A double nucleotide insertion-induced frame-shift mutation of the androgen receptor gene in a familial complete androgen insensitivity syndrome

Objective

A wide spectrum of androgen receptor (AR) gene mutations has been reported in complete androgen insensitivity syndrome (CAIS). The molecular basis of androgen resistance was investigated in a female with familial CAIS.

Study design

AR gene and protein were investigated by PCR and direct sequencing and Western immunoblotting, respectively.

Results

Sequencing analysis of DNA of the patient identified a double nucleotide insertion in exon 4 that results in the frame-shift leading to premature terminal signal in the beginning of exon 6. This mutation predicted the synthesis of a truncated AR that lacks the entire ligand-binding molecules. Immunoblotting analysis of the gonad removed from the patient detected the mutated AR protein of 94 kDa. Positive control revealed the normal apparent molecular mass of 110 kDa. DNA sequencing of her mother demonstrated the presence of both canonical and mutated sequences in the exon 4 through 8.

Conclusion

These findings suggested that the previously undescribed insertion mutation in the AR gene is the cause of CAIS in this family.     

Molecular analysis of the androgen receptor gene in 4 patients with complete androgen insensitivity

Androgen insensitivity syndromes are due to defects in the androgen receptor gene. In this study, we analyzed the androgen receptor gene in four cases with complete androgen insensitivity syndrome. In patient 1, one substitutional mutation [arginine (codon CGC) to cysteine (codon TGC) at position 774] of exon F was identified. This position was located in the hormone binding domain and appeared to be one hot spot of mutations because the mutations at the same position in several unrelated cases were reported before. In patient 2, one substitutional mutation [tyrosine (codon TAT) to cysteine (codon TGT) at position 571] of exon B was identified. This position was located in the DNA binding domain. In patients 3 and 4 (siblings), one substitutional mutation [arginine (codon CGA) to glutamine (codon CAA) at position 752] of exon E was identified. Taken together, these abnormalities might be related to the pathogenesis of complete androgen insensitivity. Received: 7 July 1997 / Accepted: 27 October 1997     

Androgen receptor expression is a biological marker for androgen sensitivity in high grade serous epithelial ovarian cancer

Objectives

In the present study we explore the effects of androgens and anti-androgens on primary cultures of EOC cells. We also investigate the effects of chemotherapy on AR expression. Epithelial ovarian cancer (EOC) arises from ovarian surface epithelial cells (OSE), which express the androgen receptor (AR). Androgen stimulation of OSE cells results in increased proliferation and protection from apoptosis. Nevertheless, in clinical trials anti-androgens have had a low objective response rate in relapsed ovarian cancer.

Methods

1. Androgen receptor (AR) expression and response to androgenic stimulation were correlated in primary ovarian cancer cells derived from ascitic fluid from patients with advanced ovarian cancer,2. AR expression in primary epithelial ovarian cancer was investigated before and after chemotherapy using paired histological samples which had been incorporated into a tissue microarray.

Results

Eleven primary ovarian cancer cultures were established from ascitic fluid. There was wide variation of expression of androgen receptor mRNA between cultures. Cell division increased after dihydro-testosterone (DHT) stimulation in 6 out of 11 primary cultures. The fraction of cells in S-phase increased from 4.4% in cells grown in serum-free medium to 8.3% in cells stimulated with 100 nM of DHT (P < 0.001). The increase in S-phase fraction was abrogated after treatment with the anti-androgen, bicalutamide in 4 out of 5 responsive cultures. There was a strong correlation (r² = 0.7) between nuclear AR expression by immunohistochemistry and S-phase fraction changes in primary cultures.Paired pre- and post-chemotherapy histological samples from 29 patients were incorporated into a tissue microarray (TMA). Nuclear and cytoplasmic AR expression by immunohistochemistry (IHC) decreased significantly after chemotherapy (P < 0.01).

Conclusion

AR expression correlates with increased S-phase fraction in response to androgenic stimulation. Immunohistochemical analysis of AR expression needs to be further tested in clinical trials to select AR positive EOC for anti-androgen therapy. Anti-androgen use early in the course of ovarian cancer is more likely to be effective as these data suggest that androgen receptor expression decreases with exposure to chemotherapy and this may explain the low response rates seen in clinical trials of patients heavily pre-treated with multiple courses of chemotherapy.     

Kurdish pregnant women's feelings: A qualitative study

Objective

to gain a deeper understanding of how Kurdish pregnant women feel about their pregnancy.

Design

a qualitative study analysed by a grounded theory approach.

