Reappraisal of progestins in endometriosis therapy.

Abstract

Endocrine treatment of endometriosis is based upon the suggestion of Kistner that regression of endometriosis can be obtained by induction of pseudo-pregnancy with a combination of oestrogen and progestin (1). The 40-year history of conservative medical therapy of endometriosis demonstrates that many substances and their combinations have been tested, including low-dose oral contraceptives, progestin alone (several candidates), danazol, gestrinone and gonadotrophin-releasing hormone (GnRH) agonist analogues (2, 3). Unfortunately, the clinical efficacy of different treatment modalities was investigated mostly retrospectively or in uncontrolled trials until the late 1980s (2, 3). The more recent studies on the efficacy of drug therapy have been prospective and based on adequate study designs with control therapy and endoscopic confirmation of endometriosis and its behaviour. They have shown that none of the agents or combinations tested so far is superior to others in efficacy. They essentially differ from each other only in tolerance, side effects and cost. Therefore it is still unclear which one of the several currently available alternatives is ‘the drug(s) of choice’ for medical treatment of endometriosis with regard to all the aspects that should be taken into account in this context. Progestin alone was the most popular medical treatment of endometriosis for about 20 years. Danazol was introduced more than 15 years ago, and since then it has widely replaced progestins in clinical practice, although there is no evidence of its superiority over progestational agents. On the contrary, subsequent studies have shown that danazol and medroxyprogesterone acetate (MPA), the most common progestin used in the treatment of this disease, are equally effective in the resolution of endometriosis and pain relief (4, 5). Studies from the USA (6) and Italy (7) have also brought evidence that progestin alone produces a good clinical response for endometriosis, which is comparable with the effect of danazol (6). During the past decade, different GnRH agonist analogues have completed the list of drugs inducing antiproliferative effects on endometriosis tissue. Comparisons with danazol have repeatedly failed to reveal any significant difference in their ability to abolish endometriosis implants or to alleviate pelvic pain and other subjective symptoms of endometriosis (3). It is also significant that MPA at doses up to 100 mg a day induces less harmful changes in lipid and lipoprotein metabolism than androgenic danazol. In addition, it is free from hypo-oestrogenic side effects and metabolic sequelae typical of GnRH analogues. We must further acknowledge that each of the present endocrine treatments is often unable to achieve complete and permanent resolution of endometriosis. Recurrences are common after surgical or medical conservative treatment. The risk of symptomatic recurrence has been as high as 40% at 9 years follow up (8). Each of the present hormonal treatment modalities, including danazol, GnRH analogues and MPA, is thus far from optimal. Consequently, more efficient and safer compounds are required for the suppressive treatment of endometriosis and the control of endometriosis-associated complaints. There are no breakthrough discoveries in sight that could open up totally new prospects for endometriosis therapy. Therefore more scientific attention should be given to potential agents that have not been tested adequately for treatment of this disease. Several progestational compounds are interesting in this respect. The most attractive alternatives are nonandrogenic and free from metabolic side effects, e.g. dydrogesterone, cyproterone acetate, and natural progesterone meet these requirements. In fact, in my department we have found that natural oral progesterone is efficacious in the treatment of endometriosis (unpublished data). Previous studies have also shown that a novel progestin, dienogest, does not affect lipid metabolism in humans (9) or rats (10). It thus also belongs to the group of agents that deserve attention from researchers. A study group in Japan has recognized this challenge and presents in this issue of European Journal of Endocrinology interesting and promising results on the efficacy and mechanism of action of dienogest in experimental endometriosis, using the model of renal subcapsular autotransplantation of endometrial tissues in rats (11). In terms of short-term effects, dienogest diminished the volume of endometriosis implants as much as danazol, which has also been a ‘gold standard’ in clinical trials on endometriosis (3). The mechanisms by which different hormonal compounds induce their suppressive actions on endometriosis are not known in detail. Possibly both direct and indirect actions are involved. According to the classic theory, suppression of the anterior pituitary– ovarian axis activity with concomitant discontinuation of the stimulatory oestrogen support to endometrial tissues is probably the central event in this process. Progesterone and possibly also androgen receptors play European Journal of Endocrinology (1998) 138 134–136 ISSN 0804-4643