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Risk factors for benign breast disease.

The importance of various risk factors for benign breast disorders has been assessed an analysis of data obtained from a multicenter cohort study of contraceptive use among women in the United Kingdom (the Oxford Family Planning Association Contraceptive Study). Cases comprised all women diagnosed as having any type of benign breast lesion; 74 had fibroadenoma, 211 had histologically confirmed chronic cystic disease, 331 had breast lumps not subjected to biopsy and 70 had other disease. Each case was individually matched with another study participant who was free from recognized breast disease. Matching factors were center of recruitment, date of recruitment, age at entry, and continuation in the study. An inverse association was found between use of oral contraceptives and the risk of the first three conditions. Current users of the pill had the lowest risk, particularly when the use was for an extended period. In contrast, past users demonstrated no reduction in risk. The reduction in risk for chronic cystic disease appeared to relate to the amount of progestogen contained in the pill. No significant association was observed between the risk of any of the conditions and either parity or age at first livebirth. Women of low social class and obese women were at low risk, perhaps reflecting diagnostic biases.

Adult↗

Autoimmune and pregnancy complications in the daughter of a kidney transplant patient.

BACKGROUND: Immunosuppressive agents taken by pregnant organ transplant recipients readily cross the placenta during development of the fetal immune system. There are few data on the long-term implications for the progeny, but evidence from animal studies suggest that second and third generations of organ transplant patients may be at risk for autoimmune disorders and reproductive problems. METHODS: We present the 23-year-old daughter of a renal allograft recipient exposed to azathioprine 75 mg/day and prednisone 5 mg/day throughout her mother's pregnancy. RESULTS: During the daughter's first pregnancy, she developed multiple autoantibodies, Raynaud's phenomenon, and fetal death occurred at 20 weeks gestation. The second pregnancy was complicated by systemic lupus erythematosus, preeclampsia, and the birth of a preterm male infant. CONCLUSIONS: It is uncertain whether the autoimmune manifestations and obstetric complications in this patient were related to fetal exposure to immunosuppressive drugs. Nevertheless, further studies on the health and pregnancies of adult offspring of transplant patients are warranted.

Adolescent↗

Gynaecological and obstetric disorders in coeliac disease: frequent clinical onset during pregnancy or the puerperium.

BACKGROUND AND AIM: While gynaecological and obstetric disorders have been reported among women with coeliac sprue, their true prevalence and relationship to the coeliac disease process has not been completely elucidated. Our aims were to determine: (1) the prevalence of gynaecological and obstetric problems in patients with coeliac disease and the influence of strict gluten restriction on their occurrence, (2) the effect of pregnancy on the clinical course of coeliac disease and (3) the clinical features of those patients with onset of coeliac disease during pregnancy and the puerperium. PATIENTS AND METHODS: The gynaecological and obstetric history of 130 coeliac patients and 130 age-matched healthy female controls were compared in a case-control study. RESULTS: In comparison to the controls, untreated coeliac disease patients exhibited significantly later menarche, an earlier menopause, an increased prevalence of secondary amenorrhoea and a greater incidence of spontaneous abortions. Patients who had adhered, in the long term, to a gluten-free diet had gynaecological and obstetric history indistinguishable from controls. Clinical deterioration of coeliac disease was observed in untreated patients during 17% of their pregnancies. In 14% of those untreated patients who were pregnant symptoms related to coeliac disease were manifested for the first time during either pregnancy (n = 7) or the puerperium (n = 4). Nine of these patients had underestimated features suggestive of coeliac disease. CONCLUSION: The early diagnosis and treatment of coeliac disease may avoid significant gynaecological and obstetric complications in affected women. Celiac sprue must always be borne in mind among patients who develop diarrhoea and weight loss during pregnancy and/or the puerperium.

Abortion, Spontaneous↗

Reproductive factors and melanoma of the skin among women.

A higher risk of reproductive system disorders, (which include benign tumors, endometriosis, dilation and curettage, hysterectomy, and other disorders requiring gynecologic biopsies) exist among women with cutaneous melanoma as compared to women with skin cancers: The odds ratio (OR) is 3.2, 95% confidence limits (1.0, 10.1), p = 0.049; as compared to a random sample of women with no melanoma or skin cancers, the OR is 3.9, 95% confidence limits (1.2, 12.4), p = 0.021. Confirming the observations of others, the authors found that melanoma was associated with red hair. The data also confirmed the finding that melanoma is associated with significantly fewer pregnancies. The mean numbers of pregnancies in the melanoma group is 1.83 +/- 1.6 (mean and standard deviation) compared to 2.99 +/- 1.9 in the skin cancer group and 2.93 +/- 1.9 in the random sample (p less than or equal to 0.05).

Analysis of Variance↗

Association between insurance status and admission rate for patients evaluated in the emergency department.

