Oral bisphosphonate use and lung cancer incidence among postmenopausal women.

Background: Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI. Patients and methods: The association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates. Results: After a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39-0.84; P < 0.01). Conclusion: In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women's Health Initiative Randomized Trial.

BACKGROUND: While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women's Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use. METHODS: The WHI enrolled 16 608 postmenopausal women into a randomly assigned, double-blind, placebo-controlled trial. Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5mg medroxyprogesterone acetate (n = 8506) as a single pill or matching placebo (n = 8102). Follow-up beyond the original trial completion date required reconsent, obtained from 12 788 (83%) of surviving participants. Analyses were by intent-to-treat. All statistical tests were two-sided. RESULTS: After 5.6 years' median intervention and 13 years' median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group (66 vs 95 case patients, yearly incidence, 0.06% vs 0.10%; hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). While there were somewhat fewer endometrial cancers during intervention (25 vs 30, respectively; HR = 0.77, 95% CI = 0.45 to 1.31), the difference became statistically significant postintervention (41 vs 65, respectively; HR = 0.59, 95% CI = 0.40 to 0.88, P = .008), but hazard ratios did not differ between phases (P difference = .46). There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group (5 vs 11 deaths, HR = 0.42, 95% CI = 0.15 to 1.22). CONCLUSION: In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.

The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

Repeated measurements of serum carotenoid, retinol and tocopherol levels in relation to colorectal cancer risk in the Women's Health Initiative.

BACKGROUND/OBJECTIVE: Previous cohort studies examining the association of serum antioxidant levels and risk of colorectal cancer have used a single (baseline) measurement only. In the present study, we assessed the association of serum levels of eight antioxidant nutrients in relation to risk of colorectal cancer, using repeated measurements. SUBJECTS/METHODS: Data on a subsample of women in the Women's Health Initiative with repeated measurements of serum retinol, α-carotene, ß-carotene, ß-cryptoxanthin, lutein+zeaxanthin, lycopene, α-tocopherol and γ-tocopherol during follow-up were included in the analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: Among 5477 women with baseline serum antioxidant values, 88 incident cases of colorectal cancer were identified over a median follow-up time of 12 years. Serum antioxidants measured at baseline generally showed no association with risk of colorectal cancer, although serum ß-carotene at baseline showed a non-significant inverse association with colon cancer alone. Furthermore, using the repeated measurements of ß-carotene, the average of all measurements was inversely associated with risk of both colorectal and colon cancer: HRs for highest vs lowest tertile 0.54, 95% CI 0.31-0.96, and 0.47, 95% CI 0.25-0.88, respectively. No associations were seen with other antioxidant nutrients in the repeated measure analyses. CONCLUSIONS: In this study, baseline levels of antioxidant nutrients were not associated with risk of colorectal or colon cancer; however, using repeated measures, a relatively high serum level of ß-carotene (average of all measurements) was inversely associated with risk of colon and colorectal cancer in postmenopausal women.

Academic models of clinical care for women: the National Centers of Excellence in Women's Health.

Between 1996 and 1999, 18 academic health centers were awarded the designation of National Center of Excellence (CoE) in Women's Health by the Office on Women's Health within the Department of Health and Human Services and were provided with seed monies to develop model clinical services for women. Although the model has evolved in various forms, core characteristics that each nationally designated CoE has adopted include comprehensive, women-friendly, women-focused, women-relevant, integrated, multidisciplinary care. The permanent success of these comprehensive clinical programs resides in the ability to garner support of leaders of the academic health centers who understand both the importance of multidisciplinary programs to the clinical care they provide women and the education they offer to the future providers of women's healthcare.

Health issues for women with epilepsy: a descriptive survey to assess knowledge and awareness among healthcare providers.

The American Academy of Neurology and the American College of Obstetricians and Gynecologists recently issued practice parameters for women with epilepsy. These parameters suggest optimal care practices. To assess knowledge of the issues covered in the parameters and to facilitate educational efforts to promote best care, the Epilepsy Foundation conducted a survey of healthcare professionals likely to provide care to women with epilepsy. The survey sampled 3535 healthcare professionals across a wide range of specialties. Most respondents did not know the specific effects of estrogen and progesterone on the seizure threshold, were not aware of menstrual-associated seizure patterns, and could not identify which antiepileptic drugs interfere with oral contraceptives. The majority of respondents did not know that women with epilepsy have higher rates of infertility, reproductive endocrine disorders, and sexual dysfunction. Most respondents did not know the frequency of birth defects in children born to women with epilepsy. Providers seeing the largest number of persons with epilepsy were more likely to have correct answers. By specialty, neurologists provided the highest number of correct responses, followed (in descending order) by endocrinologists, obstetricians/gynecologists, internal medicine physicians, family practice physicians, and pediatricians. These results suggest that women with epilepsy are not receiving adequate counseling and that care practices may not conform to those recommended.

