The impacts of menopausal hormone therapy on longer-term health consequences of ovarian hormone deficiency.

This study on the longer-term health consequences of ovarian hormone deficiency (OHD) received the Henry Burger Prize in 2022. Osteoporosis, cardiovascular disease and dementia are major degenerative diseases that are also causally associated with OHD. Two randomized controlled trials (RCTs) revealed no significant difference in bone mineral density by adding alendronate to ongoing menopausal hormone therapy (MHT) or combining alendronate at MHT initiation. Another RCT pursuing the effects on fracture recurrence and total mortality in women with hip fracture disclosed that MHT with percutaneous estradiol gel (PEG) and micronized progesterone (MP4) was comparable to risedronate. Basic studies reported that 17ß-estradiol exerted direct beneficial actions on vascular smooth muscle in cell proliferation, fibrinolysis and apoptosis. A fourth RCT showed that MP4 had a neutral impact on the PEG response of blood pressure and arterial stiffness. A fifth RCT suggested that the combination therapy of conjugated equine estrogen and MP4 was superior to tacrine in preserving activities in daily living in women with Alzheimer's disease. In addition, PEG plus MP4 attenuated cognitive decline in women with mild cognitive impairment in a sixth RCT. Finally, the all-cause mortality in recently menopausal women receiving MHT was updated using an adaptive meta-analysis of four RCTs.

Fracture recurrence in hip fracture with menopausal hormone therapy versus risedronate: a clinical trial.

OBJECTIVES: An open-label, randomized trial was conducted to examine the effects of risedronate versus menopausal hormone therapy (MHT) in postmenopausal women with recent hip fracture. METHODS: Among 1165 eligible women, 281 were recruited and randomly assigned to receive oral risedronate (35 mg/week) or percutaneous estradiol gel (1.5 mg/day) plus oral micronized progesterone (100 mg/day) for 4 years. The primary end point was recurrent fracture and the secondary end points were mortality and bone mineral density (BMD). RESULTS: Kaplan-Meier analyses showed no significant differences in fracture recurrence and mortality between the two groups. The incidence of any new fracture per 100 person-years (PY) was 8.63 in the risedronate group and 12.86 in the MHT group (p = 0.180); that of clinical fracture was 4.75 and 6.99, respectively (p = 0.265); and that of asymptomatic vertebral fracture was 4.87 and 5.58, respectively (p = 0.764). The respective incidence of death per 100 PY was 3.58 and 4.40 (p = 0.503). BMD increased comparably at the lumbar spine in both groups. BMD at the total hip did not change in the risedronate group, but increased significantly by 2.8% in the MHT group. CONCLUSIONS: MHT might not differ from risedronate in the prevention of secondary fractures and death among postmenopausal women with recent hip fracture.

17α-hydroxlyase/17, 20-lyase deficiency in three siblings with primary amenorrhea and absence of secondary sexual development.

BACKGROUND: 17α-hydroxlyase/17, 20-lyase deficiency (17OHD) is a rare phenotype of congenital adrenal hyperplasia that can cause primary amenorrhea. CASE: Three phenotypically female siblings visited the adolescent gynecologic clinic complaining of primary amenorrhea and absence of secondary sexual developments. All had constant high blood pressure and showed a hypergonadotropic hypogonadal state with high progesterone and low testosterone levels. Two were genotypically females and one was genotypically a male; all were confirmed to have 17OHD, and estrogen replacement, glucocorticoids, and antihypertensive drugs were Prescribed to the patients. SUMMARY AND CONCLUSION: Identifying a 17OHD patient complaining of primary amenorrhea in a gynecologic clinic is important for proper management.

Effects of hormone therapy on ambulatory blood pressure in postmenopausal Korean women.

