Michiyoshi Taga

A Double-Masked Multicenter Comparative Study Between Alendronate and Alfacalcidol in Japanese Patients with Osteoporosis

Abstract:To evaluate the efficacy and safety of alendronate, a double-masked, active (alfacalcidol) controlled comparative study for 48 weeks was carried out in a total of 210 Japanese patients with osteoporosis. The doses of alendronate and alfacalcidol were 5 mg/day and 1 μg/day, respectively. The lumbar bone mineral density (LBMD) values observed at 12, 24, 36 and 48 weeks after the initiation of alendronate treatment were 3.53 ± 0.53%, 5.37 ± 0.62%, 5.87 ± 0.74% and 6.21 ± 0.59% (mean ± SE), respectively, higher than the baseline value. Corresponding values in the alfacalcidol group were 1.50 ± 0.43%, 0.69 ± 0.63%, 1.12 ± 0.60% and 1.36 ± 0.63%, respectively. There was a significant difference between the two groups at each time point (p<0.05 or p<0.001). The bone turnover markers were depressed during treatment in the alendronate group: −32.2% for alkaline phosphatase, −53.7% for N-terminal osteocalcin and −45.0% for urinary deoxypyridinoline compared with the corresponding baseline values. On the contrary, no notable changes in these parameters were observed in the alfacalcidol group. Treatment with alendronate caused a transient decrease in serum calcium concentrations associated with an increase in the serum level of intact parathyroid hormone. In contrast, treatment with alfacalcidol resulted in a tendency of these parameters to change in the opposite direction. No difference in fracture incidence between the two groups was observed. The overall safety of alendronate was comparable to that of alfacalcidol. In conclusion, although it was a relatively short-term study of 48 weeks, the results of the present study indicate that alendronate at the daily dose of 5 mg was effective in increasing LBMD and that no serious drug-related adverse events were observed in the alendronate-treated patients. Alendronate is more efficacious than alfacalcidol in increasing bone mineral density, although the mechanisms of the actions of the two drugs are apparently different.

Reduction of bone mineral density by gonadotropin‐releasing hormone agonist, nafarelin, is not completely reversible at 6 months after the cessation of administration

Study Objective. To determine the reversibilty of bone mineral density after the cessation of GnRH agonist treatment for endometriosis.

Cell Adhesion and Reproduction

Cell adhesion is essential for the regulation of many cellular functions. The adhesion molecule plays a critical role as a fundamental substance in various processes of reproduction such as trophoblast-endometrial interaction. Our understanding of the physiology of adhesion molecules will be helpful for clinical application of these molecules in the treatment and assessment of disorders of many processes of reproduction. We will briefly review integrins, cadherins, and laminin, which were the principal subjects of discussion in this conference.

Gene expression of gonadotrophin-releasing hormone, but not its receptor, in human endometrium and decidua

Gonadotropin-releasing hormone (GnRH) has been reported to exist in extrahypothalamic tissues such as the placenta, gonads and mammary glands. While we have reported the presence of GnRH-mRNA in the rodent uterus, there have been no reports concerning gene expression of GnRH and its receptor (GnRH-R) in human endometrial tissue. In order to investigate the role of GnRH as a local regulator in the human endometrium, we examined the gene for GnRH and GnRH-R in non-pregnant endometrium and decidua of early pregnancy. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis we found GnRH-mRNA but not GnRH-R-mRNA transcripts in the human endometrium and decidua at 7-9 weeks gestation. This is the first report that suggests GnRH gene expression in the human endometrium/decidua.

Comparison of Bone Metabolic Markers between Maternal and Cord Blood

We studied 41 normal pregnant women and their neonates in order to compare bone metabolism between them. We examined more specific bone formation markers (intact osteocalcin, bone-specific alkaline phosphatase) and a recently developed and more sensitive bone resorption marker (C-telopeptide of type I collagen; CTX) than previously available in maternal and umbilical cord venous blood taken at delivery. The concentrations of all markers of bone turnover, including CTX, in cord serum were significantly higher than those in maternal serum. There was no significant correlation between maternal and cord serum levels for any marker. These results indicate that fetal bone turnover is markedly enhanced compared with maternal bone turnover and is independent of maternal bone metabolism in late pregnancy.

Regulation of human decidual function by epidermal growth factor.

