1 Departments of Obstetrics and Gynecology, 2 Radiology, University of Pennsylvania Medical Center and 3 Biochemistry, University of Pennsylvania School of Dental Medicine and Biosyn Inc, Philadelphia, PA, USA
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: microbicide/MRI/Nonoxynol-9/spermicide/vagina
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Little is known about the optimal distribution of a vaginally placed gel used for sexually transmitted diseases (STD) prophylaxis and protection from unwanted pregnancy. The in-vivo mechanism of action of topical spermicide/microbicide is not known, but it has been presumed to act locally in the vaginal canal. A spermicide may act at, or near, the exocervix to kill spermatozoa before they enter the upper female genital tract. The sites of HIV infection within the female reproductive tract are not known. There is evidence to suggest that macrophages and Langerhans' cells, located throughout the vaginal epithelium, are likely targets (Spira et al., 1996; Miller, 1998
; Sodora et al., 1998
). Thus, a topical anti-HIV preparation would optimally cover the entire vaginal epithelium to prevent transmission of the virus. It is possible, however, that the cells of the upper genital tract such as the endocervical, endometrial or tubal mucosa may also be target sites of infection. Currently it is unknown if a topical microbicide migrates, or is transported, into the upper genital tract. If so, does such migration serve any function?
Magnetic resonance imaging (MRI) has been successfully used to image the female pelvis and detect vaginal or other Mullerian anomalies with high sensitivity (Siegelman et al., 1997; Barnhart et al., 2001
). This investigation was performed to establish if MRI could be used to determine the intravaginal distribution of an over-the-counter vaginal product in a human subject and determine if any of the gel could be detected outside the vaginal canal.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The amount and spread of gel were quantified. Measurements were obtained using electronic callipers of digitally stored images at the following anatomical structures: (i) at the posterior vaginal fornix [measurements taken in the anterior and posterior (AP) and longitudinal plane (craniocaudal)]; (ii) 1 cm below the cervix (measurement taken in the AP and transverse plane); (iii) at the flexure of the vagina as it passes through the pelvic diaphragm (AP and transverse); (iv) at the midlower vagina, 3 cm above the introitus (AP and transverse); and (v) just above (1 cm) the introitus (AP and transverse).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It has been assumed that, to provide contraception, a spermicidal compound should kill spermatozoa before they enter the upper genital tract (Sangi-Haghpeykar et al., 1996; Mauck et al., 1997a
,b
). However, spermatozoa are located in the cervical mucus almost immediately after coitus (Sobrero and McLeod, 1962
). Additionally, spermatozoa are transported to the oviduct and peritoneal cavity almost immediately after insemination in rabbits (Overstreet and Cooper, 1978
) and are located in the human Fallopian tube within 5 min (Settlage et al., 1973
). The speed of passage far exceeds the swimming velocity of spermatozoa. In fact, artificial insemination with dead spermatozoa results in rapid transport into the upper genital tract (Drobnis and Overstreet, 1993
). There is evidence that rapid sperm transport though the female genital tract is provided by uterine contractions (Kunz et al., 1996
). Imaging with hysterosalpingoscintigraphy has demonstrated that there is immediate ascension of macrospheres (the size of spermatozoa) into the Fallopian tubes following deposition at the external os of the cervix (Kunz et al., 1996
). This process is thought to be mediated by uterine peristalsis controlled by endocrine and possibly paracrine events (Kunz et al., 1998
). Thus, it is not surprising that there may be transport of vaginal topical medications into the upper tract by similar mechanisms.
The initial bolus of gel was delivered into the upper portion of the vagina, above the urogenital diaphragm. This is determined by the design and dimensions of the applicator. Thereafter, the bolus of gel is spread into the vaginal fornices and `flattened' to cover the lateral aspects of the vagina. Without ambulation, the majority of this early spread was confined to the upper vagina. With ambulation and longer elapsed time, there was further spread of gel in the upper vagina, as well as spread into the lower vagina and a concomitant significant increase in overall vaginal surface coverage (Barnhart et al., 2001). The amount of material and the confined dimensions of the vagina allow reproducible quantification of gel thickness to 1 mm. The amount of material transported to the upper tract cannot be easily quantified. Small amounts of gel are likely to be taken up into the upper tract. The material is diluted as it moves from the vagina, to the endocervical canal, into the endometrial cavity and possibly into the Fallopian tubes.
It is critical to describe and quantify the distribution of intravaginal products in order to optimize their formulation (e.g. volume, viscosity, bioadhesive properties). The demonstration of transport of topical vaginal medications into the upper genital tract has important clinical implications. Transport into the cervix, uterus and tubes may represent an important unrecognized contraceptive or microbicidal mechanism of action of these compounds. The vaginal mucosa is relatively inert compared with that of the endocervix or endometrium (Barnhart and Shalaby, 1998). Gonorrhoea in women usually involves the endocervix and may result in pelvic inflammatory disease. Primarily, gonococcal infection of the vagina is rare (Sweet and Gibbs, 1995). Chlamydia trachomatis has been implicated in endocervicitis, endometritis and pelvic inflammatory disease. It does not cause vaginitis or appear to grow in vaginal squamous epithelium (Sweet and Gibbs, 1985
). The site of HIV transmission in the female genital tract has yet to be definitively determined, but the portal of entry may be via endocervical or other upper genital tract mucosa. Thus, spread of a compound prophylactic against sexually transmitted infection to the upper tract, where infection may be more likely to take place, may be advantageous or even optimal. Conversely, since topically placed compounds may enter the upper tract, or be absorbed systemically, their safety should be demonstrated.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Barnhart, K.T., Pretorius, E.S., Stolpen, A. and Malamud, D. (2001) Distribution of topical medication in the human vagina as imaged by MRI. Fertil. Steril., in press.
