The purpose of this study is to learn if the study drug, doxycycline, can decrease the amount of unplanned vaginal bleeding that women commonly experience when taking combined oral contraception (COC)- pills with estrogen and progestin - in a continuous fashion - no hormone-free week. The study drug, doxycycline, is an antibiotic used commonly for many conditions (i.e. acne, Chlamydia infections, pneumonia) and can be safely used on a daily basis. Doxycycline has been shown to decrease unplanned vaginal bleeding in progestin-only contraception but has not been studied in combined hormonal contraception.

We intend to conduct a prospective, randomized, placebo controlled, double blind study at Oregon Health and Science University. This study will be conducted over four 28-day cycles (112 days of active COC hormone). All women enrolled in the study will take the same daily low dose COC. This protocol will be divided into two studies, a bleeding study and an endometrial biopsy study, each with two treatment arms; typical dose doxycycline (Arm 1), and controlled release subantimicrobial dose doxycycline (CRSD)(Arm 2).

The first arm (Arm 1) of this study will constitute the typical dose doxycycline arm. In this arm, there will be two study groups. Group 1, the treatment group, will take doxycycline 100 mg orally twice a day for five days starting on the first day of bleeding if breakthrough bleeding occurs. The control group will take a placebo orally twice a day for five days starting on the first day of bleeding if breakthrough bleeding occurs. After three months, both groups will stop doxycycline (or placebo) and will continue on a COC alone for the remaining 28 days of the study.

The second arm (Arm 2) of the study will constitute the controlled release subantimicrobial dose doxycycline (CRSD doxycycline)arm. Subjects in this arm of the study will be divided into Group 3 and Group 4. Group 3 will take CRSD doxycycline (40mg) daily for three months. Group 4 will take a daily placebo. Similarly to the first arm of the trial, after three months, both groups will stop doxycycline (or placebo) and will continue in a COC alone for the remaining 28 days of the study.

This study also includes a endometrial biopsy sub-study: At the time of recruitment we will identify participants who are willing to undergo endometrial biopsy during the study period. These subjects will constitute a separate cohort who will enroll in the prospective, randomized, double blind, placebo controlled endometrial biopsy study.

Inclusion Criteria:

• General good health
• Willing and able to agree to randomization and sign informed consent
• Currently having regular menstrual cycles (24-36 days), with combined cyclic hormonal method (COCs, Nuva Ring, Ortho Evra), without intermenstrual bleeding in last 2 years.

Exclusion Criteria:

• Intrauterine device (IUD) in place

• Abnormal pap smear that has not been treated or followed up

• Those with hypersensitivity reactions to doxycycline or any of the tetracyclines

• Use of depomedroxyprogesterone acetate within 9 months of the start of the study.

• Use of hormonal medications (excluding cyclic contraceptives and plan B) within 2 months of the start of the study.

• Any one unwilling to keep a daily menstrual diary or otherwise unwilling to follow the study criteria

• Currently taking medications that interfere with COCs (rifampin, carbamazepine, St. Johns wort)

• Currently has a progestin implant

• Positive Gonorrhea or Chlamydia cultures at enrollment examination

• Smoking more than 5 cigarettes per month

• Any medical condition that is a contraindication to the use of COCs in accordance with product labeling including:

  • History of thrombophlebitis, deep venous thrombosis, thrombogenic vasculopathies, thrombogenic rhythm disorders or thromboembolic disorders
  • Current or past history of cerebrovascular or coronary artery disease
  • Scheduled major surgery in the next six months with prolonged immobilization
  • Diabetes with vascular involvement
  • Headache with focal neurologic symptoms
  • Uncontrolled hypertension
  • Suspected or known carcinoma of the breast or personal history of breast cancer
  • Carcinoma of the endometrium or other known or suspected estrogen dependent neoplasms
  • Undiagnosed genital bleeding
  • History of cholestatic jaundice of pregnancy or cholestatic jaundice with prior oral contraceptive use
  • Hepatic adenoma or carcinoma or active liver disease if liver function has not returned to normal
  • Known or suspected pregnancy
  • Hypersensitivity to estrogen or progesterone containing products

Treatment Arm: Subjects had difficulty understanding when to start and stop treatment.