Prospective Randomized Study of the Effect of “Add-Back” Hormone Replacement on Vascular Function During Treatment With Gonadotropin-Releasing Hormone Agonists

BACKGROUND: Gonadotropin-releasing hormone agonists (GnRHas) are a group of drugs that with long-term use induce a pseudomenopausal state in which estrogen production is suppressed. They are commonly used in the treatment of sex steroid-dependent conditions. "Add-back" hormone replacement therapy is used to prevent menopause-like symptoms and bone loss during GnRHa treatment, but it is also recognized that hypoestrogenism adversely affects vascular function. The aim of this study was to examine the effect of GnRHa and add-back therapy on vascular reactivity. This model serves as a paradigm for the effect of hormone replacement therapy in postmenopausal women. METHODS AND RESULTS: Measurements of endothelium-dependent and endothelium-independent vascular reactivity were compared in 2 groups of women treated with a GnRHa for 6 months. One group received estrogen/progestogen add-back therapy during the second 3 months of GnRHa treatment. Vascular reactivity was examined by use of ultrasound measurements of changes in brachial artery diameter. Endothelium-dependent changes were assessed during reactive hyperemia, whereas endothelium-independent changes were measured after the administration of glyceryl trinitrate sublingual spray. Treatment with the GnRHa alone had an inhibitory effect on endothelium-dependent relaxation. However, endothelium-dependent relaxation significantly improved in the group receiving add-back therapy (14.6%) compared with the group treated with GnRHa alone (8.6%) (P<0.01). There were no significant endothelium-independent changes in either group. CONCLUSIONS: These results suggest that the administration of add-back therapy has a protective effect on vascular function in GnRHa-induced hypoestrogenism. As a model for the menopause, these results also suggest that the long-term administration of hormone replacement therapy would result in endothelium-dependent arterial relaxation, an observation previously attributed only to the acute administration of estrogen.