Unaffected Women Research Articles

Expression of Allograft Inflammatory Factor-1 in Human Eutopic Endometrium and Endometriosis: Possible Association with Progression of Endometriosis

Allograft inflammatory factor-1 (AIF-1) is a cytokine originally identified in rat cardiac allografts with chronic rejection. AIF-1 is expressed in various human immune-related tissues and is thought to play a role in inflammatory responses and the immune activation and function of macrophages. Expression has also been shown in human placentas and bovine embryos, suggesting that AIF-1 may be involved in reproductive function. Immune factors are thought to be involved in the pathogenesis of endometriosis. High concentrations of activated macrophages and various cytokines have been found in the peritoneal fluid of patients with endometriosis. In the current work we examined the expression of AIF-1 in human eutopic endometrium and endometriosis, and measured AIF-1 in peritoneal fluid samples from women with and without endometriosis. RT-PCR, Western blot analysis, and immunohistochemistry showed that AIF-1 mRNA and protein were expressed both in eutopic endometrium and in endometriotic tissue. In eutopic endometrium, expression was greater in the late secretory and menstrual phases than in other phases of the menstrual cycle (P < 0.01). AIF-1 protein was present in greater amounts in peritoneal fluid from patients with endometriosis than in women without it (P < 0.01), and its concentration correlated with the Revised American Society for Reproductive Medicine score (rs = 0.693; P < 0.0001). Peritoneal macrophages from endometriosis patients secreted more AIF-1 than those from unaffected women (P < 0.05). AIF-1 release from macrophages was stimulated by IL-1beta (P < 0.01) and interferon-gamma (P < 0.05). These results demonstrate for the first time that AIF-1 is expressed in eutopic endometrium and endometriotic tissue, suggesting that AIF-1 is one cytokine in the local network involved in the onset of menstruation. AIF-1 derived from peritoneal macrophages may also possibly play a significant role in the pathophysiology and progression of endometriosis.

Psychological Impact of Genetic Testing for Breast Cancer Susceptibility in Women of Ashkenazi Jewish Background: A Prospective Study

The recognition that the prevalence of three founder mutations in the BRCA1 and BRCA2 genes is over 2% in Ashkenazi Jews has resulted in numerous epidemiological research studies of this ethno-religious group. To determine the effects of incorporating research into clinical practice, a psychological impact study of women participating in an epidemiological study was conducted. Sixty women of Ashkenazi Jewish background who underwent genetic testing for founder mutations were assessed using mailed, self-administered questionnaires with validated measures of psychological outcome. Forty-three women elected to learn their results and 17 women declined to do so. Women who elected to learn their results were also assessed 7-10 days, 4 months, and 12 months after results disclosure. Women who chose to learn their results had significantly higher baseline breast cancer anxiety, compared to those who elected not to learn their results (z = -2.27; p = 0.023). Unaffected women who elected to learn their results showed a significant decrease in breast cancer anxiety 4 months (z = -2.37, p = 0.018) and 12 months (z = -3.06, p = 0.002) post-notification compared to baseline. Genetic testing for mutations common in Ashkenazi Jewish women with result disclosure does not lead to adverse psychological outcomes.

PSYCHOSEXUAL OUTCOME IN WOMEN AFFECTED BY CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in increased adrenal androgen secretion. When the deficiency is severe, the result is the salt losing (SL) form, and when the deficiency is partial, the result is the simple virilizing (SV) form of CAH. We documented long-term satisfaction with gender, cosmetic appearance and function of the genitalia, and surgical management practices in a group of women with CAH due to 21-hydroxylase deficiency. Psychosexual and surgical outcome were assessed in 41 women with CAH using an interview, a written questionnaire and a physical examination. When appropriate, outcome measures were compared to those in unaffected control women. Women in the SL group were more likely to question their female gender and report sexual concerns, and less likely to have sexual relations with a partner than those with the SV form or control women. Overall women with CAH were moderately satisfied with the cosmetic appearance of the genitalia but the SL group reported worse genital function than the SV group. Physician rated appearance of the genitalia was better than ratings provided by patients and women with the SL form were judged to have a worse cosmetic outcome of genital reconstruction than women with the SV form. The most common response concerning the optimal timing for genital reconstruction was during infancy and early childhood, although a number of women favored waiting until later for these procedures or did not respond to this question. Women with the SV form reported greater satisfaction and fewer concerns regarding their psychosexual and surgical outcome than women with the SL form.