BACKGROUND: Previous studies of the effects of postmenopausal hormone therapy (HT) on blood pressure have yielded inconsistent results. OBJECTIVES: To examine the impact of HT on 24-h ambulatory blood pressure. METHODS: A total of 67 postmenopausal Korean women (age 57.1 ± 5.7 years) received 2 months of HT consisting of conjugated equine estrogen (CEE, 0.625 mg/day) with or without micronized progesterone (100 mg/day). Ambulatory blood pressure monitoring was performed at baseline and after HT. Subjects were divided into those with normal blood pressure (n = 25) and those with high blood pressure (n = 42), based on their baseline daytime blood pressure. RESULTS: Parity and body mass index were higher in the group with high blood pressure than in the group with normal blood pressure. For both systolic and diastolic blood pressures throughout the day, significant negative correlations were observed between basal blood pressure and blood pressure difference after HT. During the daytime period, HT increased systolic and diastolic blood pressures in the subjects with normal blood pressure and decreased systolic and diastolic blood pressures in those with high blood pressure. When micronized progesterone was added to the CEE treatment, the increase in daytime blood pressure in the group with normal blood pressure was abolished, and the decrease in systolic blood pressure throughout the day in the group with high blood pressure was potentiated. CONCLUSIONS: HT had either blood pressure-elevating or blood pressure-lowering effects in postmenopausal Korean women, depending on basal blood pressure. CEE increased the daytime blood pressure in women with normal blood pressure, but reduced it in women with high blood pressure. Micronized progesterone may provide beneficial effects on blood pressure when combined with CEE.

Clinical features and management of facial nerve paralysis in children: analysis of 24 cases.

OBJECTIVES: To evaluate the causes, treatment modalities and recovery rate of paediatric facial nerve paralysis. MATERIALS AND METHODS: We analysed 24 cases of paediatric facial nerve paralysis diagnosed in the otolaryngology department of Gachon University Gil Medical Center between January 2001 and June 2006. RESULTS: The most common cause was idiopathic palsy (16 cases, 66.7 per cent). The most common degree of facial nerve paralysis on first presentation was House-Brackmann grade IV (15 of 24 cases). All cases were treated with steroids. One of the 24 cases was also treated surgically with facial nerve decompression. Twenty-two cases (91.6 per cent) recovered to House-Brackmann grade I or II over the six-month follow-up period. CONCLUSION: Facial nerve paralysis in children can generally be successfully treated with conservative measures. However, in cases associated with trauma, radiological investigation is required for further evaluation and treatment.

Efficacy and tolerability of estradiol 1 mg and drospirenone 2 mg in postmenopausal Korean women: a double-blind, randomized, placebo-controlled, multicenter study.

OBJECTIVES: The aim of this study was to demonstrate that the therapeutic efficacy of an estradiol 1mg/drospirenone 2mg (E2/DRSP) preparation is superior to a placebo in postmenopausal Korean women with hot flushes and other climacteric symptoms, and to demonstrate that this treatment is both safe and tolerable. METHODS: This was a double-blind, randomized, placebo-controlled, multicenter study over four 28-day treatment cycles. A total of 158 subjects were screened and 90 women were randomized into two treatment groups (E2/DRSP group, n=45; placebo group, n=45). The primary efficacy parameter was the individual relative change of hot flushes. The secondary efficacy parameters such as other climacteric, urogenital symptoms and vaginal bleeding patterns were also evaluated, and the occurrence of any adverse events was noted. In addition, physical, gynecological examinations and laboratory analyses were performed at the beginning and end of the study. RESULTS: The mean number of hot flushes per week during treatment weeks 3-16 decreased by 48.1% during treatment with placebo, and by 84.4% during treatment with E2/DRSP (p<0.001). The E2/DRSP combination also reduced the incidence and intensity of menopausal symptoms in postmenopausal women. Most of adverse events was mild or moderate degree of intensity. None of the parameters measured in the study, including laboratory analyses, physical and gynecological examinations, vital signs, and weight, led to any concerns of safety. CONCLUSIONS: The E2 1mg/DRSP 2mg combination tested in the study was efficacious and safe in the treatment of hot flushes and other climacteric symptoms in postmenopausal Korean women.

Aqueous extract of Schizandra chinensis fruit causes endothelium-dependent and -independent relaxation of isolated rat thoracic aorta.