Setting

the study was conducted among women in the third trimester of their pregnancy in either their homes or the health-care centres in Sanandaj in the western part of Iran.

Participants

22 pregnant women were recruited and interviewed.

Findings

during pregnancy, women experienced a variety of feelings: ‘satisfied and happy’, ‘unpleasant’ and ‘ambivalent’.

Conclusions and implications for practice

it is important for midwives to ask pregnant women about their feelings concerning their current pregnancy, childbirth and future motherhood. If they express negative or ambivalent feelings, these should be discussed in greater detail and their causes identified. Special consideration should be given to primiparous women and multiparous women with negative experiences of previous pregnancies.     

Brachial artery conductance during reactive hyperemia is increased in women with polycystic ovary syndrome

Objective

To examine changes in brachial artery conductance (BAC) during reactive hyperemia in women with polycystic ovary syndrome (PCOS) compared to controls.

Study design

This is a pilot case-control study performed at a single academic medical center. Changes in BAC during reactive hyperemia were evaluated in 31 women with PCOS and 11 healthy control women. Fasting glucose, insulin, lipids and androgen levels were also determined. A mixed-effects model was used to compare the PCOS curve to the control curve for change in BAC from baseline during reactive hyperemia.

Results

Body mass index (BMI) and testosterone levels were significantly increased in the PCOS group compared to controls (P < 0.05). In addition, the PCOS group had higher total and LDL cholesterol levels (P = 0.05 and 0.09, respectively). Change in BAC from baseline during reactive hyperemia was significantly increased in the PCOS group compared to controls even after adjusting for age, BMI and LDL cholesterol levels (P < 0.0001). There were no significant differences between the two groups in age, blood pressure, or fasting glucose or insulin levels.

Conclusions

Brachial artery conductance during reactive hyperemia is significantly increased in women with PCOS compared to controls and may be a novel early indicator of increased cardiovascular risk in women with PCOS.     

Disorders of androgen action

Disorders of androgen action are the main cause of male pseudohermaphroditism and include 5alphaR deficiency and androgen receptor defects. 5alphaR deficiency is characterized by female genitalia with some degree of masculinization, clitoromegaly, and severely bifid scrotum corresponding to the so-called pseudovaginal perineoscrotal hypospadias. At the onset of puberty, increased muscle mass, development of pubic hair, and phallic growth are associated with the acquisition of male gender identity. Normal or increased levels of testosterone and an elevated testosterone-to-dihydrotestosterone ratio after human chorionic gonadotropin stimulation testing suggest 5alphareductase deficiency, and the diagnosis can be ascertained by identifying the mutation in the 5alphaR-2 gene. Whatever the patient's age at diagnosis, psychological evaluation with 5alphaRD is vital. Androgen receptor defects encompass two clinical expressions: the complete and partial androgen insensitivity syndromes. Complete androgen insensitivity syndrome should be suspected at birth in the presence of inguinal hernia in a girl without genital ambiguity. At puberty, the sign of alert is primary amenorrhea with normal female phenotype and harmonious mammary development but no pubic hair growth. Partial androgen insensitivity syndrome covers a wide spectrum of undervirilized phenotypes ranging from clitoromegaly at birth to infertile men. In all cases, complementary investigations should include plasma testosterone and luteinizing hormone as well as androgen-binding capacity in cultured genital skin fibroblasts. Diagnosis is confirmed by identification of the androgen receptor gene mutation. Although patients with complete androgen insensitivity syndrome are raised as females, patients with partial androgen insensitivity syndrome should be managed according to age at diagnosis, response to treatment with exogenous androgens, and the presence of an androgen gene mutation. Gonadectomy in complete androgen insensitivity syndrome should be performed before puberty, and androgen substitution may improve the development of external genitalia in some patients with partial androgen insensitivity syndrome. Psychological follow-up is necessary.     

Factors associated with failure to achieve birth emphasizing a successful singleton at term following in vitro fertilization

Objective

To evaluate the factors that might affect birth emphasizing a successful singleton at term (BESST) outcomes in women undergoing in vitro fertilization.

Methods

A retrospective review of assisted reproduction cases from January 1, 2001, to July 31, 2005, at the Far Eastern Memorial Hospital, Taipei, Taiwan. Variables that were potentially associated with failure to achieve BESST were evaluated using univariate and multivariate logistic regression analysis.

