Freedolph D. Anderson

A multicenter, randomized study of an extended cycle oral contraceptive

OBJECTIVE To assess the efficacy and safety of Seasonale, 91-day extended cycle oral contraceptive (OC). METHODS A parallel, randomized, multicenter open-label, 1-year study of the OC Seasonale [30 microg ethinyl estradiol (EE)/150 microg levonorgestrel (LNG), and Nordette-28 (30 microg EE/150 microg LNG)] in sexually active, adult women (18-40 years) of childbearing potential. Patients received either four 91-day cycles of extended cycle regimen OC, or 13 cycles of the conventional 28-day OC with daily monitoring of compliance and bleeding via electronic diaries. RESULTS When taken daily for 84 days followed by 7 days of placebo, the extended cycle regimen was effective in preventing pregnancy and had a safety profile that was comparable to that observed with the 28-day OC regimen that served as the control. While unscheduled (breakthrough) bleeding was reported among patients treated with the extended cycle regimen, it decreased with each successive cycle of therapy and was comparable to that reported by patients who received the conventional OC regimen by the fourth extended cycle. CONCLUSION This study demonstrated that Seasonale, 91-day extended cycle OC containing 84 days of 30 microg EE/150 microg LNG followed by 7 days of placebo, was effective, safe and well tolerated.

Initial and steady-state pharmacokinetics of a vaginally administered formulation of progesterone

OBJECTIVE The pharmacokinetics of a 100 mg vaginal progesterone suppository was evaluated on days 1 and 7 and a 200 mg suppository on day 14. All the volunteers were given oral 17 beta-estradiol during the study. STUDY DESIGN Ten postmenopausal women volunteered for this study. Progesterone was given as a vaginal suppository. Peripheral venous samples were obtained at appropriate intervals and analyzed for 17 beta-estradiol and progesterone levels. Area under the curve for progesterone was assessed by the trapezoidal method. Statistical analysis was performed by a one-way analysis of variance. RESULTS Serum 17 beta-estradiol levels ranged from 22 to 182 pg/ml. Maximal serum progesterone levels ranged from 5.7 to 20.9 ng/ml, with the mean maximal levels 13.97, 16.09, and 12.68 ng/ml (not significantly different) and a mean area under the curve of 168.13, 207.64 and 227.71 ng/ml per hour on days 1, 7, and 14 (not statistically different). CONCLUSIONS These data indicate that vaginal absorption of progesterone is efficient. The lack of difference in the area under the curve for both doses suggests that the vaginal mucosa or the total surface area of the vagina may limit the absorption of progesterone from the vagina.

Endometrial effects of a 91-day extended-regimen oral contraceptive with low-dose estrogen in place of placebo

BACKGROUND The study was conducted to evaluate the effects of a 91-day extended-regimen oral contraceptive (OC) containing levonorgestrel (LNG) with low-dose ethinyl estradiol (EE) in place of placebo on endometrial histology. STUDY DESIGN Endometrial biopsies were obtained prior to initiation and posttreatment, between cycle Days 60 and 84 (during combination EE/LNG tablets), between cycle Days 85 and 91 (during low-dose EE tablets) or after completion of therapy. RESULTS Paired endometrial biopsy samples obtained before and after treatment were available for 63 subjects. Biopsy results demonstrated that this OC regimen did not promote unexpected changes in the endometrium, either during the course of active treatment with EE/LNG or during the 7-day low-dose EE interval. Endometrial hyperplasia or malignancy was not observed in any endometrial biopsy sample. CONCLUSION Use of a 91-day extended-regimen OC with low-dose EE in place of placebo was not associated with any untoward effects on the endometrium.

Tissue response to bioerodible, subcutaneous drug implants : a possible determinant of drug absorption kinetics

The fibrous tissue compartments that develop in response to the subcutaneous implantation of bioerodible heat-fused rods of norethindrone and cholesterol (85 and 15%, respectively) were studied by light and electron microscopy at various intervals after implantation to determine whether the biological inflammatory response may play a role in drug absorption. Thirty-five regularly menstruating, sterilized (tubal ligation), healthy females each received four Annuelle rods. The microanatomy of seven of the largest implants (135 mg norethindrone) was studied. A dense fibrous biological compartment was found to surround each rod. By light microscopy no abnormal tissue response was revealed. Scanning and transmission electron microscopy showed that the surfaces of the rods were covered by a cellular matrix of mononuclear cells. The fibrous compartment was composed of a loose cellular bed immediately surrounding the norethindrone rod, a dense fibrous connective tissue envelope containing blood and lymphatic vessels, and an outer fatty connective tissue layer. Transmission electron microscopy confirmed that the cellular tissue immediately surrounding the rods was composed mainly of lipid laden macrophages. Norethindrone levels in tissue capsules at 3 and 10.5 months were 0.05 and 8.4% by weight, respectively. These observations suggest that the local imflammatory response plays a role in the active processing of this delivery system. This picture is qualitatively different from the general view of the fibrous capsule as a simple rate limiting membrane. The effects observed in this study suggest that a more complex, functional biological system develops in response to the subcutaneous introduction of a drug delivery device.