OBJECTIVES: To determine if differences exist in hospital and intensive care unit (ICU)/operating room admission rates based on health insurance status. METHODS: This was a retrospective, cross-sectional study of data from hospital clinical and financial records for all 2001 emergency department (ED) visits (80,209) to an academic urban hospital. Hospital admission and intensive care unit (ICU)/operating room admissions were analyzed, controlling for triage acuity, primary complaint, diagnosis, diagnosis-related group (DRG) severity, and demographics. Multivariate logistic regression models identified factors associated with hospital admission for under insured (self-pay and Medicaid) compared with other insured (private health maintenance organization, preferred provider organization, worker's compensation, and Medicare) patients. RESULTS: Compared with the other insured group, under insured patients were less likely, overall, to be admitted to the hospital (odds ratio [OR], 0.82; 95% CI = 0.76 to 0.90), controlling for all other factors studied. Subgroup analysis of common complaints showed under insured patients with a chief complaint of abdominal pain (OR, 0.67; 95% CI = 0.55 to 0.80) or headache (OR, 0.61; 95% CI = 0.39 to 0.95) had the lowest adjusted ORs for admission to the hospital, compared with other insured patients. Under insured patients with DRG of "menstrual and other female reproductive system disorders" (OR, 0.17; 95% CI = 0.06 to 0.51) or "esophagitis, gastroenteritis, and miscellaneous digestive disorders" (OR, 0.55; 95% CI = 0.28 to 0.96) also were less likely to be admitted compared with the other insured group. No significant differences in ICU/operating room admission rates were found between insurance groups. CONCLUSIONS: Whereas there was no difference in admission rates to the ICU/operating room by insurance status, this single-center study does suggest an association between insurance status and admission to a general hospital service, which may or may not be causally related. Factors other than provider bias may be responsible for this observed difference.

Adult↗

Non-oncogenic sequelae of cancer chemotherapy.

The delayed effects of anticancer drugs and late complications in 334 long-term survivors of childhood cancer were reviewed. Sequelae associated with chemotherapy were uncommon. Two men in the series exhibited disorders in reproductive function, possibly due to chlorambucil. A third male patient had cyclophosphamide-induced hematuria which persisted for two years after cessation of therapy. Other abnormalities were renal, hepatic, skeletal and cardiopulmonary, ascribed chiefly to radiotherapy, although the deleterious effect of drugs on irradiated organs cannot be excluded. The data indicate that the skillful and judicious application of chemotherapeutic agents produces a minimum of delayed consequences.

Adolescent↗

Gonadotropin-releasing hormone: physiological and therapeutic aspects, agonists and antagonists.

Rapid advances in the understanding of gonadotropin-releasing hormone (GnRH) actions and in development of new agonist and antagonist analogues of GnRH have taken place over the past several years. As a result, new compounds are now available to treat patients with various disorders of reproductive function. Used as probes of biologic processes, these compounds will also allow a greater depth of understanding of basic biologic processes.

Animals↗

Normalization of menstrual pattern after liver transplantation: consequences for contraception.

We studied menstrual abnormalities before and after liver transplantation in 31 women. The incidence of menstrual abnormalities is high before transplantation. Soon after transplantation, in most patients below 45 years of age, the menstrual pattern normalizes. Pregnancy can occur. Consequently, tubal sterilization should be avoided in transplant candidates. After transplantation adequate contraceptive measures should be taken to prevent unwanted pregnancy.

Adult↗

Quantitation of mucin mRNA in respiratory and intestinal epithelial cells.

Mucin glycoproteins (mucins) are the major macromolecular constituents of mucus gels in mammalian respiratory, gastrointestinal, and reproductive tracts. Disorders of mucin glycosylation, which may result from either abnormal post-translational processing or differences in mucin protein gene expression, have been indicated in several diseases. Quantitation of mucin gene expression has been hindered by two features of human mucin genes: variable numbers of tandemly repeating nucleotides per mRNA molecule and polydisperse mRNA transcripts. We report here a method to quantitate mucin mRNA levels in epithelial cells and have evaluated three mucin genes, MUC1, MUC2, and MUC5, which are expressed in respiratory epithelium. The method uses the 3' non-tandem repeat mucin cDNA sequences, as they were shown to have a single-size transcript when amplified by the polymerase chain reaction, consistent with a one-to-one relationship with the mRNA molecule. The 3' non-tandem repeat cDNA sequences were cloned and transcribed in vitro to prepare complementary RNA (cRNA) standards. By comparison to a cRNA standard curve, mucin gene expression was evaluated in colon adenocarcinoma, pancreatic adenocarcinoma, and transformed respiratory epithelial cells and in nasal polyp tissue by slot blot analysis. CFPAC-1, a pancreatic adenocarcinoma cell line, expressed the highest MUC1 transcript levels. Colon adenocarcinoma cell lines varied in MUC2 expression levels, and one colon adenocarcinoma cell line, HT-29, had higher levels of MUC5 than MUC2. Nasal polyp tissue expressed more MUC5 mRNA than MUC1 or MUC2 mRNA. This mucin mRNA slot blot method provides a quantitative method for investigating the regulation of mucin gene expression in health and disease.

