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Ten women with cystic fibrosis (CF) were evaluated with regard to hormonal profiles during a natural and a clomiphene citrate (CC) stimulated cycle. Five of the women were found to be anovulatory during a natural cycle. All women except one did respond with ovulation to CC stimulation indicating adequate ovarian response. Neither did they show increased follicle-stimulating hormone (FSH) concentrations on day 10 after CC treatment confirming normal ovarian reserve. Clinically the anovulatory women differed from the ovulating in two aspects: more profound essential fatty acid deficiency (EFAD) and higher peak/basal insulin response during an oral glucose tolerance test. The anovulatory women had significantly lower luteal oestradiol and progesterone but higher total testosterone concentrations when compared to healthy controls and the ovulatory CF women. The pathological insulin response and high testosterone concentrations resemble those seen in women with polycystic ovarian (PCO) syndrome. However, the CF patients in our study had normal ovaries, as deduced from ultrasound examination and normal luteinizing hormone (LH)/FSH ratio. It is suggested that EFAD as well as hypersecretion of insulin may be of importance for the observed ovarian dysfunction. Further studies are needed to evaluate the relation between ovulatory mechanisms and EFAD in CF women as well as studies to compare anovulatory CF women with women with PCO syndrome. [ABSTRACT FROM AUTHOR]

Sex hormones are known to interact with the immune system on multiple levels but information on the types of sex hormone receptors (SHR) and their expression levels in immune cells is scarce. Estrogen, testosterone and progesterone are all considered to interact with the immune system through their respective cell receptors (ERα and ERβ including the splice variant ERβ2, AR and PGR). In this study expression levels of SHR genes in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4 + and CD8 + T-cells, CD56 + NK-cells, CD14 + monocytes and CD19 + B-cells) were analyzed using standard manual qPCR or a qPCR array (TLDA). Nine healthy individuals including men ( n = 2), premenopausal (Pre-MP, n = 5) and postmenopausal (post-MP, n = 2) women were sampled for PBMCs which were separated to cell subsets using FACS. Ten Pre-MP women were longitudinally sampled for total PBMCs at different phases of the menstrual cycle. We found that ERα was most abundant and, unexpectedly, that ERβ2 was the dominant ERβ variant in several FACS sorted cell subsets. In total PBMCs, SHR (ERα, ERβ1, ERβ2, and AR) expression did not fluctuate according to the phase of the menstrual cycle and PGR was not expressed. However, several immune response genes ( GATA3, IFNG, IL1B, LTA, NFKB1, PDCD1, STAT3, STAT5A, TBX21, TGFB1, TNFA ) were more expressed during the ovulatory and mid-luteal phases. Sex hormone levels did not correlate significantly with gene expression of SHR or immune response genes, but sex hormone-binding globulin (SHBG), a steroid hormone transporting protein, was positively correlated to expression of ERβ1 gene. This study provides new insights in the distribution of ERs in immune cells. Furthermore, expression patterns of several immune response genes differ significantly between phases of the menstrual cycle, supporting a role for sex hormones in the immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with several of the authors, PB, B-ML, MS, J-AG, and IN, at time of review., (Copyright © 2021 Brundin, Landgren, Fjällström, Shamekh, Gustafsson, Johansson and Nalvarte.)

Men and women respond differently to infectious diseases. Women show less morbidity and mortality, partially due to the differences in sex hormone levels which can influence the immune response. Torque teno virus (TTV) is non-pathogenic and ubiquitously present in serum from a large proportion (up to 90%) of adult humans with virus levels correlating with the status of the host immune response. The source of TTV replication is unknown, but T-lymphocytes have been proposed. In this study we investigated the presence and levels of TTV in peripheral blood mononuclear cells (PBMCs) in premenopausal (pre-MP) women, post-menopausal (post-MP) women, and men, and determined their serum sex hormone levels. Of the examined subjects ( n = 27), we found presence of TTV in PMBC from 17.6% pre-MP ( n = 17), 25.0% post-MP ( n = 4) and 50.0% men ( n = 6). The levels of TTV/μg DNA were lower among TTV-positive men and post-MP women compared to pre-MP women. All the positive pre-MP women were either anovulatory, hypothyroid, or both. In addition, the TTV-positive pre-MP women had significantly lower progesterone levels compared to TTV-negative pre-MP women. Although our study was performed on a limited number of subjects, the data suggests that TTV in PBMC is associated with an anovulatory menstrual cycle with low progesterone levels, and possibly with male sex., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors.)

Background: Idiopathic recurrent miscarriage, defined as three or more consecutive miscarriages, is a distressing early pregnancy complication. Although, the etiology of recurrent miscarriage is still unknown, an aberrant regulation of the endometrial receptivity marker hyaluronan-binding protein 2 (HABP2) has been suggested. The objective of the present study was to investigate the effect of genetic variations of HABP2 in women with idiopathic recurrent miscarriage compared to fertile women., Methods: This study was designed as a case-control study. In total, 165 women who had three or more consecutive miscarriages and 289 fertile women were included in the study. Polymorphisms in the HABP2 gene were analyzed using TaqMan SNP Genotyping Assays. Three polymorphisms in the HABP2 gene, rs1157916, rs2240879 and rs7080536 (Marburg I) were studied., Results: Polymorphism in HABP2 showed no significant difference in women with recurrent miscarriage compared to fertile women, except for rs1157916 minor A allele that was more prevalent among RM patients (p = 0.058). Significantly higher live birth rate was observed among women with three to four miscarriages compared to those with more miscarriages (p = 0.001)., Conclusions: Variations in the HABP2 gene did not seem to be involved in the etiology of recurrent miscarriage, while, the number of previous miscarriages had an impact on the live birth rate.