An aqueous extract of Schizandra chinensis fruit (ScEx) has long been used to promote the vascular health of postmenopausal women in Korea. This study investigated the ability of ScEx to relax rat aorta constricted with norepinephrine (NE) and the mechanism(s) of such relaxation. ScEx induced partial, endothelium-dependent relaxation. In particular, the relaxation induced by lower concentrations of ScEx (0.1 and 0.3 mg/ml) was largely endothelium-dependent, and was essentially abolished by NG-nitro-L-arginine, methylene blue, 1H-[1,2,3] oxadiazole [4,4-a] quinoxalin-1-one, indomethacin, or ICI 182,780. The results indicate that the response to ScEx involves enhancement of the nitric oxide (NO)-cGMP system, and that it occurs via estrogen receptors. The magnitude of the inhibition with these treatments decreased with increasing ScEx concentration, however, indicating that other vasorelaxation mechanisms are involved, which depend on the ScEx concentration. Calcium concentration-dependent contraction curves in high potassium depolarization medium were shifted significantly to the right and downward after incubation with ScEx (0.3 and 1.0 mg/ml), implying that ScEx is also involved in inhibition of the extracellular calcium influx to vascular smooth muscle. These data demonstrate that ScEx caused both endothelium-dependent and -independent vasorelaxation, which may contribute to understanding the cardiovascular protective effect of ScEx.

The biological significance of phospholipase C beta 1 gene mutation in mouse sperm in the acrosome reaction, fertilization, and embryo development.

PURPOSE: We carried out this study to evaluate the biological significance of phospholipase C beta 1 gene mutation in mouse sperm in the acrosome reaction, fertilization, and embryo development. METHODS: Study subjects were divided into two groups according to the sperm [intact phospholipase C (PLC) beta 1 and PLC beta 1-/- C57BL/6J x CBA F1 mouse sperm] used. The positive acrosome reaction rate labeled with fluorescein isothiocyanate-Pisum sativum agglutinin, the fertilization rate, and the rate of embryos developed to the stage of morula or blastocyst in the two groups were compared. RESULTS: The mouse sperm null for the PLC beta 1 gene showed a lower acrosome reaction rate than control sperm (69.2 vs 50.9%, P < 0.05). And the fertilization rate and the rate of embryos developed to the stage of morula or blastocyst were also lower in the group using PLC beta 1-/- mouse sperm compared to the intact group (P < 0.05; 73.5 vs 51.8% and 15.7 vs 4.3%, respectively). CONCLUSIONS: Mutation of the PLC beta 1 gene in the mouse sperm reduces the acrosome reaction rate, fertilization rate, and embryo development rate, which may be the etiologic factors responsible for the low reproductive rate of PLC beta 1-/- mouse.

17Beta-estradiol inhibits proliferation of cultured vascular smooth muscle cells induced by lysophosphatidylcholine via a nongenomic antioxidant mechanism.

OBJECTIVE: Lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, stimulates proliferation of vascular smooth muscle cells (VSMC). We investigated the direct impact of 17beta-estradiol (E2) on the proliferation of VSMC from rat aorta. RESULTS: VSMC derived from both female and male rats expressed estrogen receptors alpha and beta. Treatments with 1% fetal bovine serum or 5 microM lysoPC increased the incorporation of [3H]-thymidine in VSMC obtained from female rats. 17Beta-E2 did not alter the response to fetal bovine serum, but significantly suppressed the enhanced deoxyribonucleic acid synthesis which had been induced by lysoPC in a dose-dependent manner (10(-4)-10(-6) M). Estrogen also inhibited the proliferation of VSMC from male animals. ICI 182,780, a specific estrogen receptor antagonist, and 17alpha-E2, an inactive form of estradiol, also decreased the mitogenic response to lysoPC in VSMC. In addition, N-acetyl-L-cysteine, a potent antioxidant, inhibited the lysoPC effect. Flow cytometric analysis using the oxidation-sensitive probe 2',7'-dichlorofluorescin diacetate revealed that elevated intracellular formation of reactive oxygen species elicited with lysoPC was depressed significantly by 17beta-E2, ICI 182,780, or 17alpha-E2 as well as by N-acetyl-L-cysteine. CONCLUSION: 17Beta-E2 inhibits in vitro VSMC proliferation induced by lysoPC via a nongenomic antioxidant mechanism.

Intactness of zona pellucida does not affect the secretion of a trypsin-like protease from mouse blastocyst.

