Humanes Plazenta-Laktogen (hPL)

Zusammenfassung

Das humane Plazenta-Laktogen (hPL) ist vor etwas mehr als 40 Jahren charakterisiert worden. Seit dieser Zeit gibt es eine Vielzahl von neuen Erkenntnissen, die es sinnvoll erscheinen lassen, sich mit der Physiologie dieses Hormons noch einmal zu beschäftigen. Beim hPL, einem Produkt des Trophoblasten, handelt es sich um ein Proteohormon, das in seiner Struktur und Funktion dem Wachstumshormon und dem Prolaktin verwandt ist. Alle drei Hormone werden von unterschiedlichen Genen, die in unmittelbarer Nachbarschaft auf dem Chromosom 17 lokalisiert sind, kodiert. HPL ist ein Stoffwechselhormon, das im mütterlichen Organismus lipolytisch wirkt. Die freigesetzten Fettsäuren können von der Mutter als Energiesubstrat verwertet werden, dadurch spart die Mutter Glukose ein, die der Plazenta und insbesondere dem Feten als Energieträger verfügbar gemacht werden. Darüber hinaus besitzt hPL im fetalen Organismus eine direkte wachstumsstimulierende Wirkung durch eine gesteigerte Freisetzung von Wachstumsfaktoren, u. a. IGF-1 und IGF-2.

Neben hPL synthetisiert die Plazenta auch ein eigenes plazentares Wachstumshormon mit vergleichbaren biologischen Wirkungen, das vor allen Dingen aber wachstumsfördernd im kindlichen Organismus zur Wirkung kommt. Die Regulation der hPL-Freisetzung unterliegt einem komplexen Kontrollsystem, an dem sich vor allen Dingen Insulin, Glukose, Lipoproteine, Neuropeptide und Neurotransmitter beteiligen. Trotz dieser vielschichtigen Bedeutung des hPL für die physiologischen Vorgänge während der Schwangerschaft gilt die Bestimmung dieses Hormons zur Beurteilung des kindlichen Befindens angesichts der modernen Methoden der Sonographie und Doppler-Sonographie als obsolet.

HPL konnte inzwischen auch in verschiedenen Tumoren nachgewiesen werden. Die spezifische Bedeutung dieses Hormons für das Tumorwachstum bzw. die Tumorzellproliferation sind allerdings bis heute unklar.

Abstract

HPL was first described and characterized some 40 years ago. Since then a lot of new data on its structure, regulation and physiological significance have been published which will be summarized in this review.

HPL is secreted by the trophoblast as a proteohormone composed of 191 amino acides in structure and function similar to growth hormone (GH) and prolactin (hPRL). The coding genes for all three hormones are located in close vicinity on chromosome 17. In the first place hPL is a lipolytic agent in the maternal compartment. Elevated levels of free fatty acids can be utilized as energy resources resulting in a glucose sparing effect. Glucose is essential for placental function and fetal development. In addition hPL induces increased secretion of growth factors like IGF-1 and IGF-2 in the fetal organism. Besides hPl the placenta synthesizes and secretes a specific growth hormone (PGH) with similar biological effects. Its growth promoting effects apply especially to the fetal organism.

The regulation of hPL scretion is controlled by a rather complex - yet not completely understood - system including insulin and glucose levels, lipoproteins, neuropeptides and neurotransmitters. In spite of these complex functions of human placental lactogen its determination in maternal serum as a marker of fetal development is obsolete as today ultrasound and Doppler sonography are applied in this field.

There are several reports on the determination of hPL in different tumours. However until today the role of hPL for the induction of tumour cell proliferation and tumour growth is not yet understood.

