MORPHOMETRIC STUDY OF THE HUMAN ENDOMETRIUM FOLLOWING CONTINUOUS EXPOSURE TO LEVONORGESTREL RELEASED FROM VAGINAL RINGS DURING 90 DAYS

The effects of vaginal devices releasing levonorgestrel (LNG) at a constant rate of approximately 20-mu-g/24 hrs on the human endometrium were studied in a group of 69 normally menstruating women during a period of 90 days of continuous use. Peripheral blood samples were withdrawn three times weekly starting at day 10 of a pretreatment (control) cycle and then three times weekly from day 60 to 90 of the treatment period. The levels of LNG, estradiol, progesterone and sex hormone binding globulin (SHBG) were analyzed by radioimmunoassay techniques. Endometrial biopsies were obtained in the luteal phase of the pretreatment cycle and on day 84-87 of the treatment period. Increased bleeding occurred in most subjects exposed to the LNG-releasing device, the mean number of bleeding and spotting days was 26.4 +/- 8.9 S.D. which exceeded that found in their control cycle. Morphometric analyses of the endometrial biopsies using 9 quantitative indices, revealed highly significant changes in glands and stroma following the use of the LNG-releasing vaginal device. Irrespective of the circulating steroid levels, the administration of LNG significantly diminished the glandular diameter (p < 0.001), reduced the volume density of the glands (p < 0.001) and of the glandular epithelium (p < 0.001) and modified the ratio glandular epithelium: glands (p < 0.001). It is concluded that levonorgestrel released at a rate of 20-mu-g/24 hrs, induces characteristic changes in the histologic structure of the human endometrium. Although no simple correlation has been found between any of the endometrial indices and the numbers of bleeding/spotting days or bleeding days, the changes as such may represent biochemical alterations which could be predisposing factors for intermenstrual bleeding and spotting. To prove a causal relationship between morphological and biochemical changes and changes in bleeding patterns, further in-depth studies may be required.