Results

Successful embryo transfer occurred in 297 of the 323 cases of assisted reproduction. In total, 123 women became pregnant and were enrolled for analysis, of whom 94 had live births and 55 achieved BESST. Multivariate analysis indicated that the number of embryos transferred, the presence of ovarian hyperstimulation syndrome, female infertility factors (other than tubal factors), and embryo quality were associated with increased relative risk of BESST failure, with odds ratios of 1.02 (95% confidence interval [CI], 1.01-1.02), 1.21 (95% CI, 1.08-1.36), 1.41 (95% CI, 1.22-1.62), and 0.79 (95% CI, 0.68-0.91), respectively.

Conclusion

The number of embryos transferred, the presence of ovarian hyperstimulation syndrome, female infertility factors other than tubal factors, and embryo quality correlate with the risk of failure to achieve BESST.     

A qualitative study of the information needs of premenopausal women with breast cancer in terms of contraception, sexuality, early menopause, and fertility

Objectives

To evaluate the information needed and received by premenopausal Turkish women with breast cancer regarding contraception, early menopause, infertility, fertility preservation, and sexuality.

Methods

A qualitative exploratory methodology was used whereby an interviewer met on 2 occasions with women with breast cancer. The participants—who were recruited from the oncology clinic of Adnan Menderes University Hospital, Ayd?n, Turkey—were premenopausal, younger than 50 years of age, and had been diagnosed with breast cancer within the past year. Raw data were sorted under themes.

Results

Premenopausal women with breast cancer received insufficient counseling on contraception, early menopause, infertility, fertility preservation, and sexuality, despite their willingness to receive information.

Conclusion

In Turkey, premenopausal women with breast cancer should receive comprehensive information and counseling from oncology staff on the issues studied. The present study may guide future research on this topic.     

Case-loading midwifery in New Zealand: bridging the normal/abnormal divide ‘with woman’

Objectives

to explore the way that case-loading midwives in New Zealand construct midwifery (and in so doing, the concepts of woman and childbirth). This paper illuminates the fundamental features of this construction (continuity and woman-centred care) and discusses this with regard to the role of midwives vis-à-vis normal/abnormal birth.

Design

semi-structured interviews and official publications constituted the ‘text’ which was analysed using a poststructural approach that was informed by theorists Foucault, Grosz and Braidotti.

Participants and setting

48 case-loading midwives practising throughout New Zealand participated in this study. These included facility-employed and self-employed midwives and those from rural and urban settings.

Findings

many midwives follow women through their maternity experience providing continuity of care regardless of whether the experience is considered ‘normal’ or ‘abnormal’.

Key conclusions

continuity and woman-centred care are fundamental features of the construction of midwifery in New Zealand.

Implications for practice

a focus on the midwifery concept of ‘with woman’ can bridge the divide between the polarising concepts ‘normal’ and ‘abnormal’ and enable a more fluid and dynamic reading of midwifery.     

Fetal myocardial morphological and functional changes associated with well-controlled gestational diabetes

Objective

To make a global evaluation of the fetal myocardial changes in a well-controlled gestational diabetic population.

Study design

Twenty-four pregnant well-controlled diabetic patients were selected. Sixteen normal pregnancies were randomly collected as a control group. Measurements of morphological and functional myocardial parameters were performed. Data from the left ventricular outflow tract and peripheral Doppler data were obtained.

Result

The thickness of the interventricular septum was increased in diabetic pregnancies (p < 0.001). Tricuspid E/A index was the only functional parameter showing a significant variation, with lower values in diabetic pregnancies. Doppler parameters from the left ventricular outflow tract and peripheral Doppler waveforms were similar between groups.

Conclusion

A tendency towards interventricular septum hypertrophy was observed even in well-controlled diabetic pregnancies. Mild hypertrophic cardiac changes were not associated with abnormal cardiac function or signs of left ventricular outflow obstruction, although minor changes in right ventricular diastolic function were recorded.     

Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines

Purpose

The role of the insulin-like growth factor (IGF) system in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR signaling pathways. The aim of the present study was to investigate the anti-proliferative activity of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines.

Methods

Type I (ECC-1, Ishikawa) and Type II (USPC-1, USPC-2) endometrial cancer cell lines were treated with NVP-AEW541 in the presence of IGF-I, and the following parameters were measured: IGF-IR, AKT and ERK phosphorylation, apoptosis, proliferation, cell cycle progression and IGF-IR internalization.

Results

Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated, whereas it abolished AKT and ERK phosphorylation preferentially in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor.

Conclusion

Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer.     

Genetic abnormalities in Turkish women with premature ovarian failure

Objective

To identify the distribution of cytogenetic abnormalities among Turkish women with premature ovarian failure (POF).

