Endometriosis is an estrogen-dependent inflammatory disease that affects 6-10% of females of reproductive age . It is characterized by the presence of endometrium-like tissue outside the uterine cavity, primarily on the ovaries, and represents one of the most common causes of chronic pelvic pain, dysmenorrhea and infertility . The main aims of treatment are to alleviate pain and other symptoms, reduce the size of the endometriotic lesions and improve the quality of life of affected individuals. Nonsteroidal anti-inflammatory drugs are frequently used by patients with endometriosis in an attempt to relieve pelvic pain, although clinical trial evidence to support the efficacy of these agents in endometriotic patients is lacking . Gonadotropin-releasing hormone (GnRH) agonists are an established therapy for endometriosis. Although GnRH agonists provide effective pain relief and reduce the progression of endometriotic implants , the hypoestrogenic state they induce is associated with negative effects such as accelerated bone mineral density loss, hot flashes and vaginal dryness . Oral contraceptives (OCs) are widely used to treat the symptoms of endometriosis, although they are not approved for this indication in the majority of countries due to the lack of supportive trial evidence . Progestins have long been used for the treatment of endometriosis to relieve pain by suppressing ovarian estrogen biosynthesis, in turn, suppressing growth and inflammation . Unfortunately, the relief of pain appears to be relatively short-term , and approximately 9% of females with endometriosis simply do not respond to progestin therapy due to unknown reasons . In fact, a general tendency for relative progesterone resistance within the eutopic and ectopic endometrium of females with endometriosis is well-documented [1, 10].
Recently, two major progesterone receptor (PR) isoforms were identified, namely PR-A and PR-B (11). PR-A is a 94-kDa protein, whereas PR-B is a 114-kDa protein that contains an additional NH2-terminal stretch of approximately 165 amino acids containing a region encoding a transactivation function. These isoforms may arise as a result of either initiation of translation from alternative sites in the same messenger RNA (mRNA)  or by transcription from alternative promoters . Although the exact functions of each of these isoforms remain unclear, there is increasing evidence that they are functionally different [12, 13]. PR-B tends to be a stronger activator of progesterone target genes, whereas PR-A has been shown to act as a dominant repressor of PR-B [14, 15].
Endometriosis is associated with a reduced response to progesterone in both eutopic and ectopic endometrium. According to recent reports, the resistance of endometriotic tissue to progesterone, evident in both laboratory and clinical observations, can be explained by alterations in the distribution of ER and PR isoforms and dysregulation of progesterone target genes [10, 16–18]. Because the effects of progesterone on target genes are conferred primarily by PR-B in the endometrium , the presence of the inhibitor isoform-A and the absence of the stimulatory isoform-B provide a possible explanation for progesterone resistance in endometriotic implants. In fact, a decreased PR-B/PR-A ratio has been demonstrated in ectopic tissue [20, 21], and recent reports suggest that the tendency toward progesterone resistance in patients with endometriosis is likely the result of the promotion of hypermethylation of PR-B, which renders PR-B either silenced or downregulated . Moreover, a number of investigators have reported markedly elevated levels of ERβ and lower levels of ERα in human endometriotic tissues and primary stromal cells compared with that observed in eutopic endometrial tissues and cells [16, 22, 23]. ERβ, acting as an ERα suppressor, might contribute to the decreased PR levels and progesterone resistance observed in patients with endometriosis .
Dienogest (17a-cyanomethyl-17b-hydroxyestra-4,9-dien-3-one) is an oral progestin that has been systematically investigated for the treatment of endometriosis in dose-ranging , placebo-controlled [26, 27], active comparator-controlled [28, 29] and long-term trials  conducted in Europe and Japan. The main anti-endometriotic effect of dienogest has been suggested to be attributable to central inhibition of ovulation. Furthermore, direct antiproliferative effects of dienogest have been demonstrated in human eutopic endometrial stromal cells . Recent studies demonstrate that dienogest inhibits the proliferation of endometriotic stromal cells , prostaglandin E2 production and the aromatase mRNA expression of the endometrial epithelial cell line . However, there is no evidence regarding whether dienogest improves progesterone resistance in patients with endometriosis. In the present study, therefore, we examined the effects of dienogest on alterations in the ratios of PR-B to PR-A and ERβ to ERα in ectopic endometrial tissue obtained from endometriotic females.