Literatur

• 1 Aloj S M, Edelhoch H, Handeger S, Sherwood L M. Correlation of the structure and function of human placental lactogen and human growth hormone II. The effects of disulfide bond modification on the conformation of human placental lactogen.  Endocrinology. 1972;  91 728-737
• 2 Anthony R V, Limesand S W, Jeckel K M. Transcriptional regulation in the placenta during normal and compromised fetal growth.  Biochem Soc Trans. 2001;  29 42-48
• 3 Arato G, Fulop V, Degrell P. et al . Placental site trophoblastic tumor. Clinical and pathological report of two cases.  Pathol Oncol Res. 2000;  6 292-294
• 4 Barbour L A, Shao J, Qiao L. et al . Human placental growth hormone causes severe insulin resistance in transgenic mice.  Am J Obstet Gynecol. 2002;  186 512-517
• 5 Barret J, Golander A, Conn P M, Handwerger S. Characterization and partial purification of a serum protein which stimulates the release of human placental lactogen in vitro.  J Clin Endocrinol Metab. 1986;  63 336-342
• 6 Beck J S. Time of appearance of human placental lactogen in the embryo.  N Engl J Med. 1970;  283 189-190
• 7 Bersinger N A, Groome N, Muttukrishna S. Pregnancy-associated and placental proteins in the placental tissue of normal pregnant women and patients with pre-eclampsia at term.  Eur J Endocrinol. 2002;  147 785-793
• 8 Björklund A O, Adamson U KC, Carlström K AM, Hennen G, Igout A, Lins P ES, Westgren L MR. Placental hormones during induced hypoglycaemia in pregnant women with insulin dependent diabetes mellitus: evidence of an active role for placenta in hormonal counter-regulation.  Brit J Obstet Gynaecol. 1998;  105 649-655
• 9 Cao J, Gowri P M, Ganguly T C. et al . PRL, placental lactogen and GH induce Na(+)/taurocholate-cotransporting polypeptide gene expression by activating signal transducer and activator of transcription-5 in liver cells.  Endocrinology. 2001;  142 4212-4222
• 10 Carretti N, l Marca A. Maternal serum levels of human chorionic somatotropin correlated with transferrin and erythropoietin in pregnancy.  Gynecol Obstet Invest. 2002;  53 28-31
• 11 Caruso A, Paradisi G, Ferrazziani S, Lucchese A, Moretti S, Fulghesu A M. Effect of maternal carbohydrate metabolism on fetal growth.  Obstet Gynecol. 1998;  92 8-11
• 12 Chen E Y, Liao Y-C, Smith D H, Barrera-Saldana H A, Gelinas R E, Seeburg P H. The human growth hormone locus: nucleotide sequence, biology and evolution.  Genomics. 1989;  4 1989
• 13 Cirelli N, Lebrun P, Gueuning C, Delogne-Desnoeck J, Vanbellinghen A M, Graff G, Meuris S. Physiological concentrations of albumin stimulate chorionic gonadotrophin and placental lactogen release from human term placental explants.  Hum Reprod. 2001;  16 441-448
• 14 Coleman R L, Lindberg G, Muller C Y. et al . Ectopic production and localization of beta-human chorionic gonadotropin in lymphoepithelioma-like carcinoma of the cervix: a case report.  Int J Gynecol Pathol. 2000;  19 179-182
• 15 Corbacho A M, Martinez De La Escalera G, Clapp C. Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis.  J Endocrinol. 2002;  173 219-238
• 16 Cranny A, Crowley P, Whelan A. Effects of human placental lactogen on the expression of CD163 and CD14 on human monocytes in culture.  Clin Exp Immunol. 2002;  128 275-278
• 17 Cross J C, Anson-Cartwright L, Scott I C. Transcription factors underlying the development and endocrine functions of the placenta.  Recent Prog Horm Res. 2002;  57 221-234
• 18 Dirnhofer S, Freund M, Rogatsch H. et al . Selective expression of trophoblastic hormones by lung carcinoma: neurendocrine tumors exclusively produce human chorionic gonadotropin alpha-subunit (hCGalpha).  Hum Pathol. 2000;  31 966-972
• 19 Erhan Y, Ozdemir N, Zekioglu O. et al . Breast carcinomas with choriocarcinomatous features: case reports and review of the literature.  Breast J. 2002;  8 244-248
• 20 Fleenor D, Petryk A, Driscoll P. et al . Constitutive expression of placental lactogen in pancreatic beta cells: effects on cell morphology, growth and gene expression.  Pediatr Res. 2000;  47 136-142
• 21 Frankenne F, Rentier-Delure F, Sippo M L, Martial J, Hennen G. Expression of the growth hormone variant gene in human placenta.  J Clin Endocrinol Metab. 1987;  64 635-637