Adenocarcinoma↗

Molecular abnormalities of FSH and LH action.

The identification of naturally occurring genetic mutations in individuals with disorders of reproductive function is the first logical step to therapy. To date, diagnostic investigations have been assisted by polymerase chain reaction and the development of an increasing number of effective screening techniques to scan genomic DNA (deoxyribonucleic acid) for causative mutations. The continued expansion of these technologies, coupled with high throughput gene sequencing, will ultimately result in automated DNA diagnosis for the practicing clinician at the point of care. At that time, the direct examination of a patient's DNA will be the definitive means of establishing the presence of specific genetic changes that cause or increase one's susceptibility to disease. This presentation selects important candidate genes in the human hypothalamic-pituitary-ovarian axis (HPG), reviews our knowledge of the spontaneously occurring human mutations that affect these genes, and reviews the biological implications of this information. To date, causative mutations in candidate genes have provided important insights into the transcription factors, receptors, and hormones that regulate the HPG axis at many levels. A major challenge in this field is that mutations in many of these genes and others remaining to be identified lead to infertility. The reduction in reproductive fitness due to these mutations limits the ability of investigators to use traditional genetic linkage and association studies to identify and clone important unidentified reproductive genes. Fortunately analysis of human gametes and new strategies that are being developed for the identification and mapping of complex human diseases will become increasingly important in continuing studies of idiopathic human infertility. At this time, it is helpful for the reader to become acquainted with some of the prototype mutations in candidate genes, their phenotypic consequences, and their prevalence. This presentation is designed to describe the known mutations in the gonadotropin genes and the genes encoding their respective receptors. The phenotypic effects of these mutations is compared, and evidence for causation is reviewed.

Animals↗

Dysregulation of cytochrome P450 17alpha-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by ovarian hyperandrogenism. Theca interna cells isolated from the ovaries of women with PCOS are characterized by increased expression of cytochrome P450 17alpha-hydroxylase (CYP17) [steroid 17alpha-hydroxylase/17,20 lyase (P450c17)], a steroidogenic enzyme obligatory for the biosynthesis of androgens. Augmented expression of the gene encoding P450c17 (CYP17) in PCOS theca has been attributed, in part, to differential transcriptional regulation of the CYP17 promoter in normal and PCOS cells. The present studies examine whether CYP17 gene expression is also posttranscriptionally regulated at the level of mRNA stability in normal and PCOS theca cells maintained in long-term culture. Determination of endogenous CYP17 mRNA half-life by pharmacological inhibition of transcription demonstrated that the half-life of CYP17 mRNA increased 2-fold in PCOS theca cells, compared with normal theca cells. Forskolin treatment also prolonged CYP17 mRNA half-life in both normal and PCOS theca cells. In vitro mRNA degradation studies demonstrated that the 5'-untranslated region confers increased stability to CYP17 mRNA in PCOS theca cells and showed that the 5'-untranslated region of CYP17 also confers forskolin-stimulated stabilization of CYP17 mRNA. These studies indicate that a slower rate of CYP17 mRNA decay contributes to increased steady-state mRNA accumulation and augmented CYP17 gene expression in PCOS theca cells.

3' Untranslated Regions↗

Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives.

Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders of reproductive age women, is associated with an increased risk of type 2 diabetes mellitus. Defects in both insulin action and insulin secretion contribute to this predisposition to diabetes, but the extent to which these defects are heritable among PCOS families has not been examined. In the present study we used the frequently sampled iv glucose tolerance test to quantitate insulin secretion (AIRg), insulin action (Si), and their product (AIRg x Si) among women with PCOS (n = 33) and their nondiabetic first degree relatives (n = 48). We then quantitated the heritability of these measures from familial correlations estimated within a genetic model. Familial (spousal, rhoMF; parent-offspring, rhoPO; and sibling, rhoSS) correlations were derived for log-transformed body mass index (BMI) as well as for AIRg, Si, and AIRg x Si, the latter three of which were adjusted for BMI. There was no evidence of significant heritability for either lnBMI or lnSi in these families. In contrast, the sibling correlation (rhoSS = 0.74) for lnAIRg was highly significant (chi(2) = 7.65; 1 df; P = 0.006). In addition, the parameter quantitating insulin secretion in relation to insulin sensitivity [i.e. ln(AIRg x Si)] was significant among siblings (rho(SS) = 0.74; chi(2) = 4.32; 1 df; P = 0.04). In summary, the results of the present study indicate that there is an heritable component to beta-cell dysfunction in families of women with PCOS. We conclude that heritability of beta-cell dysfunction is likely to be a significant factor in the predisposition to diabetes in PCOS.

Adolescent↗