Circulating LH/hCG receptor (LHCGR) may identify pre-treatment IVF patients at risk of OHSS and poor implantation

Reproductive Biology and Endocrinology

Subhasis Banerjee²  Gillian M Lockwood¹  Walter E Mills²  Krishnaveni P Nayini¹  Anne E Chambers² 

[1] Midland Fertility Services, Aldridge WS9 8LT, UK;Origin Biomarkers, BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AX, UK

关键词: Pregnancy;    IVF;    OHSS;    FSH;    AMH;    LH-LHCGR;    soluble LHCGR;   

Others  :  1151171
DOI  :  10.1186/1477-7827-9-161

 received in 2011-11-01, accepted in 2011-12-23,  发布年份 2011

【 摘 要 】

Background

Successful pregnancy via in vitro fertilization (IVF) depends on the recovery of an adequate number of healthy oocytes and on blastocyst implantation following uterine transfer. Two hormones, LH and hCG, utilize a common LH/hCG receptor (LHCGR), variations in which have profound implications in human reproduction. Soluble LHCGR (sLHCGR) is released from experimental cell lines and placental explants and it can be detected in the follicular fluid and serum.

Methods

To evaluate the impact of circulating soluble LHCGR (sLHCGR) in fertility treatment, we measured sLHCGR and LH-sLHCGR complex in serum from women seeking IVF using specifically developed quantitative enzyme-linked immunosorbent assays (ELISA). Following an IVF cycle of treatment, patients were grouped according to oocyte yield into low (lower than or equal to 7 oocytes), intermediate (8-14 oocytes) and high (greater than or equal to 15 oocytes) responders and pregnancy outcome noted.

Results

Pre-treatment sLHCGR identified many women at risk of ovarian hyperstimulation. Low levels of sLHCGR were associated with pregnancy in both high and low responders but sLHCGR did not significantly affect the treatment outcome of intermediate responders. Low responders who failed to become pregnant had high levels of circulating sLHCGR bound to LH (LH-sLHCGR).

Conclusions

Pre-treatment measurement of sLHCGR could be used to tailor individual fertility treatment programs and improve outcomes by avoiding ovarian hyperstimulation and poor embryo implantation.

