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Multiple luteinizing hormone receptor (LHR) protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer's disease.

Bukovsky A, Indrapichate K, Fujiwara H, Cekanova M, Ayala ME, Dominguez R, Caudle MR, Wimalsena J, Elder RF, Copas P, Foster JS, Fernando RI, Henley DC, Upadhyaya NB - Reprod. Biol. Endocrinol. (2003)

Bottom Line: Besides ovaries, LHR immunoreactivity (LHRI) was also found in other tissues, such as the brain, fallopian tube, endometrium, trophoblast and resident tissue macrophages.In normal human term placentae, villous LHRI was associated with blood sinusoids and cytotrophoblast cells, and rarely detected in trophoblastic syncytium.Our observations indicate that, in contrast to the theory on the role of vascular hormone receptors in preferential pick up of circulating hormones, there is no need to enhance selective pick up rather only prevent LH/CG transport to inappropriate sites.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory for Development, Differentiation and Cancer, Department of Obstetrics and Gynecology, The University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, USA. buko@utk.edu

ABSTRACT
Distinct luteinizing hormone receptor (LHR) protein variants exist due to the posttranslational modifications. Besides ovaries, LHR immunoreactivity (LHRI) was also found in other tissues, such as the brain, fallopian tube, endometrium, trophoblast and resident tissue macrophages. The 3B5 mouse monoclonal antibody was raised against purified rat LHR. In rat, porcine and human ovaries, the 3B5 identified six distinct LHR bands migrating at approximately 92, 80, 68, 59, 52 and 48 kDa. Characteristic LHRI was detected in rat, human and porcine corpora lutea. During cellular differentiation, subcellular LHR distribution changed from none to granular cytoplasmic, perinuclear, surface, nuclear and no staining. There were also differences in vascular LHR expression--lack of LHRI in ovarian vessels and strong staining of vessels in other tissues investigated. In normal human term placentae, villous LHRI was associated with blood sinusoids and cytotrophoblast cells, and rarely detected in trophoblastic syncytium. In all abnormal placentae, the LHRI of sinusoids was absent, and syncytium showed either enhanced (immature placental phenotypes) or no LHRI (aged placental phenotype). LHRI in human brain was identified in microglial cells (CD68+ resident macrophages). Protein extracts from human vaginal wall and levator ani muscle and fascia showed strong approximately 92 and 68 kDa species, and LHRI was detected in smooth muscle cells, fibroblasts, resident macrophages and nuclei of skeletal muscle fibers. Our observations indicate that, in contrast to the theory on the role of vascular hormone receptors in preferential pick up of circulating hormones, there is no need to enhance selective pick up rather only prevent LH/CG transport to inappropriate sites. Abnormal placental LHR expression may play a role in the development of abnormal pregnancy. Expression of LHR in the pelvic floor compartments suggests that high LH levels in postmenopausal women may contribute to the pelvic floor relaxation and increased incidence of pelvic floor disorders. Since chorionic gonadotropin increases secretion of a variety of cytokines by monocytes, and induces their inflammatory reaction and phagocytic activity, high LH levels in aging individuals may also activate microglia (mononuclear phagocyte system in the central nervous system) and contribute to the development of Alzheimer's disease and other inflammation-mediated neurodegenerative diseases.

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LHR immunoreactivity and resident macrophages in the female pelvic floor. A) Vaginal smooth muscle (Vag SM): cytoplasmic (full arrowhead) and nuclear LHR immunoreactivity (white arrowhead). B) Vaginal connective tissue (Vag ct): fibroblast type cells (white arrowhead), rounded mesenchymal cells (full arrowhead) and vessels (red arrowhead). C) Vaginal epithelium (Vag Ep): basal (stem) cells (b), parabasal cells (full arrowhead) and intermediate cells (yellow and green arrowheads). Superficial layer (middle inset): nuclear staining (red arrowhead) and diminution of staining in the surface cells (white arrowhead). D) Levator ani fascia (LF): principal cells (fibroblasts; white arrowhead) and rounded mesenchymal cells (full arrowhead). E) Levator ani muscle (see also F for detail): mesenchymal cells among muscle fibers (full arrowhead) and muscle cell nuclei (white arrowheads). CD68 staining in vaginal connective tissue (G), levator fascia (H) and levator muscle (I). Insets indicated as ctr show control staining. No hematoxylin counterstain except panels G–I. Bar in I for all panels except E.
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Figure 7: LHR immunoreactivity and resident macrophages in the female pelvic floor. A) Vaginal smooth muscle (Vag SM): cytoplasmic (full arrowhead) and nuclear LHR immunoreactivity (white arrowhead). B) Vaginal connective tissue (Vag ct): fibroblast type cells (white arrowhead), rounded mesenchymal cells (full arrowhead) and vessels (red arrowhead). C) Vaginal epithelium (Vag Ep): basal (stem) cells (b), parabasal cells (full arrowhead) and intermediate cells (yellow and green arrowheads). Superficial layer (middle inset): nuclear staining (red arrowhead) and diminution of staining in the surface cells (white arrowhead). D) Levator ani fascia (LF): principal cells (fibroblasts; white arrowhead) and rounded mesenchymal cells (full arrowhead). E) Levator ani muscle (see also F for detail): mesenchymal cells among muscle fibers (full arrowhead) and muscle cell nuclei (white arrowheads). CD68 staining in vaginal connective tissue (G), levator fascia (H) and levator muscle (I). Insets indicated as ctr show control staining. No hematoxylin counterstain except panels G–I. Bar in I for all panels except E.

