*4.1.5 Different routes of administration for progesterone/progestins to increase positive effects in alleviation progesterone attenuation/resistance and estrogen dominance*

Since many years one discusses non conventional routes for drug administration in order to avoid the second liver passage, and to increase bioavailable active substance where is necessary. Vaginal route for progesterone and medicated intrauterine devices are most analyzed for their beneficial endometrial effects, without or with less systemic effects of progesterone/progestins.

#### *4.1.5.1 Vaginal route for micronized progesterone*

Natural Progesterone has far more anti- inflammatory properties, fewer side effects, is very versatile in how it can be used, and the micronization of P4 is very important, and the oral micronized progesterone capsules were re-directed to be used vaginally [149]. Micronized P4 has a more selective effect on PRs, and results in less interaction with androgenic and mineral-corticoid receptors compared with progestins.

The vaginal route for P4 was proposed since many years ago [150] but the new hypothesis regarding the higher endometrial P4 levels than that obtained after intravenous administration was presented by Cicinelli and de Ziegler [151]. This phenomenon of preferential uterine distribution after vaginal administration was named "first uterine pass effect" [38] or "uterine specificity of vaginal progesterone" [152]. The high uterine level of P4 vaginally administered is explained by various putative modes of transport including direct diffusion through tissue, intracervical aspiration, absorption into the venous or lymphatic circulatory systems and countercurrent vascular exchange with diffusion from utero-vaginal veins/ lymphvessels to arteries. While the serum P4 concentration is often low or "subphysiological", endometrial effects show in most cases clear and complete secretory changes, or pseudodecidual aspects, or atrophy after long duration of therapy [153]. In USA at Brigham and Women's Hospital [154] one recommends vaginal gel, cream, or suppositories, in a higher dosage for endometriosis control than that for replacement therapy recommanded in menopause, such as 300 mg twice a day for minimum 3 months, then 300 mg at bed-time.

#### *4.1.5.2 Medicated intrauterine systems to restore estrogen-progesterone balance*

The direct application of progesterone or a progestin (usually LNG), or of a SPRM (ulipristal acetate was proposed) was another potential option to control estrogen dominance in eutopic endometrium, for avoidance irregular effects of systemic progestins, considering a consistent inhibition of ERs expression in eutopic endometrium [107, 155] with pain reduction, or to avoid pain relapse in

postoperative period, and a total patients' satisfaction when compared to their attention for daily pills intake [156].
