The vaginal rugae increase the surface area of the vagina, helping to retain a medication that is placed in the vagina and enhancing drug absorption (Figure 2). The rugae also permit the vagina to expand to accommodate intercourse and allow placement of a speculum, diaphragm, or vaginal ring without trauma.

The vaginal histology is defined by a stratified squamous epithelium; the upper vagina is a mucous membrane that is highly vascular and contains elastic fibers, as well as dense connective tissue and muscle (Figure 3). Arteries and veins form a plexus around the vagina, and venous drainage of the vagina does not immediately pass through the liver (Figure 4). These features make the vagina effective in the uptake of many drugs and stable for long-term, continuous drug delivery systems such as a vaginal ring.

The vaginal defense system is analogous to those in the gastrointestinal (GI) and respiratory tracts. Langerhans cells (specialized macrophages) scavenge for bacterial antigens on the vaginal surface and then "present" those antigens to the T and B cells, which results in cell-mediated immunity and in the secretion of vagina-specific antibodies. In addition, continuous epithelial sloughing creates a physical barrier to bacterial invasion.

Lactobacilli are the most prominent microbes in a healthy vagina. These organisms maintain the low pH of the vagina and attach with specific pili to the vaginal epithelium to block adhesion of competing pathogens. These and other microbes produce lactic acid to maintain the acidic pH of the vagina. They compete with other microbes for nutrients and generate antimicrobial bacteriocides, including hydrogen peroxides.

According to Dr. Nelson, the attributes of the vagina can be used to introduce a woman to the concept of vaginal drug administration. "Typically, most women think of the vagina as an unhealthy environment, because they associate it with unpleasant vaginal discharge, infection, or aroma," she said. "We can use the protective properties of the vagina, such as the presence of lactobacilli, as a way of creating a positive image of the vagina in our patient's mind, emphasizing how it is protected on an ongoing basis by a robust defense system and hormonal influences. We can also educate the patient about how a method of birth control such as the vaginal contraceptive ring might be of benefit, for example, in terms of enhancing vaginal lubrication."

She noted that 1 trial showed that the contraceptive ring does not cause vaginal infections, does not affect vaginal pH or adversely change microflora content, and does not damage the vagina or cervix.^[1] In addition, this trial suggested that there may actually be a vaginal benefit associated with use of the ring, because it confers an intact, thick epithelial layer, a low pH that optimizes conditions for lactobacilli to resist potential pathogens, and a minimal inflammatory response.^[1]

Vaginal drug administration has a long history dating back to the Middle Ages, reported Dr. Nelson. This route of administration has long been employed for postmenopausal delivery of hormones, and vaginal administration of recreational drugs such as cocaine has been reported in the medical literature. "Clinicians are already using drugs routinely in the vagina; we use bromocriptine vaginally in the treatment of hyperprolactinoma in women who suffer from nausea and vomiting with oral administration. In many cases, vaginal administration has proven to be superior to oral administration," she said. Of note, a recent study of vaginal delivery of misoprostol compared with oral administration for the induction of labor showed the vaginal route to be superior, while another study demonstrated that vaginally administered indomethacin was more effective than oral indomethacin for halting preterm labor.^[2,3]

The vaginal contraceptive ring confers steady serum hormone levels (Figure 5) and produces lower serum concentrations compared with oral or transdermal delivery (ethinyl estradiol, 15 µg/d) (Table 1). It also avoids hepatic first-pass metabolism, as well as GI interference with absorption. Finally, Dr. Nelson noted that there is no need for daily administration and the ring is a discreet method, which appeals to many women.

Dr. Nelson suggested that the vaginal contraceptive ring is a "breakthrough product for reproductive-age women. It is a way of introducing them to the concept of vaginal administration for systemic drugs." In addition to contraceptive hormones, menopausal hormones can be administered through the vagina. In the future, vaginal administration of glyminox gel for contraception and prevention of sexually transmitted infections (STIs), terbutaline gel for dysmenorrhea and endometriosis, cecropin-containing gel for the prevention of STIs, a lidocaine-releasing intravaginal ring for cervical anesthesia, an oxybutynin ring for overactive bladder, tenofovir gel and other microbicides for the prevention of vaginal HIV transmission, and an antibody III-174 vaginal implant for the prevention and treatment of herpes simplex virus-2 infection may be routine.^[4]

"I believe we need to start talking about vaginal drug administration at a younger age, so that at any time in her life, a woman will feel comfortable considering different drug delivery systems," she said. "We want women to recognize that the vagina is a very natural place to deliver medication. Vaginal administration often minimizes side effects associated with oral or transdermal routes. And finally, vaginal administration is very easy to use and is very discreet." Using the vagina as a route for contraception instead of just for the treatment of vaginal infections or vaginal dryness conveys to the woman that her vagina is an integral part of her body and an important, healthy part of being a woman.