Increased Expression of LH/hCG Receptors in Endometrial Hyperplasia and Carcinoma in Anovulatory Women

Konishi, Ikuo; Koshiyama, Masafumi; Mandai, Masaki; Kuroda, Hisao; Yamamoto, Shinichi; Nanbu, Kanako; Komatsu, Takayuki; Matsushita, K; Rao, Ch.V.; Mori, Takahide

doi:10.1006/gyno.1997.4656

Cited by 56 publications

(29 citation statements)

References 16 publications

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“…One possibility for this discrepancy is the type of cell line used. Previous studies [43] utilized HEC-1B cells derived from the endometrial adenocarcinoma cells, which may have a greater LH/CG receptor density compared with normal endometrium [44,45]. In addition, these studies were done in the presence of steroids.…”

Section: Discussionmentioning

confidence: 99%

Signal Transduction Pathways Activated by Chorionic Gonadotropin in the Primate Endometrial Epithelial Cells1

Srisuparp¹,

Straková²,

Brudney³

et al. 2003

Biology of Reproduction

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Successful implantation requires synergism between the developing embryo and the receptive endometrium. In the baboon, infusion of chorionic gonadotropin (CG) modulates both morphology and physiology of the epithelial and stromal cells of the receptive endometrium. This study explored the signal transduction pathways activated by CG in endometrial epithelial cells from baboon (BE) and human (HES). Incubations of BE and HES cells with CG did not significantly alter adenylyl cyclase activity or increase intracellular cAMP when compared with Chinese hamster ovarian cells stably transfected with the full-length human CG/luteinizing hormone (LH) receptor (CHO-LH cells). However, in BE and HES cells, CG induced the phosphorylation of several proteins, among them, extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2). Phosphorylation of ERK 1/2 in uterine epithelial cells was protein kinase A (PKA) independent. This novel signaling pathway is functional because, in response to CG stimulation, prostaglandin E(2) (PGE(2)) was released into the media and increased significantly 2 h following CG stimulation. CG-stimulated PGE(2) synthesis in epithelial cells was inhibited by a specific mitogen-activated protein kinase (MEK 1/2) inhibitor, PD 98059. In conclusion, immediate signal transduction pathways induced by CG in endometrial epithelial cells are cAMP independent and stimulate phosphorylation of ERK 1/2 via a MEK 1/2 pathway, leading to an increase in PGE(2) release as the possible result of cyclooxygenase-2 activation.

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Section: Discussionmentioning

confidence: 99%

Signal Transduction Pathways Activated by Chorionic Gonadotropin in the Primate Endometrial Epithelial Cells1

Srisuparp¹,

Straková²,

Brudney³

et al. 2003

Biology of Reproduction

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show abstract

“…For example, these tissues overexpress LH/hCG receptors (7,51), LH and hCG are mitogenic in human endometrial cancer cells (52)(53)(54), and bioactive LH levels are elevated in postmenopausal obese women with endometrial carcinoma compared with those women without this disease (55). If COX-2 is also overexpressed in endometrial hyperplasias and cancers, as in some of the other cancers (56), then further constant stimulation of the enzyme by LH may predispose nor- …”

Section: Discussionmentioning

confidence: 99%

Treatment of Human Endometrial Gland Epithelial Cells with Chorionic Gonadotropin/Luteinizing Hormone Increases the Expression of the Cyclooxygenase-2 Gene

Zhou

Lei

Rao

1999

The Journal of Clinical Endocrinology & Metabolism

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Endometrial glands contain higher levels of LH/hCG receptors than other cells in the human uterus. The present study investigated their functional importance. Northern and Western blotting and covalent receptor cross-linking demonstrated that human endometrial gland epithelial cells in culture contained multiple LH/hCG receptor transcripts and an 80-kDa receptor protein that can bind [125 I]hCG in a hormone-specific manner. Culturing cells with highly purified hCG resulted in a time-and dose-dependent increase in steady state levels of cyclooxygenase-2 (COX-2) messenger ribonucleic acid and protein and the secretion of PGE 2 . Although human LH could mimic hCG, FSH, TSH, and ␣-or ␤-subunits of hCG had no effect on COX-2 protein levels.Studies on signaling revealed that treatment of cells with hCG resulted in an increase in cAMP levels and protein kinase A (PKA) activity. Inhibition of PKA activity by cotreatment with isoquinolinesulfonamide (H-89) prevented hCG from increasing COX-2 protein levels. Treatment with 8-bromo-cAMP mimicked the effect of hCG, and cotreatment with a selective inhibitor of type I PKA, 8-chlorocAMP, prevented 8-bromo-cAMP and hCG from increasing COX-2 protein levels.The requirement of receptors for LH/hCG action was investigated by 24-h treatment of human endometrial gland epithelial cells with 21-mer phosphorothioate oligodeoxynucleotides (ODNs) synthesized from human receptor sequence. Treatment with 2 mol/L antisense, but not sense, ODN resulted in a dramatic reduction in LH/hCG receptor protein levels. hCG was unable to increase COX-2 protein, PGE 2 , and cAMP levels in an antisense, but not in sense, ODN-treated cells.In summary, we conclude that hCG and LH treatment can increase expression of the COX-2 gene in human endometrial gland epithelial cells. The effect was time and dose dependent, hormone specific, and mediated by the cAMP/type I protein kinase A signaling pathway. The hCG actions require a normal complement of its receptors in cells. These hCG and LH effects may be another action of these hormones in human endometrium that is important for implantation of the blastocyst and continuation of pregnancy. (J Clin Endocrinol Metab 84: 3364 -3377, 1999)

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“…In particular, LH hypersecretion could be associated with overexpression of LH/hCG receptors, and this condition could be a feature of endometrial hyperplasia and carcinoma in young anovulatory women, including PCOS subjects (320). In addition, Li et al (321) showed that the expression of the progesterone receptor, of which dysregulation is involved in the promotion of endometrial neoplasia in the stroma of hyperplastic endometrium from PCOS women, is unevenly distributed and significantly less than seen in the normal endometrium found in non-PCOS women.…”

Section: B Cancer Implicationsmentioning

confidence: 99%

Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review

et al. 2008

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Metformin is an insulin sensitizer widely used for the treatment of patients affected by type 2 diabetes mellitus. Because many women with polycystic ovary syndrome (PCOS) are insulin resistant, metformin was introduced in clinical practice to treat these patients also. Moreover, metformin's effect has other targets beside its insulin-sensitizing action. The present review was aimed at describing all evidence-based and potential uses of metformin in PCOS patients. In particular, we will analyze the uses of metformin not only for the treatment of all PCOS-related disturbances such as menstrual disorders, anovulatory infertility, increased abortion, or complicated pregnancy risk, hyperandrogenism, endometrial, metabolic and cardiovascular abnormalities, but also for the prevention of the syndrome. (Endocrine Reviews 30: 1-50, 2009)

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Increased Expression of LH/hCG Receptors in Endometrial Hyperplasia and Carcinoma in Anovulatory Women

Cited by 56 publications

References 16 publications

Signal Transduction Pathways Activated by Chorionic Gonadotropin in the Primate Endometrial Epithelial Cells1

Signal Transduction Pathways Activated by Chorionic Gonadotropin in the Primate Endometrial Epithelial Cells1

Treatment of Human Endometrial Gland Epithelial Cells with Chorionic Gonadotropin/Luteinizing Hormone Increases the Expression of the Cyclooxygenase-2 Gene

Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review

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