Swaziland has the highest HIV prevalence in the world – 32% of adults are currently living with HIV — and many Swazis are chronically food insecure — in 2011 one in four Swazis required food aid from the World Food Programme. In southern Africa, food insecurity has been linked to high-risk sexual behaviors, difficulty with antiretroviral therapy (ART) adherence, higher rates of mother-to-child HIV transmission, and more rapid HIV progression. Sex workers in Swaziland are a population that is most at risk of HIV. Little is known about the context and needs of sex workers in Swaziland who are living with HIV, nor how food insecurity may affect these needs.
In-depth interviews were conducted with 20 female sex workers who are living with HIV in Swaziland. Interviews took place in four different regions of the country, and were designed to learn about context, experiences, and health service needs of Swazi sex workers.
Hunger was a major and consistent theme in our informants’ lives. Women cited their own hunger or that of their children as the impetus to begin sex work, and as a primary motivation to continue to sell sex. Informants used good nutrition and the ability to access “healthy” foods as a strategy to manage their HIV infection. Informants discussed difficulty in adhering to ART when faced with the prospect of taking pills on an empty stomach. Across interviews, discussions of CD4 counts and ART adherence intertwined with discussions of poverty, hunger and healthy foods. Some sex workers felt that they had greater trouble accessing food through social networks as result of both their HIV status and profession.
Informants described a risk cycle of hunger, sex work, and HIV infection. The two latter drive an increased need for ‘healthy foods’ and an alienation from social networks that offer material and emotional support against hunger. Services and interventions for sex workers which address the pathways through which food insecurity generates vulnerability to HIV and social marginalization, build sex workers collective efficacy to mobilize, consider poverty alleviation, and address social and policy level changes are necessary and likely to have the greatest success.
HIV/AIDS; Sex work; Food insecurity
Despite the knowledge that men who have sex with men (MSM) are more likely to be infected with HIV across settings, there has been little investigation of the experiences of MSM who are living with HIV in sub-Saharan Africa. Using the framework of positive health, dignity and prevention, we explored the experiences and HIV prevention, care and treatment needs of MSM who are living with HIV in Swaziland.
We conducted 40 in-depth interviews with 20 HIV-positive MSM, 16 interviews with key informants and three focus groups with MSM community members. Qualitative analysis was iterative and included debriefing sessions with a study staff, a stakeholders’ workshop and coding for key themes using Atlas.ti.
The predominant theme was the significant and multiple forms of stigma and discrimination faced by MSM living with HIV in this setting due to both their sexual identity and HIV status. Dual stigma led to selective disclosure or lack of disclosure of both identities, and consequently a lack of social support for care-seeking and medication adherence. Perceived and experienced stigma from healthcare settings, particularly around sexual identity, also led to delayed care-seeking, travel to more distant clinics and missed opportunities for appropriate services. Participants described experiences of violence and lack of police protection as well as mental health challenges. Key informants, however, reflected on their duty to provide non-discriminatory services to all Swazis regardless of personal beliefs.
Intersectionality provides a framework for understanding the experiences of dual stigma and discrimination faced by MSM living with HIV in Swaziland and highlights how programmes and policies should consider the specific needs of this population when designing HIV prevention, care and treatment services. In Swaziland, the health sector should consider providing specialized training for healthcare providers, distributing condoms and lubricants and engaging MSM as peer outreach workers or expert clients. Interventions to reduce stigma, discrimination and violence against MSM and people living with HIV are also needed for both healthcare workers and the general population. Finally, research on experiences and needs of MSM living with HIV globally can help inform comprehensive HIV services for this population.
men who have sex with men; positive health dignity and prevention; people living with HIV; qualitative research; Swaziland
Androgens initiate a complex network of signals within the UGS that trigger prostate lineage commitment and bud formation. Given its contributions to organogenesis in other systems, we investigated a role for canonical Wnt signaling in prostate development. We developed a new method to achieve complete deletion of beta-catenin, the transcriptional coactivator required for canonical Wnt signaling, in early prostate development. Beta-catenin deletion abrogated canonical Wnt signaling and yielded prostate rudiments that exhibited dramatically decreased budding and failed to adopt prostatic identity. This requirement for canonical Wnt signaling was limited to a brief critical period during the initial molecular phase of prostate identity specification. Deletion of beta-catenin in the adult prostate did not significantly affect organ homeostasis. Collectively, these data establish that beta-catenin and Wnt signaling play key roles in prostate lineage specification and bud outgrowth.
