Intravaginal rings as delivery systems for microbicides and multipurpose prevention technologies

International Journal of Women's Health

Volumn 5, Issue 1, 2013, Pages 695-708

  Thurman, Andrea Ries ^a   Clark, Meredith R ^a   Hurlburt, Jennifer A ^a   Doncel, Gustavo F ^a  

^a EASTERN VIRGINIA MEDICAL SCHOOL   (United States)

Author keywords

Contraception; Hiv; Microbicides

Indexed keywords

CLINDAMYCIN; CONJUGATED ESTROGEN; DAPIVIRINE; ESTRADIOL; ESTRADIOL ACETATE; ETHINYLESTRADIOL PLUS ETONOGESTREL; FERTIRING; LEVONORGESTREL; MARAVIROC; MEDROXYPROGESTERONE ACETATE; METRONIDAZOLE; MICROBICIDE; NONOXINOL 9; PIPERAZINE ESTRONE SULFATE; PROGESTERONE; SPONGE TODAY; TENOFOVIR DISOPROXIL; UNCLASSIFIED DRUG; VAGINAL CONTRACEPTIVE FILM;

CHRONIC DRUG ADMINISTRATION; CLINICAL ASSESSMENT; CLINICAL EFFECTIVENESS; CONTROLLED DRUG RELEASE; DEVICE REMOVAL; DRUG ADMINISTRATION ROUTE; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG MARKETING; DRUG SAFETY; EQUIPMENT DESIGN; ESTROGEN THERAPY; FEMALE SEXUAL DYSFUNCTION; FIRST PASS EFFECT; HORMONE BLOOD LEVEL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INFECTION PREVENTION; LOW DRUG DOSE; MAINTENANCE THERAPY; MENOPAUSAL SYNDROME; METRORRHAGIA; NONHUMAN; PATIENT ATTITUDE; PATIENT COMPLIANCE; POSTMENOPAUSE; PRODUCT DEVELOPMENT; REPEATED DRUG DOSE; REVIEW; SEXUALLY TRANSMITTED DISEASE; SIMIAN ACQUIRED IMMUNODEFICIENCY SYNDROME; SUSTAINED DRUG RELEASE; UNPLANNED PREGNANCY; VAGINA ATROPHY; VAGINA CONTRACEPTION; VAGINA FLORA; VAGINA MUCOSA; VAGINA RING; VAGINAL ULCER; WOMEN'S HEALTH;

EID: 84886662623     PISSN: None     EISSN: 11791411     Source Type: Journal    
DOI: 10.2147/IJWH.S34030     Document Type: Review

References (141)

1. UNAIDS. Global Report. UNAIDS Report on the Global AIDS Epidemic. Geneva: UNAIDS; 2012. Available from: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_en.pdf. Accessed August 24, 2013.
2. Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE ttudy (MTN 003). Presented at: the 20th Conference of Retroviruses and Opportunistic Infections (CROI 2013); March 3-6; 2013; Atlanta, GA.
3. van der Linde I. HIV/AIDS in South Africa: At last the glass is half full. Presented at: the 6th SA AIDS Conference; June 18-21; 2013; Durban, South Africa.
4. Karim QA, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science Express. 2010;329(5996):1168-1174.
5. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599.
6. Dobard C, Sharma S, Martin A, et al. Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue. J Virol. 2012;86(2): 718-725.
7. Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410.
8. Denton P W, Othieno F, Martinez-Torres F, et al. One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol. 2011;85(15):7582-7593.
9. Karim SS, Kashuba AD, Werner L, Karim QA. Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV prevention in women. Lancet. 2011;378(9787):279-281.
10. Dai J Y, Gilbert PB, Hughes J P, Brown ER. Estimating the efficacy of preexposure prophylaxis for HIV prevention among participants with a threshold level of drug concentration. Am J Epidemiol. 2013;177(3): 256-263.
11. World Health Organization; UNICEF; UNFPA; World Bank. Maternal Mortality in 2005. Geneva: World Health Organization; 2007. Available from: http://whqlibdoc.who.int/publications/2007/9789241596213_eng.pdf. Accessed July 15, 2010.
