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Hormone replacement therapy (HRT) is effective in alleviating vasomotor symptoms but the effect on psychological symptoms is less clear. This study aimed to compare the psychological effects of two regimens of HRT in perimenopausal women in a randomized, initially double-blind, controlled trial. Thirty-eight women reporting climacteric symptoms were randomly allocated into either oral conjugated equine estrogen 0.625 mg daily plus progestogen (norgestrel) 150 micrograms for the last 12 days of each 28 day cycle, or tibolone 2.5 mg/day for 28 days. They were assessed using standardized psychological assessments. There were no significant differences in changes from baseline between the two types of therapy. For both groups combined there were significant improvements compared with baseline in vasomotor symptoms in the first month, plus anxiety, sleep, memory and somatic dysfunction by the second and third months, but not in scores of depression. Log linear analysis of weekly scores showed that depression scores were significantly related to improvement in vasomotor scores independent of type of therapy and time on HRT. Memory problems were related to vasomotor symptoms independent of depression. No difference between the two types of therapy was found, nor any direct effect of HRT on anxiety or depression. The results support the domino theory, suggesting that psychological improvement follows alleviation of vasomotor symptoms.

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Remodelling of endometrial tissues is fundamental to the cyclical changes that occur during the menstrual cycle, implantation and, in the absence of pregnancy, at menstruation. The enzyme matrix metalloproteinase-9 (MMP-9) is recognized as important in these processes but its regulation is not well defined. These studies have demonstrated that MMP-9 activity is present in the endometrium and exhibits cyclical changes in its distribution in the glandular and stromal cells. MMP-9 protein is present throughout the cycle with highest expression, as determined by semiquantitative analysis of specific MMP-9 immunoreactivity, in glandular cells during the mid secretory phase. A similar distribution was observed in first trimester decidua. In women with a levonorgestrel intrauterine system (LNG-IUS), which delivers high local concentrations of progestagen to the uterine cavity, MMP-9 is highly expressed in both endometrial glandular and stromal cells, and in the vasculature (in endothelial and perivascular cells). It can be concluded that MMP-9 is stimulated directly or indirectly by progesterone. Furthermore, MMP-9 may play a role in the remodelling of the endometrium that occurs during the menstrual cycle and in the aetiology of the morphological changes and breakthrough bleeding associated with long-term progestagen administration via a LNG-IUS.

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This study has examined endometrial tissue in 14 normal women prior to insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) and thereafter longitudinally for up to 12 months post-insertion. The specific endpoints examined by immunohistochemistry were progesterone receptor (PR) subtypes A + B, oestrogen receptor (ER) and prostaglandin dehydrogenase (PGDH). Two antiprogesterone receptor antibodies, one specific to PR(B) subtype and the other to PR subtype A + B, were employed to examine the localization of both PR isoforms. The activity of PGDH, a progesterone dependent enzyme, was also measured. ER and PR(A+B) and PR subtype B were significantly down-regulated in glands and stroma in the presence of continuous intrauterine LNG delivery. There was an apparent increase in PR(A) immunoreactivity in endometrial glands between 6 and 12 months post-insertion. Consistent with down-regulation of both isoforms of PR was reduced glandular PGDH immunostaining following LNG-IUS insertion, and PGDH activity (as measured by metabolism of excess substrate in vitro). Furthermore, PGDH activity, known to be localized in the glands, significantly increased (P < 0.05) at 12 months post-insertion, coinciding with the observed increase in glandular PR(A+B) immunoreactivity at this time. Since the LNG-IUS suppresses the PR(B) so strongly, PR(A) is likely to be the subtype that mediates long term LNG action in the endometrium. PR(B) is the more suppressed of the two subtypes, and only PR(A) rises along with PGDH activity. Alterations to normal endometrial morphology and function, e.g. perturbation of normal sex steroid receptor expression, following exposure to high concentrations of local LNG, may play a role in the aetiology of bleeding disorders associated with the LNG-IUS. Further elucidation of local uterine mediators involved in the mechanism of bleeding problems is required.

PIP: The effects of a levonorgestrel-releasing intrauterine system (LNG-IUS) on endometrial tissue were investigated in 14 UK women who were followed for 12 months after its insertion. Of particular interest was the etiology of menstrual aberration associated with progestogen-only contraception. In the presence of continuous intrauterine LNG delivery, estrogen receptor and progesterone receptor (PR) subtype A + B and subtype B were significantly downregulated in the endometrial glands and stroma. There was no apparent increase in PR subtype A immunoreactivity in endometrial glands 6-12 months after LNG-IUS insertion. Also observed was reduced glandular prostaglandin dehydrogenase (PGDH) staining and activity. PGDH activity significantly increased at 12 months post-insertion coinciding with the increase in glandular PR subtype A + B. Since the LNG-IUS suppresses the PR subtype B so strongly and only PR subtype A rises along with PGDH activity, PR A is likely the subtype that mediates long-term LNG action in the endometrium. Perturbation of normal sex steroid receptor expression after exposure to high concentrations of local LNG may play a role in the bleeding disorders associated with use of the LNG-IUS. Examination of more local mechanisms in endometrium exposed to an LNG-IUS should help elucidate some of the potential mechanisms regulating endometrial bleeding.