【 授权许可】

   
2011 Chambers et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Edwards RG: Widening perspectives of intracytoplasmic sperm injection. Nat Med 1999.
• [2]Daya S: Luteal support: progestogens for pregnancy protection. Maturitas 2009, 1(65 Suppl):S29-S34.
• [3]Chiazze L Jr, Brayer FT, Macisco J Jr, Parker MP, Duffy BJ: The length and variability of the human menstrual cycle. JAMA 1968, 203(6):377-380.
• [4]Lainas T, Zorzovilis J, Petsas G, Stavropoulou G, Cazlaris H, Daskalaki V, Lainas G, Alexopoulou E: In a flexible antagonist protocol, earlier, criteria-based initiation of GnRH antagonist is associated with increased pregnancy rates in IVF. Hum Reprod 2005, 20(9):2426-2433.
• [5]Nelson SM, Yates RW, Lyall H, Jamieson M, Traynor I, Gaudoin M, Mitchell P, Ambrose P, Fleming R: Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod 2009, 24(4):867-875.
• [6]Johnson SR, Miro F, Barrett S, Ellis JE: Levels of urinary human chorionic gonadotrophin (hCG) following conception and variability of menstrual cycle length in a cohort of women attempting to conceive. Curr Med Res Opin 2009, 25(3):741-748.
• [7]Chen SU, Chen RJ, Shieh JY, Chou CH, Lin CW, Lu HF, Yang YS: Human chorionic gonadotropin up-regulates expression of myeloid cell leukemia-1 protein in human granulosa-lutein cells: implication of corpus luteum rescue and ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 2010, 95(8):3982-3992.
• [8]La Marca A, Sighinolfi G, Radi D, Argento C, Baraldi E, Artenisio AC, Stabile G, Volpe A: Anti-Müllerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update 2010, 16(2):113-130.
• [9]Lekamge DN, Barry M, Kolo M, Lane M, Gilchrist RB, Tremellen KP: Anti-Müllerian hormone as a predictor of IVF outcome. Reprod Biomed Online 2007, 14(5):602-610.
• [10]Li HWR, Yeung WSB, Lau EYL, Ho PC, Ng EHY: Evaluating the performance of serum antimullerian hormone concentration in predicting the live birth rate of controlled ovarian stimulation and intrauterine insemination. Fertil Steril 2010, 94(6):2177-2181.
• [11]Chambers AE, Banerjee S: Natural antisense LHCGR could make sense of hypogonadism, male-limited precocious puberty and pre-eclampsia. Mol Cell Endocrinol 2005, 241(1-2):1-9.
• [12]Filicori M, Fazleabas AT, Huhtaniemi I, Licht P, Rao CV, Tesarik J, Zygmunt M: Novel concepts of human chorionic gonadotropin: reproductive system interactions and potential in the management of infertility. Fertil Steril 2005, 84(2):275-284.
• [13]Rahman NA, Rao CV: Recent progress in luteinizing hormone/human chorionic gonadotrophin hormone research. Mol Hum Reprod 2009, 15(11):703-711.
• [14]Kolena J, Seböková E: Porcine follicular fluid containing water-soluble LH/hCG receptor. Arch Int Physiol Biochim 1986, 94(4):261-270.
• [15]West AP, Cooke BA: Regulation of the truncation of luteinizing hormone receptors at the plasma membrane is different in rat and mouse Leydig cells. Endocrinology 1991, 128:363-370.
• [16]Tsai-Morris CH, Buczko E, Wang W, Dufau ML: Intronic nature of the rat luteinizing hormone receptor gene defines a soluble receptor subspecies with hormone binding activity. J Biol Chem 1990, 265(32):19385-19388.
• [17]VuHai-LuuThi MT, Misrahi M, Houllier A, Jolivet A, Milgrom E: Variant forms of the pig lutropin/choriogonadotropin receptor. Biochemistry 1992, 31(35):8377-8383.
• [18]Remy JJ, Nespoulous C, Grosclaude J, Grébert D, Couture L, Pajot E, Salesse R: Purification and structural analysis of a soluble human chorionogonadotropin hormone-receptor complex. J Biol Chem 2001, 276(3):1681-1687.
• [19]Chambers AE, Stanley PF, Randeva H, Banerjee S: Microvesicle-mediated release of soluble LH/hCG receptor (LHCGR) from transfected cells and placenta explants. Reprod Biol Endocrinol 2011, 9:64. BioMed Central Full Text
• [20]Meduri G, Charnaux N, Loosfelt H, Jolivet A, Spyratos F, Brailly S, Milgrom E: Luteinizing hormone/human chorionic gonadotropin receptors in breast cancer. Cancer Res 1997, 57(5):857-864.
• [21]Lobel LI, Pollak S, Klein J, Lustbader JW: High-level bacterial expression of a natively folded, soluble extracellular domain fusion protein of the human luteinizing hormone/chorionic gonadotropin receptor in the cytoplasm of Escherichia coli. Endocrine 2001, 14(2):205-212.
• [22]Fralish GB, Narayan P, Puett D: High-level expression of a functional single-chain human chorionic gonadotropin-luteinizing hormone receptor ectodomain complex in insect cells. Endocrinology 2001, 142(4):1517-1524.
• [23]Tremellen K, Kolo M: Serum anti-Müllerian hormone is a useful measure of quantitative ovarian reserve but does not predict the chances of live-birth pregnancy. Aust N Z J Obstet Gynaecol 2010, 50(6):568-572.
• [24]Kaya C, Pabuccu R, Satiroglu H: Serum anti-Müllerian hormone concentrations on day 3 of the in vitro fertilization stimulation cycle are predictive of the fertilization, implantation, and pregnancy in polycystic ovary syndrome patients undergoing assisted reproduction. Fertil Steril 2010, 94(6):2202-2207.