12. Singh S, Wulf D, Hussain R, Bankole A, Sedgh G, Institute G. Abortion Worldwide: A Decade of Uneven Progress. New York, NY: Guttmacher Institute; 2009. Available from: http://www.guttmacher.org/pubs/Abortion-Worldwide.pdf. Accessed August 24, 2013.
13. Singh S, Sedgh G, Hussain R. Unintended pregnancy: worldwide levels, trends, and outcomes. Stud Fam Plann. 2010;41(4):241-250.
14. Stuart JE, Secura GM, Zhao Q, Pittman ME, Peipert JF. Factors associated with 12-month discontinuation among contraceptive pill, patch, and ring users. Obstet Gynecol. 2013;121(2 Pt 1):330-336.
15. Friend DR, Doncel GF. Combining prevention of HIV-1, other sexually transmitted infections and unintended pregnancies: Development of dual-protection technologies. Antiviral Res. 2010;88 Suppl 1: S47-S54.
16. World Health Organization. Figure 3-1 Comparing Typical Effectiveness of Contraceptive Methods. Geneva: World Health Organization; 2007. Available from: http://www.contraceptivetechnology.org/table.html. Accessed August 24, 2013.
17. Seidman DS. Non-contraceptive benefits of hormonal contraception: time for renewed awareness. Eur J Contracept Reprod Health Care. 2011;16(6):407-408.
18. Padian NS, van der Straten A, Ramjee G, et al; MIRA Team. Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomised controlled trial. Lancet. 2007;370(9583): 251-261.
19. Johnson TJ, Clark MR, Albright TH, et al. A 90-day tenofovir reservoir intravaginal ring for mucosal HIV prophylaxis. Antimicrob Agents Chemother. 2012;56(12):6272-6283.
20. Macht DI. On the absorption of drugs and poisons through the vagina. J Pharmacol Exp Ther. 1918;10(7):509-522.
21. Dziuk PJ, Cook B. Passage of steroids through silicone rubber. Endocrinology. 1966;78(1):208-211.
22. Mishell DR, Talas M, Parlow AF, Moyer DL. Contraception by means of a silastic vaginal ring impregnated with medroxyprogesterone acetate. Am J Obstet Gynecol. 1970;107(1):100-107.
23. Mishell DR, Lumkin ME. Contraceptive effect of varying dosages of pro-gestogen in silastic vaginal rings. Fertil Steril. 1970;21(2):99-103.
24. World Health Organization; Task Force on Long-Acting Systemic Agents for Fertility Regulation. Intravaginal and intracervical devices for the delivery of fertility regulating agents. J Steroid Biochem. 1979;11(1B):461-467.
25. Koetsawang S, Ji G, Krishna U, et al. Microdose intravaginal levonorg-estrel contraception: a multicentre clinical trial. I. Contraceptive efficacy and side effects. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation. Contraception. 1990;41(2):105-124.
26. Koetsawang S, Ji G, Krishna U, et al. Microdose intravaginal levonorg-estrel contraception: a multicentre clinical trial. II. Expulsions and removals. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation. Contraception. 1990;41(2): 125-141.
27. Bounds W, Szarewski A, Lowe D, Guillebaud J. Preliminary report of unexpected local reactions to a progestogen-releasing contraceptive vaginal ring. Eur J Obstet Gynecol Reprod Biol. 1993;48(2): 123-125.
28. Weisberg E, Fraser IS, Baker J, et al. A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with non-use of a ring. Contraception. 2000;62(2):83-89.
29. Mulders TM, Dieben TO, Bennink HJ. Ovarian function with a novel combined contraceptive vaginal ring. Hum Reprod. 2002;17(10): 2594-2599.
30. Brache V, Payán LJ, Faundes A. Current status of contraceptive vaginal rings. Contraception. 2013;87(3):264-272.
31. Malcolm K, Woolfson D, Russell J, Andrews C. In vitro release of nonoxynol-9 from silicone matrix intravaginal rings. J Control Release. 2003;91(3):355-364.
32. Van Damme L, Ramjee G, Alary M, et al; COL-1492 Study Group. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet. 2002;360(9338):971-977.