Method

A karyotype analysis was performed at the Medical Genetics Department of Zekai Tahir Burak Women's Hospital, Ankara, Turkey, for 75 women younger than 40 years found to have POF over a 5-year period.

Results

There were 18 familial cases (24%), 1 of which involving an abnormality of the X chromosome [46,X,del(X)(q22)]. Sixteen patients (21.3%) had chromosomal abnormalities such as Xq and Xp deletions, translocations, and numerical aberrations; 2 had Swyer syndrome; 2 were fragile X premutation carriers; and 1 had galactosemia.

Conclusion

A genetic cause of POF was identified in 39 (52%) of 75 patients. A thorough genetic evaluation of women with POF should be performed regardless of clinical features suggestive of chromosomal abnormality.     

Association between intimate partner violence and induced abortion in Cameroon

Objective

To examine the association between intimate partner violence (IPV; physical, sexual, and emotional violence) and induced abortion in Cameroon.

Methods

We used data from the 2004 Cameroon Demographic Health Survey (DHS) and hierarchic multivariate modeling to compare the rates of induced abortion by IPV type.

Results

In 2004, 2570 women were administered the domestic violence module of the DHS. Of those women, 126 (4.9%) reported having had at least 1 induced abortion. Cameroonian women reported high rates of IPV: physical violence (995 [38.7%]); emotional violence (789 [30.7%]); and sexual violence (381 [14.8%]). After adjusting for covariates, physical and sexual IPV increased the risk for induced abortion, whereas the association between emotional violence and induced abortion was not significant in multivariate models.

Conclusion

Given the increased risk for maternal morbidity and mortality following unsafe induced abortions in Cameroon, the association between induced abortion and IPV is of interest in terms of public health. Programs targeted at preventing IPV might reduce the rate of maternal morbidity and mortality.     

Behavioral therapy for urinary incontinence in India

Objective

To ascertain the prevalence of urinary incontinence in a sample of women from northern India, and the impact of behavioral therapy to treat its occurrence and severity.

Methods

A randomized controlled trial conducted from 2005-2006 to test the null hypothesis that behavioral therapy would not have an effect on urinary incontinence. Following a prevalence study, a total of 198 women with urinary incontinence were randomized into 2 groups: an intervention group (behavioral therapy) and a control group (no therapy).

Results

The prevalence of urinary incontinence was 11.6%. After an 8-month follow-up period, 41 women (52.5%) in the intervention group had become continent, and severity had shifted from severe to mild in 19 women (24.4%). In contrast, 11 women (12.8%) in the control group had become continent. In the intervention group, mean daytime voiding frequency decreased from 9.56 to 7.64, mean nighttime voiding frequency decreased from 1.45 to 0.69, and mean episodes of urine leakage decreased from 1.97 to 0.23.

Conclusion

Behavioral therapy was effective in treating urinary incontinence, particularly in women with mild and moderate incontinence.     

Women want proactive psychosocial support from midwives during transition to motherhood: a qualitative study

Objective

to explore low-risk pregnant women's views on their preferences for psychosocial support from midwives during their transition to motherhood.

Design

a qualitative design with focus-group interviews and thematic analysis of the discussions.

Settings and respondents

21 Dutch participants were included in three focus groups. Groups 1 (n=7) and 3 (n=8) consisted of pregnant women from four semi-urban midwifery practices, and group 2 (n=6) included participants from three urban midwifery practices.

Findings

the women wanted to take responsibility for their own well-being during pregnancy. In addition to informal support, they explicitly expressed a need for professional support from their midwives when undergoing the transition to motherhood. They wanted informational and emotional support from their midwives that addressed psychological and physical changes during pregnancy. They expressed a strong desire to be informed during pregnancy of how to prepare physically and psychologically for birth, recovery and motherhood. They also wanted help with sifting and interpreting information and, ultimately, wanted to make their own choices.

Key conclusions and implications for practice

during their transition to motherhood, healthy low-risk pregnant women want attentive, proactive, professional psychosocial support from midwives. They expect their midwives to oversee the transition period and to be capable of supporting them in dealing with changes in pregnancy and in preparing for birth and motherhood.     

Carcinosarcoma of the ovary: a review of the literature

Objective

Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. This article critically reviews the literature pertinent to the pathology, pathogenesis, diagnosis, management, and outcome of patients with ovarian carcinosarcoma (OCS).

Methods

MEDLINE was searched for all research articles published in English between January 1, 1981 and August 30, 2011 which reported on patients diagnosed with carcinosarcoma of the ovary. Given the rarity of this tumor, studies were not limited by design or number of reported patients.

