Transcription factor SOHLH1 potentially associated with primary ovarian insufficiency.

OBJECTIVE: To investigate whether gene variants of SOHLH1 exist in Chinese and Serbian patients with primary ovarian insufficiency (POI). DESIGN: Case-control genetic study. SETTING: University hospitals. PATIENT(S): A total of 364 Han Chinese and 197 Serbian women with nonsyndromic POI and ethnically matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): SOHLH1 gene sequencing. RESULT(S): We found 10 novel heterozygous variants in our cohorts of 561 women with POI but none in the 600 ethnically matched controls. Statistical and bioinformatic analyses indicated that three of the eight variants in Chinese POI cases are potentially disease causing. They comprise two missense variants (p.Ser317Phe and p.Glu376Lys) that might each change activity of the SOHLH1 protein as a transcription factor and one variant (c.*118C>T) located in the 3' untranslated region of the SOHLH1 gene, which might generate a new binding site for the microRNA hsa-miR-888-5p. Of the two variants in the Serbian POI cases, both were synonymous, and no missense variant was identified. The allele frequencies of some known single-nucleotide polymorphisms were statistically significantly different between patients and controls in both the Chinese and Serbian groups. CONCLUSION(S): Our results suggest that SOHLH1 may be regarded as a new candidate gene for POI.

ISGE statement on oral emergency contraception.

Unintended pregnancy is an important public health problem worldwide. Unwanted pregnancies may end in induced abortion (legal or illegal, safe or unsafe) or in childbirth. In many parts of the world both can be life threatening. Even where both are safe, abortion is distressing for all concerned while unwanted births often lead to poor health and social outcomes for both the mother and her child.

Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure.

OBJECTIVE: To determine whether variants in the SOHLH2 gene contribute to human premature ovarian failure (POF) in different ethnicities. DESIGN: Case-control genetic study. SETTING: University hospitals. PATIENT(S): Chinese (364 cases) and Serbian (197 cases) women with nonsyndromic POF and ethnically matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Variation analysis of the SOHLH2 gene. RESULT(S): Eleven novel heterozygous variants were identified in cohorts of POF but were absent in matched controls. These included the nonsynonymous variants p.Glu79Lys (n = 2 cases), p.Glu105Gly, and p.Thr321Pro, which were found among four Chinese POF cases, and p.Leu120Phe (n = 3 cases) and p.Leu204Phe, which were found among four Serbian women. Protein alignments reveal that p.Glu79Lys and p.Glu105Gly involve amino acids highly conserved among mammals, both of which are predicted to be deleterious. The c.-210G>T found in the Chinese POF cohort lies in the core promoter region, which is enriched with transcription factor binding sites and CpG islands. In the Serbian cohort, the variant most likely to have a deleterious effect is c.530+6T>G, which is predicted to affect RNA splicing and result in nonsense mediated decay of transcripts. The other variants are less likely to be deleterious. Disturbing the expression, transactivation or homo-/ heterodimerization of the SOHLH2 protein could result in ovarian failure. Overall, four of the 11 novel variants seem plausible explanations for POF; the other seven variants are less likely but cannot be categorically excluded. CONCLUSION(S): Our identification of novel variants in the SOHLH2 gene, in women with POF of both Chinese and Serbian origin, strongly suggests an important role for SOHLH2 in human POF etiology.

Ethnic specificity of variants of the ESR1, HK3, BRSK1 genes and the 8q22.3 locus: no association with premature ovarian failure (POF) in Serbian women.

OBJECTIVE: To identify whether variants found in a large Han Chinese cohort - 8q22.3 SNPs rs3847153 and rs3108910; and one SNP each in HK3 (rs2278493), ESR1 (rs2234693) and BRSK1 (rs12611091) - are associated with premature ovarian failure (POF) in a different ethnic group (Serbian). DESIGN: Case-control genetic association study in 197 Serbian POF cases and 552 matched controls. RESULTS: None of the SNPs found associated with POF in Chinese cohort were found to be associated in the Serbian sample. CONCLUSIONS: In contrast to Han Chinese, no association was found between POF in Serbian women and any of the four tested loci: 8q22.3, HK3, ESR1 and BRSK1. This indicates that ethnically distinct populations may show differences in gene-regulating pathways and genes causing POF.

