This randomized study had as the primary endpoint to investigate the efficacy of E2 / NOMAC or DNG intake in women with CPP associated with endometriosis-associated CPP, during 12 months of treatment. The design of the study was based on critical observation of the survey length. In fact, efficacy studies are usually limited to 3–6 months. By adopting such a design, we often cannot know what longer-term effects and benefits the treatment may have and how many people discontinue it.13
Although women of both groups had an improvement in their endometriosis-associated pain, from the 3-month follow-up to the end of the study, women on DNG had a better improvement of their pain symptoms than those on E2/NOMAC.
However, the improvement of QoL and sexual life of both groups could be due to the progressive reduction of the pain syndrome reported by women. Moreover, the intergroup comparison showed a better improvement of QoL and sexual function in women who were using DNG than in those on E2/NOMAC, mainly for the somatic scores at the 6- and 12-month follow-ups.
Today, several progestogens, although not approved to treat pain syndrome associated with endometriosis, are widely prescribed.3 DNG, unlike other progestogens, has been approved for medical treatment of endometriosis6, by continuous or extended regimens.14 DNG 2 mg daily has been shown to have insufficient contraceptive activity15, therefore women who do not wish to become pregnant could use an estrogen-progestogen contraceptive. One of its catabolic characteristics consists in its half-life of 10 h, in a continuous or extended regimen; therefore, it must be administered on a continuous or extended regimen, associated or combined with an estrogen. Treatment of endometriosis-associated pain symptoms should exclude hormone-free interval regimens. In fact, if this were the regimen, women may complain of symptoms returning during the hormone-free interval. Authors showed that DNG combined with estradiol valerate in a 26/2 four-phase association was effective on the pain syndrome.16 The proliferative activity of the endometrial epithelium induced by estrogen is well known, as well as the inhibitory activity of progesterone towards its proliferation. The synchronous activity of the two steroids in ectopic endometrial tissue is not respected. In fact, the unbalanced activity between the two steroids, with estrogen predominance, promotes a chronic inflammatory state. The inability of progesterone to balance the proliferative activity of estrogen depends on altered or reduced of its receptor expression in endometriosis tissues.17 Reduced progesterone activity is accompanied by low levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 production, whereby E2 is not converted to estrone, its biologically less potent metabolite; moreover, Furthermore, in endometriosis tissue, there is an anarchic production of p450 aromatase expression which increases E2 level.18 Increased neuroinflammation and neoangiogenesis due to increased E2 supports the persistence of the CPP.19 Because of what has been mentioned above, when E2 is used in hormonal contraception, it could have metabolic and tissue effects that are less than those of EE, Indeed, it is interesting to know that 5mg of EE is equivalent to about 1 mg E2. Therefore, the common usage of low-dose OCs containing 20 to 30mg of EE is equivalent to 4 to 6 times the physiologic dose of E2.20
The main therapeutic activity of progestogens in endometriosis is due to progesterone receptor signaling, which induces downregulation of estrogen receptors.21 Dienogest is able to inhibit aromatase expression and, as a result, local estrogen production is reduced.22 Moreover, Dienogest inhibits the expression of 17β-HSD type 1, the enzyme that catalyzes the reduction of estrone to estradiol, and upregulates the expression of the oxidative 17β-HSD type 2, which inactivates estradiol. 23
NOMAC is a 19-norprogesterone derivative that binds specifically to the progesterone receptor; it has strong antiestrogenic effects, inhibiting 17β-HSD type 1, with a consequent reduction of conversion of estrone to estradiol. 24 Moreover, it reaches a peak serum concentration within 4 h after oral administration and, unlike DNG, its half-life is approximately 50 h.5 Thus, in the 24/4 E2/NOMAC OC regimen, the steroidal activity of NOMAC is able to cover the 4-day hormone-free interval. In fact, women on E2/NOMAC usually have reduced bleeding, and some women experience amenorrhea.25 In our study 30.3% of women had amenorrhea, however, less than the women on DNG (65.3%). Reduction in bleeding or even more so the amenorrhea observed in both groups could decrease or disrupt, respectively, the retrograde flow of menstrual tissue through the fallopian tubes, that is one of the most established hypotheses of endometriosis pathogenesis.26
It is important to consider that CPP and dysmenorrhea usually start during adolescence, but treatments are often started several years later and are not always adequate to limit or reduce the progression of endometriosis. Early diagnosis and treatment are essential in order to decrease neoangiogenesis and neuroinflammation and so the chronic inflammatory status, and preserve future fertility.27 Pain symptoms usually reappear when estrogen-progestin or only progestin intake is discontinued. In fact, progestins and combined hormonal contraceptives do not eliminate endometriotic lesions but induce their quiescence. 28 Consequently, their usage has to be for a long time. However, unlike progestin-only contraceptives, biological data support the results that prolonged use of estrogen-progestogen contraception could promote a progression of endometriotic lesions. Consequently, some authors support the use of progestin-only contraceptives rather than OCs, considering them as first-line therapy for treating endometriosis CPP. 29
In all the women using E2/NOMAC or DNG, QoL and sexual function improved. Even if receptor binding studies showed that DNG has approximately one-third of the anti-androgenic activity of cyproterone acetate, and could affect the libido of long-term users, recent studies showed that the quality of sexual life, particularly, improves during DNG treatment of women with endometriosis.13 On the other hand, women using E2/NOMAC had benefits on their sexual function and sexual distress.30 In fact, E2 could have less antiandrogenic activity than EE by inducing less SHBG improvement.31 In addition to the effects due to the biological activity of steroids, the reduction of painful symptoms could favor subjective well-being, such as improving the quality of sexual life. In fact, although DNG has an antiandrogenic activity that could reduce sexual desire and arousal, the decrease in painful symptoms, especially dyspareunia, may be capable of promoting satisfactory sexual function.13