Background: Untreated and subclinical hypothyroidism (SCH) has been associated with adverse pregnancy complications such as increased risk of miscarriage, hypertension, preeclampsia, and preterm delivery. However, in Sweden, screening for thyroid dysfunction during pregnancy is only recommended for women with a high risk of thyroid disease. Therefore, the aim of this study was to determine the incidence of clinical and SCH in women in the first trimester of pregnancy., Materials and Methods: In this prospective study, 1298 pregnant women were divided into three groups: one unselected general screening group (n = 611), one low-risk group comprising women without risk factors for thyroid disorder (n = 511), and one high-risk group comprising women with an inheritance or suspicion of thyroid disease or undergoing treatment for thyroid disease (n = 88). Serum was obtained up to gestational week 13, and thyrotropin (TSH) was analyzed., Results: The incidences of thyroid dysfunction in the three screening groups were 9.8% in the general screening group, 9.6% in the low-risk group, and 10.2%, p = 0.948, in the high-risk group. In the women with known hypothyroidism on levothyroxine treatment, 50.6% had serum TSH levels above 2.0 mIU/L., Conclusions: High-risk screening is not useful in predicting which women are at risk of thyroid disease in early pregnancy since ∼10% of women with SCH or hypothyroidism could not be diagnosed in this way.

Objective: This study aims to assess whether the timing of menopausal hormone therapy initiation in relation to onset of menopause and hormone therapy duration is associated with myocardial infarction risk., Methods: This study was based on the Stockholm Heart Epidemiology Program, a population-based case-control study including 347 postmenopausal women who had experienced a nonfatal myocardial infarction and 499 female control individuals matched for age and residential area. Odds ratios (with 95% CIs) for myocardial infarction were calculated using logistic regression., Results: Early initiation of hormone therapy (within 10 y of onset of menopause or before age 60 y), compared with never use, was associated with an odds ratio of 0.87 (95% CI, 0.58-1.30) after adjustments for lifestyle factors, body mass index, and socioeconomic status. For late initiation of hormone therapy, the corresponding odds ratio was 0.97 (95% CI, 0.53-1.76). For hormone therapy duration of 5 years or more, compared with never use, the adjusted odds ratio was 0.64 (95% CI, 0.35-1.18). For hormone therapy duration of less than 5 years, the odds ratio was 0.97 (95% CI, 0.63-1.48)., Conclusions: Neither the timing of hormone therapy initiation nor the duration of therapy is significantly associated with myocardial infarction risk.

Trefoil factor 3 (TFF3) gene is an inflammatory mediator expressed in human endometrium during the window of implantation. The aim of this study was to evaluate the possible genetic association of TFF3 variants in recurrent spontaneous abortion. Women with a history of recurrent spontaneous abortion (n = 164) and healthy pregnant women (n = 143) were genotyped for five TFF3 polymorphisms (rs225439 G/A, rs533093 C/T, rs225361 A/G, rs11701143 T/C and rs77436142 G/C). In addition, haplotypes formed within the gene were analysed. Within the recurrent spontaneous abortion group, women who at some point had given birth and childless women had 4.19 ± 1.75 and 5.34 ± 3.42 consecutive spontaneous abortions, respectively. Women who had experience recurrent spontaneous abortions had a lower allele frequency of the rs11701143 promoter region minor C allele compared with fertile women (0.02 versus 0.05, P = 0.015). Patients with rs225361 AG genotype had significantly more successful pregnancies before spontaneous abortion than those with homozygous AA and GG genotypes (P = 0.014). No significant differences in haplotype frequencies between patients and controls were detected. Possible genetic risk factors identified that might contribute to the pathogenesis of idiopathic recurrent spontaneous abortion were TFF3 gene variants., (Copyright © 2014. Published by Elsevier Ltd.)