Wnt signaling; Prostate development; Urogenital sinus; Mouse
The parabrachial nucleus (PB) is a brainstem cell group that receives a strong input from the nucleus tractus solitarius regarding the physiological status of the internal organs and sends efferent projections throughout the forebrain. Since the neuroanatomical organization of the PB remains unclear, our first step was to use specific antibodies against two neural lineage transcription factors: Forkhead box protein2 (FoxP2) and LIM homeodomain transcription factor 1 beta (Lmx1b) to define the PB in adult rats. This allowed us to construct a cytoarchitectonic PB map based on the distribution of neurons that constitutively express these two transcription factors. Second, the in situ hybridization method combined with immunohistochemistry demonstrated that mRNA for glutamate vesicular transporter Vglut2 (Slc17a6) was present in most of the Lmx1b+ and FoxP2+ parabrachial neurons, indicating these neurons use glutamate as a transmitter. Third, conscious rats were maintained in a hypotensive or hypertensive state for two hours, and then, their brainstems were prepared by the standard c-Fos method which is a measure of neuronal activity. Both hypotension and hypertension resulted in c-Fos activation of Lmx1b+ neurons in the external lateral-outer subdivision of the PB (PBel-outer). Hypotension, but not hypertension, caused c-Fos activity in the FoxP2+ neurons of the central lateral PB (PBcl) subnucleus. The Kölliker-Fuse nucleus as well as the lateral crescent PB and rostralmost part of the PBcl contain neurons that co-express FoxP2+ and Lmx1b+, but none of these were activated after blood pressure changes. Salt-sensitive FoxP2 neurons in the pre-locus coeruleus and PBel-inner were not c-Fos activated following blood pressure changes. In summary, the present study shows that the PBel-outer and PBcl subnuclei originate from two different neural progenitors, contain glutamatergic neurons, and are affected by blood pressure changes, with the PBel-outer reacting to both hypo- and hypertension, and the PBcl signaling only hypotensive changes.
We present and test a theory in which self-control is distinguished from broader acts of self-regulation when it is both effortful and conscious. In two studies, we examined whether acts of behavioral management that do not require effort are exempt from resource depletion. In Study 1, we found that a self-regulation task only reduced subsequent self-control for participants who had previously indicated that completing the task would require effort. In Study 2, we found that participants who completed a self-regulation task for two minutes did not evidence the subsequent impairment in self-control evident for participants who had completed the task for four or more minutes. Our results support the notion that self-regulation without effort falls below the self-control threshold and has different downstream consequences than self-control.
SELF-CONTROL; SELF-REGULATION; EGO-DEPLETION
Biomarkers of organochlorine pesticides were measured in both venous and umbilical cord blood from 35 pregnant Hispanic women living in Brownsville, Texas, USA. Gas chromatography with an electron capture detector was used to analyze specimens for 30 individual pesticides or their metabolites. Results indicate that blood concentrations were relatively low for most individual compounds, but that high-end (upper 10th percentile) values for total DDT were comparatively high. Although health effects associated with measured blood concentrations are uncertain, there is concern that fetal exposure to low levels of these OC compounds, either individually or in combination, might contribute to subsequent health problems, including neurodevelopmental effects, cancer, endocrine disruption, obesity and diabetes.
biomarkers; fetal exposure; maternal exposure; organochlorine pesticides
We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.
