The effects of postmenopausal hormone therapy on serum estrogen, progesterone, and sex hormone-binding globulin levels in healthy postmenopausal women

Differences in disease outcomes between users and nonusers of hormone therapy (HT) and between users of estrogen therapy (ET) and users of estrogen + progesterone therapy (EPT) may relate to differences in serum hormone concentrations between these populations. In this study, we examined the response of serum hormone levels in healthy postmenopausal women after 1 year of HT. A representative subsample of 200 healthy adherent participants from the active and placebo groups of the Women's Health Initiative randomized controlled clinical trials of ET (conjugated equine estrogens 0.625 mg daily) or EPT (ET plus medroxyprogesterone acetate 2.5 mg daily) were selected for the determination of selected sex hormone levels at baseline and 1 year after randomization. In participants receiving active ET intervention compared with placebo, estrogenic hormone levels increased from baseline to year 1 by 3.6-fold for total estrone, 2.7-fold for total estradiol, and 1.8-fold for bioavailable and free estradiol concentrations. Serum sex hormone-binding globulin concentrations also increased 2.5-fold. In contrast, progesterone levels decreased slightly in women taking exogenous EPT. The response of serum estrogens and sex hormone-binding globulin did not differ substantially with the addition of progesterone. In subgroup analyses, hormone response varied by age, ethnicity, body mass index, smoking status, vasomotor symptoms, and baseline hormone levels. These data provide a reference point for the serum hormone response to HT and demonstrate that the response of serum estrogens is similar for ET and EPT. The implications of the slight decrease in serum progesterone levels with EPT therapy are uncertain. Potential treatment interactions for estrogenic hormones were identified, which suggest a larger response to HT in women with low endogenous levels

Detection of non-CLL-like monoclonal B cell lymphocytosis increases dramatically in the very elderly, while detection of CLL-like populations varies by race: findings in a multiethnic population-based cohort of elderly women

Monoclonal B cell lymphocytosis (MBL) is both a marker of immune senescence and a potential precursor of B cell malignancy. Most MBL populations have a chronic lymphocytic leukemia-like (CLL-like) immunophenotype, but those that are CD5-negative (non-CLL-like) are also recognized and may represent a distinct diagnostic entity. To date, MBL studies have taken place in relatively homogenous populations, although risk of CLL varies across racial groups and geographic regions. We report flow cytometry data from 597 ethnically diverse 64-94-year-old women from across the USA who are participants in the Women\u27s Health Initiative (WHI) Long-Life Study (LLS). Overall, MBL was detected in 26 % of the participants and included 20.9 % with a CLL-like immunophenotype, 5 % with a non-CLL-like immunophenotype, and 1.3 % with both. White and Hispanic women were more than twice as likely to have a CLL-like MBL population detected than African American women, corrected for age (P = 0.003). By contrast, detection of non-CLL-like MBL did not vary significantly by race, but did increase markedly with advancing age, being present in 12.7 % of those aged 85 and older. We provide new evidence that rates of detection of CLL-like MBL are lower in African Americans, and further suggest that non-CLL-like clonal expansions should be regarded as distinct from CLL-like MBL

Clinicopathologic Findings in Patients With Initial Diagnosis of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT) in Colorectal Mucosa

To evaluate clinicopathologic features, management, and behavior of colorectal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). Clinical data, laboratory studies, and radiographic records were reviewed (2005-2018), and fluorescence in situ hybridization studies were performed. Eleven patients were identified, six of whom were discovered as an incidental finding on endoscopy. Morphologic and immunophenotypic features were similar to MALT lymphomas at other sites except that lymphoepithelial lesions were uncommon. Three of nine patients were positive for BIRC3/MALT1 fusions, two of whom had identical B-cell clones identified in subsequent gastric biopsy specimens. Eight of 10 patients had no clinically evaluable disease after observation (±antibiotics; n = 4) or radiation/chemotherapy (n = 4). Patients with incidental and localized colonic MALT lymphoma demonstrated an excellent prognosis with conservative management, although longer follow-up and data based on consistent staging and surveillance methods (including gastric evaluation) are necessary for informed management

Markers of B-cell activation in relation to risk of non-Hodgkin lymphoma.

B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women's Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk of B-NHL. In addition, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (<3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9 to 13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development as early as 9 years before diagnosis

Cytokines in serum in relation to future non-Hodgkin lymphoma risk: evidence for associations by histologic subtype.

Specific associations for lymphoma in the general population suggest that chronic immune dysfunction/dysregulation may be associated with the development of B-cell non-Hodgkin lymphoma (NHL). Furthermore, polymorphisms in several cytokine genes have been associated with increased lymphoma risk, most consistently with genes for TNF and IL10. To evaluate the hypothesis that prediagnostic circulating cytokine levels would be associated with increased B-cell lymphoma risk, we conducted a nested case-control study within the Women's Health Initiative Observational Study cohort involving 491 B-cell NHL cases and 491 controls. Levels of eleven cytokines, including IL1β, IL2, IL4, IL5, IL6, IL10, IL12, IL13, TNF, IFNγ and GM-CSF, were measured using a Luminex suspension bead-based multiplexed array in prediagnostic serum samples collected a median of 6 years prior to the lymphoma diagnosis. We observed a modestly increased risk of all B-cell NHL in women with increased levels of the cytokines TNF and IL10 (OR1.22, CI 1.07-1.38 and OR 1.09, CI 1.04-1.15, respectively, per doubling in the serum cytokine concentration) and this association showed some variation according to histologic subtype. The increased risk was strongest for those neoplasms diagnosed in close proximity to the blood draw for some histologic subtypes but not others, suggesting a component of reverse causation. Further study will be required to better understand how genetic polymorphisms in TNF and IL10 genes may interact with circulating cytokine levels and states of chronic immune dysfunction/stimulation to contribute to the risk of B-cell NHL

Markers of B-cell activation in relation to risk of non-Hodgkin lymphoma.

B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women's Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk of B-NHL. In addition, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (<3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9 to 13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development as early as 9 years before diagnosis

Investigation of epstein-barr virus as a potential cause of B-cell non-Hodgkin lymphoma in a prospective cohort.

BackgroundWe hypothesized that poor control of Epstein-Barr virus (EBV) infection, leading to reactivation of the virus, increases the risk of non-Hodgkin lymphoma (NHL) in the general population of primarily immunocompetent persons.MethodsWe conducted a case-control study nested within the Women's Health Initiative Observational Study cohort in which we measured antibodies to EBV antigens [immunoglobulin G (IgG) to viral capsid antigen (VCA), nuclear antigen (EBNA1), and early antigen-diffuse (EA-D)] and EBV DNA load in prediagnostic samples of 491 B-cell NHL cases and 491 controls.ResultsWe found no association with established EBV infection, based on seropositivity for VCA. Seropositivity for EBNA1 was associated with decreased risk of B-cell NHL, overall [OR = 0.5; 95% confidence interval (CI), 0.3-0.8] and for each of the histologic subtypes examined. Increased risk of chronic lymphocytic leukemia (CLL) and related subtypes was observed with higher levels of EBV DNA and antibody to EA-D, both markers reflective of reactivation. These associations were strongest for cases with the shortest time interval between blood draw and diagnosis.ConclusionsIn balance, these results do not provide strong evidence of EBV playing a causal role in B-cell NHL in general population women. The associations we observed may reflect increased risk of NHL with underlying immune impairment or could be due to reverse causation.ImpactFurther characterization of the subtype-specific association with CLL is warranted. Exclusion of cases with preclinical disease markers (such as monoclonal B-lymphocytosis for CLL) may help rule out reverse causation in future studies