in kilograms divided by the square of the height in meters) was high (39.8), her dose was increased to 250 μg twice a day; after the increase in dose, the frequency of flushing was reduced by 80% within 5 days. Figure 1Figure 1Long-Term Response to Cetrorelix in the Three Patients. shows the results of long-term outpatient treatment with an initial dose of 250 μg once a day in Patients 1 and 2 and of 250 μg twice a day in Patient 3. Suppression of serum LH and FSH levels and a marked decrease in the frequency of flushing occurred in all three patients, with maximal responses occurring within 4 weeks. The frequency of flushing plateaued at about 12 episodes per day in Patient 2. An increase in the dose to 250 μg twice a day (arrow in Figure 1) further decreased the frequency of flushing to five episodes per day. Patient 3 reported increased flushing after the first month, possibly owing to stressful events in her life. Discontinuation of cetrorelix at week 20 in Patient 1 was associated with an increase in LH levels and FSH levels within 5 days, whereas flushing did not return until about 6 weeks after discontinuation of the drug. The observed efficacy of cetrorelix approaches that observed with estrogen-replacement therapy and markedly exceeds the 25 to 30% decreases observed with placebo.5 Despite the limitations of this pilot study (i.e., it was uncontrolled, included few subjects, and did not include objective recordings of flushes), we feel that responses of this magnitude merit a systematic, placebo-controlled evaluation of LHRH receptor blockade.

Hans de Boer, M.D., Ph.D.
Petri van Gastel, M.D.
Adriaan van Sorge, Ph.D.
Rijnstate Hospital, Arnhem, the Netherlands
hdeboer@alysis.nl

Supported by the Department of Internal Medicine, Rijnstate Hospital.

5 References

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Citing Articles (1)

Citing Articles

1. 1

   Santiago Vilar-González, Alberto Pérez-Rozos, Ruben Cabanillas-Farpón. (2011) Mechanism of hot flashes. Clinical and Translational Oncology 13:3, 143-147
   CrossRef