• 22 Frankenne F, Closset J, Gomez F, Sippo M L, Smal J, Hennen G. The physiology of growth hormones (GHs) in pregnant women and partial characterization of the placental variant.  J Clin Endocrinol Metab. 1988;  66 1171-1180
• 23 Freemark M. Ontogenesis of prolactin receptors in the human fetus: roles in fetal development.  Biochem Soc Trans. 2001;  29 38-41
• 24 Freinkel N, Metzger B E. Metabolic changes in pregnancy. Wilson JD, Foster DW Williams Textbook of Endocrinology. Philadelphia; Saunders 1992: 993-1005
• 25 Gaspard U J, Sandront H M, Luyckx A S, Lefebre P J. Hormonal and metabolic changes induced by elevated plasma free fatty acids in term pregnancy: I. Effect on materna blood glucose, insulin and humanplacental lactogen circulating levels.  J Clin Endocrinol Metab. 1975;  40 1066-1072
• 26 Gertler A, Djiane J. Mechanism of ruminant placental lactogen action: molecular and in vivo studies.  Mol Genet Metab. 2002;  75 189-201
• 27 Handwerger S, Freemark M. The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development.  J Pediatr Endocrinol Metab. 2000;  13 343-356
• 28 Harper M E, Barrera-Saldana H A, Saunders G F. Chromosomal localization of the human placental lactogen-growth hormone gene cluster to 17 q22 - 24.  Am J Hum Genet. 1982;  34 227-234
• 29 Hill D J, Freemark M, Strain A J, Handwerger S, Milner R DG. Placental lactogen and growth hormone receptors in human fetal tissues; relationship to fetal plasma human placental lactogen concentrations and fetal growth.  J Clin Endocrinol Metab. 1988;  66 1283-1290
• 30 Josimovich J B, MacLaren J A. Presence in the human placenta and term serum of a highly lactogenic substance immunologically related topituitary growth hormone.  Endocrinology. 1962;  71 209-220
• 31 Kamoi S, Ohaki Y, Mori O. et al . Epithelioid trophoblastic tumor of the uterus: cytological and immunohistochemical observation of a case.  Pathol Int. 2000;  52 75-81
• 32 Kanda Y, Richards R G, Handwerger S. Apolipoprotein A-I-stimulates placental lactogen release by activation of MAP kinase.  Mol Cell Endocrinol. 1988;  143 125-131
• 33 Kim Y J, Felig P. Plasma chorionic somatomammotropin levels during starvation in midpregnancy.  J Clin Endocrinol Metab. 1971;  32 864-867
• 34 Kim H J, Koh P O, Kang S S. et al . The localization of dopamine D2 receptor mRNA in the human placenta and the anti-angiogenic effect of apomorphine in the chorioallantoic membrane.  Life Sci. 2001;  68 1031-1040
• 35 Kirwan J P, Hauguel-De Mouzon S, Lepercq J. et al . TNF-alpha is a predictor of insulin resistance in human pregnancy.  Diabetes. 2002;  51 2207-2213
• 36 Lacroix M C, Guibourdenche J, Frendo J L. et al . Human placental growth hormone - a review.  Placenta. 2002;  23 (Suppl A) 87-94
• 37 Lacroix M C, Bolifraud P, Durieux D. et al . Placental growth hormone and lactogen production by perifused ovine placental explants: regulation by growth hormone-releasing hormone and glucose.  Biol Reprod. 2002;  66 555-561
• 38 Latham C, Zhang A, Nalbanti A. et al . Frequent co-amplification of two different regions on 17 q in aneuplid breast carcinomas.  Cancer Genet Cytogenet. 2001;  127 16-23
• 39 Linnemann K, Malek A, Sager R, Blum W F, Schneider H, Fusch C. Leptin production and release in the dually in vitro perfused human placenta.  J Clin Endocrinol Metab. 2000;  85 4298-4301
• 40 Longhi S A, Blank V C, Roguin L P. et al . Relative localization of the prolactin receptor binding sites for lactogenic hormones.  Growth Horm IGF Res. 2001;  11 324-328
• 41 McManus M J, Dembroske S E, Pienkowski M M, Anderson T J. et al . Sucessful transplantation of human benign breast tumors into the athymic nude mouse and demonstration of enhanced DNA synthesis by human placental lactogen.  Cancer Res. 1978;  38 2343-2349
• 42 McManus M J, Welsch C W. The effect of estrogen, progesterone, thyroxine and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice.  Cancer. 1984;  54 1920-1927
• 43 Meydanli M M, Kucukali T, Usubutun A. et al . Epithelioid trophoblastic tumor of the endocervix: a case report.  Gynecol Oncol. 2002;  87 219-224
• 44 Merimee T J, Zapf J, Froesch E R. Insulin-like growthfactor in pregnancy: Studies in a growth hormone deficient dwarf.  J Clin Endocrinol Metab. 1982;  54 1101-1103