The purpose of this study was to assess the ovarian function, fertility and bone mineral density in women who previously had treatment for different haematological malignancies (HMs). The overall survival and cure rates of patients with HMs have improved dramatically. The treatment affects fertility and bone density. Fifty-two premenopausal women, from Stockholm region, were included in the study between 1998 and 2002, followed until 2011. The diagnoses were acute lymphoblastic leukaemia (n = 6), acute myeloid leukaemia (n = 10), chronic lymphocytic leukaemia (n = 1), chronic myeloid leukaemia (n = 12), Hodgkin lymphoma (n = 12) and non-Hodgkin lymphoma (n = 11). Before treatment, women without children (43/52), when possible, were offered fertility preservation options. The mean age at diagnosis was 27, at final evaluation 39 yr. Thirty-seven patients received HSCT; 26 allogeneic, 11 autologous. Before allogeneic HSCT, nineteen patients had myeloablative conditioning; seven had reduced-intensity conditioning. Eleven patients got total body irradiation. Eight patients were transplanted with grafts from an HLA-identical sibling donor, while 18 had unrelated donors. All women were in a menopausal state post-therapy. Hormone replacement therapy (HRT) was given, and bone mineral density (BMD) was measured every other year. The serum levels of parathyroid hormone (PTH), free and bound calcium was within normal range. BMD measurements showed a slight increase over time in the spine with a mean of 0.015 g/cm(2) /yr. Four spontaneous pregnancies resulted in two babies and two discontinued pregnancies; two pregnancies were achieved with oocyte donation and surrogacy and one woman adopted a child. HRT sustains BMD in long-term survivors from HMs. This study highlights the importance of HRT and fertility issues in this patient group., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Histidine-rich glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage., Methods: The study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP., Results: The results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p<0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p<0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p<0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p<0.05)., Conclusions: Women who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Infertile women might get pregnant sometime after fertility treatment, but today, there is no prediction model on who will eventually have children. The objective of the present study was to characterize hormone levels in an arbitrary menstrual cycle in women with unexplained infertility and male infertility, and to determine the predictive value for long-term possibility of live birth., Methods: In this cross-sectional study, with 71 infertile women with diagnosis unexplained infertility and male infertility, blood samples were obtained during the proliferative and secretory phases of an arbitrary menstrual cycle. Serum concentrations of FSH, LH, AMH, inhibin B, estradiol, progesterone, PRL and TSH were determined. The predictive value of ovulation and hormonal analysis was determined by identifying the proportion of women with at least one live birth. Mann Whitney U test, chi2 test and Spearman's correlation were used for statistical analysis. A value of p < 0.05 was considered statistically significant., Results: There were no differences in hormone values and live birth rates between women with unexplained infertility and male infertility. The best sole predictors of live birth were age of the women, followed by ovulatory cycle, defined as serum progesterone concentration of greater than or equal to 32 nmol/L, and a serum TSH concentration of less than or equal to 2.5 mIU/L. Combining the age with the ovulatory cycle and serum TSH less than or equal to 2.5 mIU/L or serum AMH greater than or equal to 10 pmol/L the predictive value was close to 90%., Conclusions: Age in combination with the presence of an ovulatory cycle and serum TSH or serum AMH is predictive for long-term live birth. The advantage of serum AMH compared with serum TSH is the very little variation throughout the menstrual cycle, which makes it a useful tool in infertility diagnosis.

Objective: The aim of this study was to evaluate among postmenopausal women the effects of a 3-month treatment with estradiol (E2) alone or in combination with norethindrone acetate (NA) on expression of hormone receptors and proliferation in the breast as well as on lipids and climacteric symptoms., Methods: Sixty healthy postmenopausal women were computer-randomized into two groups, with one group receiving 1 mg of E2 and the other group receiving 1 mg of E2 and 0.5 mg of NA daily for 12 weeks. Before and after treatment, middle-needle biopsies were obtained for histology and investigation of the expression levels of estrogen receptors (ERs; ER-α and ER-β), progesterone receptors (PRs; PR-A and PR-B), androgen receptor (AR), the proliferation marker Ki67, and collagen. Climacteric symptoms were recorded, and serum was collected to measure lipoprotein levels., Results: Fifty-six women finished the 12-week study. Proliferating cells (Ki67-positive) were very rare in all but a few of the untreated women. There were proliferating cells in both E2- and E2/NA-treated groups; however, these were not widespread and limited to nests of cells that amounted to 2% of the total epithelial cells. Some of these nests were positive for human epithelial growth factor receptor 2. Treatments caused no marked changes in the expression of ER-α, ER-β, or AR. However, both treatments resulted in an increase in PR-A and PR-B expressions. The presence of collagen was clearly associated with a mammographic diagnosis of dense breasts, but neither hormone treatment affected breast density. Both E2 and E2/NA treatments were effective in relieving hot flashes and sweating without adverse effects on blood pressure, weight, and liver, kidney, and thyroid functions. A decrease in cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was induced by E2/NA but not by E2., Conclusions: This short-term prospective study shows that E2 and estrogen-progestogen treatment can up-regulate PRs but do not significantly affect ERs, AR, proliferation, or breast density.

Background: Recurrent miscarriage affects approximately 1% of all couples. There is a known relation between hypothyroidism and recurrent miscarriage. Phosphodiesterase 8B (PDE8B) is a regulator of cyclic adenosine monophosphate (cAMP) with important influence on human thyroid metabolism. Single nucleotide polymorphism (SNP) rs 4704397 in the PDE8B gene has been shown to be associated with variations in serum Thyroid Stimulating Hormone (TSH) and thyroxine (T4) levels. The aim of this study was to investigate whether there is an association between the SNP rs 4704397 in the PDE8B gene and recurrent miscarriage., Methods: The study was designed as a retrospective case control study. 188 cases with recurrent miscarriage were included and compared with 391 controls who had delivered at least once and with no history of miscarriage or assisted reproduction., Results: No difference between cases and controls concerning age was found. Bivariate associations between homozygous A/A (OR 1.57, 95% CI 0.98-2.52) as well as G/G carriers (OR 1.52, 95% CI 1.02-2.25) of SNP rs 4704397 in PDE8B and recurrent miscarriage were verified (test for trend across all 3 genotypes, p=0.059). After adjustment for known confounders such as age, BMI and smoking the association between homozygous A/A (AOR 1.63, 95% CI 1.01-2.64, p=0.045) and G/G (AOR 1.52, 95% CI 1.02-2.27, p=0.039) carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage remained., Conclusions: Our findings suggest that there is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage.

