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Endometriosis is defined as endometriotic tissues growing outside the uterine cavity. The cell biological processes responsible for the pathogenesis of this disease are not well understood. In order to detect differences in proliferative activity between endometria and endometriotic lesions, Ki67 staining was analysed. In addition, expression of epidermal growth factor (EGF) and its receptor was examined using immunohistochemistry. For dedifferentiation processes pointing to invasive properties of the uterine epithelium, the presence of the adhesion complex E-cadherin with the associated alpha- and beta-catenin was investigated. Specimens of endometrium in the proliferative phase of 36 patients without, and 79 patients with, endometriosis together with endometriotic lesions were studied. The study revealed a significantly reduced proliferation activity in uterine epithelium within the ectopic lesions but no differences between eutopic endometria of non-affected and affected patients. Furthermore, a lower expression of both EGF and its receptor in the epithelial cells of the ectopic glands was observed. The adhesion complex E-cadherin, together with alpha-, and beta-catenin, was slightly reduced in uterine epithelial cells of women with endometriosis and less expressed in endometriotic lesions. The results indicate that epithelial cells of endometriotic lesions are not hyperproliferative, but do appear to dedifferentiate, displaying an invasive character.

Integrins are cell adhesion molecules that undergo cell-specific dynamic changes during the normal menstrual cycle in the human endometrium. Here, using immunohistochemistry, we have investigated the expression pattern of the integrins alphav, alpha2beta1, alpha3beta1, alpha3, alpha6, beta1, beta2 and beta3 in the human ectopic endometrium of 30 patients and in nine cases in the corresponding eutopic endometrium. The biopsies were obtained during the early or late follicular phase (25 cases), during the corpus luteum phase (four cases) and in one case after 6 months' treatment with a gonadotrophin releasing hormone (GnRH) agonist. The integrin expression was independent of the ovarian steroid situation at the time of biopsy. The integrin alpha6 was expressed in all endometriotic and endometrium samples. The integrin alpha3 was absent in all endometrium tissues of patients with endometriosis. However, the corresponding endometriotic lesions re-expressed this adhesion molecule in 15 cases. No change in integrin beta3 expression pattern could be demonstrated in either endometriotic lesions or endometrium samples, regardless of the menstrual cycle phase. A correlation between serum oestradiol and progesterone concentrations and the expression of the investigated integrins was not observed, thus indicating that these two hormones play a minor role in the regulation of the cell adhesion molecules examined. Our investigation suggests that endometriosis is a dedifferentiated disease as it expressed different integrins in comparison with the eutopic endometrium, and independently of the hormonal situation. The ability of endometriotic tissues to express integrins may explain the high recurrence rates in patients with endometriosis, as these samples retain their adhesion potency after retrograde menstruation and are thus able to establish cell-cell and cell-matrix interactions with the surrounding peritoneum.

There is an increasing prevalence of high levels of thyroid stimulating hormone (TSH) with age - particularly in postmenopausal women - which are higher than in men. The incidence of thyroid disease in a population of postmenopausal women is as follows: clinical thyroid disease, about 2.4%; subclinical thyroid disease, about 23.2%. Among the group with subclinical thyroid disease, 73.8% are hypothyroid and 26.2% are hyperthyroid. The rate of thyroid cancer increases with age. The symptoms of thyroid disease can be similar to postmenopausal complaints and are clinically difficult to differentiate. There can also be an absence of clinical symptoms. It is of importance that even mild thyroid failure can have a number of clinical effects such as depression, memory loss, cognitive impairment and a variety of neuromuscular complaints. Myocardial function has been found to be subtly impaired. There is also an increased cardiovascular risk, caused by increased serum total cholesterol and low-density lipoprotein cholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxine replacement therapy. Such treatment has been found to be cost-effective. With time, overt hypothyroidism can develop. Therefore, routine screening of thyroid function in the climacteric period to determine subclinical thyroid disease is recommended. Hormone replacement therapy (HRT) in women with hypothyroidism treated with thyroxine causes changes in free thyroxine and TSH. Increased binding of thyroxine to elevated thyroxine-binding globulin causes an elevation of TSH by feedback. Since adaptation is insufficient, there is an increased need for thyroxine in these women taking HRT. TSH levels should be controlled at 12 weeks after the beginning of therapy. At higher age the need for iodine and thyroxine is decreased. Therefore, therapy has to be controlled. For bone metabolism thyroid hormones play a dominant role. While there are only marginal differences between hypothyroid patients and euthyroid controls, there are large differences for hyperthyroid patients. Previous thyrotoxicosis and subsequent long-lasting L-thyroxine treatment are together associated with reduction in femoral and vertebral bone density in postmenopausal women. In these cases HRT is important for the control of bone loss.

To examine the pathogenesis of hyperthyroidism in women with trophoblastic diseases, the biological activity of human chorionic gonadotropin (hCG) molecules in women with normal pregnancy (n = 85) and in women with trophoblastic diseases (vesicular mole, n = 30; and choriocarcinoma, n = 12) was compared. Hyperthyroidism (thyroid stimulating hormone (TSH) < 0.3 mIU/l) was observed more frequently in women with trophoblastic diseases. All the sera were then subjected to Chinese hamster ovary cells transfected with the human TSH receptor (CHO-hTSHr cells) and cAMP production was compared. Sera from the women with choriocarcinoma showed the highest cAMP production. Interestingly, significant correlation between serum hCG level and cAMP production in CHO-hTSHr cells was observed only in women with trophoblastic disease. All the sera were then applied to CHO cells transfected with hCG/luteinizing hormone (LH) receptor (CHO-hCG/LHr cells). In contrast to the findings with the TSH receptor, sera from the women with normal pregnancy showed the highest cAMP production in these cells. Correlation between serum hCG level and cAMP production in CHO-hCG/LHr cells was significant only in normal pregnancy. These results indicate that the hCG molecule from women with trophoblastic diseases displays enhanced thyrotropic activity.

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The expression of gap junction connexins (Cx) in the female reproductive tract of rodents and in the human endometrium is highly regulated by steroid hormones. Here we have investigated the distribution and regulation properties of Cx43, Cx26 and Cx32 in the human ectopic endometrium of 41 patients, using immunohistochemistry. The biopsies were obtained during the early or late follicular phase (26 cases), during the corpus luteum phase (five cases) and after a 6 month treatment with a gonadotrophin-releasing hormone (GnRH) agonist (three cases) or progestin (seven cases). Aberrant expression of Cx43 was found in the epithelium of nearly all endometriotic glands whereas Cx26, typical for human uterine epithelium cells, was only detected in 18 cases; in 17 it was co-expressed with Cx43. The stromal compartment of the tissues did not express any connexins investigated. Staining for Cx32 was absent in all endometriotic tissues. Strong expression of Cx43 was correlated with a high serum value of 17 beta-oestradiol, whereas a strong expression of Cx26 was found with high values of progesterone mainly in patients after progestin treatment. The epithelium of endometriotic implants collected after GnRH agonist treatment expressed Cx26 and Cx43 only moderately. The patterns described demonstrate an aberrant connexin expression and a different hormonal regulation pattern in endometriotic tissues compared to the normal cyclic uterine endometrium, thus indicating a high dedifferentiation from the normal situation. However, endometriosis still remains a hormonally-dependent benign disease, and hence, can be treated hormonally.

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