33. Kiser PF, Johnson TJ, Clark JT. State of the art in intravaginal ring technology for topical prophylaxis of HIV infection. AIDS Rev. 2012;14(1):62-77.
34. Gupta KM, Pearce SM, Poursaid AE, et al. Polyurethane intravaginal ring for controlled delivery of dapivirine, a nonnucleoside reverse tran-scriptase inhibitor of HIV-1. J Pharm Sci. 2008;97(10):4228-4239.
35. Malcolm RK, Woolfson AD, Toner CF, Morrow RJ, McCullagh SD. Long-term, controlled release of the HIV microbicide TMC120 from silicone elastomer vaginal rings. J Antimicrob Chemother. 2005;56(5): 954-956.
36. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defc Syndr. 2009;51(4): 416-423.
37. Woolfson AD, Malcolm RK, Morrow RJ, Toner CF, McCullagh SD. Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide. Int J Pharm. 2006;325(1-2):82-89.
38. Hendrix C W, Chen BA, Guddera V, et al. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS ONE. 2013;8(1):e55013.
39. Thurman A, Kimble T, Hall P, Schwartz JL, Archer DF. Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics. Contraception. 2013;87(6):738-743.
40. Mishell DR. Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med. 1996;41(Suppl 5):S381-S390.
41. van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72(3):168-174.
42. Timmer CJ, Mulders TM. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet. 2000;39(3):233-242.
43. Magnusdóttir EM, Bjarnadóttir RI, Onundarson PT, et al. The contraceptive vaginal ring (NuvaRing) and hemostasis: a comparative study. Contraception. 2004;69(6):461-467.
44. Nahoul K, Dehennin L, Jondet M, Roger M. Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone. Maturitas. 1993;16(3):185-202.
45. Coutinho EM, Coutinho EJ, Gonçalves MT, Barbosa IC. Ovulation suppression in women following vaginal administration of oral contraceptive tablets. Fertil Steril. 1982;38(3):380-381.
46. Kobayashi K, Mimura N, Fujii H, et al. Role of human cytochrome P450 3A4 in metabolism of medroxyprogesterone acetate. Clin Cancer Res. 2000;6(8):3297-3303.
47. Tseng A, Hills-Nieminen C. Drug interactions between antiretrovi-rals and hormonal contraceptives. Expert Opin Drug Metab Toxicol. 2013;9(5):559-572.
48. Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-422.
49. Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med. 1995;40(5):355-360.
50. Blumenthal PD, Voedisch A, Gemzell-Danielsson K. Strategies to prevent unintended pregnancy: increasing use of long-acting reversible contraception. Hum Reprod Update. 2011;17(1):121-137.
51. Massai R, Quinteros E, Reyes M V, et al. Extended use of a progesterone-releasing vaginal ring in nursing women: a phase II clinical trial. Contraception. 2005;72(5):352-357.
52. Gilliam ML, Neustadt A, Kozloski M, Mistretta S, Tilmon S, Godfrey E. Adherence and acceptability of the contraceptive ring compared with the pill among students: a randomized controlled trial. Obstet Gynecol. 2010;115(3):503-510.
53. Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E. Why consider vaginal drug administration? Fertil Steril. 2004;82(1): 1-12.
54. Romano J, Variano B, Coplan P, et al. Safety and availability of dapi-virine (TMC120) delivered from an intravaginal ring. AIDS Res Hum Retroviruses. 2009;25(5):483-488.
55. Malcolm RK, Fetherston SM, McCoy CF, Boyd P, Major I. Vaginal rings for delivery of HIV microbicides. Int J Womens Health. 2012;4: 595-605.
56. Fetherston SM, Boyd P, McCoy CF, et al. A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action. Eur J Pharm Sci. 2012;48(3):406-415.
57. Clark JT, Johnson TJ, Clark MR, et al. Quantitative evaluation of a hydrophilic matrix intravaginal ring for the sustained delivery of tenofovir. J Control Release. 2012;163(2):240-248.
58. Smith J, Rastogi R, Teller RS, et al. A tenofovir disoproxil fumarate intravaginal ring completely protects against repeated SHIV vaginal challenge in nonhuman primates. Presented at: the 20th Conference of Retroviruses and Opportunistic Infections (CROI 2013); March 3-6; 2013; Atlanta, GA.
