Both time (chronological aging) and ovarian aging contributed to substantial changes in body composition (fat and skeletal muscle mass) and waist circumference. These changes have important ramifications for establishing a metabolic environment that can be healthy or unhealthy.

Time spans and overall patterns of change in serum FSH and E2 across the menopausal transition were not related to age at FMP or smoking, whereas time spans but not overall patterns were related to obesity and race/ethnicity.

SUMMARY Recent studies have identified genes and core pathways that are altered in human glioblastoma. However, the mechanisms by which alterations of these glioblastoma genes singly and cooperatively transform brain cells remain poorly understood. Further, the cell-of-origin of glioblastoma is largely elusive. By targeting a p53 in-frame deletion mutation to the brain, we show that p53 deficiency provides no significant growth advantage to adult brain cells, but appears to induce pleiotropic accumulation of cooperative oncogenic alterations driving gliomagenesis. Our data show that accumulation of a detectable level of mutant p53 proteins occurs first in neural stem cells in the subventricular zone (SVZ) and that subsequent expansion of mutant p53-expressing Olig2+ transit-amplifying progenitor-like cells in the SVZ-associated areas initiates glioma formation. SIGNIFICANCE Glioblastoma is the most malignant form of astrocytic gliomas and the most common primary brain cancer in adults. The poor prognosis of glioblastoma emphasizes the urgent need for a greater understanding of disease pathogenesis. We demonstrate that p53 deficiency can cooperate with diverse mitogenic signaling pathways to induce malignant glioma. For example, inactivation of the Nf1 tumor suppressor, activation of mitogen-activated protein kinase, or activation of phosphatidylinositol-3-OH kinase pathways are not essential, but can promote p53-mediated glioma formation. Furthermore, expression of mutant p53 proteins is identified as a marker for glioma cells in all stages. Analysis of brain cells with a detectable level of mutant p53 expression provides important insights into the role of neural stem cells and transit-amplifying progenitors in p53-mediated gliomagenesis.

Recent evidence suggests that alterations in the self-renewal program of stem/progenitor cells can cause tumorigenesis. By utilizing genetically engineered mouse models of neurofibromatosis type 1 (NF1), we demonstrated that plexiform neurofibroma, the only benign peripheral nerve sheath tumor with potential for malignant transformation, results from Nf1 deficiency in fetal stem/progenitor cells of peripheral nerves. Surprisingly, this did not cause hyperproliferation or tumorigenesis in early postnatal period. Instead, peripheral nerve development appeared largely normal in the absence of Nf1 except for abnormal Remak bundles, the nonmyelinated axon-Schwann cell unit, identified in postnatal mutant nerves. Subsequent degeneration of abnormal Remak bundles was accompanied by initial expansion of nonmyelinating Schwann cells. We suggest abnormally differentiated Remak bundles as a cell of origin for plexiform neurofibroma.

Population mean serum E2 levels were sustained until approximately 2 yr prior to the FMP. In the ensuing 4-yr period, E2 levels declined 67%. A secondary E2 decline, commencing about 6 yr after the FMP, was observed in nonobese but not obese women.