Long-term gonadotropin-releasing hormone agonist therapy: the evolving issue of steroidal "add-back" paradigms

The introduction of steroid "add-back" regimen draws on the recognition that several clinical entities targeted for treatment with GnRHa are not "six-month diseases". Included under this heading are individuals suffering from symptomatic endometriosis (not desirous of pregnancy), uterine fibroids (ineligible or disinterested in definitive surgical therapy), ovarian hyperandrogenism, premenstrual syndrome, menopausal transition, or dysfunctional uterine bleeding. A six month course of therapy with a GnRHa does not adversely affect lipoprotein economy and therefore presumably the corresponding cardiovascular risk. A six month course of GnRHa therapy appears to be associated with a substantial decrease (of up to 8.2%) in lumbar bone density, a phenomenon which may not be entirely reversible six months after discontinuation of therapy. In principle, steroid "add-back" therapy should diminish some or all of the side effects associated with GnRHa therapy, may provide a medical treatment option for patients representing a high surgical risk, and may delay surgical intervention if desired. On the other hand, a steroid "add-back" therapy may delay tissue diagnosis, be associated with a substantial cost as well as with the need in parenteral route of administration. Norethindrone-only (but not medroxyprogesterone acetate-only) "add-back" regimens have proved promising in the context of endometriosis. Non-concurrent estrogen/progestin "add-back" regimens proved promising in the context of uterine fibroids. Substantial additional studies would have to be carried out to validate the utility of steroid "add-back" regimens. Special emphasis will have to be placed on the evaluation of long-term utility with an eye towards assessing clinical efficacy, impact on lipoprotein economy, impact on bone density, impact on urogenital tissues, and impact on the hot flash. The concurrent or non-concurrent use of non-steroid "add-back" regimen will also most likely constitute a major component of future studies.