Mentions: Porcine preovulatory follicles showed distinct LHR staining of theca interna, lack of LHR expression in vascular layer under the follicular membrane, and transition of granular cytoplasmic to surface LHR immunoreactivity in granulosa cells (Fig. 3A,3B,3C, vs. control D). Mature CL showed strong surface LHR immunoreactivity of luteal cells (Fig. 7E), and old corpora lutea showed diminution of LHR immunoexpression (Fig. 3F). Ovarian surface epithelium, the source of most ovarian tumors, was also stained (arrowhead, Fig. 3G). In porcine fallopian tube (Fig. 3H), the LHR immunostaining was similar to that in human oviduct. Strong LHR immunoreactivity in vascular walls was detected in the skin (Fig. 3I), which does not represent a classic LH/CG target. This contrasted with a lack of staining in ovarian vessels, except weak nuclear staining of endothelial cells (arrowhead, Fig. 3J). Insets in Fig. 7E,7F,7G,7H,7I,7J show the control procedure.


Multiple luteinizing hormone receptor (LHR) protein variants, interspecies reactivity of anti-LHR mAb clone 3B5, subcellular localization of LHR in human placenta, pelvic floor and brain, and possible role for LHR in the development of abnormal pregnancy, pelvic floor disorders and Alzheimer's disease.

Bukovsky A, Indrapichate K, Fujiwara H, Cekanova M, Ayala ME, Dominguez R, Caudle MR, Wimalsena J, Elder RF, Copas P, Foster JS, Fernando RI, Henley DC, Upadhyaya NB - Reprod. Biol. Endocrinol. (2003)

LHR immunoreactivity and resident macrophages in the female pelvic floor. A) Vaginal smooth muscle (Vag SM): cytoplasmic (full arrowhead) and nuclear LHR immunoreactivity (white arrowhead). B) Vaginal connective tissue (Vag ct): fibroblast type cells (white arrowhead), rounded mesenchymal cells (full arrowhead) and vessels (red arrowhead). C) Vaginal epithelium (Vag Ep): basal (stem) cells (b), parabasal cells (full arrowhead) and intermediate cells (yellow and green arrowheads). Superficial layer (middle inset): nuclear staining (red arrowhead) and diminution of staining in the surface cells (white arrowhead). D) Levator ani fascia (LF): principal cells (fibroblasts; white arrowhead) and rounded mesenchymal cells (full arrowhead). E) Levator ani muscle (see also F for detail): mesenchymal cells among muscle fibers (full arrowhead) and muscle cell nuclei (white arrowheads). CD68 staining in vaginal connective tissue (G), levator fascia (H) and levator muscle (I). Insets indicated as ctr show control staining. No hematoxylin counterstain except panels G–I. Bar in I for all panels except E.
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Figure 7: LHR immunoreactivity and resident macrophages in the female pelvic floor. A) Vaginal smooth muscle (Vag SM): cytoplasmic (full arrowhead) and nuclear LHR immunoreactivity (white arrowhead). B) Vaginal connective tissue (Vag ct): fibroblast type cells (white arrowhead), rounded mesenchymal cells (full arrowhead) and vessels (red arrowhead). C) Vaginal epithelium (Vag Ep): basal (stem) cells (b), parabasal cells (full arrowhead) and intermediate cells (yellow and green arrowheads). Superficial layer (middle inset): nuclear staining (red arrowhead) and diminution of staining in the surface cells (white arrowhead). D) Levator ani fascia (LF): principal cells (fibroblasts; white arrowhead) and rounded mesenchymal cells (full arrowhead). E) Levator ani muscle (see also F for detail): mesenchymal cells among muscle fibers (full arrowhead) and muscle cell nuclei (white arrowheads). CD68 staining in vaginal connective tissue (G), levator fascia (H) and levator muscle (I). Insets indicated as ctr show control staining. No hematoxylin counterstain except panels G–I. Bar in I for all panels except E.
Mentions: Porcine preovulatory follicles showed distinct LHR staining of theca interna, lack of LHR expression in vascular layer under the follicular membrane, and transition of granular cytoplasmic to surface LHR immunoreactivity in granulosa cells (Fig. 3A,3B,3C, vs. control D). Mature CL showed strong surface LHR immunoreactivity of luteal cells (Fig. 7E), and old corpora lutea showed diminution of LHR immunoexpression (Fig. 3F). Ovarian surface epithelium, the source of most ovarian tumors, was also stained (arrowhead, Fig. 3G). In porcine fallopian tube (Fig. 3H), the LHR immunostaining was similar to that in human oviduct. Strong LHR immunoreactivity in vascular walls was detected in the skin (Fig. 3I), which does not represent a classic LH/CG target. This contrasted with a lack of staining in ovarian vessels, except weak nuclear staining of endothelial cells (arrowhead, Fig. 3J). Insets in Fig. 7E,7F,7G,7H,7I,7J show the control procedure.