Results

Patients with OCS generally present with advanced stage disease, and symptoms similar to those of patients with epithelial ovarian cancer (EOC). Retrospective studies have shown that cytoreductive surgery improves outcomes in patients with OCS. Similarly, platinum-based chemotherapy appears to be active in the treatment of OCS.

Conclusions

Ovarian carcinosarcomas are rare and aggressive tumors, associated with a poor prognosis. The mainstay of treatment remains cytoreductive surgical effort for metastatic disease followed by platinum-based chemotherapy. The role of targeted therapies may be promising in the treatment of OCS.     

Validity of a rapid assay for antisperm antibodies in semen

Objective

To determine the validity of a rapid assay for antisperm antibodies in semen.

Design

Prospective comparison of the results of standard and rapid antisperm antibody assays performed simultaneously.

Setting

Tertiary care infertility center.

Patient(s)

Couples who presented for infertility evaluation.

Intervention(s)

Semen analysis and measurement of antisperm antibodies in semen using a standard and a rapid immunobead binding test (IBT).

Main outcome measure(s)

[1] Comparison of sperm parameters between semen-containing antisperm antibodies and semen free of antisperm antibodies. [2] Validation of the rapid test by calculation of sensitivity, specificity, positive and negative predictive values of the rapid assay using the standard assay as a gold standard. [3] Cost comparison of the standard and rapid test.

Result(s)

[1] Nine semen specimens with antisperm antibodies had a significantly lower sperm concentration, motility, and total motile fraction compared to 44 specimens without antisperm antibodies. Also, specimens with antisperm antibodies had a significantly higher percentage of vibratory sperm and percent of bound antisperm antibodies. The strict morphology, liquefaction time, semen volume, and white blood cell concentration were no different between the two groups. [2] Using a threshold of ≥12% of bound antisperm antibodies in the rapid assay, the sensitivity, specificity, positive and negative predictive values of the test are 100% when correlated with a threshold of ≥20% in the standard assay. Increasing the threshold in the standard assay decreases the specificity and positive predictive value of the rapid assay but not the sensitivity and the negative predictive value. [3] The cost of the rapid assay was 16% that of the standard test and its performance took 20% of the time it took to set and perform the standard test.

Conclusion(s)

A rapid test for antisperm antibodies is valid, reliable, and more cost and labor effective than a standard IBT.     

Eficacia y seguridad de la utilización del óxido nitroso al 50% como analgesia en el parto

Objectives

To evaluate the safety and efficacy of 50% nitrous oxide with oxygen as an inhaled analgesic during delivery.

Material and methods

We performed a systematic review of the literature through a literature search (2010) of electronic databases. Studies comparing administration of inhaled nitrous oxide at 50% with another intervention in adult women during labor and reporting results on efficacy and safety were included.

Results

A total of 230 references were obtained and 24 studies that met the inclusion criteria were selected. After analysis of the texts, one systematic review and three clinical trials were selected. The quality of the trials included was moderate-high. Nitrous oxide as an analgesic technique produced acceptable results when compared with placebo but the results were less satisfactory when nitrous oxide was compared with other analgesics. Safety results were similar to those found with other analgesic treatments.

Conclusions

Administration of inhaled 50% nitrous oxide in women during labor could be an alternative to routinely used techniques.     

Cesarean delivery-related fistulae in the Democratic Republic of Congo

Objective

To compare the characteristics of urogenital fistulae after cesarean delivery with those after spontaneous vaginal delivery.

Methods

A retrospective analysis of hospital records of 597 consecutive patients with a urogenital fistula who received treatment at Panzi Hospital, Bukavu, Democratic Republic of Congo, during 2005-2007.

Results

Of 576 women with an obstetric fistula, 229 (40%) had had a cesarean delivery; 55 (24%) of the 229 fistulae were considered to be iatrogenic. The distribution of risk factors (age, stature, parity, and labor duration) was similar to that among 226 women with a spontaneous vaginal delivery, but the odds ratios for having a ureterovaginal or a vesicouterine fistula were 11.9 (95% confidence interval [CI] 2.8-51.2) and 9.5 (95% CI 2.8-31.9), respectively. Vesicovaginal fistulae with cervical involvement were also significantly more frequent in the cesarean delivery group. The fistulae in this group had less surrounding fibrosis and there was less treatment delay. Stillbirth rates were 87% (cesarean delivery) and 95% (spontaneous vaginal delivery).

Conclusion

The data indicate that cesarean delivery-related fistulae are a separate clinical entity. Focus on this condition is important for fistula prevention and provision of adequate obstetric care, particularly for training in surgery and alternative delivery methods.