A clinical study was conducted to assess the effects of oestrogen in controlling increased endometrial bleeding problems in the first year of Norplant use. Three treatment groups were studied: (i) 50 micrograms ethinyl oestradiol (EE); (ii) a combined pill containing 30 micrograms EE and 150 micrograms levonorgestrel (LNG); and (iii) placebo. Based on menstrual diary records, women with prolonged, frequent or irregular bleeding, as defined by World Health Organization criteria, were randomly allocated to one treatment for 21 days. A first endometrial biopsy was taken before commencing treatment and a second biopsy at either day 14 or 21 of treatment. Following treatment, all subjects kept a menstrual diary card for 90 days. In this preliminary study, 48 subjects had completed the full 90 day post-treatment record. Within 21 days of EE treatment, the number of bleeding/spotting days was reduced significantly (P < 0.02). In the 90 days following treatment, the administration of EE and EE + LNG significantly decreased the number of bleeding/spotting days (P < 0.05). There was no reduction in the number of bleeding/spotting episodes in the EE and EE + LNG groups, but the length of each bleeding/spotting episode was significantly shorter (P < 0.05). Histopathological findings of endometrium on day 0 revealed consistent progestogenic effects, and there was no apparent change in response by day 14 or 21 of EE or EE + LNG treatment. The results of this study confirm the clinical effectiveness of EE and EE + LNG for the treatment of irregular, frequent and prolonged bleeding in Norplant users.
The expression of endometrial progesterone receptor mRNA during the human menstrual cycle and in Norplant users was studied using digoxigenin-labelled ribonucleic probes for in-situ hybridization on 6 microns paraffin embedded endometrial sections. The staining intensity was scored blind semi-quantitatively. Blood ovarian steroid concentrations were measured in Norplant users. All data were analysed by analysis of variance. Glandular progesterone receptor mRNA concentrations were low during the menstrual-to-early proliferative stage but increased during the early-to-mid to late-proliferative stage then declined non-significantly over the secretory stage. No such variation was observed in stromal cells. Progesterone receptor mRNA concentrations were lower in Norplant than controls during early-to-mid to late-proliferative stages (in glandular epithelium and stroma) and during secretory stage (in stroma only). Norplant subjects with amenorrhoea had higher concentrations of stromal progesterone receptor mRNA but lower plasma oestrogen concentrations than subjects with breakthrough bleeding. The pattern of variation in progesterone receptor mRNA concentrations during the normal menstrual cycle resembles the published pattern for the receptor protein. The results demonstrate: (i) a differential sensitivity of glandular and stromal progesterone receptors to steroid regulation; (ii) in contrast to previous findings of an increase in immunoreactive progesterone receptor protein in Norplant endometrium, progesterone receptor mRNA concentrations in these tissues were reduced; and (iii) there was significantly more progesterone receptor mRNA in subjects with amenorrhoea than in those with breakthrough bleeding.
Endometrial progesterone receptor plays an important role in determining the biological activity of progestogens in fertility regulation. Studies during the normal menstrual cycle have shown that the concentrations of endometrial progesterone receptor and its mRNA vary in glandular epithelia but remain steady in stromal cells. There is general agreement between progesterone receptor mRNA and protein levels during the normal menstrual cycle. Norplant endometrium had an increase in immunoreactive progesterone receptor concentration but a reduction in progesterone receptor mRNA levels compared with controls. An immunohistochemical study, using the expression of the lysosomal protease cathepsin D as a marker for the functional status of progesterone receptors, failed to confirm the functionality of the receptors in Norplant endometrium. Together, these results suggest that (i) there is a differential sensitivity of glandular and stromal progesterone receptors to steroid regulation during the normal menstrual cycle; (ii) there appears to be a dissociation between the concentrations of progesterone receptor and its mRNA in Norplant endometrium; and (iii) there was significantly more progesterone receptor mRNA and lower plasma oestrogen concentrations in Norplant subjects with amenorrhoea than with endometrial bleeding. The clinical significance of the differences in progesterone receptor mRNA levels and plasma oestrogen concentrations between the amenorrhoea group and the bleeding group requires further investigation.
A series of 191 endometrial biopsy procedures were performed on Indonesian women who had received between 3 and 12 months exposure to Norplant. In all, 87 biopsy procedures were attempted with a microhysteroscope using biopsy forceps, and 104 procedures were attempted with either Pipelle or Karman suction curettes. Regardless of the biopsy method, diagnosable endometrium was obtained in only approximately 50% of procedures. Myometrium was often found in microhysteroscope but not in suction biopsies. An analysis of a number of clinical characteristics showed that women from whom diagnosable endometrial tissue was obtained had higher mean peripheral oestrogen concentrations in the 2 weeks prior to biopsy (439 +/- 35 versus 289 +/- 33 pmol/l; P = 0.0018) and significantly more days when endometrial bleeding occurred in the 90 days prior to biopsy (26.5 +/- 2.1 versus 16.2 +/- 1.8; P = 0.0003). These results suggest that after 3-12 months exposure to Norplant approximately 50% of women have an endometrium too thin to sample, and that this group is characterized by lower peripheral oestrogen concentrations and reduced menstrual bleeding.
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