To evaluate true acupuncture to control acupuncture (CTRL) (non-insertive stimulation at non-acupuncture points) in breast cancer patients treated with adjuvant tamoxifen suffering from hot flushes and sweatings. Eighty-four patients were randomized to receive either true acupuncture or CTRL twice a week for 5 weeks. Seventy-four patients were treated according to the protocol. In the true acupuncture group 42% (16/38) reported improvements in hot flushes after 6 weeks compared to 47% (17/36) in the CTRL group (95% CI, -28 to 18%). Both groups reported improvement regarding severity and frequencies in hot flushes and sweatings but no statistical difference was found between the groups. In a subanalysis regarding the severity of sweatings at night a statistically significant difference P = 0.03 was found in the true acupuncture group. Former experience of true acupuncture did not influence the perception of true acupuncture or CTRL. No significant differences in hormonal levels were found before and after treatment. In conclusion, convincing data that true acupuncture is more effective than CTRL in reducing vasomotor symptoms is still lacking. Our study shows that both true and CTRL reduce vasomotor symptoms in breast cancer patients treated with adjuvant tamoxifen.

Adrenomedullin (AM) and its receptor subunit, calcitonin receptor-like receptor (CLR) are known to be important for endothelial function. The genotypes and phenotypes of AM and CLR in the endometrium were studied in relation to unexplained infertility. Endometrial biopsies from 12 fertile and 11 infertile women and blood samples from 156 fertile and 106 infertile women were collected. Protein and mRNA expression of AM and CLR was determined using immunohistochemistry and real time PCR. Allele and genotype frequencies in the AM (rs4399321 and rs7944706) and CLR genes (rs696574, rs1528233 and rs3771073) were performed using Taqman genotyping assays. Unexplained infertility was characterised by lower number of vessels stained with CLR in endometrium compared to fertile controls. There was no difference in AM expression. This could not be explained by SNP analysis in the AM or CLR genes. Imbalance in the AM/CLR system might alter endothelial function in women with unexplained infertility.

The aim of this study was to investigate tissue factor (TF) and its inhibitors TFPI and TFPI2 in secretory endometrium of fertile women and in women with unexplained infertility in relation to endometrial receptivity. In addition, common variation in the regulatory area of TF and TFPI genes was studied. Immunostaining of TF and TFPI, together with the appearance of pinopodes, revealed similar expression pattern in fertile endometrium throughout the secretory phase, being highest at the time of implantation. When compared protein expression levels at the time of implantation, infertile women demonstrated significantly higher TFPI expression in luminal epithelium. Furthermore, polymorphism TF -603 A/G was associated with the endometrial protein level in infertile women, being highest in women with GG genotype, and variation TFPI -287 T/C was associated with unexplained infertility, where infertile women presented more frequently T allele than fertile women. Contrary to TF and TFPI, TFPI2 showed different mRNA and protein expression patterns in fertile endometrium, and no differences between fertile and infertile women were detected. We conclude that the TF pathway is involved in normal endometrial maturation, where TF and TFPI seem to have important roles at the time of embryo implantation. Higher TFPI expression level during the time of embryo implantation and TFPI -287 T allele could be risk factors for unexplained infertility. No distinct involvement of TFPI2 in the regulation of endometrial receptivity and unexplained infertility was found.