Assisted hatching (AH), which is known to improve the hatching potential of mammalian embryos, has been used to increase the pregnancy rate in in vitro fertilization cycles. However, the effect of AH on a trypsin-like protease, which is known to be associated with the hatching process, has not been studied. In this study, we evaluate whether the intactness of zona pellucida affects the secretion of a trypsin-like protease from mouse blastocyst. Four- to 8-cell stage mouse embryos were collected at 66- to 68 hr after hCG injection and divided into 3 groups according to the manipulation of zona pellucida. The groups are no treatment (control), drilling of zona pellucida (ZD) and thinning of zona pellucida (ZT). The activity of a trypsin-like protease, blastocyst development and hatching rate were compared among the three groups at 110 and 135 hr after hCG injection, respectively. The protease activity and blastocyst development were not significantly different among control, ZD and ZT groups at 110 and 135 hr after hCG injection, respectively. However, the hatching rate of ZD and ZT groups was significantly higher than that of control group at each time, respectively (p<0.001). Even in the zona pellucida removed embryos, the protease activity did not differ from the control group. In conclusion, the secretion of a trypsin-like protease from mouse blastocyst does not seem to be affected by the intactness of zona pellucida.

Effects of electric stimulation on bovine oocyte activation and embryo development in intracytoplasmic sperm injection procedure.

PURPOSE: This study was carried out to investigate the efficacy of electric stimulation before and/or after intracytoplasmic sperm injection (ICSI) on bovine oocyte activation and embryo development. METHODS: The oocytes were treated with electric shock before (B), before and after (B&A), and after (A) sperm injection. In each group, sham ICSI (ICSI-s) was performed to exclude the effect of parthenogenesis (B ICSI-s, B&A ICSI-s, and A ICSI-s). An electric pulse was applied with a single direct current (DC) pulse (0.8 kV/cm, 70 microseconds). RESULTS: One pronucleus (PN) formation in the B&A ICSI-s group was slightly higher than that found in B and B&A ICSI group; however, the difference was not significant. Two PN formation in B&A ICSI group was higher than that found in sham ICSI groups (P < 0.05). There were no differences among treatment groups in the cleavage rate; however, morulae and blastocyst formation in the B&A embryos was significantly higher than that of other groups (P < 0.05) and got pregnant. CONCLUSIONS: Electric stimulation before and after injection was an effective method in inducing bovine oocyte activation and in sustaining embryo development to the morulae and blastocyst stage.

Changes in biochemical bone markers during pregnancy and puerperium.

To elucidate the changes in bone turnover during pregnancy and puerperium, we measured serially the levels of serum osteocalcin and urine deoxypyridinoline (Dpy) as markers of bone formation and bone resorption, respectively, in 22 healthy women with normal pregnancy. Nineteen non-pregnant women served as control. The Dpy levels increased significantly at 16 weeks of pregnancy and remained elevated thereafter. The levels of osteocalcin, however, were significantly decreased at 16 weeks of pregnancy and elevated later at 6 weeks postpartum. Bone turnover ratio (Dpy/osteocalcin) continued to rise during pregnancy, but returned to control levels 6 weeks after delivery. Dpy levels and bone turnover ratio during puerperium tended to be higher in 17 breast-feeding women than those of 5 exclusive bottle-feeders. In conclusion, bone resorption begins to increase from the second trimester of pregnancy and calcium release from bone tissue might play a major role in calcium homeostasis during the whole period of pregnancy as well as during lactation.

Clinical correlation of cyclin D2 mRNA expression in human luteinized granulosa cells.

PURPOSE: The aim was to evaluate whether the expression of cyclin D2 mRNA in human luteinized granulosa cells correlates with the clinical parameters of women undergoing in vitro fertilization-embryo transfer (IVF-ET) programs. METHODS: Using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques, the cyclin D2 mRNA in human luteinized granulosa cells of large follicles was measured. Correlation analysis between cyclin D2 mRNA expression and clinical parameters [age; day 3 follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2); E2 and P4 at the day of human chorionic gonadotropin (hCG); total amount of gonadotropin and the number of days of gonadotropin administration; pregnancy outcome] were performed. RESULT(S): Cyclin D2 mRNA expression showed negative correlation with patient's age (R = -0.60, P < 0.005) and total amount of gonadotropins (R = -0.45, P < 0.03), and also showed positive correlation with serum E2 levels at the day of hCG administration (R = 0.55, P < 0.02). Other clinical parameters showed no statistical significance. Cyclin D2 mRNA expression of pregnant group was higher than that of nonpregnant group (P < 0.03). CONCLUSIONS: Cyclin D2 mRNA expression in human luteinized granulosa cells positively correlates with clinical parameters of ovarian function and may be a novel marker for the health of human ovarian follicle.