Short‐ and Long‐Term Impact of Receiving Genetic Mutation Results in Women at Increased Risk for Hereditary Breast Cancer

Forty-seven unaffected women from high-risk breast cancer families who had received results for hereditary breast/ovarian predisposition genes between 1 month and 5 years ago were interviewed regarding their experiences. Women responded to open-ended questions. The initial emotional turmoil reported by most was generally short lived. However, the impact of genetic testing went beyond the individual to the extended family and social context, particularly in the short-term. A common theme was the difficulty associated with divulging a result to family members, who were also adjusting to their own result. The majority of carriers reported advantages that were both physical (options for surveillance programs and prophylactic surgery) and emotional (reduced uncertainty, increased awareness of options and knowledge about risk, preparation time). Most carriers reported no change in lifestyle although some reported discovering their mutation status as a positive life-changing experience. Implications for genetic counseling and further research are discussed.

Non-random transmission of mutant alleles to female offspring of BRCA1 carriers in Poland

Constitutional mutations in the BRCA1 gene predispose to an autosomal dominant syndrome of breast and ovarian cancer. The lifetime penetrance of BRCA1 gene mutations is high; approximately 50% of women with mutations will be affected by cancer by the age of 50 years, and over 80% of women with mutations will be affected with cancer by the age of 75 years.1 At birth, it is expected that 50% of the children of a carrier parent will inherit a mutant allele. If the mortality in carriers is higher in carriers than in non-carriers, then the proportion of carriers among offspring is expected to decline with age. Similarly, among unaffected women, the proportion of carriers is expected to decline with age. For example, if the gene is 50% penetrant by by the age of 50 years, then one third of a sample of healthy 50 year old female offspring of carriers are expected to be carriers. Under the assumption that a mutant allele is transmitted to 50% of offspring, it is therefore possible to estimate age-specific penetrance values of the BRCA1 gene by counting the relative number of carriers and non-carriers in a sample of healthy offspring, of varying ages, of carrier parents. Three founder mutations in BRCA1 are common in Poland (5382insC, C61G, and 4153delA).2 In an attempt to estimate the age-specific penetrance of these three mutations, we systematically reviewed the genotypes of mothers and daughters in a selected group of …

Androgen and psychosexual development: Core gender identity, sexual orientation, and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH)

We assessed core gender identity, sexual orientation, and recalled childhood gender role behavior in 16 women and 9 men with congenital adrenal hyperplasia (CAH) and in 15 unaffected female and 10 unaffected male relatives, all between the ages of 18 and 44 years. Women with CAH recalled significantly more male‐typical play behavior as children than did unaffected women, whereas men with and without CAH did not differ. Women with CAH also reported significantly less satisfaction with the female sex of assignment and less heterosexual interest than did unaffected women. Again, men with CAH did not differ significantly from unaffected men in these respects. Our results for women with CAH are consistent with numerous prior reports indicating that girls with CAH show increased male‐typical play behavior. They also support the hypotheses that these women show reduced heterosexual interest and reduced satisfaction with the female sex of assignment. Our results for males are consistent with most prior reports that boys with CAH do not show a general alteration in childhood play behavior. In addition, they provide initial evidence that core gender identity and sexual orientation are unaffected in men with CAH. Finally, among women with CAH, we found that recalled male‐typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood. Although prospective studies are needed, these results suggest that those girls with CAH who show the greatest alterations in childhood play behavior may be the most likely to develop a bisexual or homosexual orientation as adults and to be dissatisfied with the female sex of assignment.

CYP1A1 alleles in women with focal nodular hyperplasia of the liver (FNH).

Disorders of steroid hormone metabolism might be related to the etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor, especially prevalent in women. The cytochrome P450 1A1 (CYP1A1) enzyme is implicated in the bioactivation of multiple precarcinogens as well as in the metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with altered catalytic activity in the hydroxylation of sex hormones and this may account for interindividual variability in exposure to hormone-mediated cell proliferation signals and reactive steroid metabolites. In the study at hand, we aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4 alleles and FNH. Genotyping of 26 affected female patients of Caucasian origin was carried out using PCR/RFLP. Allele frequencies for the CYP1A1 variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and 0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95% CI 0.23-2.44), 0.72 (95% CI 0.10-5.34) and 1.96 (95% CI 0.59-6.50), respectively. There were no significant differences between these values and corresponding allele frequencies obtained in a large German sample of unaffected Caucasian women. The present data do not suggest a relevant association between CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female Caucasians.