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Irregular bleeding remains a common reason for the discontinuation of progestin-only contraception. The levonorgestrel releasing intrauterine system (LNG-IUS) has profound morphological effects upon the endometrium. Specific features are gland atrophy and extensive decidual transformation of the stroma. Morphological changes in the endometrium may be associated with perturbation of mechanisms regulating normal endometrial function. This study describes endometrial stromal and glandular features prior to and up to 12 months following insertion of the LNG-IUS. Comparison is made with first trimester decidua. In order to elucidate further mechanisms governing endometrial function with local intrauterine delivery of LNG, we here report histological features consistent with decidualization; a significant increase in granulocyte-macrophage colony stimulating factor (GM-CSF) immunoreactivity in decidualized stromal cells; glandular and stromal prolactin receptor expression and an infiltrate of CD56 + large granular lymphocytes and CD68 + macrophages. We are unaware of previous reports which have documented longitudinally both morphological and functional observations in endometrium exposed to local intrauterine levonorgestrel delivery. These studies demonstrate that long-term administration of intrauterine levonorgestrel results in features of altered morphology and function. No correlation was apparent between the end points in the study and the bleeding patterns described by the subjects. Further evaluation of these features in the context of menstrual bleeding experience may contribute to a better understanding of this troublesome side-effect which often leads to dissatisfaction and discontinuation of the intrauterine system.

PIP: The levonorgestrel-releasing intrauterine system (LNG-IUS) has profound morphologic effects on the endometrium, including gland atrophy and extensive decidual transformation of the stroma. The present study investigated these morphologic changes in tissue samples collected from 14 UK women up to 12 months after insertion of the LNG-IUS. Observed histologic features consistent with decidualization included a significant increase in granulocyte-macrophage colony stimulating factor immunoreactivity in decidualized stromal cells, glandular and stromal prolactin receptor expression, and an infiltrate of CD56+ large granular lymphocytes and CD68+ macrophages. The features of pseudo-decidualization closely resembled the morphology of early pregnancy decidua. These findings confirm that the stromal compartment of the endometrium undergoes changes consistent with decidualization for at least up to 12 months after insertion of an LNG-IUS. There was no correlation between the study endpoints and the menstrual patterns reported by study subjects. Further study of the decidualized nature of the stromal cells in the LNG-exposed endometrium should enhance understanding of the mechanisms responsible for breakthrough bleeding in users of progestogen-only contraceptives.

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Once hormone replacement therapy (HRT) has been commenced, it becomes extremely difficult to advise women approaching the menopause on the need for contraception. In this study of twenty women, neither the regularity of their pre-existing menstrual cycle nor a random FSH concentration predicted the likelihood of subsequent ovulation whilst taking HRT. HRT is not reliably contraceptive and women commencing HRT whilst still menstruating spontaneously must be advised on the need for additional contraception.

PIP: In Scotland, providers determined the incidence of ovulation before and during use of oral hormone replacement therapy (HRT) among 20 women aged 42-52 attending the Family Planning and Well Woman Services menopause clinic in Edinburgh and their need for contraception. Ovulation was defined as a pregnanediol concentration of more than 0.5 mmol/g creatine. HRT consisted of 1.25 mg/day of conjugated estrogens with 150 ug cyclical norgestrel for 12 of 28 days (Prempak-C). Women with irregular cycles were older than those with regular cycles (47.3 vs. 45.5 years; p 0.02). They also had considerably higher mean follicle stimulating hormone (FSH) levels (26 vs. 14.2 IU/l; p 0.001). One woman had a very high FSH level (67 IU/l) before HRT use and ovulated in the subsequent cycle with urinary pregnanediol levels indicating normal ovarian function. All 10 women who had regular cycles ovulated before HRT use. Six still ovulated during HRT use. Among women with irregular cycles, 4 of the 10 women ovulated before HRT use. Three of these women had anovulatory cycles during HRT use while 3 of the 6 who did not ovulate before HRT use ovulated during HRT use. These findings reveal that HRT with the higher dose Prempak-C does not suppress ovulation and that an elevated FSH does not always indicate the absence of ovulation. They also show that neither age nor regularity of menstrual cycles can be used to predict the need for contraception in perimenopausal women using HRT.

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