59. Sahota J, Barnes PM, Mansfeld E, Bradley JL, Kirkman RJ. Initial UK experience of the levonorgestrel-releasing contraceptive intravaginal ring. Adv Contracept. 1999;15(4):313-324.
60. Landgren BM, Johannisson E, Masironi B, Diczfalusy E. Pharmacokinetic and pharmacodynamic investigations with vaginal devices releasing levonorgestrel at a constant, near zero order rate. Contraception. 1982;26(6):567-585.
61. Lockhat FB, Emembolu JE, Konje JC. Serum and peritoneal fluid levels of levonorgestrel in women with endometriosis who were treated with an intrauterine contraceptive device containing levonorgestrel. Fertil Steril. 2005;83(2):398-404.
62. Seeber B, Ziehr SC, Gschließer A, et al. Quantitative levonorgestrel plasma level measurements in patients with regular and prolonged use of the levonorgestrel-releasing intrauterine system. Contraception. 2012;86(4):345-349.
63. Hidalgo MM, Hidalgo-Regina C, Bahamondes M V, Monteiro I, Petta CA, Bahamondes L. Serum levonorgestrel levels and endome-trial thickness during extended use of the levonorgestrel-releasing intrauterine system. Contraception. 2009;80(1):84-89.
64. Bayer Healthcare. Highlights of Prescribing Information [Package Insert for Skyla Intrauterine System]. Wayne, NJ: Bayer HealthCare Pharmaceuticals; 2013. Available from: http://labeling.bayerhealthcare.com/html/products/pi/Skyla_PI.pdf. Accessed August 24, 2013.
65. Natavio MF, Taylor D, Lewis RA, et al. Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system. Contraception. 2013;87(4):426-431.
66. Lähteenmäki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids. 2000;65(10-11):693-697.
67. Munuce MJ, Nascimento JA, Rosano G, Faundes A, Bahamondes L. Doses of levonorgestrel comparable to that delivered by the levonorgestrel-releasing intrauterine system can modify the in vitro expression of zona binding sites of human spermatozoa. Contraception. 2006;73(1):97-101.
68. Moss JA, Malone AM, Smith TJ, et al. Simultaneous delivery of tenofovir and acyclovir via an intravaginal ring. Antimicrob Agents Chemother. 2012;56(2):875-882.
69. Gunawardana M, Moss JA, Smith TJ, et al. Microbial biofilms on the surface of intravaginal rings worn in non-human primates. J Med Microbiol. 2011;60(Pt 6):828-837.
70. Miller L, MacFarlane SA, Materi HL. A scanning electron microscopic study of the contraceptive vaginal ring. Contraception. 2005;71(1): 65-67.
71. Hazan Z, Zumeris J, Jacob H, et al. Effective prevention of microbial biofilm formation on medical devices by low-energy surface acoustic waves. Antimicrob Agents Chemother. 2006;50(12):4144-4152.
72. Pruthi V, Al-Janabi A, Pereira BM. Characterization of biofilm formed on intrauterine devices. Indian J Med Microbiol. 2003;21(3): 161-165.
73. Creinin MD, Meyn LA, Borgatta L, et al. Multicenter comparison of the contraceptive ring and patch: a randomized controlled trial. Obstet Gynecol. 2008;111(2 Pt 1):267-277.
74. Dieben TO, Roumen FJ, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol. 2002;100(3):585-593.
75. Novák A, de la Loge C, Abetz L, van der Meulen EA. The combined contraceptive vaginal ring, NuvaRing: an international study of user acceptability. Contraception. 2003;67(3):187-194.
76. Oddsson K, Leifels-Fischer B, de Melo NR, et al. Efficacy and safety of a contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive: a 1-year randomized trial. Contraception. 2005;71(3): 176-182.
77. Sivin I, Mishell DR Jr, Alvarez F, et al. Contraceptive vaginal rings releasing Nestorone and ethinylestradiol: a 1-year dose-finding trial. Contraception. 2005;71(2):122-129.