Objective: To see if progesterone support has a beneficial effect on live birth rate after frozen embryo transfer in natural cycles., Design: Prospective randomized controlled trial., Setting: University-based hospital., Subject(s): Four hundred thirty-five women undergoing embryo transfer in natural cycles., Intervention(s): The women received either vaginal progesterone, 400 mg twice a day from the day of embryo transfer in natural cycles, or no progesterone support., Main Outcome Measure(s): Live birth rate, biochemical pregnancy rate, pregnancy rate, and spontaneous abortion rate., Result(s): Live birth rate were significantly greater in women receiving vaginal progesterone as luteal phase support after frozen-thawed embryo transfer in natural cycles compared with those who did not take progesterone. There were no differences in biochemical pregnancy rate, pregnancy rate, or spontaneous abortion rate., Conclusion(s): Progesterone supplementation improves live birth rate after embryo transfer in natural cycles., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study the expression, distribution, and function of thyroid-stimulating hormone receptor (TSHR) and thyroid hormone receptors (TR) α1, α2, and β1 in human endometrium., Design: Experimental clinical study., Setting: University hospital., Patient(s): 31 fertile women., Intervention(s): Endometrial biopsy samples obtained throughout the menstrual cycle., Main Outcome Measure(s): Real-time reverse transcriptase polymerase chain reaction, immunohistochemistry and Western blot to study the expression of TSHR, TRα1, TRα2, and TRβ1 messenger RNA (mRNA) and proteins in human endometrium., Result(s): We found TSHR, TRα1, TRα2 and TRβ1 mRNA and proteins expressed in human endometrium. Immunostaining for TSHR in the luminal epithelium and TRα1 and β1 in the glandular and luminal epithelium increased statistically significantly on luteinizing hormone (LH) days 6 to 9, coinciding with appearance of pinopodes. Endometrial stromal and Ishikawa cells expressed mRNA for TSHR, TR, and iodothyronine deiodinases 1-3. After 48 hours, TSH significantly increased leukemia inhibitory factor (LIF) and LIF receptor (LIFR) messenger RNA (mRNA) in endometrial stromal cells, but decreased their expression in Ishikawa cells. Glucose transporter 1 mRNA was up-regulated by TSH in Ishikawa cells. We found that TSH statistically significantly increased secretion of free triiodothyronine (T3) and total thyroxin (T4) by Ishikawa cells compared with nonstimulated cells., Conclusion(s): Thyroid hormones are directly involved in endometrial physiology., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study the expression of leukemia inhibitory factor (LIF), its receptors LIFR and gp130, and its inhibitor SOCS1 in endometria from fertile women and infertile women with unexplained infertility. Signaling through the LIF pathway is involved in maintenance of a receptive state of human endometrium. Impaired endometrial receptivity may be a cause of female infertility., Design: Prospective clinical study., Setting: Hospital-based IVF unit and university-affiliated reproductive research laboratories., Patient(s): Twenty-six healthy fertile women and 14 women with unexplained infertility., Intervention(s): Endometrial biopsy., Main Outcome Measure(s): Pinopode formation, expression of LIF, LIFR, gp130, and SOCS1 protein and mRNA in endometrial biopsies., Result(s): The expression of LIFR in the endometrium was negatively correlated to the expression of SOCS1 and positively correlated to the formation of pinopodes. In control fertile women, simultaneous intense apical staining of LIFR and gp130 together with faint SOCS1 staining was observed in epithelial cells, whereas the opposite was seen in most women with unexplained infertility., Conclusion(s): Unexplained infertility in some women might be explained by disturbances in the LIF pathway in midsecretory-phase endometrium.

The human endometrium undergoes a unique process of benign angiogenesis under the control of ovarian steroids during reproductive life. Aberrant angiogenesis has been implicated in idiopathic menorrhagia, a common gynaecological complaint. One of the key factors involved in endometrial angiogenesis is adrenomedullin (AM), a multifunctional 52-amino acid peptide. AM mediates the activities of endometrial angiogenesis via calcitonin receptor-like receptor (CLR). The objective of the present study was to compare the endometrial expression of AM and CRL in women with and without idiopathic menorrhagia. Endometrial biopsies were obtained from 9 women with menorrhagia (≥80 ml per menstruation) and 12 women with normal blood loss (<80 ml per menstruation). Protein and mRNA expression levels of AM and CLR were determined using immunohistochemistry and real-time PCR. Compared to the controls, patients with menorrhagia exhibited low immunostaining intensity of AM, while high CLR staining was observed in the epithelium (p<0.05). No difference in mRNA expression was observed between the groups. These data suggest that an imbalance in the AM/CLR system might alter endometrial angiogenesis in menorrhagia.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and its receptors (HER1 and HER4) play a role in the human implantation process. Amphiregulin is a member of the EGF family but with unknown function in human fertility. It has been suggested that some women with unexplained infertility have defective endometrial development. The aim of this study is to determine the presence of amphiregulin and the receptors HER1 and HER4 in normal human endometrium throughout the menstrual cycle. In addition, the present study aims to compare endometrium from women with unexplained infertility with endometrium from women with male factor infertility and healthy fertile controls. Immunohistochemistry and real-time polymerase chain reaction were used to determine the expression of HB-EGF, HER1, HER4, and amphiregulin. The stromal staining of HER1 and the epithelial staining of HER4 were most intense in the mid- and late-secretory-phase endometrium. Amphiregulin did not vary during the menstrual cycle. In the mid-secretory phase, the protein expression of HB-EGF was lower in endometrium from women with unexplained infertility versus normal endometrium and endometrium from women with male factor infertility. HB-EGF and HER4 mRNA expression in mid-secretory endometrium of women with unexplained and male factor infertility were increased compared with normal controls. Impaired endometrial expression of certain members of the EGF family may contribute to infertility in some women with unexplained infertility.

Context: Endothelial dysfunction in resistance arteries after menopause is important for the development of high blood pressure and cardiovascular disease., Objectives: Our objectives were to study the effects of different hormone replacement therapies on the function and morphology of isolated resistance arteries, and to look for their mechanistic basis., Design and Setting: This was a randomized, placebo-controlled double-blind study in a University hospital, along with laboratory based studies., Patients and Interventions: We isolated resistance arteries in sc biopsies from 55 postmenopausal women before and after 3-month therapy with estradiol (E2), medroxyprogesterone acetate (MPA), E2 plus MPA, or placebo. In addition, we studied isolated human endothelial cells., Main Outcome Measures and Results: Artery flow-mediated dilatation was augmented after treatment with E2 or E2 plus MPA, whereas MPA or placebo had no effect. Pressure-induced myogenic tone was reduced by E2 plus MPA, whereas it was unchanged in the other groups. Scanning microscopy showed that E2 improved endothelial cell morphology and decreased signs of endothelial apoptosis, but the addition of MPA impaired these events. E2, MPA, or the combination all increased the expression and phosphorylation of the actin-binding protein, moesin and of the focal adhesion complex controller, focal adhesion kinase, and induced the rearrangement of cytoskeletal actin and vinculin fibers. All treatments promoted endothelial cell horizontal migration, with E2 inducing the strongest effect., Conclusions: This study suggests that hormone replacement therapy with estrogens or in combination with MPA may benefit the function of resistance arteries and may preserve the morphological integrity of endothelial cells by regulatory actions on the cytoskeleton.

