Vaginally Administered Aromatase Inhibitors

The patented Bologna Pharma technology enables vaginally administering (AI) aromatase inhibitors (e.g. anastrozole, letrozole, exemestane) to be administered to women with endometriosis in order to flood the pelvic cavity with high concentrations of these lipophilic inhibitors.  Unlike previous therapies which block systemic estrogen production, our unique technology blocks local estrogen production by inhibiting aromatase in the endometrial tissue itself. With the use of these bioadhesive with gels therapeutic levels of AI can be maintained in the pelvic cavity with barely detectable levels in the systemic circulation, a first pelvic pass effect. A first uterine pass effect was first described in (Bologna William J US5543150A) and a first pelvic pass effect in (Bologna William J US20200121589A1).

Previous studies with lipophilic progesterone (P4) have demonstrated this phenomenon; tissue concentrations in both the endometrium and myometrium are dramatically higher than serum concentrations. When compared with systemic administration via the intra-muscular route this difference is magnified.

It is postulated that an AI administered transvaginally preferentially transits to the uterus and pelvic cavity with negligible drug partitioning into general circulation. The exact mechanism of this “first pelvic pass” effect is not yet completely understood. Three hypothesis can be put forth for explaining the data supporting the first pelvic pass effect: (1) transvaginally administered AI may transit to the uterus through the local circulatory system and then lipophilic drugs such as AI’s will partition into the pelvic cavity , (2) there may be direct diffusion of lipophilic drugs such as AI directly into the uterus and pelvic cavity, or (3) the AI may reach the uterus through the lymphatics then partition into the pelvic cavity. In support of this later hypothesis it is the established knowledge that vaginal cancer from the upper one-third of the uterus tends to disseminate following the uterine lymphatic tracks. According to the second hypothesis, an AI could diffuse passively between cells and reach the uterus and pelvic cavity given the partition coefficient of these lipophilic drugs.


When lipophilic vaginal AI’s are administered concomitantly with systemic estrogen, the AI will concentrate in the pelvic cavity with barely detectable levels in the systemic circulation. The low concentrations in serum is the result of the lipophilic, AI tendency to minimally partition into serum from tissue. Competitive binding at the estrogen receptors in pelvic tissue including the peritoneum, ovaries, and rectovaginal septum will be overwhelmingly dominated by the aromatase inhibitory action of the AI. Concurrently, since the AI will not be systemically distributed in therapeutic concentrations exogenous estrogen will dominate at estrogen receptors outside of the pelvic cavity e.g. brain, bone, skin, etc.

The Bologna Pharma technology allows direct transport of therapeutic levels of a pharmacologically active agent such as an AI from the vagina to the pelvic cavity while minimizing systemic exposure, making the treatment more tolerable than systemically administered GnRH agonists or antagonists.

The simultaneous administration of menopausal treatment levels of estrogen will prevent stimulation of the ovaries by negative feed-back of the pituitary-ovarian-axis (which would cause secretion of gonadotropins and stimulation of ovarian follicular growth and ovarian cysts). Moreover, the simultaneous administration of estrogen will prevent hot flashes, tiredness, problems sleeping, headache, depression, joint and muscle stiffness, bone loss, and vaginal dryness associated with the estrogen deprivation of prior therapies.

For women who wish to become pregnant there is a two month washout period for the AI due to its long half-life.  The patent also teaches that as part of the dosing regimen these women should be prescribed an oral contraceptive for this period for two reasons. First, to help prevent the endometriosis from recurring. Second many women become pregnant right away after stopping regular-dose or low-dose hormonal birth control. When oral contraception is stopped, there is a rebound in Follicle Stimulating Hormone (FSH) production. FSH stimulates the growth of ovarian follicles which ultimately release an egg. Even if a women doesn’t become pregnant immediately, about half of women will become pregnant in the first 3 months after stopping an oral contraceptive, and most women become pregnant within 12 months after stopping.