Endometriosis is a gynecological pathology that occurs in 5-10% of women of reproductive age and in 25-30% of women with infertility, in which hormonally reactive endometrial cells grow outside the inner walls of the uterus [1]. The most common form is genital endometriosis, accounting for 92-95% of cases. The extragenital form of endometriosis occurs in 6-8% of patients [2]. The clinical manifestations of the disease are pain of varying severity (secondary dysmenorrhea, deep dyspareunia, chronic pelvic pain) and tubal infertility. At the same time, in 15-20% of women, the disease is asymptomatic [3]. Currently, the main therapeutic options for the treatment of endometriosis are conservative (hormone therapy), surgical methods, and a combination thereof [4].

Keywords: endometriosis, genital endometriosis, hormone therapy, progestins, dienogest, Vigest-KV.

Hormone therapy is the most common method of treating endometriosis [5]. It aims to suppress menstrual function, leading to a state of iatrogenic menopause or pseudopregnancy. Modern hormone therapy does not provide a complete cure for endometriosis, but it allows you to control pain, prevent or delay surgical treatment, and control the course of the disease for a long time [6].

The first line of hormone therapy for endometriosis is progestins [7] – gestagens that affect progesterone receptors, reduce the secretion of follicle-stimulating and luteinizing hormones, causing anovulation, a state of relative hypoestrogenism and amenorrhea, and thereby reduce endometrioid foci and manifestations of dysmenorrhea. In addition, progestins have an antiestrogenic effect, causing pseudodecidualization of the endometrium, which suppresses the inflammatory response in endometriosis [8].

Progestin drugs, which are most commonly used to treat endometriosis, contain dienogest, norethindrone acetate, medroxyprogesterone acetate, and desogestrel. Progestins are considered the first-line drugs for the treatment of endometriosis, given their high efficacy, good tolerability, and low recurrence rate [9, 10].

The purpose of the review is to evaluate current approaches to the use of progestogens in the treatment of endometriosis, using literary sources; to provide examples of their effectiveness, based on data from global and domestic practice.

Analysis of literature data

A review of literature sources devoted to modern approaches to the treatment of endometriosis was conducted using the Google Scholar, Research4Life, ScienceDirect, PubMed, and Scopus search databases. The analysis was performed using content analysis, comparative analysis, and bibliosemantics methods.

A total of 41 publications by foreign authors were selected and reviewed based on their relevance to the topic. The review also provides information on the effectiveness of the domestic progestogen drug Vigest-KV in the author’s own practice of endometriosis management.

Currently, the newest progestin is dienogest, a derivative of 19-nortestosterone. This type of progestin has shown high efficacy in patients with various clinical manifestations of endometriosis, as well as its recurrence [11, 12].

Compared to danazol and combined oral contraceptives, dienogest is an alternative treatment for pelvic pain in endometriosis. There is no information on its effect on reducing bone mineral density [13, 14].

As for the effect of dienogest on various phenotypes of endometriosis, it contributes to a significant reduction in the volume of both the endometrium itself and ovarian endometriomas, while preserving the ovarian reserve of the latter, which is very important for maintaining a woman’s reproductive function [15, 16]. Dienogest also effectively controls pain caused by rectovaginal and deep infiltrative endometriosis and helps improve quality of life, including sexual quality of life [17].

Long-term dienogest therapy regimens (60 months) are promising, as they effectively reduce pain and the risk of endometriosis recurrence, particularly after surgical treatment [18, 19]. A very important advantage of dienogest is the low incidence of side effects (1.2-2.5%), especially with regard to the reduction of bone mineral density [20].

Norethindrone is a derivative of 19-nortestosterone, a progestogen drug with a pronounced progestogenic effect. In low doses (2.5 mg/day) during long-term treatment, norethindrone is considered an effective, inexpensive drug that is well tolerated in the treatment of symptomatic rectovaginal endometriosis, which causes intense chronic pelvic pain and deep dyspareunia [21, 22]. This drug is widely used in the United States due to its good efficacy and safety profiles during long-term treatment of the disease [23, 24].

