Clinically, a high percentage of women using progestin-only contraception experience breakthrough bleeding spotting that causes impaired lifestyle and results in decreased compliance with this contraceptive method. There is a need for an effective, low-cost, easily adapted treatment to reduce the bleeding and spotting in progestin only contraceptives. The molecular environment of the endometrium of women with breakthrough bleeding [BTB] and spotting, like many other inflammatory disorders, contains abnormally high levels of pro-inflammatory cytokines (TNF-alpha and IL-1beta)and abnormally high levels of proteases (matrix metalloproteinases [MMPs] and neutrophil elastase), which prevent normal tissue repair. Doxycycline [DOX] is an inexpensive, FDA approved antibiotic that inhibits MMPs, TACE activity, and reduces NO synthesis. The therapeutic benefit of DOX in animal models and clinical studies of periodontal and ulcerative diseases is due to its inhibition of MMPs, not to its antibiotic effect. We do not anticipate any reduction in contraceptive efficacy with the use of DOX. We propose to clinically evaluate DOX treatment of progestin-only contraceptive induced BTB and spotting, and to biochemically characterize the endometrial molecular biologic changes that occur in DOX treated patients. If successful, DOX treatment could become an important adjuvant for treatment of this and possibly other inflammatory disorders effecting reproductive tract tissues.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DRG-D (16))
Program Officer
Mackay, H Trent
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Eastern Virginia Medical School
Obstetrics & Gynecology
Schools of Medicine
United States
Zip Code
Kovalevsky, George; Ballagh, Susan A; Stanczyk, Frank Z et al. (2010) Levonorgestrel effects on serum androgens, sex hormone-binding globulin levels, hair shaft diameter, and sexual function. Fertil Steril 93:1997-2003
Choksuchat, Chainarong; Zhao, Shumei; Deutch, Todd D et al. (2009) Effects of progesterone, levonorgestrel and medroxyprogesterone acetate on apoptosis in human endometrial endothelial cells. Contraception 79:139-45
Zhao, Shumei; Choksuchat, Chainarong; Zhao, Yueqin et al. (2009) Effects of doxycycline on serum and endometrial levels of MMP-2, MMP-9 and TIMP-1 in women using a levonorgestrel-releasing subcutaneous implant. Contraception 79:469-78
Chegini, N; Luo, X; Pan, Q et al. (2007) Endometrial expression of epithelial neutrophil-activating peptide-78 during the menstrual cycle or in progestin-only contraceptive users with breakthrough bleeding and the influence of doxycycline therapy. Hum Reprod 22:427-33
Li, Rongxiu; Luo, Xiaoping; Archer, David F et al. (2007) Doxycycline alters the expression of matrix metalloproteases in the endometrial cells exposed to ovarian steroids and pro-inflammatory cytokine. J Reprod Immunol 73:118-29
Li, Rongxiu; Luo, Xiaoping; Pan, Qun et al. (2006) Doxycycline alters the expression of inflammatory and immune-related cytokines and chemokines in human endometrial cells: implication in irregular uterine bleeding. Hum Reprod 21:2555-63
Rhoton-Vlasak, Alice; Chegini, Nasser; Hardt, Nancy et al. (2005) Histological characteristics and altered expression of interleukins (IL) IL-13 and IL-15 in endometria of levonorgestrel users with different uterine bleeding patterns. Fertil Steril 83:659-65
Chegini, Nasser; Rhoton-Vlasak, Alice; Williams, R Stan (2003) Expression of matrix metalloproteinase-26 and tissue inhibitor of matrix metalloproteinase-3 and -4 in endometrium throughout the normal menstrual cycle and alteration in users of levonorgestrel implants who experience irregular uterine bleeding. Fertil Steril 80:564-70