In order to clarify a regulatory mechanism of epidermal growth factor (EGF) in the decidualization process, EGF gene expression, the change in EGF receptor, and the cell proliferative effect of EGF in the human endometrium/decidua were assessed in both in vivo and in vitro decidualization systems. Northern blot hybridization showed that, although no hybridized band was found in the proliferative and secretory phase endometria, a specific band of 5 kb was detected in decidua of early pregnancy as well as in in vitro medroxyprogesterone acetate-induced decidual cells. In situ hybridization revealed that prepro-EGF mRNA was observed in the stromal cells of decidua. Scatchard plot analysis of 125I-EGF-binding studies for the homogenates from these endometria/decidua revealed that its binding sites increased in accordance with the decidualization process, and its dissociation constant remained unchanged. EGF had a stimulatory action on cell proliferation in the early pregnant decidual cells. These results demonstrate that EGF production, EGF receptor, and decidual cell growth increase in accordance with the process of decidualization, suggesting that EGF may play an important role in the regulation of decidualization in human endometrium through an autocrine/paracrine system.

Prolactin secretion in endometriotic patients

OBJECTIVE To clarify a significance of prolactin (PRL) for infertility in endometriosis. STUDY DESIGNS For seventy endometriotic patients with or without infertility, serum PRL concentrations measured by radioimmunoassay before and 30 min after 500 micrograms of thyrotropin-releasing hormone (TRH) injection were analyzed in relation to the Revised American Fertility Society score in endometriosis as well as to the outcome of the treatment for endometriotic infertility. RESULTS While no significant relationship was found between the basal PRL levels and the stage of endometriosis or the outcome of the treatment for infertility, the PRL value after TRH injection was significantly greater in the patients who did not become pregnant than those who did (P < 0.05). CONCLUSIONS Occult hyperprolactinemia may be involved in infertility in endometriotic patients.

Immunohistological localization of tenascin in the human endometrium.

Tenascin (TN) is an extracellular matrix glycoprotein that seems to be involved in embryogenesis, carcinogenesis and wound healing. In order to clarify the biological significance of TN in the human endometrium, we investigated its expression in the normal as well as in the hyperplastic and neoplastic human endometrium, using immunohistochemistry. We also investigated the coexistence of TN with proliferating cell nuclear antigen (PCNA), a marker of cell proliferation, in endometrial carcinoma to further assess the involvement of TN in regulating cell proliferation. TN expression was observed in the stroma surrounding the endometrial gland in the proliferative phase, whereas it could not be found in the secretory phase. The localization of TN and PCNA coincided frequently, as the stromal portion where the expression of TN was observed always showed positive for PCNA. These results suggest that TN is involved in cell proliferation and carcinogenesis in the human endometrium.

Gene expression and specific binding of platelet-derived growth factor and its effect on DNA synthesis in human decidual cells

To clarify the biological significance of platelet-derived growth factor (PDGF) in human decidual cell function, which is important for the maintenance of pregnancy, we investigated gene expression of the PDGF subunits, PDGF-A and PDGF-B, specific binding of the PDGF isoform, and the effect of PDGF dimers on DNA synthesis in human decidual cells. We detected in decidua from early pregnancy the expected DNA bands of PDGF-A and PDGF-B by reverse transcriptase-polymerase chain reaction (RT-PCR) as well as mRNAs of each PDGF subunit by Northern blot hybridization, demonstrating that both PDGF subunits exist in this tissue. Scatchard plot analysis showed that decidual cells had both PDGF-alpha and PDGF-beta receptors. PDGF-AA, -AB and -BB stimulated [3H]-thymidine incorporation in cultured decidual cells in a dose-dependent manner. These results indicate the importance of PDGF in human decidua.

Gene expression of gonadotropin-releasing hormone in early pregnant rat and steroid hormone exposed mouse uteri

While gonadotropin-releasing hormone (GnRH) or GnRH-like substance have been reported to exist in nonhypothalamic tissues such as placenta, gonads, and mammary gland, there have been no reports concerning the detection of GnRH mRNA in uterine tissue. In order to investigate the presence of GnRH in decidual tissues and its possible involvement in the regulation of placental function, we examined the gene for GnRH in the rodent uterus in early pregnancy and in nonpregnant animals treated with female sex steroids. Using RT-PCR and in situ hybridization we found GnRH mRNA transcripts in the rat uterus of 3- and 6- day gestation and in the mouse uterus treated with estrogen and progesterone. In situ hybridization revealed that GnRH mRNA was localized in the endometrial stromal cells of the 3rd and 6th day of gestation. These results suggest the existence of GnRH gene expression in uterine stromal cells and its possible paracrine effect derived from the decidual cells.