78. van der Straten A, Montgomery ET, Cheng H, et al. High acceptability of a vaginal ring intended as a microbicide delivery method for HIV prevention in African women. AIDS Behav. 2012;16(7):1775-1786.
79. Jung-Hoffman C, Kuhl H. Pharmacokinetics and pharmacodynamics of oral contraceptive steroids: factors influencing steroid metabolism. Am J Obstet Gynecol. 1990;163(6 Pt 2):2183-2197.
80. Koetsawang S, Ji G, Krishna U, et al. Microdose intravaginal levonorg-estrel contraception: a multicentre clinical trial. IV. Bleeding patterns. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation. Contraception. 1990;41(2):151-167.
81. Brache V, Mishell DR, Lahteenmaki P, et al. Ovarian function during use of vaginal rings delivering three different doses of Nestorone. Contraception. 2001;63(5):257-261.
82. Xiao BL, Zhang XL, Feng DD. Pharmacokinetic and pharmacody-namic studies of vaginal rings releasing low-dose levonorgestrel. Contraception. 1985;32(5):455-471.
83. Landgren BM, Johannisson E, Masironi B, Diczfalusy E. Pharmacokinetic and pharmacodynamic effects of small doses of norethisterone released from vaginal rings continuously during 90 days. Contraception. 1979;19(3):253-271.
84. Johannisson E, Brosens I, Cornillie F, et al. Morphometric study of the human endometrium following continuous exposure to levonorgestrel released from vaginal rings during 90 days. Contraception. 1991;43(4): 361-374.
85. Van de Perre P, Segondy M, Foulongne V, et al. Herpes simplex virus and HIV-1: deciphering viral synergy. Lancet Infect Dis. 2008;8(8): 490-497.
86. Greenblatt RM, Lukehart SA, Plummer FA, et al. Genital ulceration as a risk factor for human immunodeficiency virus infection. AIDS. 1988;2(1):47-50.
87. Wasserheit JN. Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis. 1992;19(2):61-77.
88. Royce RA, Seña A, Cates W, Cohen MS. Sexual transmission of HIV. N Engl J Med. 1997;336(15):1072-1078.
89. Thurman AR, Doncel GF. Herpes simplex virus and HIV: genital infection synergy and novel approaches to dual prevention. Int J STD AIDS. 2012;23(9):613-619.
90. Nath A, Sitruk-Ware R. Progesterone vaginal ring for contraceptive use during lactation. Contraception. 2010;82(5):428-434.
91. Sivin I, Díaz S, Croxatto HB, et al. Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD. Contraception. 1997;55(4):225-232.
92. Roumen FJ, Apter D, Mulders TM, Dieben TO. Efficacy, tolerability and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl oestradiol. Hum Reprod. 2001;16(3):469-475.
93. Fraser IS, Lacarra M, Mishell DR, et al. Vaginal epithelial surface appearances in women using vaginal rings for contraception. Contraception. 2000;61(2):131-138.
94. Fraser IS, Lähteenmäki P, Elomaa K, et al. Variations in vaginal epithelial surface appearance determined by colposcopic inspection in healthy, sexually active women. Hum Reprod. 1999;14(8):1974-1978.
95. Mayer KH, Venkatesh KK. Antiretroviral therapy as HIV prevention: status and prospects. Am J Public Health. 2010;100(10):1867-1876.
96. Schwartz JL, Rountree W, Kashuba ADM, et al. A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel. PLoS One. 2011;6(10):e25974.
97. Abdool Karim SS. CAPRISA 004 two years on: Ten key lessons and their implications. Presented at: Microbicides 2012; April 12, 2012; Sydney, Australia.
98. Martin HL, Richardson BA, Nyange PM, et al. Vaginal lactobacilli, micro-bial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999;180(6):1863-1868.
99. Laga M, Manoka A, Kivuvu M, et al. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS. 1993;7(1):95-102.
100. Myer L, Denny L, Telerant R, Souza MD, Wright TC Jr, Kuhn L. Bacterial vaginosis and susceptibility to HIV infection in South African women: a nested case-control study. J Infect Dis. 2005;192(8):1372-1380.