Assessing clinical competence of medical students in women's health care: use of the objective structured clinical examination.

OBJECTIVE: To assess clinical competency of third-year medical students completing a problem-oriented, primary care emphasis clerkship in obstetrics and gynecology using an objective structured clinical examination, and to determine the feasibility of implementing the objective structured clinical examination in the curriculum. METHODS: Sixteen groups of third-year medical students were evaluated prospectively on their exit performances with a six-station objective structured clinical examination designed to test clinical competency in basic primary care obstetrics-gynecology. Consistency of scores across stations, differences in performance for separate groups, and relationship of objective structured clinical examination scores compared with other indicators of medical proficiency, such as written examinations and faculty evaluations, were assessed. RESULTS: One hundred ninety-eight students were evaluated over 25 months. Test reliability across stations revealed alpha values ranging between .50 and .56. Correlations between performance on the objective structured clinical examination and the written test (r = .10) were low, demonstrating that the objective structured clinical examination clearly tests a separate domain of student capability. Cost of the objective structured clinical examination was $81.66 per student. CONCLUSION: The objective structured clinical examination is a reliable and valid test of the clinical competence of medical students in the primary health care of women. It provides information that is not obtained by more traditional assessment modalities at a reasonable cost.

Hormone replacement therapy in the menopause: a pro opinion.

The preponderance of data support the benefits of HRT in estrogen-deprived and menopausal women to reduce the risks of osteoporosis and cardiovascular disease and to enhance quality of life and life expectancy. Controversies exist with regards to the risk-benefit ratio in women with a history of estrogen-dependent gynecologic tumors or breast cancer. Until these issues are resolved, physicians must carefully weigh, on an individual basis for each patient, the potential risks against the known benefits. Women should be counseled regarding the benefits of exercise, weight control, breast feeding, and cessation of cigarette smoking or excessive alcohol to reduce their risks of cancer, cardiac disease, and/or osteoporosis. HRT is not a panacea for an unhealthy lifestyle. When ERT is contraindicated, viable alternatives to retard bone loss and/or control vasomotor symptoms include calcium supplementation and progestin therapy. The role of tamoxifen as an alternative HRT in women at increased risk for breast cancer development is currently under investigation.

Recombinant 8 syndrome: the pool of Hispanic pericentric inversion 8 carriers expands numerically and geographically.

Recombinant 8 syndrome is a well-established syndrome with mental and developmental retardation and usually severe cardiac anomalies. A carrier parent will produce affected offspring in 6% of pregnancies and carrier offspring in 53% of such pregnancies. Four New Mexican kindres ascertained by the discovery of four apparently unrelated probands with cytogenetically confirmed recombinant 8 syndrome were studied. We found that (1) recombinant 8 syndrome will soon no longer be confined to New Mexico and southern Colorado, (2) the number of persons at risk may be higher than previously considered, and (3) through proper pedigree techniques and increased professional education, most carriers can be identified.

Gene-rich chromosome regions and autosomal trisomy. A case of chromosome 3 trisomy mosaicism.

Cases of autosomal trisomy and trisomy mosaicism among liveborn infants are reviewed, and a second case of chromosome 3 trisomy mosaicism is described. The occurrence of autosomal trisomy for a particular chromosome is in general negatively correlated with the number of genes which have been localized to that chromosome. It is also positively related to the Q-brightness of the chromosome, which reflects its content of intercalary heterochromatin. Furthermore there are significantly fewer autosomal trisomics for chromosomes which contain hot spots for mitotic chiasmata in Bloom syndrome (chromosomes 1, 3, 6, 11, 12, 17, 19, and 22), compared with similar-sized control chromosomes 2, 4, 7, 9, 10, 18, 20, and 21. This is interpreted as further evidence for the gene richness of the hot spots which, being active, are extended in interphase and are therefore available for mitotic crossing over. The gene richness of these short Q-dark regions is also borne out by the scarcity of trisomic abortions for the chromosomes involved (the embryo dies before the abortion is recognized) and by the higher number of genes localized to these chromosomes compared with the control chromosomes.

What causes the abnormal phenotype in a 49,XXXXY male?

The chromosome replication pattern of a man with 49,XXXXY was analyzed using 3H-thymidine and autoradiography as well as BrdU and acridine orange. The former technique showed a highly irregular replication pattern; the latter revealed one early replicating X chromosome, and the other three more or less asynchronously replicating. Two hypotheses seem to explain best the abnormal phenotype of males with an XXXXY sex chromosome constitution: The number of the always active regions (tip of Xp) and of the possibly always active regions (the Q-dark regions on both sides of the centromere) is increased from one to four. The replication pattern of the late-replicating X chromosomes is highly asynchronous, which might affect the phenotype. The possibility that more than one X chromosome might remain active in some cells, an even more abnormal and obviously deleterious situation, is still open.

