Estrogen receptor ␣ (ER␣) is essential for male fertility. Its activity is responsible for maintaining epithelial cytoarchitecture in efferent ductules and the reabsorption of fluid for concentrating sperm in the head of the epididymis. These discoveries and others have helped to establish estrogen's bisexual role in reproductive importance. Reported here is the molecular mechanism to explain estrogen's role in fluid reabsorption in the male reproductive tract. It is shown that estrogen regulates expression of the Na ؉ ͞H ؉ exchanger-3 (NHE3) and the rate of 22 Na ؉ transport, sensitive to an NHE3 inhibitor. Immunohistochemical staining for NHE3, carbonic anhydrase II (CAII), and aquaporin-I (AQP1) was decreased in ER␣ knockout (␣ERKO) efferent ductules. Targeted gene-deficient mice were compared with ␣ERKO, and the NHE3 knockout and CAIIdeficient mice showed ␣ERKO-like fluid accumulation, but only the NHE3 knockout and ␣ERKO mice were infertile. Northern blot analysis showed decreases in mRNA for NHE3 in ␣ERKO and antiestrogen-treated mice. The changes in AQP1 and CAII in ␣ERKO seemed to be secondary because of the disruption of apical cytoarchitecture. Ductal epithelial ultrastructure was abnormal only in ␣ERKO mice. Thus, in the male, estrogen regulates one of the most important epithelial ion transporters and maintains epithelial morphological differentiation in efferent ductules of the male, independent of its regulation of Na ؉ transport. Finally, these data raise the possibility of targeting ER␣ in developing a contraceptive for the male.

Paraneoplastic glomerulonephritis is a rare complication of malignancy that is frequently mistaken for idiopathic glomerulonephritis. Failure to recognize paraneoplastic glomerulonephritis can subject patients to ineffective and potentially harmful therapy. Pathology of paraneoplastic glomerulonephritis varies between different types of malignancies. This Review describes the association of glomerulonephritis with both solid tumors and hematological malignancies The pathogenetic mechanisms of many glomerular lesions seem to relate to altered immune responses in the presence of a malignancy Studies in the Buffalo/Mna rat model of spontaneous thymoma and nephrotic syndrome indicate that polarization of the immune response toward a T-helper-2 (T H 2) profile has an important role in the development of thymoma-associated glomerular lesions. Furthermore, overexpression of the T H 2 cytokine interleukin 13 in transgenic rats induces minimal change disease. Such findings from experimental studies might facilitate the identification of biomarkers that can distinguish paraneoplastic glomerulonephritis from idiopathic and other secondary glomerulonephritides. This Review describes potential pathogenetic mechanisms for paraneoplastic glomerulonephritides associated with different malignancies and highlights the need for a multidisciplinary approach to the management of patients with paraneoplastic glomerulonephritis.