Effectiveness of phytoestrogens in climacteric medicine.

The increased interest in phytoestrogens in the management of menopausal symptoms followed the publication of the Women's Health Initiative study. A wide-spread perception that these plant-derived compounds are equivalent to estrogen was established. These compounds evolved to fulfill the needs of plant physiological processes and are natural for the plant cells but not natural to the human cell. Epidemiological data suggest a possible protective effect of phytoestrogen if consumed during adolescence, but later on in life this effect is not clear. The utility of phytoestrogen as a "natural and safe" alternative to estrogen in alleviating vasomotor symptoms has failed the test in randomized clinical trials. Because many breast cancer sufferers seek in phytoestrogen a relief of estrogen deficiency symptoms, the possible interaction of such remedies with risk of recurrence of breast cancer or interference with tamoxifen action should not be overlooked.

Report on the 8th European Congress on Menopause.

The 8th European Congress on Menopause (EMAS), held 16-19 May 2009 in London, UK, was organized by the European Menopause and Andropause Society and hosted by the British Menopause Society (BMS). The Congress invited speakers from a range of European countries as well as some from the USA, Ecuador, Chile, Australia and South Africa, and attracted 1470 participants from over 70 countries as far afield as the Americas and East Asia.

Mechanism of androgen receptor action.

Recent research provides a much more detailed understanding of the role of the androgen receptor in normal human development and physiology, its structure, and its functioning. This review discusses genomic and non-genomic actions of the androgen receptor, as well as their co-regulators. We also explore several clinically relevant aspects of the molecular biology of the androgen receptor and its co-regulators.

Hormonal changes during menopause.

Ovarian senescence occurs gradually during the fourth and fifth decades of life, leading to menopause at an average age of about 51 years. This senescence results in a changing hormonal milieu, with decreases in the levels of estrogens and androgens. Similar changes may be induced by surgical menopause (bilateral oophorectomy) or ovarian failure resulting from cancer treatment. The declining levels of estrogens and androgens affect many tissues of the body and can produce a variety of signs and symptoms, including vasomotor symptoms, decreased bone density, changes in mood and energy, loss of pubic hair and changes in the genital tissues, and effects on sexual function. Accurate measurement of testosterone levels in postmenopausal women requires methods that are validated in the lower ranges of testosterone level observed in this population.

Differing transcriptional responses to pulsed or continuous estradiol exposure in human umbilical vein endothelial cells.

This study used human umbilical vein endothelial cells (HUVECs) that were treated with 17beta-estradiol for 5 days as 1h pulse or 24h continuous treatment at concentrations such that the 24h exposure (concentration x time) was identical in both conditions. Cell proliferation was studied and gene expression profiling was carried out using the Affymetrix GeneChip microarray analysis. Changes in morphology and apoptosis in HUVECs were examined with electron microscopy. Time-course studies of expression of genes vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were performed by quantitative PCR. We observed that cell proliferation was significantly decreased over days 3-5 with pulsed estradiol treatment relative to constant exposure. Microarray results showed that after 5 days, 801 genes differed (P<0.05) between continuous versus pulsed estradiol treatment. Functional analysis showed a significant number of genes to be associated with apoptosis and cell cycle pathways. We did not find any evidence of apoptosis from flow cytometry or electron microscopy examination. Our study highlights a large number of significantly different molecular responses to estradiol depending upon the mode of administration of estradiol. Significant changes were observed in genes involved in apoptosis and proliferation including VEGF, IGF receptors, and tumor protein p53.

Changes in transcription profile and cytoskeleton morphology in pelvic ligament fibroblasts in response to stretch: the effects of estradiol and levormeloxifene.

