Clinical dynamics of Dienogest for the treatment of endometriosis: from bench to bedside

KEYWORDS:

• Dienogest
• endometriosis
• chronic pelvic pain
• pharmacokinetics
• clinical use

1. Endometriosis onset and progression: targeting the disease

Endometriosis is a common benign and proliferative chronic disorder, characterized by the presence of endometrial glands and stroma outside the uterus: in particular, ectopic endometrial tissue undergoes similar cyclic changes of the eutopic endometrium, following phase-specific hormonal stimuli. According to the European Society of Human Reproduction and Embryology (ESHRE) guidelines [1], endometriosis affects about 6–10% of reproductive-aged women with an average age at diagnosis ranging from 25 to 30 years. The most diffused classification was proposed and revised by the American Fertility Society, using a score system based on the presence of subtle, typical, cystic, or deep infiltrating endometriosis (DIE). Among the classical symptoms and signs, menstrual irregularities, chronic pelvic pain (CPP), dysmenorrhea, dyspareunia, and infertility can play a detrimental role on patient’s quality of life [2]. Despite the large amount of published articles, the pathogenesis of endometriosis still remains controversial due to the lack of robust evidence: immune, hormonal, genetic, and epigenetic factors may be all involved, and several theories have been proposed to explain it. Epigenetics may underlie the pathogenesis of endometriosis better than genetics: on one hand, accurate meta-analysis [3] failed to show robust evidence of a possible correlation between gene polymorphisms (CYP1A1, CYP2E1, EPHX1, AHR, ARNT, AHRR, NAT1, and NAT2) and endometriosis; on the other hand, epigenetic modifications could be considered causes or effects of the pro-inflammatory microenvironment and progesterone resistance, typical of the disease. Indeed, the altered expression of progesterone receptor or its diminished activity may lead to attenuated response to progesterone and decreased expression of progesterone-responsive genes [3]. During the recent past, the treatment of endometriosis consisted of combined oral contraceptives (COCs): nevertheless, it is widely accepted that endometriosis is an estrogen-dependent disease, since estrogens are able to enhance endometriotic cell proliferation and induce the differentiation of regulatory T cells, which further amplify the so-called ‘immune-escaping’ [4]. Based on these elements, to date, progestins (synthetic progestational agents) are used in the management of symptomatic endometriosis both as first-line therapy and after surgery. As recently reviewed by Angioni et al. [5], progestins are usually well tolerated and offer similar efficacy for the treatment of endometriosis-related CPP and prevention of recurrence with respect to other drugs. Nevertheless, ESHRE clearly stated that there is no overwhelming evidence to support particular treatments over others among hormonal contraceptives, progestagens and anti-progestagens, gonadotropin-releasing hormone (GnRH) agonists and antagonists, and aromatase inhibitors for endometriosis-associated CPP [1].

2. Weapon of choice, Dienogest: why, how, when

Among the progestins, Dienogest (17-hydroxy-3-oxo-19-nor-17alfa-pregna-4,9-diene-21-nitrile) combines several beneficial effects of the 19-norprogestin and progesterone derivative classes, including high specificity for the progesterone receptor and negligible binding affinities for estrogen, androgen, glucocorticoid, and mineralocorticoid receptors. In addition, it has progestogenic and antiestrogenic effects on both eutopic and ectopic endometrium [6]. Compared to other 19-norprogestin-derived drugs, Dienogest does not bind to the androgen receptor and, consequently, lacks androgenic effects [6]. Conversely, it maintains the typical antiandrogenic effect of the progesterone derivatives (approximately one third that of cyproterone acetate) and does not cause metabolic dysbalances. Despite accumulating evidence suggests that Dienogest has a favorable safety profile, a recent systematic review [7] found a lack of studies comparing Dienogest with first-line therapy, such as progestins and estrogen–progestogen combinations, which are proved to be effective in the treatment of endometriosis, are less expensive, and also can be used for contraception [1]. In addition, the Dienogest-only therapy has several contraindications similar to other progestins, including pregnancy (also suspected), lactation, cardiovascular and thromboembolic disorders, history of hepatic disease, sex hormone-dependent malignancies, and undiagnosed abnormal vaginal bleeding.

It was already showed that Dienogest significantly decreases estrogen levels in endometriotic tissue, through inhibition of aromatase and 17β-hydroxysteroid dehydrogenase type 1 in stromal cells of ovarian endometriomas, increases apoptosis of endometriotic cells, and reduces the production of pro-inflammatory cytokines by endometriotic stromal cells [8]. Furthermore, it decreases the production and release of estradiol-induced angiogenic factors such as vascular endothelial growth factor and stromal cell-derived factor in endometrial stromal cells, corroborating the already promising suppression of angiogenesis previously showed in the mouse model [9]. For all these reasons, Dienogest is primarily indicated for the clinical management of pelvic pain associated with endometriosis as 2 mg oral tablet per day, for a maximum of 15 months. Although based on a limited population of patients affected by endometriosis stage I–III, recent data showed that Dienogest is able to reduce the dimension of endometriotic lesions (laparoscopic second-look) both as 2 and 4 mg/day after 24 weeks of oral treatment: in particular, it significantly reduced mean rAFS scores from 11.4 to 3.6 in the 2-mg group and from 9.7 to 3.9 in the 4-mg group [10]. Nevertheless, this study did not subdivide among subtle, typical, cystic, or DIE lesions.