Cook, R.L. and Rosenberg, M.J. (1998) Do spermicides containing nonoxynol-9 prevent sexually transmitted infections? A meta-analysis. Sex. Trans. Dis., 25, 144150.[ISI][Medline]
Drobnis, E.Z. and Overstreet, J.W. (1993) Natural history of mammalian spermatozoa in the female reproductive tract. Oxf. Rev. Reprod. Biol., 14, 145.
Elias, C.J. and Coggins, C. (1996) Female-controlled methods to prevent sexual transmission of HIV. AIDS, 10 (Suppl. 2), S4351.[ISI][Medline]
Gerbase, A.C., Rowley, J.T., Heymann, D.H. et al. (1998) Global prevalence and incidence estimates of selected curable STDs. Sex. Transm. Infect., 74 (Suppl. 1), S1216.
Hitchcock, P. (2000) In Stanberry, L. and Bernstein, D. (eds) Sexually transmitted diseases: vaccines, prevention and control. Academic Press, London, pp. 149183.
Kunz, G., Beil, D., Deininger, H. et al. ( 1996) The dynamics of rapid sperm transport through the female genital tract: evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy. Hum. Reprod., 11, 627632.[Abstract]
Kunz, G., Herbertz, M., Noe, M. and Leyendecker, G. (1998) Sonographic evidence for the involvement of the utero-ovarian counter-current system in the ovarian control of directed uterine sperm transport. Hum. Reprod. Update, 4, 667672.
Louv, W.C., Austin, H., Alexander, W.J. et al. (1998) A clinical trial of nonoxynol-9 for preventing gonococcal and chlamydial infections. J. Infect. Dis., 158, 518523.
Mauck, C.K., Baker, J.M., Barr, S.P. et al. (1997a) A phase I comparative study of contraceptive vaginal films containing benzalkonium chloride and nonoxynol-9. Postcoital testing and colposcopy. Contraception, 56, 8996.[ISI][Medline]
Mauck, C.K., Baker, J.M., Barr, S.P. et al. (1997b) A phase I comparative study of three contraceptive vaginal films containing nonoxynol-9. Postcoital testing and colposcopy. Contraception, 56, 97102.[ISI][Medline]
Miller, C.J. (1998) Localization of Simian immunodeficiency virus-infected cells in the genital tract of male and female Rhesus macaques. J. Reprod. Immunol., 41, 331339.[ISI][Medline]
Niruthisard, S., Roddy, R.E. and Chutivongse, S. (1992) Use of nonoxynol-9 and reduction in rate of gonococcal and chlamydial cervical infections. Lancet, 339, 13711375.[ISI][Medline]
Overstreet, J.E. and Cooper, G.W. (1978) Sperm transport in the reproductive tract of the female rabbit: I. The rapid transit phase of transport. Biol. Reprod., 19, 101114.[ISI][Medline]
Roddy, R.E., Zekeng, L., Ryan, K.A. et al. (1998) A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted disease. N. Engl. J. Med., 339, 504510.
Sangi-Haghpeykar, H., Poindexter, A.N. 3rd and Levine, H. (1996) Sperm transport and survival post-application of a new spermicide contraceptive. Advantage 24 Study Group. Contraception, 53, 353356.[ISI][Medline]
Settlage, D.S.F., Motoshima, M. and Tredway, D.R. (1973) Sperm transport from the external cervical os to the Fallopian tubes in women: a time and quantitation study. Fertil. Steril., 24, 655658.[ISI][Medline]
Siegelman, E.S., Outwater, E.K., Banner, M.P. et al. (1997) High-resolution MR imaging of the vagina. Radiographics, 17, 11831203.[Abstract]
Sobrero, A.J. and McLeod, J. (1962) The immediate postcoital test. Fertil Steril., 13, 184189.[ISI][Medline]
Sodora, D.L., Gettie, A., Miller, C.J. and Marx, P.A. (1998) Vaginal transmission of SIV: assessing infectivity and hormonal influences in macaques inoculated with cell-free and cell-associated viral stocks. Aids Res. Hum. Retrovir., 14 (Suppl. 1), S119123.
Spira, A.I., Marx, P.A., Patterson, B.K. et al. (1996) Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J. Exp. Med., 183, 215225.[Abstract]
Sweet R.L. and Gibbs, R.S. (eds) (1985) Infectious diseases of the female genital tract. Williams and Wilkins, Baltimore, pp. 2045.
Weir, S.S., Roddy, R.E., Sekeng, L. and Fledblum, P.J. (1995) Nonoxynol-9 use, genital ulcers, and HIV infection in a cohort of sex workers. Genitourin. Med., 71, 7881.[ISI][Medline]
Submitted on December 19, 2000; accepted on March 7, 2001.