• 45 Merviel P, Muller F, Guibourdenche J, Berkane N, Gaudet R, Breart G, Uzan S. Correlations between serum assays of human chorionic gonadotrophin (hCG) and human placental lactogen (hPL) and pre-eclampsia or intrauterine growth restriction (IUGR) among nulliparas younger than 38 years.  Eur J Obstet Gynecol Reprod Biol. 2001;  95 59-67
• 46 Morrish D W, Bhardwaj D, Dabbag L K, Marusyk H, Siy O. Epidermal growth factor induces differentiation and secretion of human chorionic gonadotropin and placental lactogen in normal human placenta.  J Clin Endocrinol Metab. 1987;  65 1282-1290
• 47 Nakano H, Shimada A, Imai K. et al . Bovine trophoblastic cell differentiation on collagen substrata: formation of binucleate cells expressing placental lactogen.  Cell Tissue Res. 2002;  307 225-235
• 48 Neilson J P, Cloherty L J. Hormonal placental function tests for tetal assessment in high risk pregnancies. Cochrane Database Syst Rev 2000; PCD000108. 
• 49 Neulen J, Breckwoldt M. Beeinflussung des Fettstoffwechsels durch hPL in der späten Schwangerschaft.  Geburtsh Frauenheilk. 1987;  47 270-273
• 50 Ohira S, Yamazaki T, Hatano H. et al . Epithelioid trophoblastic tumor metastatic to the vagina: an immunohistochemical and ultrastructural study.  Int J Gynecol Pathol. 2000;  19 381-386
• 51 Ozbilim G, Karaburu S P, Zorlu G. et al . Immunohistochemical staining properties of PCNA, Ki-67, p53, beta-hCG and hPL in trophoblastic disease.  Eur J Gynaecol Oncol. 2000;  21 200-204
• 52 Patten K F, Mathur S P, Roudebush W E. Immunologic detection of placental lactogen during pregnancy in a mouse model: a preliminary report.  Am J Reprod Immunol. 2001;  45 116-122
• 53 Peake G T, Buckman M T, Davis L E, Standefer J. Pituitary a placentally derived hormones in cerebrospinal fluid during normal human pregnancy.  J Clin Endocrinol Metab. 1983;  56 46-52
• 54 Pedersen J F, Soerensen S, Moelsted-Pedersen L. Serum levels of human placental lactogen, pregnancy-associated plasma protein A and endometrial secretory protein PP14 in first trimester of diabetic pregnancy.  Acta Obstet Gynecol Scand. 1998;  77 155-158
• 55 Reis J M, Florio P, Cobellis L. et al . Human placenta as a source of neuroendocrine factors.  Biol Neonate. 2001;  79 150-156
• 56 Richardson B D, Langland R A, Bachurski C J, Richards R G, Kessler C A, Cheng Y H, Handwerger S. Activator protein-2 regulates human placental lactogen gene expression.  Mol Cell Endocrinol. 2000;  25 183-192
• 57 Sorensen S, von Tabouillot D, Schioler V, Greisen G, Petersen S, Larsen T. Serial measurements of serum human placental lactogen (hPL) and serial ultrasound examinations in the evaluation of fetal growth.  Early Hum Dev. 2000;  60 25-34
• 58 Tarrade A, Lai Kuen R, Malassine A. et al . Characterization of human villous and extravillous trophoblasts isolated from first trimester placenta.  Lab Invest. 2001;  81 1199-1211
• 59 Thyson J E, Austin K L, Farinholt J W. Prolonged nutritional deprivation in pregnancy: changes in human chorionic somatomammotropin and growth hormone secretion.  Am J Obstet Gynecol. 1971;  109 1080-1082
• 60 Untergasser G, Herrmann M, Rumpold H, Pfister G, Berger P. An unusual member of the human growth hormone/placental lactogen (GH/PL) family the testicular alternative splicing variant hPL-A2: recombinant expression revealed a membrane-associated growth factor molecule.  Mol Cell Endocrinol. 2000;  25 117-125
• 61 Vasavada R C, Garcia-Ocana A, Zawalich W S. et al . Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation ad hypoglycemia.  J Biol Chem. 2000;  275 15399-15406
• 62 Welsch C W, McManus M J. Stimulation of DNA synthesis by human placental lactogen or insulin in organ cultures of benign human breast tumors.  Cancer Res. 1977;  37 2257-2261
• 63 Wolf H J, Ebenbichler C F, Huter O. et al . Fetal leptin and insulin levels only correlate inlarge-for-gestational age infants.  Eur J Endocrinol. 2000;  142 623-629
• 64 Yue W C, Guan X Y, Ngan H Y. et al . Malignant placental site trophoblastic tumor: a cytogenetic study using comparative genomic hybridization and chromosome in situ hybridization.  Cancer. 2002;  94 2288-2294