Segregation after mitotic crossing-over in isodicentric X chromosomes.

Segregation after mitotic crossing-over in an isodicentric (idic) X chromosome with one active and one inactive centromere has given rise to two new cell lines, one in which the idic(Xpter) chromosome has two active centromeres (most of these chromosomes also have an inversion) and another in which neither centromere is active. The two X chromosomes are attached at the telomeres of their short arms. Similar segregation has given rise to two other cell lines with idic(Xq-) chromosomes. Other observations on segregation after mitotic crossing-over are reviewed. Unequal crossing-over has apparently played a major role in the evolution of various genes and heterochromatin. Retinoblastoma and Wilms tumor are in some cases associated with homozygosity of a chromosome segment resulting from mitotic crossing-over. Similarly, the high incidence of cancer in Bloom syndrome may be caused by mitotic crossing-over leading to homozygosity or amplification of oncogenes.

Dicentric chromosomes and the inactivation of the centromere.

The origin and behavior of human dicentric chromosomes are reviewed. Most dicentrics between two nonhomologous or two homologous chromosomes (isodicentrics), which are permanent members of a chromosome complement, probably originate from segregation of an adjacent quadriradial; such configurations are the result of a chromatid translocation between two nonhomologous chromosomes, or they represent an adjacent counterpart of a mitotic chiasma. The segregation of such a quadriradial may also give rise to a cell line monosomic for the chromosome concerned (e.g., a 45, X line). Contrary to the generally held opinion, isodicentrics rarely result from an isolocal break in two chromatids followed by rejoining of sister chromatids. In this case the daughter centromeres go to opposite poles in the next anaphase, and the resulting bridge breaks at a random point. This mechanism, therefore, leads to the formation of an isodicentric chromosome only if the two centromeres are close together, or if one centromere is immediately inactivated. Observations on the origin of dicentrics in Bloom syndrome support these conclusions. One centromere is permanently inactivated in most dicentric chromosomes, and even when the dicentric breaks into two chromosomes, the centromere is not reactivated. The appearance and behavior of the "acentric" X chromosomes show that their centromeres are similarly inactivated and not prematurely divided. Two Bloom syndrome lymphocytes, one with an extra chromosome 2 and the other with an extra chromosome 7, each having an inactivated centromere, show that this can also happen in monocentric autosomes.

The course of endomitosis in human cells.

The course of endomitosis in human hydatidiform moles has been analyzed. It differs from the classical description of endomitosis in that endoprophase is completely missing and, very probably, so is a typical interphase. The chromosomes are even less synchronized in their replication and condensation cycle than in normal mitosis. At no point do all chromosomes decondense, but a part remains condensed while others are extended and in the process of synthesizing DNA. Even two paired sister chromosomes may replicate nonsynchronously. The latest replicating chromosome is usually a large darkly staining chromosome, which we tentatively identify as the inactive X. No DNA synthesis takes place during "endometaphase" or "endoanaphase" stages, when the chromosomes are most condensed. Some polyploid "endoanaphases" or "endotelophases" with stretched out chromosomes obviously represent end-stages of the endomitotic pathway, and the nuclei are in the process of reverting into evenly stained nuclei. In some "endometaphases," a near-haploid number of chromosomes can be counted. In others, the endochromosomes seem to be compound structures consisting of several chromosomes that have not separated during the previous endomitoses. This is seen also in normal trophoblast and cervical cancer. In large cancer cells, such bundles can be seen in the process of falling into individual chromosomes.

Mechanisms of growth in hydatidiform moles.

Nuclear morphology and DNA synthesis were analyzed to determine the mechanism through which hydatidiform moles proliferate. Hydatidiform moles are characterized by a great variation in nuclear morphology and size. There are cells with small nuclei of variable size that have chromocenters and Barr bodies which do not undergo DNA synthesis or mitosis, as well as cells in the diploid range that have evenly stained nuclei that display numerous mitoses and a high proportion of interphase nuclei in the process of DNA synthesis. Nuclei in the medium range show classical endomitotic stages. Endomitotic nuclei in endometaphase do not label with tritiated thymidine; endoanaphase nuclei may have one or a few chromosomes labeled, and endotelophase nuclei are heavily labeled. Nuclei that are evenly stained and are in the medium- to giant-size range label differently, depending upon their size. Many of the medium-sized nuclei are labeled, indicating DNA synthesis; the large nuclei are rarely labeled, and the giant nuclei are never labeled. The growth of a hydatidiform mole appears to be the result of normal mitosis and cytokinesis, as well as polyploidization and accompanying cell enlargement achieved through endomitosis and endoreduplication.