Medroxyprogesterone acetate is a derivative of 17-OH-progesterone, effective in the treatment of dysmenorrhea [25, 26]. The disadvantage of this drug is that with prolonged use (up to 2 years), it increases the risk of fractures due to estrogen deficiency [27]. It is used only when other methods of therapy are unacceptable.

Desogestrel (75 mg/day) is an effective treatment for pain associated with endometriosis [28, 29]. Profuse bleeding during use is the main side effect [29, 30].

The use of intrauterine devices containing levonorgestrel has been evaluated in a number of studies [30-32]. Levonorgestrel induces glandular atrophy of the endometrium and decidual transformation of the stroma and reduces the proliferation of endometrial cells [33]. After 6-12 months of treatment, there was a reduction in pelvic pain in peritoneal and rectovaginal endometriosis, as well as a reduction in the risk of recurrence of dysmenorrhea after conservative surgery [34, 35]. In addition, patients who were prescribed this method of therapy showed a decrease in the frequency of treatment refusal, which indicates its effectiveness in controlling postoperative pain and preventing recurrence. However, there are currently no data on the effectiveness of levonorgestrel-releasing intrauterine devices in preventing recurrence of ovarian endometrioma [36, 37].

Several experimental studies are currently being conducted on selective progesterone receptor modulators, which are ligands of progesterone receptors [38, 39]. They act in a complex manner, suppressing ovulation and endometrial proliferation, inhibiting endometrial bleeding by directly affecting the blood vessels of the endometrium, and reducing the production of endometrial prostaglandins.

Thus, it can be assumed that selective progesterone receptor modulators are effective in the treatment of endometriosis. However, there are currently no data on their use in clinical practice [40, 41].

The clinical experience of the authors of the article allows them to recommend the use of the drug Vigest-KV (manufactured by Kyiv Vitamin Plant), which contains 2 mg of dienogest in one tablet, for the treatment of various types of endometriosis. The advantages of the drug are its special mechanism of ovulation blockade, aimed at apoptosis of granulosa cells of the growing follicle. Long-term use of Vigeest-KV also leads to inhibition of follicle-stimulating and luteinizing hormone secretion and a moderate decrease in estradiol levels, which remain within physiological limits. This is very important for avoiding symptoms of estrogen deficiency while maintaining the antiproliferative effect. This drug also has powerful antiangiogenic, anti-inflammatory, and immunomodulatory effects.

Daily intake of one Vigest-KV tablet (daily dose of dienogest 2 mg) for 65 weeks provides effective reduction of pain syndrome in various types of endometriosis. There is also a significant reduction in the number and size of endometrioid lesions. The drug is well tolerated during long-term use; after 6 months of treatment, the frequency of disease recurrence is minimal.

Conclusions

Given the clearly defined endocrine pathogenesis of endometriosis, hormone therapy is currently the cornerstone of its management. It not only reduces the clinical symptoms of endometriosis, but also serves as a first-line treatment, particularly before and after surgery, to reduce the risk of recurrence. The most popular and widespread hormonal treatment for endometriosis is the use of progestins (dienogest), which, on the one hand, reduces clinical manifestations and the risk of recurrence, and on the other hand, preserves ovarian reserve (i.e., a woman’s reproductive function).

Dienogest, as the most common and effective progestin, has a pronounced antiproliferative effect on endometrial cells, as well as anti-inflammatory and immunomodulatory effects with minimal risk of side effects. Oral administration of dienogest at a dose of 2 mg/day provides a progressive reduction in clinical symptoms, improved quality of life, and preservation of reproductive function.

Based on the clinical experience of the authors of the article regarding the use of the domestic drug Vigeest-KV for various types of endometriosis, its widespread use in gynecological practice can be recommended.

Bibliography – under review.

First published in: Reproductive Endocrinology, No. 2(72)/June, 2024.