The present study demonstrates that serotonin (5-hydroxytryptamine, 5-HT)-containing axons project to two sets of neurons in the dorsolateral pons that have been implicated in salt appetite regulation. These two neuronal groups are the pre-locus coeruleus (pre-LC) and a region in the parabrachial nucleus termed the external lateral-inner subdivision (PBel-inner). Neurons in both regions constitutively express the transcription factor Forkhead protein2 (FoxP2), and become c-Fos activated after prolonged sodium depletion. They send extensive projections to the midbrain and forebrain, including a strong projection to the ventral tegmental area (VTA) – a reward processing site. The retrograde neuronal tracer cholera toxin β-subunit (CTb) was injected into the VTA region; this was done to label the cell bodies of the pre-LC and PBel-inner neurons. After one week, the rats were killed and their brainstems processed by a triple-color immunofluorescence procedure. The purpose was to determine whether the CTb-labeled pre-LC and PBel-inner neurons, which also had FoxP2 immunoreactive nuclei, received close contacts from 5-HT axons. Neurons with these properties were found in both sites. Since the origin of this 5-HT input was unknown, a second set of experiments was carried out in which CTb was injected into the pre-LC or lateral PB. One week later, the rats were perfused and the brainstems from these animals were analyzed for the presence of neurons that co-contained CTb and tryptophan hydroxylase (synthetic enzyme for 5-HT) immunoreactivity. Co-labeled neurons were found mainly in the area postrema and to a lesser degree, in the dorsal raphe nucleus. We propose that the 5-HT inputs to the pre-LC and PBel-inner may modulate the salt appetite-related functions that influence the reward system.
area postrema; dorsal raphe nucleus; parabrachial nucleus; pre-locus coeruleus; salt appetite; ventral tegmental area
The transcription factor Forkhead box protein 2 (FoxP2) is expressed in two cell groups of the brainstem that have been implicated in sodium appetite regulation: the pre-locus coeruleus (pre-LC) and parabrachial nucleus - external lateral-inner subdivision (PBel-inner). Because the connections of these two groups are unknown, neuroanatomical tracing methods were used to define their central projections. The pre-LC outputs were first analyzed using an anterograde axonal tracer - Phaseolus vulgaris leucoagglutinin (PHAL) to construct a brain map. Next, we examined whether the FoxP2 immunoreactive (FoxP2+) neurons of the pre-LC contribute to these projections using a retrograde neuronal tracer - cholera toxin β-subunit (CTb). CTb was injected into selected brain regions identified in the anterograde tracing study. One week later the rats were killed, and brainstem sections were processed by a double immunohistochemical procedure to determine whether the FoxP2+ neurons in the pre-LC and/or PBel-inner contained CTb. FoxP2+ pre-LC neurons project to: 1) ventral pallidum; 2) substantia innominata and bed nucleus of the stria terminalis; 3) paraventricular, central medial, parafascicular, and subparafascicular parvicellular thalamic nuclei; 4) paraventricular (PVH), lateral, perifornical, dorsomedial (DMH), and parasubthalamic hypothalamic nuclei; and 5) ventral tegmental area (VTA), periaqueductal gray matter (PAG), dorsal and central linear raphe nuclei. FoxP2+ PBel-inner neurons project to the PVH and DMH, with weaker connections to the LHA, VTA, and PAG. Both the pre-LC and PBel-inner project to central sites implicated in sodium appetite, and related issues, including foraging behavior, hedonic responses to salt intake, sodium balance, and cardiovascular regulation, are discussed.
bed nucleus of stria terminalis; parabrachial nucleus; pre-locus coeruleus; hypothalamus; thalamus; substantia innominata; ventral pallidum; ventral tegmental area
Child mortality in the United States has decreased over time, with advance in biomedicine. Little is known about patterns of current pediatric health care delivery for children with the leading causes of child death (high-impact conditions). We described patient and hospital characteristics, and hospital resource use, among children hospitalized with high-impact conditions, according to illness severity.
We conducted a retrospective study of children 0–18 years of age, hospitalized with discharge diagnoses of the ten leading causes of child death, excluding diagnoses not amenable to hospital care, using the 2006 version of the Kid’s Inpatient Database. National estimates of average and cumulative hospital length of stay and total charges were compared between types of hospitals according to patient illness severity, which was measured using all-patient refined diagnosis related group severity classification into minor-moderate, major, and extreme severity.
There were an estimated 3,084,548 child hospitalizations nationally for high-impact conditions in 2006, distributed evenly among hospital types. Most (84.4%) had minor-moderate illness severity, 12.2% major severity, and 3.4% were extremely ill. Most (64%) of the extremely ill were hospitalized at children’s hospitals. Mean hospital stay was longest among the extremely ill (32.8 days), compared with major (9.8 days, p < 0.0001), or minor-moderate (3.4 days, p < 0.001) illness severity. Mean total hospital charges for the extremely ill were also significantly higher than for hospitalizations with major or minor-moderate severity. Among the extremely ill, more frequent hospitalization at children’s hospitals resulted in higher annual cumulative charges among children’s hospitals ($ 7.4 billion), compared with non-children teaching hospitals ($ 3.2 billion, p = 0.023), and non-children’s non-teaching hospitals ($ 1.5 billion, p < 0.001). Cumulative annual length of hospital stay followed the same pattern, according to hospital type.