• [25]Lamazou F, Genro V, Fuchs F, Grynberg M, Gallot V, Achour-Frydman N, Fanchin R, Frydman R: [Serum AMH level is not a predictive value for IVF in modified natural cycle: analysis of 342 cycles]. J Gynecol Obstet Biol Reprod (Paris) 2011, 40(3):205-210.
• [26]Weghofer A, Dietrich W, Barad DH, Gleicher N: Live birth chances in women with extremely low-serum anti-Müllerian hormone levels. Hum Reprod 2011, 26(7):1905-1909.
• [27]Heaney ML, Golde DW: Soluble receptors in human disease. J Leukoc Biol 1998, 64:135-46.
• [28]Baumann G, Stolar MW, Amburn K, Barsano CP, DeVries BC: A specific growth hormone-binding protein in human plasma: initial characterization. J Clin Endocrinol Metab 1986, 62:134-141.
• [29]Herington AC, Ymer S, Stevenson J: Identification and characterization of specific binding proteins for growth hormone in normal human sera. J Clin Invest 1986, 77(6):1817-1823.
• [30]Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D: Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 1992, 175(2):323-329.
• [31]Levine SJ: Molecular mechanisms of soluble cytokine receptor generation. J Biol Chem 2008, 283(21):14177-14181.
• [32]Drakakis P, Loutradis D, Beloukas A, Sypsa V, Anastasiadou V, Kalofolias G, Arabatzi H, Kiapekou E, Stefanidis K, Paraskevis D, Makrigiannakis A, Hatzakis A, Antsaklis A: Early hCG addition to rFSH for ovarian stimulation in IVF provides better results and the cDNA copies of the hCG receptor may be an indicator of successful stimulation. Reprod Biol Endocrinol 2009, 7:110. BioMed Central Full Text
• [33]Banerjee S, Smallwood A, Chambers AE, Papageorghiou A, Loosfelt H, Spencer K, Campbell S, Nicolaides K: A link between high serum levels of human chorionic gonadotrophin and chorionic expression of its mature functional receptor (LHCGR) in Down's syndrome pregnancies. Reprod Biol Endocrinol 2005, 3:25. BioMed Central Full Text
• [34]Pidoux G, Gerbaud P, Marpeau O, Guibourdenche J, Ferreira F, Badet J, Evain-Brion D, Frendo JL: Human placental development is impaired by abnormal human chorionic gonadotropin signaling in trisomy 21 pregnancies. Endocrinology 2007, 148(11):5403-5413.
• [35]Yen SC, Llerena LA, Pearson OH, Littell AS: Disappearance rates of endogenous follicle-stimulating hormone in serum following surgical hypophysectomy in man. J Clin Endocrinol Metab 1970, 30(3):325-329.
• [36]Kohler PO, Ross GT, Odell WD: Metabolic clearance and production rates of human luteinizing hormone in pre- and postmenopausal women. J Clin Invest 1968, 47:38-47.
• [37]Wide L, Eriksson K, Sluss PM, Hall JE: Serum half-life of pituitary gonadotropins is decreased by sulfonation and increased by sialylation in women. J Clin Endocrinol Metab 2009, 94(3):958-964.
• [38]Toner GC, Geller NL, Tan C, Nisselbaum J, Bosl GJ: Serum tumor marker half-life during chemotherapy allows early prediction of complete response and survival in nonseminomatous germ cell tumors. Cancer Res 1990, 50(18):5904-5910.
• [39]Alcamí A, Smith GL: A soluble receptor for interleukin-1 beta encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection. Cell 1992, 71:153-167.
• [40]Clark DE, Smith SK, He Y, Day KA, Licence DR, Corps AN, Lammoglia R, Charnock-Jones DS: A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod 1998, 59(6):1540-1548.
• [41]Lockwood GM, Muttukrishna S, Groome NP, Knight PG, Ledger WL: Circulating inhibins and activin A during GnRH-analogue down-regulation and ovarian hyperstimulation with recombinant FSH for in-vitro fertilization-embryo transfer. Clin Endocrinol (Oxf) 1996, 45(6):741-748.
• [42]Berndt S, Perrier d'Hauterive S, Blacher S, Péqueux C, Lorquet S, Munaut C, Applanat M, Hervé MA, Lamandé N, Corvol P, van den Brûle F, Frankenne F, Poutanen M, Huhtaniemi I, Geenen V, Noël A, Foidart JM: Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium. FASEB J 2006, 20(14):2630-2632.
• [43]Tsampalas M, Gridelet V, Berndt S, Foidart JM, Geenen V, Perrier d'Hauterive S: Human chorionic gonadotropin: a hormone with immunological and angiogenic properties. J Reprod Immunol 2010, 85:93-98.
• [44]Regan L, Owen EJ, Jacobs HS: Hypersecretion of luteinising hormone, infertility, and miscarriage. Lancet 1990, 336(8724):1141-1144.
• [45]Fauser BC, Pache TD, Lamberts SW, Hop WC, de Jong FH, Dahl KD: Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease. J Clin Endocrinol Metab 1991, 73(4):811-817.
• [46]Galeraud-Denis I, Bouchard P, Herlicoviez M, Marie E, Carreau S: Inhibitory effect of plasma obtained from hypophysectomized and control women on the assay of bioactive luteinizing hormone. Hum Reprod 1999, 14(2):312-317.
• [47]Ding YQ, Huhtaniemi I: Human serum LH inhibitor(s): behaviour and contribution to in vitro bioassay of LH using dispersed mouse Leydig cells. Acta Endocrinol (Copenh) 1989, 121:46-54.
• [48]Dunkel L, Raivio T, Laine J, Holmberg C: Circulating luteinizing hormone receptor inhibitor(s) in boys with chronic renal failure. Kidney Int 1997, 51(3):777-784.