*4.1.3 Not all progestins are equal in restoring estrogen- progesterone balance in endometriosis. New trends-dienogest*

If there were questions if progestins are all equaly capable of acting on endometriosis lesions to induce apoptosis, or to inhibit cell proliferation, adhesion, invasiveness, angiogenesis/neuroangiogenesis, and inflammation, actually one knows their different actions and effects, according to their biochemical structure, and cross effects on glucocorticoid, mineralocorticoid and androgen receptors [117]. In the last 20 years, starting with the Japanese experiments [118] on rats induced- endometriosis, the progestin dienogest (DNG) was much analyzed in Japon, USA, Europe (The European Clinical Study Program) [119] in order to avoid progesterone resistance or progesterone attenuance, by reducing estrogen deleterious effects on endometrium- normal, eutopic and ectopic increasing PRs expression and decreasing proinflammatory cytokines, and the necessity of "add back" therapy imposed by GhRh agonists [120, 121] as it will be further discussed. It was demonstrated that DNG 2 mg/day (once/day in Europe, and 1 mg twice/day in Japon) [120] after 24–52 weeks of administration reduces lesions size, [122] without changing bleeding pattern [123] and with a good score regarding chronic pelvic pains [120]. Because it was proved an *in vitro* dose-dependent inhibition of human endometrial stomal cells proliferation together with morphological and functional changes [124], an Italian clinical study on 20 cases of endometriosis [125] had evaluated doses of 20 mg/day effects, for 24 weeks, with no comparative studygroup, and showed no clinically significant effects on hemostasis, haematologic parameters, thyroid and adrenal, liver functions, glucose and lipid metabolism, or electrolyte balance, with maintainance of mean high-density lipoprotein-3 cholesterol from the baseline.

The morphological studies reported inhibition of endometrial cells proliferation, by down-regulation of ESR2/ESR1 *ratio* [126] and aromatase expression [127] with local estrogen synthesis reduction, and the inhibition of human endometrial stomal cells proliferation, together with functional changes, as it is prolactin synthesis- a typical marker for decidualisation [124] and the association of increased apoptosis in endometriotic lesions [128]. DNG increases the PR-B/PR-A *ratio* in ovarian endometriosis [126] and down-regulates the expression of CYP19A1, and inflammatory, and neuroangiogenesis factors through PR- A and B- isoforms [129]. Some studies have revealed that DNG reverses some alterations of the immune system by increasing natural killer cells in the peritoneal fluid, and spleen, parallel to

the decrease of peritoneal fluid cellular content, and lower peritoneal macrophages synthesis of inflammatory cytokine IL-1β [118], and inhibits IL-1β release by the endometriotic epithelial cells [130].

## *4.1.4 Extended regimen of continuous combined hormonal contraceptives in endometriosis*

The continuous regimen or extended cycle vs. cyclic use of combined hormonal contraceptives was first proposed by Loudon [131] in a family planning clinic from Ediburgh (UK) by skipping the tablet-free interval of 7 or 4 days. The innitial proposed non traditional regimen was with 84 active pill with etyhil estradiol 50 μg plus linestrenol 250 μg /day and 7 days free, and it obtained a great adherence in women suffering of endometriosis, according to suppression of withdrawal bleeding, and inducing atrophy in ectopic and eutopic endometrium, as it is recognized by *Cochrane Database Syst Rev*., 2014 [132]. The regimen was recommended with levonorgestrel – LNG (90 or 100 μg/day), drospirenone- DRS (3 mg/day) [133, 134] desogestrel (150 μg/day) [135], NETA (1000 μg/day) [136], and recently dienogest (2 mg/day) [137] as progestins, associated to 20 or 30 μg/day of ethinyl estradiol. The regimen of ethinyl estradiol 20 μg plus LNG 90 μg/day was reported for 364 days at Eastern Virginia Medical School, Norfolk (USA) [138] and in Italy during 6 months with ethinyl estradiol 20 μg plus LNG 100 μg/day [139], or during 3 to 6 months in Germany, Frankfurt University [140, 141], and recently the Italian prospective open label study [137] analyzed ethinyl estradiol 30 μg/day plus dienogest 2 mg/day in a continuous regimen vs. 21/7 to assess quality of life and sexual function in women with endometriosis. The pharmaceutical industry created some drugs combinating ethinyl estradiol 30 μg/LNG 150 mg/day for 84 days plus 7 days *placebo*, or the combination of ethinyl estradiol 30 μg/LNG 150 mg/day for 84 days plus ethinyl estradiol 10 μg/day for 10 days, or of ethinyl estradiol 20 μg/LNG 150 mg/day for 84 days plus ethinyl estradiol 10 μg/day for 10 days [142] after the concept called "tricycle regimen" or "tricycling", first named so in Sweden in 1993 very easy to be followed, and very well appreciated by users [135].

The literature describes some attempts to short free hormones interval for the reduction of hormone withdrawal symptoms, as pelvic pains, headaches [143] and this regimen used LNG, norethindrone (1 mg/day), desogestrel, and norgestimate with ethinyl estradiol 35 μg or less/day. All these attempts were followed by better results of pelvic pain control, but after a longer duration of administration (as after 6 months of norethindrone).

One must consider the tricycle regimen of contraceptives in adolescents suffering of menorrhagia, dysmenorrhea, or with family history of endometriosis, in order to reduce the concerns of a future progress of an eventually later diagnosed endometriosis, existing already findings on this cathegory of women, at the Department of Adolescent Medicine of the University of Pitsburg (USA), with a significant ovarian suppression, endometrial atrophy, no metabolic change, and adolescents safety [144]. At this study one must add a recent one [145] sustaining that women who used the new generation of COC or only progestins have lower circulatory inflammatory biomarkers [IL-6, sTNFR2 (soluble tumor necrosis factor α receptor 2), and in a lower degree C-reactive protein] similar to the effect of a higher number of lifetime ovulatory years. The presence of progesterone after ovulation, the new generation of COCs, and the effects of progestins can be the explanation for the benefits in reducing systemic inflammation; being considered that chronic inflammation reduces ovulation rate in premenopausal women, and ovulation and menstruation increase local inflammation.

*Potential Therapeutic Options and Perspectives for Alleviation of Endometrial Estrogen… DOI: http://dx.doi.org/10.5772/intechopen.100039*

There are recent reviews on the comparison of flexible/extended COCs to cyclic COC use in endometriosis, published in 2018 in USA (on dysmenorhheea, non- pelvic pains, dyspareunia [146]), or in Europe [147] and the systematic review (2019) of only 8 RTC published between 1934 and 2018 (of a total 743 studies) on dysmenorrheea [148] and in 2021 [79]. It is shown a statistically significant, though modest, improvement in dysmenorrhea - a reduction of 50% when COCs were given for four months compared to *placebo* [147] and a shorter duration of only 4 days of the pains, with conflicting results on interference with daily activity, pain severity, and pain reccurence [148].
