The Current Place of Progestins in the Treatment of Endometriosis

Karl-Werner Schweppe


Expert Rev of Obstet Gynecol. 2012;7(2):141-148. 

In This Article

Effects on Target Tissue

The mode of action on the endometriotic implant is still a contentious issue. Earlier studies on the subject postulated activities via the steroid receptor mechanism as known from the uterine mucosa, meaning that secretory changes in ectopic lesions were followed by decidual transformation and atrophy. Later studies cast doubt over this hypothesis. Endometriotic foci either contain progesterone receptors in very low concentrations, or else they are absent,[2] and enzyme systems differ widely between eutopic and ectopic endometrial tissue.[3] Progestins reduce the synthesis of their own receptors, resulting in diminished sensitivity of the implants during long-term treatment. Morphological studies have revealed different reactions of endometriosis: after long-term use (9 months) of progestin influence, some implants remained unchanged; however, some demonstrated arrested epithelium and some had abortive secretory reactions, but decidual reaction and necrosis could not be demonstrated.[4] On comparative ultrastructural examinations between eutopic and ectopic endometrium, significant differences were seen during the menstrual cycle: endometriotic foci are delayed with respect to the uterine endometrium and still proliferative in the luteal phase.[5] It is thought that this insensitivity to the influence of progestins (known as progesterone blockage) may be caused by specific changes in enzyme systems,[6] in addition to low or reduced receptor concentrations. The 17-β-hydroxysteroid-dehydrogenase type 2 is defective and can not be activated by progestins, resulting in increased proliferation, as estradiol is not inactivated.[7] In addition, a pathologic activity of aromatase is found in ectopic implants. Therefore, more estradiol is produced by the endometriotic foci itself, converting androgens to estrogens. Horie et al. described a new mechanism of controlling the growth of endometriosis by progesterone and progestogens.[8] TNF-α and estradiol induced, via NF-κB activation, the proliferation of endometriotic stromal cells, whereas progestogens were found to reduce TNF-α-induced NF-κB activation. In addition, progestins induce suppression of matrix metalloproteinases, which are involved in the implantation and progression of ectopic endometrium. For dienogest, a C19 steroid with a cyanomethyl group at C17 and a double bond between C-9 and C-10, it has been demonstrated using a rat endometrial autograft model that this substance inhibits angiogenesis in the ectopic endometrium through structural changes in the microvessels and decreased microvessel density, which can reduce the development and progression of endometriotic implants.[9] Furthermore, dienogest can inhibit proliferation of endometrial stromal cells in vitro due to an increase in the arrest of cells in the G0/G1 phase of the cell cycle.[10]

Up to now, the details of the mechanisms of action and the morphological changes induced by progestins in humans have only been partly understood (Figure 1), even though progestins have been used in the treatment of endometriosis in many different countries for a number of years.

Figure 1.

Mechanism of action of progestins in the treatment of endometriosis. The cause of endometriosis may be implantation or metaplasia but the local reaction is the same: the implants grow and invade the tissue in their vicinity, causing inflammatory reactions. Progestins reduce the elevated activity of metalloproteinases and growth factors. The inflammatory reactions in and around the endometriotic implant are suppressed and, in addition, the peripheral estrogen levels are minimized via negative feedback to the hypothalamic–pituitary axis.


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