Gradation of increasing illness severity among children hospitalized for high-impact conditions was associated with concomitantly increased resource consumption. These findings have significant implications for children’s hospitals which appear to accrue the highest resource use burden due to preferential hospitalization of the most severely ill at these hospitals.
Smac mimetics are being developed as a new class of anticancer therapies. Since the single-agent activity of Smac mimetics is very limited, rational combinations represent a viable strategy for their clinical development. The combination of Smac mimetics with TRAIL may be particularly attractive due to the low toxicity of TRAIL to normal cells and the synergistic antitumor activity observed for the combination. In the present study, we have investigated the combination synergy between TRAIL and a potent Smac mimetic, SM-164 in vitro and in vivo and the underlying molecular mechanism of action for the synergy. Our study demonstrates that SM-164 is highly synergistic with TRAIL in vitro in both TRAIL-sensitive and TRAIL-resistant cancer cell lines of breast, prostate, and colon cancer. Furthermore, the combination of SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Our data shows that XIAP and cIAP1, but not cIAP2, work in concert to attenuate the activity of TRAIL; SM-164 strongly enhances TRAIL activity by concurrently targeting XIAP and cIAP1. Moreover, while RIP1 plays a minimal role in TRAIL's activity as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. Our present study provides a strong rationale to develop the combination of SM-164 and TRAIL as a new therapeutic strategy for the treatment of human cancer.
Smac Mimetic; TRAIL; Synergy; Tumor Regression
Two specific groups of neurons in the dorsolateral pons are activated by dietary sodium deprivation. These two groups are the pre-locus coeruleus (pre-LC) and the inner subdivision of the external lateral parabrachial nucleus (PBel-inner). In each site, after rats are fed an extremely low-sodium diet for over a week, neurons increase their expression of an activity-induced transcription factor, c-Fos. Here, we confirm this observation and extend it by demonstrating that these two groups of neurons express a common marker gene, the constitutively-expressed transcription factor Forkhead box protein 2 (FoxP2). That is, virtually all of the c-Fos activated neurons in both regions also express FoxP2. The expression of FoxP2 by both these groups of neurons suggests that they are developmentally-related subsets derived from the same basic population. Given that FoxP2, unlike c-Fos, is expressed independent of sodium deprivation, this marker may be useful in future studies of the pre-LC and PBel-inner. The molecular definition of these neurons, which project to circuits in the forebrain that influence visceral, appetitive, and hedonic functions, may allow direct experimental exploration of the functional role of these circuits using genetic tools.
nucleus tractus solitarius; parabrachial nucleus; pre-locus coeruleus; salt appetite; sodium intake; transcription factor
Increased focus on the number and type of physicians delivering health care in the United States necessitates a better understanding of changes in graduate medical education (GME). Data collected by the Accreditation Council for Graduate Medical Education (ACGME) allow longitudinal tracking of residents, revealing the number and type of residents who continue GME following completion of an initial residency. We examined trends in the percent of graduates pursuing additional clinical education following graduation from ACGME-accredited pipeline specialty programs (specialties leading to initial board certification).
Using data collected annually by the ACGME, we tracked residents graduating from ACGME-accredited pipeline specialty programs between academic year (AY) 2002–2003 and AY 2006–2007 and those pursuing additional ACGME-accredited training within 2 years. We examined changes in the number of graduates and the percent of graduates continuing GME by specialty, by type of medical school, and overall.
The number of pipeline specialty graduates increased by 1171 (5.3%) between AY 2002–2003 and AY 2006–2007. During the same period, the number of graduates pursuing additional GME increased by 1059 (16.7%). The overall rate of continuing GME increased each year, from 28.5% (6331/22229) in AY 2002–2003 to 31.6% (7390/23400) in AY 2006–2007. Rates differed by specialty and for US medical school graduates (26.4% [3896/14752] in AY 2002–2003 to 31.6% [4718/14941] in AY 2006–2007) versus international medical graduates (35.2% [2118/6023] to 33.8% [2246/6647]).