Bottom Line: Besides ovaries, LHR immunoreactivity (LHRI) was also found in other tissues, such as the brain, fallopian tube, endometrium, trophoblast and resident tissue macrophages.In normal human term placentae, villous LHRI was associated with blood sinusoids and cytotrophoblast cells, and rarely detected in trophoblastic syncytium.Our observations indicate that, in contrast to the theory on the role of vascular hormone receptors in preferential pick up of circulating hormones, there is no need to enhance selective pick up rather only prevent LH/CG transport to inappropriate sites.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory for Development, Differentiation and Cancer, Department of Obstetrics and Gynecology, The University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37920, USA. buko@utk.edu

ABSTRACT
Distinct luteinizing hormone receptor (LHR) protein variants exist due to the posttranslational modifications. Besides ovaries, LHR immunoreactivity (LHRI) was also found in other tissues, such as the brain, fallopian tube, endometrium, trophoblast and resident tissue macrophages. The 3B5 mouse monoclonal antibody was raised against purified rat LHR. In rat, porcine and human ovaries, the 3B5 identified six distinct LHR bands migrating at approximately 92, 80, 68, 59, 52 and 48 kDa. Characteristic LHRI was detected in rat, human and porcine corpora lutea. During cellular differentiation, subcellular LHR distribution changed from none to granular cytoplasmic, perinuclear, surface, nuclear and no staining. There were also differences in vascular LHR expression--lack of LHRI in ovarian vessels and strong staining of vessels in other tissues investigated. In normal human term placentae, villous LHRI was associated with blood sinusoids and cytotrophoblast cells, and rarely detected in trophoblastic syncytium. In all abnormal placentae, the LHRI of sinusoids was absent, and syncytium showed either enhanced (immature placental phenotypes) or no LHRI (aged placental phenotype). LHRI in human brain was identified in microglial cells (CD68+ resident macrophages). Protein extracts from human vaginal wall and levator ani muscle and fascia showed strong approximately 92 and 68 kDa species, and LHRI was detected in smooth muscle cells, fibroblasts, resident macrophages and nuclei of skeletal muscle fibers. Our observations indicate that, in contrast to the theory on the role of vascular hormone receptors in preferential pick up of circulating hormones, there is no need to enhance selective pick up rather only prevent LH/CG transport to inappropriate sites. Abnormal placental LHR expression may play a role in the development of abnormal pregnancy. Expression of LHR in the pelvic floor compartments suggests that high LH levels in postmenopausal women may contribute to the pelvic floor relaxation and increased incidence of pelvic floor disorders. Since chorionic gonadotropin increases secretion of a variety of cytokines by monocytes, and induces their inflammatory reaction and phagocytic activity, high LH levels in aging individuals may also activate microglia (mononuclear phagocyte system in the central nervous system) and contribute to the development of Alzheimer's disease and other inflammation-mediated neurodegenerative diseases.

Show MeSH
Related in: MedlinePlus