In humans, pharmacokinetics of Dienogest is not influenced by sex hormone-binding globulin or corticoid-binding globulin levels. After the ingestion, it has about 91% of bioavailability: 10% of the total serum drug concentration is present as free steroid and 90% is nonspecifically bound to albumin; it is metabolized mainly through CYP3A4 and, finally, its degradation products are excreted both in urine and in stools [6].

The key point of endometriosis treatment with Dienogest is doubtless the continuative regimen of the therapy, avoiding decrease of drug steady state (usually reached after 4 days of treatment), which may allow endometriotic cell proliferation and so increase endometriotic implants. From the clinical perspective, a recent systematic review of nine randomized trials [7], which included stage I–IV endometriosis, confirmed that the treatment with Dienogest 2 mg/day has similar outcomes with respect to GnRH agonist (buserelin, leuprorelin, leuprolide acetate, and triptorelin) in controlling associated symptoms. In this regard, a Japanese study investigated Dienogest at daily doses of 1, 2, and 4 mg for 24 weeks in 183 women with endometriosis [11]: according to this data analysis, the 2 and 4 mg daily doses were equivalent in efficacy, measured as a global improvement in subjective symptoms. Nevertheless, the reduction of estradiol levels was significantly different between the two doses (37.4 and 26.2 pg/mL for Dienogest doses of 2 and 4 mg/day, respectively), suggesting a more favorable pharmacologic profile for the 2 mg dose: on one hand, this dose seems able to suppress estrogen levels sufficiently to inhibit endometriotic lesion growth; on the other hand, it is adequate to prevent hypoestrogenic side effects, such as bone mineral loss.

In addition, a pooled analysis from the European clinical study program (332 women affected by endometriosis stage I–IV, enrolled in four clinical trials and treated with Dienogest 2 mg) confirmed the favorable safety profile that all the adverse events are generally of mild-to-moderate intensity and associated with low discontinuation rates and, finally, that estradiol levels are maintained within the low physiological range over a period up to 65 weeks [12].

Nevertheless, Dienogest is slightly more expensive than other progestagens and, according to the ESHRE guidelines [1], has the same level of recommendation to reduce endometriosis-associated pelvic pain. Considering these elements, the choice of the medical treatment should take into account also the different side-effect profiles of progestagens and anti-progestagens.

3. Expert opinion

Recent and robust data have shown that Dienogest is effective for the treatment of endometriosis, reducing the dimension of endometriotic foci and their vascularization, decreasing endometriosis-related CPP and recurrence rate after surgery. In addition, this drug showed a very tolerable safety profile, maintaining the same contraindications of other progestin-only therapies and causing a negligible rate of side effects also in the long term: in particular, Petraglia et al. [13] reported potentially treatment-related adverse effects in 16.1% of women, including breast discomfort (4.2%), nausea (3.0%), and irritability (2.4%).

To date, it is widely accepted to consider endometriosis as an estrogen-dependent disease: on one hand, estrogens cause proliferation of endometriotic foci and increase their vascularization, whereas on the other hand, they enhance local immunosuppression, allowing the escape of endometriotic cells from immune surveillance by resident and recruited mononuclear cells. In this view, we suggest to use progestin-only therapy for endometriosis, leaving COCs only in case of hypoestrogenism or as add-back therapy during treatment with GnRH agonist. Despite the promising scenario, there is the necessity of future clinical (superiority, equivalence, and non-inferiority) trials on large cohorts, in order to compare Dienogest with respect to other progestin-only and COC therapies for the treatment of endometriosis. In addition, the indication and timing (only medical therapy; before or after surgery) of progestin-only therapy should be standardized and tailored according to patient’s clinical characteristics: stage of the disease, age, residual disease after surgery, parity, and offspring desire. In our opinion, the surgical approach should be balanced between a careful conservative, fertility-sparing management and the necessity to remove all the visible endometriotic lesions without causing permanent and severe decrease of quality of life; consequently, the medical therapy after surgery can have paramount importance to improve symptoms. In this regard, the administration of Dienogest for a year or more seems to be highly effective in preventing recurrence after surgery, reducing endometriosis-associated pain, and decreasing the size of recurrent endometrioma in patients who do not immediately desire pregnancy [14].

Finally, it would be interesting to further investigate the effects of Dienogest in endometrial malignancies, since recent evidence suggests that it can suppress the proliferation in vitro of endometrial cancer-derived cell lines which failed to respond to other progestins such as medroxyprogesterone acetate, and showed potent anticancer activity against endometrial neoplasms in mouse model [15].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.