Up-regulation of matrix metalloproteinase-9 in human myometrium during labour: a cytokine-mediated process in uterine smooth muscle cells.

The pregnant uterus undergoes dramatic changes of tissue remodelling during the labour and post-partum period. We studied the production of matrix metalloproteinase 9 (MMP-9), as a major contributor of tissue remodelling, in human myometrium at parturition. The regulation of proMMP-9 by interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) was also investigated in human myometrial smooth muscle cells. MMP-9 was present in myometrial smooth muscle cells, interstitial fibroblasts and inflammatory cells. The gelatinolytic activities of proMMP-9 in myometrium increased dramatically during labour. IL-1beta and TNF-alpha induced proMMP-9 in myometrial smooth muscle cells, but these effects did not seem to be mediated by protein kinase C. On the other hand, neither 17beta-oestradiol nor progesterone itself affected proMMP-9 production in myometrial smooth muscle cells. Moreover, progesterone, which is known as a physiological suppressor of MMP-9 in other species, did not decrease the IL-1beta- and TNF-alpha-induced production of proMMP-9. These results suggest that IL-1beta and TNF-alpha are effective up-regulators of proMMP-9 in the tissue remodelling of human myometrium during labour.

Induction of c-Jun mRNA without changes of estrogen and progesterone receptor expression in myometrium during human labor.

To elucidate the endocrine mechanism of human parturition, the expression of c-Jun and c-Fos mRNA were examined in relation to estrogen receptor (ER) and progesterone receptor (PR) in human myometrium. c-Jun mRNA was detected in all myometrial tissues (n=5) during labor but not before labor (n=5) and in oxytocin-resistant postterm pregnancy (n=3). c-Fos mRNA was detected in only one myometrial tissue from a woman in labor. The distribution and intensity of immunostaining for ER and PR were semiquantitatively scored. During the late pregnancies, no significant difference was seen in the receptor scores for myometrial ER and PR between the patients who experienced labor and those who did not. Receptor scores for ER and PR were significantly lower in postterm pregnancy than in late pregnancy, regardless of the labor status. These data suggest that there are no changes in ER and PR in human myometrium during parturition. On the other hand, postterm pregnancy is associated with low ER and PR. c-Jun, induced during labor without changes in ER and PR, may play a role as a signaling mechanism in human myometrium.

No association between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset Alzheimer's disease.

Butyrylcholinesterase (BChE) as well as acetylcholinesterase has been suggested to be associated with Alzheimer's disease (AD). Lehmann et al. [1997: Hum Mol Genet 6:1933-1936] recently reported the synergism between the gene for the K variant of BChE (BCHE-K) and the epsilon4 allele of apolipoprotein E (APOE epsilon4) in late-onset confirmed AD with Caucasian subjects. The authors found that the allelic frequency of BCHE-K was 0.17 in 74 subjects with late-onset histopathologically diagnosed AD, which was higher than the frequencies in elderly control subjects (0.09) and in other dementias (0.07-0.10). The association of BCHE-K with late-onset AD was limited to carriers of APOE epsilon4, giving odds ratios of confirmed late-onset AD of 6.9-12.8. In the present study, we report the BCHE-K allelic frequencies in late-onset AD cases and in age-matched controls of the Korean population, which were 0.22 and 0.17, respectively. We could not find any association between BCHE-K and AD regardless of APOE epsilon4 carrier status. However, APOE epsilon4 clearly showed higher frequency in AD (0.33) than in elderly controls (0.09), giving an odds ratio of 5.2 (95% confidence interval, 2.7-10.0). Our results do not support the conclusion that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon4 as a susceptibility gene for late-onset AD, at least in the Korean population.