Recognition and management of hereditary breast cancer syndromes.

Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.

The role of estrogens in BRCA1/2 mutation carriers: reflections on the past, issues for the future.

Persons undergoing genetic testing for an inherited predisposition to cancer often raise questions about recommendations for follow-up care. Missing from current guidelines is consideration of the role of estrogens for BRCA1/BRCA2 mutation carriers. Potential implications of hormones for risk of cancer and effectiveness of risk-reduction strategies need to be considered in the design of comprehensive guidelines for high-risk women. Patients who are mutation carriers may ask questions about the use of oral contraceptives, hormone replacement, and utility of current screening modalities. Controversy exists, even when considering these issues for the general population, but become more imperative when considering young, unaffected women who carry an inherited genetic mutation making decisions that may have long-term health consequences. Many patients have considered estrogen ablation via prophylactic surgeries as risk-reduction interventions. This article reviews data regarding these issues, makes recommendations based on available information, and offers future perspectives for those identified at high risk for cancer because of genetic predisposition. Although questions remain regarding the potential implications of hormones for risk of cancer and effectiveness of risk-reduction strategies, all information should be considered when educating and caring for such patients.

Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA).

Ancestral mutations in BRCA1 and BRCA2 are common in people of Ashkenazi Jewish descent and are associated with a substantially increased risk of breast and ovarian cancer. Women considering mutation testing usually have several personal and family cancer characteristics, so predicting mutation status from one factor alone could be misleading. The aim of this study was to develop a simple algorithm to estimate the probability that an Ashkenazi Jewish woman carries an ancestral mutation, based on multiple predictive factors. We studied Ashkenazi Jewish women with a personal or family history of breast or ovarian cancer and living in Melbourne or Sydney, Australia, or with a previous diagnosis of breast or ovarian cancer and living in the UK. DNA samples were tested for the germline mutations 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. Logistic regression was used to identify, and to estimate the predictive strength of, major determinants. A mutation was detected in 64 of 424 women. An algorithm was developed by combining our findings with those from similar analyses of a large study of unaffected Jewish women in Washington. Starting with a baseline score, a multiple of 0.5 (based on the logistic regression estimates) is added for each predictive feature. The sum is the estimated log odds ratio that a woman is a carrier, and is converted to a probability by using a table. There was good internal consistency. This simple algorithm might be useful in the clinical and genetic counselling setting. Comparison and validation in other settings should be sought.

Corpus callosum in first-episode patients with schizophrenia – a magnetic resonance imaging study

Morphometric studies on the corpus callosum (CC) in schizophrenia have yielded contradictory results. The aim of the present study was to investigate magnetic resonance imaging (MRI) abnormalities of the CC in first-episode patients with schizophrenic psychoses. We assessed volumetric MRI in 31 patients with diagnoses of schizophrenia, schizophreniform or schizoaffective disorder (DSM-IV) and a maximum exposure to neuroleptics of 2 weeks. As a control group, 12 healthy age- and sex-matched individuals were included in the study. A whole body scanner at 1.5 Tesla was used to obtain 3D T1- and T2-weighted MR datasets. The data were evaluated semi-automatically (intracranial volume, total brain volume) and manually (CC) with the software NMRwin. Patients had smaller CC and CC subdivisions than controls. Schizophrenic and unaffected women exhibited larger total CC and rostral subdivisions than men in both groups. Handedness did not exert an influence. Our findings are in line with other in vivo morphometric studies on the CC in schizophrenia. The larger CC area in women may reflect general gender-related differences in CC size as described in healthy individuals.

Impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with breast or ovarian cancer

To evaluate the impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with cancer. Longitudinal cohort study including women affected and unaffected with breast or ovarian cancer testing for a BRCA1/2 mutation. Data on well-being (anxiety, depression, cancer related distress, general health), treatment choice, and decision making about cancer prevention were collected at baseline (1 week after blood sampling; affected n = 192, unaffected n = 176) and at follow-up (2 weeks after disclosure of a positive test result; affected n = 23, unaffected n = 66). Women affected and unaffected with breast or ovarian cancer were compared using univariate statistics. Change over time was examined using repeated measures analysis of variance. With respect to well-being, affected women scored worse at baseline. At follow-up, both affected and unaffected women experienced a decline in well-being, which tended to be stronger in affected women. Women diagnosed with cancer less than 1 year previously tended to report a worse well-being than those diagnosed longer ago. With respect to treatment choice, more affected women intended to obtain prophylactic surgery and valued it higher at both time points. With respect to decision making, affected women had a lower preference for participation in decision making at baseline; no differences were found at follow-up. At follow-up, both affected and unaffected women showed an increase in strength of treatment preference and a decrease in decision uncertainty. Disclosure of a positive test result had a negative impact on well-being. Affected women, especially those who have been recently diagnosed with cancer, experienced the worst well-being and could benefit from psychosocial support.

Clinical, pathological and genetic features of women at high familial risk of breast cancer undergoing prophylactic mastectomy.

Prophylactic mastectomy (PM) is a risk-management option for women at high familial risk of breast cancer (BC). This study describes the PM experience of women enrolled in a large observational cohort study involving families with a history of hereditary breast cancer. Within 357 multiple-case BC families [119 (33%) BRCA1 or BRCA2 mutation positive], identified via family cancer clinics, 49 cases of PM [21 (43%) BRCA1 or BRCA2 mutation positive] were identified and their clinical, pathological and genetic features reviewed. Families with at least one incidence of PM displayed stronger breast/ovarian cancer histories than did families without PM. Median age at time of PM was 45 years (range 28-58). Ten cases (21%) were bilateral PMs in unaffected women and 39 cases were contralateral PMs in women with prior invasive BC (71%) or ductal carcinoma in situ (DCIS) (8%). Most (88%) underwent total mastectomy. Unnecessary axillary surgery occurred in eight subjects (16%). Malignant histology was found in three PM specimens (6%). Prior to genetic testing, PM was performed in two women who were subsequently shown not to carry the mutation specific to their family. Optimal utilization of genetic testing to guide surgical decision making, appropriate surgical technique and careful pathology examination of PM specimens, are important issues to consider prior to PM in women at high familial risk of BC.

Use of serological proteomic methods to find biomarkers associated with breast cancer.

New technologies for the detection and therapy of early stage breast cancer are urgently needed. Pathological changes in breast might be reflected in proteomic patterns in serum. A proteomic tool was used to identify proteomic patterns in serum that distinguishes neoplastic from non-neoplastic disease within the breast. Preliminary results derived from the serum analysis from 54 unaffected women and 76 patients with breast cancer were analyzed by two-dimensional (2-D) electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry, HSP27 was found up-regulated while 14-3-3 sigma was down-regulated in the serum of breast cancer patients. The two protein biomarkers were then used to classify an independent set of 104 masked serum samples. The results showed that the protein pattern on 2-D gels can completely segregate the serum of breast cancer from non-cancer. The discriminatory pattern correctly identified all 69 breast cancer cases in the masked set. Of the 35 cases of non-malignant disease, 34 were recognized as non-cancer. These findings justify a prospective population-based assessment of proteomic technology as a screening or diagnostic tool for breast cancer in high-risk and general populations. These two protein biomarkers could also be used as targets for further study in drug design and breast cancer therapy.

A simple tool for identifying unaffected women at a moderately increased or potentially high risk of breast cancer based on their family history

Family history of breast cancer is a more important aspect of clinical management following the discovery of the genes BRCA1 and BRCA2. The authors developed a short questionnaire to categorise risk according to breast cancer history in close relatives. It was completed by 559 women attending for screening mammograms in Sydney, Australia. Twenty-three per cent reported a family history sufficient to be classified at a moderately increased or potentially high risk according to national guidelines (category II or III). Only 29 women (5%) made errors such that their risk category could not be determined. Validation of responses from 89 women, 44 from category II or III, found 100% agreement with classification after interview by a genetic counsellor. This questionnaire has the potential to accurately triage risk based on a woman's knowledge of her family history, and could be used in a variety of settings to identify women who may require further assessment, management and referral advice.

Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis

Am Heart J 2003;145:190-4.