Objective: The most common etiologies of osteoporosis in women are estrogen deficiency and, later on in life, the functional changes caused by aging. There are, however, numerous causes of secondary bone loss. Little is known about the prevalence of concomitant disease in women with distal forearm fracture, which is the most common of the classical osteoporotic fractures., Method: Postmenopausal healthy women between 45 and 65 years of age with a forearm fracture were invited to join a prospective randomized study evaluating the effect of physical training on bone mineral density. The main inclusion criteria were previous forearm fracture and BMD T-score in the interval -1 to -3.0. Of the 167 postmenopausal women with a forearm fracture, 23% had a normal BMD, 59% had osteopenia, and 18% had osteoporosis., Results: Of the 119 patients meeting the BMD criteria for inclusion, one patient was found to have sprue, two were diagnosed with thyreotoxicos, and eight had primary hyperparathyroidism. The prevalence of primary hyperparathyroidism in this population was 6.7%, and thus three times higher than that previously observed in healthy Swedish postmenopausal women., Conclusion: The data suggest an increased prevalence of primary hyperparathyroidism in women with forearm fracture and low bone mass, and imply the importance of basic laboratory screening in this population.

With advancing age, the postural balance function deteriorates as a consequence of decreased functional capacity. Deteriorating balance is a risk factor for bone fractures due to increased risks of falls. It has been suggested that the loss of estrogen, which occurs in relation to the menopause, may be associated with loss of balance. Regular physical exercise without balance training has, in some studies, been shown to have positive effects on the postural balance. The aim of the present study was to examine balance function during the perimenopausal period, and evaluate the effect of estrogen plus progesterone therapy (EPT) or aerobic training on balance. Sixty perimenopausal women were recruited to the study. The subjects were then randomised to either physical training (n=20), EPT (n=20), or to a control group (n=20). The study period was 18 months. Postural stability was measured every third month using a custom-made force platform. The women using EPT achieved better results in 3 of 6 parameters, after 18 months.

Objectives: The primary objective of the Osteoporosis Prevention and Arterial effects of tiboLone study was to compare the effect of tibolone and placebo on the progression of the common carotid artery intima-medial thickness; the common carotid artery intima-medial thickness and bone data will be presented elsewhere. A secondary objective was to assess the effects of tibolone (2.5 mg), continuous combined conjugated equine estrogen/medroxyprogesterone acetate [0.625/2.5 mg], and placebo on the endometrium and vaginal bleeding; these results are the subject of this report., Study Design: This 3-year, three-arm, international, randomized, double-blind, parallel group, placebo-controlled clinical trial enrolled 866 postmenopausal women (aged 45-79 years). The endometrium was assessed by annual transvaginal ultrasound scans and end-of-study biopsies (United States/United Kingdom centers only). Vaginal bleeding was recorded in daily diaries., Results: Endometrial thickness measured by transvaginal ultrasound scan increased slightly during the first year with tibolone and conjugated equine estrogen/medroxyprogesterone acetate, without any further progression. After 3 years, there were no significant differences between the tibolone, conjugated equine estrogen/medroxyprogesterone acetate, and placebo groups in the incidence of proliferation (1.4%, 4.8%, and 0%, respectively), endometrial hyperplasia (0% in all groups), or cancer (1, 0, and 1 case, respectively). During the first 3 months, bleeding/spotting rates were greater with conjugated equine estrogen/medroxyprogesterone acetate (48%) than with tibolone (18%; P < .001) or placebo (3%; P < .001). During 3 years of treatment, the incidence of bleeding/spotting was 66%, 48%, and 23% for conjugated equine estrogen/medroxyprogesterone acetate, tibolone, and placebo, respectively. The mean number of bleeding/spotting days was greater in the conjugated equine estrogen/medroxyprogesterone acetate than the tibolone or placebo groups (61, 28, and 7 days, respectively; P = .023 vs tibolone; P < .0001 vs placebo). The mean number of bleeding/spotting episodes was also greater in the conjugated equine estrogen/medroxyprogesterone acetate group (13 episodes) compared with the tibolone group (six episodes; P < .001) and placebo group (four episodes; P < .001). Vaginal bleeding was more commonly reported as an adverse event with conjugated equine estrogen/medroxyprogesterone acetate than tibolone (26.4% vs 10.8%, P < .0001) and as the reason for premature discontinuation (9% vs 2%, P = .001)., Conclusion: Compared with conjugated equine estrogen/medroxyprogesterone acetate, tibolone has a better tolerability profile with respect to vaginal bleeding but with a similar endometrial safety. These results reinforce the endometrial safety profile of tibolone.