Failure of ligamentous support of the genital tract to resist intra-abdominal pressure is a plausible underlying mechanism for the development of pelvic organ prolapse, but the nature of the molecular response of pelvic tissue support remains unknown. We hypothesized that the expression of genes coding for proteins involved in maintaining the cellular and extracellular integrity would be altered as a result of mechanical stretch. Therefore, cDNA microarrays were used to examine the difference in transcriptional profile in RNA of primary culture fibroblasts subjected to mechanical stretch and those that remained static. Out of 34 mechano-responsive genes identified (P < 0.05), four were coding for regulation of actin cytoskeleton remodelling, and its interaction with the extracellular matrix proteins; these are phosphatidyl inositol-4-phosphate 5-kinase (PIP5K1C), the human signal-induced proliferation associated gene-1 (SIPA-1), TNFRSF1A-associated via death domain (TRADD) and deoxyribonuclease 1-like 1 (DNase 1-L1). The transcriptosomal changes led us to investigate the phenotypic consequences of stretch, levormeloxifene and estradiol (E(2)) on the cytoskeleton of cultured fibroblasts. The percentage of cells with abnormal F-actin configuration was significantly higher in fibroblasts subjected to stretch compared with the static model (P < 0.0001). Levormeloxifene caused similar significant alterations in actin morphology of the static fibroblasts. The use of E(2) did not reverse the process or protect the cells from the effect of stretch, but significantly increased the rate of fibroblast proliferation, suggestive of a role in healing process. Mechanical stretch and/or levormeloxifene disturb the fibroblasts ability to maintain the cytoskeleton architecture and we speculate that they may disrupt ligamentous integrity and result in clinical prolapse.

Prevention and treatment of osteoporosis in women.

Osteoporosis affects one in three women. There has been some confusion among women and health professionals about the management of osteoporosis since the publication of the Women's Health Initiative and Million Women studies. This guidance regarding estrogen-based and non-estrogen-based treatments for osteoporosis responds to the controversies about the benefits and risks of individual agents. Treatment choice should be based on up-to-date evidence and targeted to individual women's needs.

Which progestogen is more likely to increase the risk of fatal myocardial infarction: a combination of epidemiological and trial evidence.

OBJECTIVES: To evaluate the impact of metabolic effects of different progestogens on the risk of fatal myocardial infarction is evaluated. METHODS: The changes in (apo)lipoproteins obtained from a randomized trial of three hormone therapy regimens were applied to three models for predicting fatal myocardial infarction derived from the apolipoprotein-related mortality risk (AMORIS) study. In our trial, 487 postmenopausal women were randomized to oral estradiol, with sequential addition of two trimegestone (TMG) doses or norethisterone acetate (NETA), and studied at baseline and after 3, 6, and 12 months. RESULTS: The change from baseline in risk of fatal myocardial infarction, using AMORIS model 3, containing total cholesterol, triglycerides, and apolipoprotein AI, was a 10% reduction for the two TMG doses; NETA had no apparent impact. The differences between treatments were significant at all three time points. When apoB was added in AMORIS model 4, the difference between treatments (5% reduction in the two doses of TMG, compared to NETA) decreased over time, probably due to the effect of dropouts in the NETA group. CONCLUSIONS: This analysis shows different metabolic responses to progestogens in terms of risk of fatal myocardial infarction. Generalization of health benefits or adverse effects seen in trials of hormone therapy to other progestogens could be misleading.

Current state of hormone replacement therapy: the case for using trimegestone.

Estrogen deficiency has a negative impact on the quality of life of postmenopausal women and is associated with vasomotor symptoms, insomnia and emotional lability. Other manifestations of estrogen deficiency include dry skin, dry vagina and dyspareunia, in addition to bone loss. Estrogen replacement effectively reverses these changes. The only indication for the administration of a progestogen is to protect the postmenopausal uterus against the potential development of endometrial hyperplasia and carcinoma.