101. Valore E V, Wiley DJ, Ganz T. Reversible deficiency of antimicrobial polypeptides in bacterial vaginosis. Infect Immun. 2006;74(10): 5693-5702.
102. Davies GC, Feng LX, Newton JR, Dieben TO, Coelingh-Bennink HJ. The effects of a combined contraceptive vaginal ring releasing ethi-nyloestradiol and 3-ketodesogestrel on vaginal flora. Contraception. 1992;45(5):511-518.
103. De Seta F, Restaino S, De Santo D, et al. Effects of hormonal contraception on vaginal flora. Contraception. 2012;86(5):526-529.
104. Ravel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108 Suppl 1: S4680-S4687.
105. Camacho D P, Consolaro ME, Patussi E V, Donatti L, Gasparetto A, Svidzinski TI. Vaginal yeast adherence to the combined contraceptive vaginal ring (CCVR). Contraception. 2007;76(6):439-443.
106. Ungchusak K, Rehle T, Thammapornpilap P, Spiegelman D, Brinkmann U, Siraprapasiri T. Determinants of HIV infection among female commercial sex workers in northeastern Thailand: results from a longitudinal study. J Acquir Immune Defc Syndr Hum Retrovirol. 1996;12(5):500-507.
107. Martin HL Jr, Nyange PM, Richardson BA, et al. Hormonal contraception, sexually transmitted diseases, and risk of heterosexual transmission of human immunodeficiency virus type 1. J Infect Dis. 1998;178(4):1053-1059.
108. Baeten JM, Benki S, Chohan V, et al. Hormonal contraceptive use, herpes simplex virus infection, and risk of HIV-1 acquisition among Kenyan women. AIDS. 2007;21(13):1771-1777.
109. Morrison CS, Chen PL, Kwok C, et al. Hormonal contraception and HIV acquisition: reanalysis using marginal structural modeling. AIDS. 2010;24(11):1778-1781.
110. Heffron R, Donnell D, Rees H, et al; Partners in Prevention HSV/HIV Transmission Study Team. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2012;12(1):19-26.
111. Marx PA, Spira AI, Gettie A, et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med. 1996;2(10): 1084-1089.
112. Smith SM, Baskin GB, Marx PA. Estrogen protects against vaginal transmission of simian immunodeficiency virus. J Infect Dis. 2000;182(3):708-715.
113. Jiang Y, Tian B, Agy MB, Saifuddin M, Tsai CC. Macaca fascicu-laris are highly susceptible to an RT-SHIV following intravaginal inoculation: a new model for microbicide evaluation. J Med Primatol. 2009;38 Suppl 1:S39-S46.
114. Pal R, Nuttall J, Galmin L, Weiss D, Chung HK, Romano J. Characterization of vaginal transmission of a simian human immuno-deficiency virus (SHIV) encoding the reverse transcriptase gene from HIV-1 in Chinese rhesus macaques. Virology. 2009;386(1):102-108.
115. Sallé B, Brochard P, Bourry O, et al. Infection of macaques after vaginal exposure to cell-associated simian immunodeficiency virus. J Infect Dis. 2010;202(3):337-344.
116. Veazey RS, Shattock RJ, Pope M, et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med. 2003;9(3):343-346.
117. Miller L, Patton DL, Meier A, Thwin SS, Hooton TM, Eschenbach DA. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol. 2000;96(3):431-439.
118. Bahamondes L, Trevisan M, Andrade L, et al. The effect upon the human vaginal histology of the long-term use of the injectable contraceptive Depo-Provera. Contraception. 2000;62(1):23-27.
119. Mauck CK, Callahan MM, Baker J, et al. The effect of one injection of Depo-Provera on the human vaginal epithelium and cervical ectopy. Contraception. 1999;60(1):15-24.
120. Ildgruben AK, Sjöberg IM, Hammarström ML. Influence of hormonal contraceptives on the immune cells and thickness of human vaginal epithelium. Obstet Gynecol. 2003;102(3):571-582.
121. Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med. 2011;62: 127-139.
122. Pudney J, Quayle AJ, Anderson DJ. Immunological microenviron-ments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biol Reprod. 2005;73(6):1253-1263.