The number of graduates and the rate of continuing GME increased from AY 2002–2003 to AY 2006–2007. Our findings show a recent increase in the rate of continued training for US medical school graduates compared to international medical graduates. Our results differ from previously reported rates of subspecialization in the literature. Tracking individual residents through residency and fellowship programs provides a better understanding of residents' pathways to practice.
In 1999, the Accreditation Council for Graduate Medical Education (ACGME) Outcome Project began to focus on resident performance in the 6 competencies of patient care, medical knowledge, professionalism, practice-based learning and improvement, interpersonal communication skills, and professionalism. Beginning in 2007, the ACGME began collecting information on how programs assess these competencies. This report provides information on the nature and extent of those assessments.
Using data collected by the ACGME for site visits, we use descriptive statistics and percentages to describe the number and type of methods and assessors accredited programs (n = 4417) report using to assess the competencies. Observed differences among specialties, methodologies, and assessors are tested with analysis of variance procedures.
Almost all (>97%) of programs report assessing all of the competencies and using multiple methods and multiple assessors. Similar assessment methods and evaluator types were consistently used across the 6 competencies. However, there were some differences in the use of patient and family as assessors: Primary care and ambulatory specialties used these to a greater extent than other specialties.
Residency programs are emphasizing the competencies in their evaluation of residents. Understanding the scope of evaluation methodologies that programs use in resident assessment is important for both the profession and the public, so that together we may monitor continuing improvement in US graduate medical education.
Genome mining at the turn of the millennium uncovered a new family of type II transmembrane serine proteases (TTSPs) that comprises 17 members in humans and 19 in mice. TTSPs phylogenetically belong to one of four subfamilies: matriptase, hepsin/TMPRSS, corin and HAT/DESC. Whereas a wealth of information now has been gathered as to the physiological functions of members of the hepsin/TMPRSS, matriptase, and corin subfamilies of TTSPs, comparatively little is known about the functions of the HAT/DESC subfamily of proteases. Here we perform a combined expression and functional analysis of this TTSP subfamily. We show that the five human and seven murine HAT/DESC proteases are coordinately expressed, suggesting a level of functional redundancy. We also perform a comprehensive phenotypic analysis of mice deficient in two of the most widely expressed HAT/DESC proteases, TMPRSS11A and HAT, and show that the two proteases are dispensable for development, health, and long-term survival in the absence of external challenges or additional genetic deficits. Our comprehensive expression analysis and generation of TMPRSS11A- and HAT-deficient mutant mouse strains provide a valuable resource for the scientific community for further exploration of the HAT/DESC subfamily proteases in physiological and pathological processes.
Venous blood was drawn from 35 pregnant Hispanic women living in Brownsville, Texas, and matched cord blood was collected at birth. Gas chromatography/mass spectrometry was used to measure concentrations of 55 individual PAHs or groups of PAHs. Results indicate that these women and their fetuses were regularly exposed to multiple PAHs at comparatively low concentrations, with levels in cord blood generally exceeding levels in paired maternal blood. While the possibility of related adverse effects on the fetus is uncertain, these exposures in combination with socioeconomically-disadvantaged and environmentally-challenging living conditions raise legitimate public health concerns.
biomarkers; fetal exposure; maternal exposure; PAHs; prenatal exposure
Propiconazole is a chiral fungicide used in agriculture for control of many fungal diseases on a variety of crops. This use provides opportunities for pollution of soil and, subsequently, groundwater. The rate of loss of propiconazole from the water phase of two different soil-water slurries spiked with the fungicide at 50 mg/L was followed under aerobic conditions over five months; the t1/2 was 45 and 51 days for the two soil slurries. To accurately assess environmental and human risk, it is necessary to analyze the separate stereoisomers of chiral pollutants, because it is known that for most such pollutants, both biotransformation and toxicity are likely to be stereoselective. Micellar electrokinetic chromatography (MEKC), the mode of capillary electrophoresis used for analysis of neutral chemicals, was used for analysis of the four propiconazole stereoisomers with time in the water phase of the slurries. MEKC resulted in baseline separation of all stereoisomers, while GC-MS using a chiral column gave only partial separation. The four stereoisomers of propiconazole were lost from the aqueous phase of the slurries at experimentally equivalent rates, i.e., there was very little, if any, stereoselectivity. No loss of propiconazole was observed from the autoclaved controls of either soil, indicating that the loss from active samples was most likely caused by aerobic biotansformation, with a possible contribution by sorption to the non-autoclaved active soils. MEKC is a powerful tool for separation of stereoisomers and can be used to study the fate and transformation kinetics of chiral pesticides in water and soil.