Pharmacokinetics of a single dose of buccal testosterone

The bioavailability, pharmacokinetics, and metabolism of a novel transbuccal delivery system of testosterone was investigated in five healthy eugonadal men. Total serum testosterone (T), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) concentrations were determined from blood samples obtained at 8:00 a.m. (zero hour), and 30 min and 1, 2, 3, 4, 6, 12 and 24 hours later on day 1, and again on day 2, after dosing. This single transbuccal administration of Buccal T induced a prompt rise in serum T and DHT concentrations. The maximal concentration (Cmax) of T was 19.56 7.64 ng/mL (mean +/- SD; 5.3-fold increase from the baseline) at< 30 min (Tmax) after administration. The elimination half-life of Buccal T was about 1.75 h. Serum DHT peaked at 1 h at a concentration of 1.46 +/- 0.46 ng/mL (2.3-fold increase from the baseline). The drug was well tolerated. This study suggests that the Buccal T is a promising delivery system for natural T.

Lea's Shield®: A phase I postcoital study of a new contraceptive barrier device

Leas Shield is a new vaginal barrier contraceptive that may offer advantages over existing methods. It is made of silicone which is resistant to petroleum-based lubricants, does not absorb odors, and does not cause allergic reactions in users with latex sensitivity. It has an anterior loop for ease of insertion and removal and a one-way flutter valve. Its novel design has sufficient volume to fill the posterior fornix, which helps keep it in place and prevent sperm from entering the cervical os. This study evaluated with a standard postcoital test (PCT) the ability of the Leas Shield used with spermicide or non-spermicidal lubricant to prevent sperm from entering midcycle cervical mucus. Ten sterilized women underwent four PCT cycles: one cycle in which no contraceptive barrier was used (a baseline cycle) and 3 cycles in which one of the following was used: Leas Shield with spermicide, or with non-spermicidal lubricant, or the contraceptive diaphragm used with spermicide. All volunteers demonstrated more than 5 progressively motile sperm per high power field in the cervical mucus after intercourse in the baseline cycle. No motile sperm were found in the cervical mucus in any cycle in which Leas Shield or the diaphragm was used with spermicide. No motile sperm were found in cervical mucus in 9 of 10 cycles in which Leas Shield was used without spermicide. Only two progressively motile sperm were present in the cervical mucus of one volunteer who used the shield with non-spermicidal lubricant.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiproliferative effects of low-dose micronized progesterone*

OBJECTIVE To study the pharmacodynamic effects of oral micronized P on endometrial maturation. DESIGN This was a controlled, open, parallel group, pilot study. SETTING The experiment was performed in an outpatient academic clinical research unit. PATIENTS Twelve healthy, P-challenged, estrogen-primed, postmenopausal women participated in the study. INTERVENTIONS Patients were given 300 mg micronized P daily (8:00 A.M.) or twice (8:00 A.M. and 4:00 P.M.) daily from study days 1 through 14 after estrogen priming for 30 days. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after the 8:00 A.M. dose on study day 1 and 14 and again at 8:00 and 9:30 A.M. on days 3 and 5 fasting, days 7 and 9 after a fatty meal, and day 11 after a high fiber meal. Endometrial biopsies were taken on day 1 and 14. MAIN OUTCOME MEASURES Progesterone concentrations were measured. Endometrial biopsies were studied for effects on histology, glycogen content of glands, ribosomal RNA, and nuclear estrogen receptors in glands, surface epithelium, and stroma. RESULTS Day 1 and 14 P kinetics were similar for 8 hours. Dose-dependent increases in glandular glycogen, decrease in ribosomal RNA, and decrease in nuclear estrogen receptors were demonstrated. CONCLUSIONS Oral micronized P can induce antiproliferative changes in the human endometrium at doses lower than those required for transformation of the endometrium to a full secretory state.