Objective: Our objective was to assess vascular endothelial function and morphology in resistance vasculature from healthy pre- and postmenopausal women in vitro and to determine potential mechanisms of vascular protection by estrogenic compounds., Methods: Arteries (approximately 220 microm) were dissected from sc fat biopsies obtained from healthy premenopausal and postmenopausal women. Flow-mediated dilatation, agonist-induced endothelium-dependent and -independent relaxation, and myogenic responses to changes in intraluminal pressure were evaluated before and after incubation (3 h) with 17beta-estradiol, propyl pyrazole triol [a selective estrogen receptor-alpha (ERalpha) agonist], raloxifene (a second-generation selective ER modulator), and the phytoestrogen genistein, using pressure myography technique. In addition, endothelial morphology was assessed in arteries from pre- and postmenopausal women, and distribution of ERs within the artery wall from postmenopausal women was evaluated., Results: Functional and morphological disturbances of endothelial function were observed in small arteries from postmenopausal women. Incubation with 17beta-estradiol improved postmenopausal resistance artery function, an effect mimicked by propyl pyrazole triol but not raloxifene or genistein. Immunohistochemical staining revealed similar expression of ERalpha and ERbeta in the smooth muscle of arteries from postmenopausal women; however, ERalpha was dominant in endothelium., Conclusions: The resistance arteries from postmenopausal women show functional and morphological abnormalities. ERalpha may contribute to vascular protection by estrogens in the peripheral resistance circulation in postmenopausal women. Selective ERalpha agonists warrant further investigation as therapeutic agents for prevention of cardiovascular disease in postmenopausal women.

The effects of physical training and hormone replacement therapy (HRT) on bone mineral density in perimenopausal women were studied. Sixty perimenopausal women were randomized to either physical training (n = 20), HRT (n = 20), or control group (n = 20). The study period was 18 months. Bone mineral density (BMD) in the femoral neck and lumbar spine was measured using dual-energy X-ray absorptiometry (DXA). DXA was performed before treatment and after 6 and 18 months. Blood samples for analysis of the bone markers U-deoxypyridinoline and osteocalcin were collected at the same time points. After 18 months, BMD in the spine had not decreased in either the training group or in the HRT group. In the control group, spine BMD had significantly decreased (p = 0.0014). U-Deoxypyridinoline and osteocalcin were increased significantly in the control group (p = 0.0198, p = 0.0295, respectively). No significant changes in bone marker levels were found in the training group or the HRT group. We found that both HRT and physical training can prevent loss of spine BMD in perimenopausal women over a period of 18 months. HRT remains a cornerstone in the treatment of vasomotor symptoms and preservation of BMD. However, HRT can only be used for limited periods of time due to the potential serious adverse effects. This study indicates a beneficial effect of physical activity on spine BMD in the perimenopausal period, and highlights its potential as an alternative to HRT during this period.

Background: Controversy still exists as to the relative importance of menopausal status and lifestyle factors for the risk of coronary heart disease in women., Objective: The purpose of this study was to assess the influence of body mass index (BMI), smoking,lipoprotein levels, surgically induced menopause, hormone replacement therapy (HRT), years since menopause, and age on hemostasis in apparently healthy postmenopausal women., Methods: Lipoproteins (total cholesterol [TC], low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides [TG]), and hemostatic factors (fibrinogen, von Willebrand factor antigen [vWFag], coagulation factors VIIag [FVIlag] and VIIa [FVIIa], plasminogen activator inhibitor 1 [PAI-1]) were each measured once. A forward, stepwise, multiple regression analysis was used to assess variations in hemostatic parameters., Results: A group of 292 healthy Stockholm women recruited from the census register participated in the Stockholm Female Coronary Risk Study as controls. Of these women, 260 participated in the present study. BMI, smoking, lipoprotein levels, surgically induced menopause, and years since menopause (1-5 y) were found to be associated with a 31% increase in fibrinogen levels. A 7% increase in FVIIa levels was attributed to TC, BMI, and HRT. Years since menopause (1-15 y), TG, TC, BMI, and HRT were associated with an increase of up to 26% in FVIIag levels. A 9% increase in vWFag correlated with HDL-C and years since menopause (1-10, 11-14, and > or =15 y). BMI and TG explained a 21% and 3% increase, respectively, in PAI-1 levels. Neither the use of HRT nor years since menopause had any influence on hemostasis., Conclusion: BMI, high levels of TC and TG, and low HDL-C levels appear to be more important than hormonal status in their impact on hemostatic variables in healthy postmenopausal women.

Objective: There is currently little longitudinal data available on the serum hormonal characteristics of the menstrual cycles observed in women as they approach their final menstrual period (FMP) or menopause. We sought to determine whether the onset of irregular menses, marking the menopause transition, signifies the occurrence of anovulatory, potentially infertile cycles., Design: We studied 12 subjects, initially aged 45 to 47 years, who provided daily menstrual diaries, and had blood samples collected annually, three times weekly for 4 consecutive weeks, over a period of 36 to 98 months until FMP, for measurements of serum follicle-stimulating hormone (FSH), luteinizing hormone, estradiol, and progesterone. The definition of entry into the early menopause transition was the occurrence of more than two cycles, in any consecutive sequence of 10, where cycle length was less than 23 or more than 35 days. Entry into the late transition was determined from the first observation of either 60-day or 90-day amenorrhea. Cycles were characterized endocrinologically as normal ovulatory, abnormal luteal phase, and anovulatory with evidence of ovarian follicular activity., Results: The early transition had an average duration of 47 months from onset until FMP. Ten of the 12 subjects had one or more ovulatory cycles during the transition. Anovulatory cycles with ovarian activity were noted in 9 of the 12 subjects, only after entry into early and/or late transition., Conclusions: Ovulatory cycles occurred both before and after entry into the early and/or late menopause transition in subjects older than 45 years of age, whereas anovulatory cycles were observed only during the transition. The ovulatory cycles were generally associated with normal menses, whereas anovulatory cycles showed long duration and/or abnormal bleeding patterns. The occurrence of cycle irregularity is associated with an increasing frequency of anovulatory cycles, which herald the occurrence of FMP. No conclusion could be drawn regarding the appropriate definition of entry into the late transition. The definition adopted for entry into the early transition merits further validation.