123. Hladik F, Sakchalathorn P, Ballweber L, et al. Initial events in establishing vaginal entry and infection by human immunodeficiency virus type-1. Immunity. 2007;26(2):257-270.
124. Patton DL, Thwin SS, Meier A, Hooton TM, Stapleton AE, Eschenbach DA. Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle. Am J Obstet Gynecol. 2000;183(4):967-973.
125. Wieser F, Hosmann J, Tschugguel W, Czerwenka K, Sedivy R, Huber JC. Progesterone increases the number of Langerhans cells in human vaginal epithelium. Fertil Steril. 2001;75(6):1234-1235.
126. Wira CR, Fahey J V, Ghosh M, Patel M V, Hickey DK, Ochiel DO. Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol. 2010;63(6):544-565.
127. Chandra N, Thurman AR, Anderson S, et al. Depot medroxyproges-terone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues. AIDS Res Hum Retroviruses. 2013;29(3):592-601.
128. Naranbhai V, Abdool Karim SS, Altfeld M, et al; CAPRISA004 TRAPS team. Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. J Infect Dis. 2012;206(7):993-1001.
129. Roberts L, Passmore JA, Mlisana K, et al. Genital tract infammation during early HIV-1 infection predicts higher plasma viral load set point in women. J Infect Dis. 2012;205(2):194-203.
130. Clark MK, Sowers M, Levy BT, Tenhundfeld P. Magnitude and variability of sequential estradiol and progesterone concentrations in women using depot medroxyprogesterone acetate for contraception. Fertil Steril. 2001;75(5):871-877.
131. Fotherby K, Saxena BN, Shrimanker K, et al. A preliminary pharmacokinetic and pharmacodynamic evaluation of depot-medroxyprogesterone acetate and norethisterone oenanthate. Fertil Steril. 1980;34(2):131-139.
132. Ortiz A, Hirol M, Stanczyk FZ, Goebelsmann U, Mishell DR. Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of depo-MPA. J Clin Endocrinol Metab. 1977;44(1):32-38.
133. Wisniewski PM, Wilkinson EJ. Postpartum vaginal atrophy. Am J Obstet Gynecol. 1991;165(4 Pt 2):1249-1254.
134. Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the post-menopause - cytology, histology and pH as methods of assessment. Maturitas. 1995;21(1):51-56.
135. Roy S, Caillouette JC, Roy T, Faden JS. Vaginal pH is similar to follicle-stimulating hormone for menopause diagnosis. Am J Obstet Gynecol. 2004;190(5):1272-1277.
136. Petricevic L, Domig KJ, Nierscher FJ, et al. Characterisation of the oral, vaginal and rectal Lactobacillus flora in healthy pregnant and postmenopausal women. Eur J Obstet Gynecol Reprod Biol. 2012;160(1):93-99.
137. Pabich WL, Fihn SD, Stamm WE, Scholes D, Boyko EJ, Gupta K. Prevalence and determinants of vaginal flora alterations in postmeno-pausal women. J Infect Dis. 2003;188(7):1054-1058.
138. Gondo F, da Silva MG, Polettini J, et al. Vaginal flora alterations and clinical symptoms in low-risk pregnant women. Gynecol Obstet Invest. 2011;71(3):158-162.
139. Gorodeski GI. Estrogen modulation of epithelial permeability in cervical-vaginal cells of premenopausal and postmenopausal women. Menopause. 2007;14(6):1012-1019.
140. Jones J, Mosher W, Daniels K; Division of vital statistics. Current contraceptive use in the United States, 2006-2010, and changes in patterns of use since 1995. Natl Health Stat Report. 2012;(60):1-26. Available from: http://www.cdc.gov/nchs/data/nhsr/nhsr060.pdf. Accessed August 24, 2013.
141. un.org [homepage on the Internet]. World contraceptive use 2010. United Nations, Department of Economic and Social Affairs, Population Division; 2010 [updated February 2011; cited July 15, 2011]. Available from: http://www.un.org/esa/population/publications/wcu2010/Data/UNPD_WCU_2010_Contraceptive_prevalence_method.xls. Accessed August 24, 2013.