The Unmet Information and Support Needs of Women with a Family History of Breast Cancer: A Descriptive Survey

This study aims to survey the unmet support needs of women at increased risk of developing breast cancer. In total, 173 unaffected women with a family history of breast cancer completed a 28-item purposely-designed mailed survey. The majority of participants did not report a high level of unmet need for support. Receiving further information about cancer genetics was the most commonly reported area of unmet need. Only about 20% of participants reported a moderate to high degree of interest in attending a hypothetical support group. However, a higher degree of interest was expressed in internet-based information and supportive interventions. Amongst those interested in attending a support group, discussion, and receiving further information were the most preferred activities. Higher levels of unmet support needs were significantly associated with interest in attending groups. No demographic variables were found to predict interest in attending a support group. Implications for those considering establishing support groups are discussed.

Cystic Disease in Women: Clinical Characteristics and Medical Management

Autosomal dominant polycystic kidney disease (ADPKD) is a dominantly inherited systemic disorder equally inherited in men and women characterized by renal cyst development and expansion ultimately leading to renal failure. ADPKD women have a slower rate of progression to renal failure, with a later age of entry into end-stage renal disease (ESRD) as compared with men. Renal cyst growth and renal expansion are the hallmarks of ADPKD, and women will develop renal insufficiency with smaller renal volume than their male counterparts. As well, women have different rates of occurrence of renal and extrarenal complications in ADPKD. Renal complications related to ADPKD, including hypertension and gross hematuria, occur more frequently in men than in women, whereas liver cystic disease occurs earlier and more frequently in women than in men. The presence of polycystic liver disease is related to pregnancy number and oral contraceptive pill use in ADPKD women. Importantly, massive polycystic liver disease requiring surgical intervention occurs primarily in ADPKD women. ADKPD women have a highly successful reproductive course. The chance of a successful pregnancy is excellent in ADPKD women and comparable to healthy unaffected women as long as prepregnancy blood pressure and renal function are normal. Fetal complication rates are no greater than in the general population; however, maternal complication rates in ADPKD women are high with an increased frequency of new or worsening hypertension as well as an increased occurrence of preeclampsia and preterm deliveries. Finally, increasing pregnancy number has minimal or no effect on renal outcome in ADPKD women.

Oral contraception and epilepsy: findings in a large cohort study

There is no good evidence that oral contraceptives (OCs) increase the risk of epilepsy in unaffected women or increase the frequency of seizures in those suffering from the disorder. Nonetheless, manufacturers’ literature continues to include warnings about OCs and epilepsy. We have analyzed the available data about epilepsy in the Oxford-Family Planning Association contraceptive study that includes 17,032 women followed for periods of up to 26 years. In total, 82 women (with no record of having suffered epilepsy when recruited to the study) were referred to hospital for diagnosis or treatment of epilepsy during the follow-up period. No association was found between OC use and the occurrence of the condition. Referral to hospital was, however, more frequent in women of low social class and in those with a high body mass index.

Psychological impact of prophylactic oophorectomy in women at increased risk of developing ovarian cancer: a prospective study.

The objectives of this study were twofold: to prospectively assess whether expressed intention to undergo prophylactic oophorectomy translated into uptake and to evaluate the psychological impact of the procedure in a sample of unaffected women with a strong family history of breast/ovarian cancer. Ninety-five women, initially assessed at the time of their first attendance at a familial cancer clinic, were followed-up 3 years later. A total of 22 women (23.2%) in this study had undergone a prophylactic oophorectomy. Ten women (10.5%) who had undergone a prophylactic oophorectomy during the 3-year follow-up period were compared to 73 women (76.9%) who did not have a prophylactic oophorectomy. Twelve women (12.6%) who had the procedure prior to study entry were also assessed for psychological adjustment and associated information needs. Age emerged as a significant predictor of uptake of prophylactic oophorectomy (chi(2) = 7.13, P = 0.009). Among those who had the procedure after study entry, a significant reduction in ovarian cancer anxiety was observed (Z = -2.19, P = 0.029). Of the 22 women who had undergone a prophylactic oophorectomy in total (both before and after study entry), 86.4% reported a high degree of satisfaction with their decision to have the procedure. A low level of screening uptake was also reported by women who did not have a prophylactic oophorectomy but for whom screening was recommended. Findings demonstrate that prophylactic oophorectomy is successful in reducing anxiety about ovarian cancer. The results also suggest that women perceive that the benefit of anxiety reduction may outweigh the potentially adverse effects of the procedure, given that women expressed a high level of satisfaction with their decision.