Background: The effect of physical training on bone mineral density (BMD) in women with endometriosis treated with gonadotropin-releasing hormone (GnRH) analogs was studied., Methods: Nineteen Caucasian premenopausal women aged 23-38 years were included in the study. The subjects were all treated with 21.6 mg goserelin during 6 months. The patients were randomized to physical training n=8 or to a control group n=11. The total period of training was 12 months, whereas GnRH treatment was terminated after 6 months. BMD was measured in the femoral neck area and the lumbar spine using dual X-ray absorptiometry (DEXA). This was performed just before treatment, after 6 months and after 12 months. Six women fulfilled the training during 12 months of observation. In the control group 10 women were followed up for 12 months., Results: After 6 months the women in the physical training group were 2.1% below baseline. Six months later these women had gained BMD in the femoral neck and were 0.6% below baseline. Those in the control group lost 2.8% after 6 months and were 3.6% below baseline after 12 months. The difference in loss of BMD after 12 months between the groups was significant 0.029. In the spine there was no significant difference between the two groups., Conclusions: Physical training in women with endometriosis was found to rebuild bone after treatment with GnRH analogs when compared to a control group. This effect could be demonstrated 6 months after cessation of GnRH treatment.

Progestins have been used for contraception for more than 30 years. The main goal was to develop a contraceptive method devoid of the metabolic or clinical side-effects associated with the use of estrogens. The development of new contraceptive methods and formulations is time-consuming and requires devotion, belief, and also strong economical basis. As a result of this endeavor new methods have been developed: oral progestins, implants, injectables, intrauterine hormonal systems, and vaginal rings. Progestin-only contraceptives may be preferable in some situations, which have absolute or relative contraindications to estrogen, side-effects to estrogen containing hormonal contraception, lactation, and comfort and feasibility of formulations for long-term use. At present, emergency contraception is also performed with progestin.

The knowledge of the effects of antimicrobial agents on the normal vaginal microflora is limited. The objective of the present study was to study the ecological impact of pivmecillinam on the normal vaginal microflora. In 20 healthy women, the estimated day of ovulation was determined during three subsequent menstrual cycles. Microbiological and clinical examinations were performed on the estimated day of ovulation and on day 3 in all cycles and also on day 7 after ovulation in cycles 1 and 2. Anaerobic and facultative anaerobic gram-positive rods, mainly species of lactobacilli and actinomycetes, dominated the microflora. One woman was colonized on the third day of administration with a resistant Escherichia coli strain, and Candida albicans was detected in one woman on days 3 and 7 in cycle 2. No other major changes in the normal microflora occurred during the study. Administration of pivmecillinam had a minor ecological impact on the normal vaginal microflora.

To examine the hormonal characteristics of menstrual cycles in healthy women approaching menopause, serum hormone profiles were investigated annually in this longitudinal study of 13 healthy women between 4 and 9 yr before menopause and the year of the menopause. Serum FSH, LH, estradiol, progesterone, total inhibin, inhibins A and B, and prolactin were determined in blood samples collected annually three times weekly for 4 wk beginning with the onset of menses. Menstrual bleeding diaries covering this 4- to 9-yr period were also collected allowing the prospective identification of the final menstrual period. A change in serum hormone patterns was observed in cycles approaching menopause, exemplified by an increasing number of cycles of prolonged length with a prolonged follicular phase resulting in a failure to detect a luteal phase rise in serum progesterone within the 4-wk collection period. These prolonged cycles (designated B cycles based on a previous work) were analyzed separately and compared with the remaining ovulatory (D) cycles. No B cycles were identified in any women earlier than 27 cycles from menopause. The proportion of B cycles increased as menopause approached, reaching 62% in the last 10 cycles. The proportion of D cycles decreased accordingly. The B cycles during the initial 4-wk collection period were characterized by elevated FSH, LH, FSH/inhibin A and FSH/inhibin B ratios, and longer duration, although cycle length/subject was not significantly different presumably due to the small number of B cycles. The D cycles showed no changes in hormonal profiles over the 4- to 9-yr time period. These data indicate that there is a time-related change in the character of menstrual cycles as menopause approaches, with an increasing proportion of cycles observed with prolonged follicular phases that may either be delayed ovulatory cycles or anovulatory cycles. The increase in the proportion of B cycles with elevated early follicular phase FSH levels and low inhibin/FSH ratios toward menopause provides a basis for the apparent early increase in serum FSH and decrease in serum inhibins observed previously in studies of the menopause transition based on sampling confined to the follicular phase only. The data amplify and clarify current concepts of the endocrine basis of the menopause transition.