capillary electrophoresis; propiconazole; stereoselectivity; biotransformation
In introductory laboratory courses, many universities are turning from traditional laboratories with predictable outcomes to inquiry-inspired, project-based laboratory curricula. In these labs, students are allowed to design at least some portion of their own experiment and interpret new, undiscovered data. We have redesigned the introductory biology laboratory course at Brandeis University into a semester-long project-based laboratory that emphasizes concepts and contains an element of scientific inquiry. In this laboratory, students perform a site-directed mutagenesis experiment on the gene encoding human γD crystallin, a human eye lens protein implicated in cataracts, and assess the stability of their newly created protein with respect to wild-type crystallin. This laboratory utilizes basic techniques in molecular biology to emphasize the importance of connections between DNA and protein. This project lab has helped engage students in their own learning, has improved students’ skills in critical thinking and analysis, and has promoted interest in basic research in biology.
We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a Ki value of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.
From May through October 2009, a total of 10,624 clinical samples from 23 US states were screened for multiple respiratory pathogen gene targets. Of 3,110 (29.3%) samples positive for pandemic (H1N1) 2009 virus, 28% contained >1 other pathogen, most commonly Staphylococcus aureus (14.7%), Streptococcus pneumoniae (10.2%), and Haemophilus influenzae (3.5%).
Influenza A; H1N1 subtype; molecular diagnostic testing; respiratory infections; co-detection; viruses; bacteria; dispatch
T lymphocytes play a critical role in cell-mediated immune responses. During activation, extracellular and intracellular signals alter T cell metabolism in order to meet the energetic and biosynthetic needs of a proliferating, active cell, but control of these phenomena is not well defined. Previous studies have demonstrated that signaling from the costimulatory receptor CD28 enhances glucose utilization via the phosphatidylinositol-3-kinase (PI3K) pathway. However, since CD28 ligation alone does not induce glucose metabolism in resting T cells, contributions from T cell receptor-initiated signaling pathways must also be important. We therefore investigated the role of mitogen-activated protein kinase (MAPK) signaling in the regulation of mouse T cell glucose metabolism. T cell stimulation strongly induces glucose uptake and glycolysis, both of which are severely impaired by inhibition of extracellular signal-regulated kinase (ERK), whereas p38 inhibition had a much smaller effect. Activation also induced hexokinase activity and expression in T cells, and both were similarly dependent on ERK signaling. Thus, the ERK signaling pathway cooperates with PI3K to induce glucose utilization in activated T cells, with hexokinase serving as a potential point for coordinated regulation.
Detailed characterization of estrogen dynamics during the transition to menopause is an important step toward understanding its potential implications for reproductive cancers developing in the transition years. We conducted a 5-year prospective study of endogenous levels of total and unopposed estrogen. Participants (n=108, aged 25–58 years) collected daily urine specimens for six months in each of five consecutive years. Specimens were assayed for estrone-3-glucuronide (E1G) and pregnanediol-3-glucuronide (PDG). Linear mixed-effects models were used to estimate exposure to total and unopposed estrogen by age and reproductive stage. Reproductive stage was estimated using menstrual cycle length variance. E1G mean area under the curve (AUC), and mean E1G 5th and 95th percentiles represented total estrogen exposure. An algorithm identifying days of above-baseline E1G that coincided with the days of baseline PDG was used to identify days of unopposed estrogen. Mean E1G AUC increased with age in the pre- and early transition and decreased in the late transition. Ninety-fifth percentile E1G levels did not decline until after menopause whereas 5th percentile levels declined from the early transition to the post menopause. The number of days of unopposed estrogen was significantly higher during the transition compared with the pre-transition. Given the length of time women spend in the transition, they are exposed to more total and unopposed estrogen than has been previously appreciated. Coupled with epidemiological evidence on lifetime exposure to estrogen, these results suggest that variation in the amount of time spent in the transition may be an important risk factor for reproductive cancers.
estrogen; estrone glucuronide; pregnanediol; urinary hormones; menopause; perimenopause; reproductive aging; reproductive cancer; reproductive stage; STRAW