Ultimo aggiornamento 2020-10-29 13:12:29
Il Gn-RH (Gonadotropin Releasing Hormone) è un ormone secreto dai neuroni migrati durante la vita embrionale dal placode olfattivo ai nuclei ipotalamici medio-basali. La mancata o parziale migrazione di tali neuroni durante lo sviluppo fetale è responsabile della S. di Kallmann, dell’ipogonadismo ipogonadotropo e dell’amenorrea primaria ipotalamica (1-4).
Il Gn-RH ha una struttura peptidica composta da 10 aminoacidi: ac. glutammico, Serina, glicina, Istidina, Prolina, Tirosina, Leucina, Lisina, Isoleucina, Triptofano e Fenil-alanina.
I nuclei ipotalamici interessati alla secrezione di Gn-RH sono il n. arcuato, il n. sovraottico, il n. medio-basale e il n. paraventricolare posizionati nell’ipotalamo medio-basale tra il III° ventricolo e l’eminenza mediana in prossimità del circolo ipotalamo-ipofisario dove viene riversato il Gn-RH e trasportato all’adenoipofisi senza necessità di attraversare la barriera emato-cerebrale 2-4).
Meccanismo d’azione del Gn-RH: la secrezione di Gn-RH è soppressa durante l’infanzia, inizia ad aumentare alla pubertà e termina nel periodo post-menopausale. La secrezione è di tipo pulsatile (1 pulse ogni 60-90 minuti) e agisce sulle cellule basofile dell’adenoipofisi tramite il complesso costituito recettore specifico accoppiato a proteina G (GPCR) → fosfolipasi C (PLC) → Ca++ → Protein-chinasi C → rilascio ipofisario FSH e soprattutto di LH (5-8).
L’ampiezza dei pulses di Gn-RH è regolato con sistema feed-back lungo dalle concentrazioni ematiche di FSH ed LH e con feed-back corto dalla stessa produzione di Gn-RH. Sulla normale secrezione di Gn-RH inoltre agiscono altri numerosissimi fattori: integrità strutturale del gene del Gn-RH, stato nutritivo della paziente che deve essere dotata di un minimo di massa grassa, oppioidi, GABA, dopamina (2).
Anche la presenza o meno della luce naturale e la lunghezza del giorno influiscono sulla secrezione di Gn-RH e sull’attività dell’asse ipotalamo-ipofisario; infatti nei paesi nordici l’indice di concepimento è inferiore a quello dei paesi mediterranei e tropicali e nelle pazienti non-vedenti si presentano più frequentemente alterazioni funzionali dell’asse ipotalamo-ipofisi-ovarico (9-17).
Nelle pazienti PCOS aumenta l’ampiezza dei picchi con conseguente aumentata secrezione di LH (non di FSH). Nelle pazienti con amenorrea ipotalamica la frequenza dei picchi è molto aumentata e l’ampiezza diminuita (18-22).
La prolattina svolge un ruolo inibente sulla secrezione di Gn-RH.
Variazioni della frequenza e dell’ampiezza della secrezione del GnRH sono alla base dell’induzione della pubertà e del meccanismo che porta all’ ovulazione nella donna. Durante il ciclo mestruale, la secrezione di Gn-RH aumenta in fase follicolare fino a raggiungere l’acme in fase immediatamente pre-ovulatoria (23-30).
I neuroni si spingono giù fino all’eminenza mediana, infundibolo e peduncolo superiore dell’ipofisi dove sfociano nei vasi portali che trasportano il Gn-RH alle cellule basofile dell’adenoipofisi.
Il n. arcuato è costituito da 1000-3000 cellule che sono capaci di una secrezione pulsatile di Gn-RH (1 pulse ogni 60-90 minuti).
USI CLINICI:
La somministrazione pulsatile di Gn-RH, mediante pompa da infusione, è utilizzata per stimolare la secrezione di di FSH ed LH, per confermare la diagnosi e terapia di ipogonadismo ipogonadotropo, amenorrea ipotalamica e anovulazione ipotalamica (31-35),
La somministrazione im/sc di Analoghi (Gn-RH-a), ormoni di sintesi simili al Gn-RH, in preparazione depot comporta inibizione della secrezione di LH/FSH (dopo un flare-up iniziale) e riduzione dell’espressione del recettore. Viene utilizzata per la terapia di Pubertà precoce centrale, Carcinomi prostatico e mammario, iperplasia endometriale steroido-dipendente, Leiomiomi uterini, Endometriosi, Sindrome dell’ovaio policistico, Irsutismo, Turbe sessuali. Alcuni nomi commerciali di Gn-RH-a:
- leuprorelina (Lupron, Eligard)
- buserelina (Suprefact, Suprecor)
- nafarelina (Synarel)
- istrelina (Supprelin LA, Vantas)
- goserelina (Zoladex)
- deslorelina (Suprelorin, Ovuplant)
- triptorelina (Gonapeptyl, Decapeptyl)
(Decapeptyl® 0.1 mg/ml fl sc 1 ml (quotidiano), Decapeptyl fl 2 ml im 3,75 mg (mensile), Decapeptyl fl im 11,25 mg (trimestrale); Gonapeptyl depot® 3,75 mg, Zoladex® fl sc 3,60 mg (mensile), Zoladex 10,8 mg (trimestrale); Suprefact® fl im 5,5 ml 1 mg/ml (mensile), Suprefact® spray nasale 10 mg soluzione 0,1% una spruzzata = 0.1 mg per narice per 3-6 volte al dì)
Effetti avversi analoghi GnRH:
- Iniziale iperstimolazione gonadotropinica (flare-up)
- Ipogonadismo
- Vampate di calore
- Secchezza e atrofia vaginale
- Impotenza
- Osteoporosi
Antagonisti recettoriali del Gn-RH (Ganirelix, Cetrorelix): Stessi usi clinici degli analoghi però non inducono il flare up iniziale.
Test al Gn-RH
Il test può rilevare la presenza di ipogonadismo primario o secondario. Si determina la concentrazione ematica basale di LH. Di seguito vengono somministrati per via endovenosa 200 mg di LHRH sintetico, l’analogo del GnRH naturale. Prelievi vengono effettuati dopo 15-30-60-90-120 minuti (36-58).
Normalmente l’LH aumenta del 30-100% dopo 15-30 minuti dalla somministrazione di Gn-RH mentre l’FSH presenta un aumento del 10-50% dopo 30-60 minuti.
Alterazioni gonadotropiniche:
- Deficit ovarico: aumento di LH e FSH
- Deficit ipotalamico: LH e FSH ridotti
- Deficit ipofisario: LH in aumento e FSH ridotto
- Iperprolattinemia: LH e FHS leggermente aumentati
- Pubertà precoce: aumento di FSH e LH
- PCOS: LH aumentato ed FSH ridotto o inalterato
Gn-RH recettori: Il Gn-RH regola l’endocrinologia della riproduzione legandosi e stimolando specifici recettori posti sulle cellule gonadotrope dell’adenoipofisi così che esse possano secernere FSH ed LH.
l recettori Gn-RH mancano di una coda carbossi-terminale citoplasmatica ma possiedono una sequenza aminoacidica caratteristica dei recettori accoppiati a proteine di classe A, G rodopsina-simili (GPCR). I ligandi si legano a superfici extracellulari variabili, mentre le sette eliche α-membrana trasmettono il segnale di attivazione alla superficie del recettore citoplasmatico, che lega e attiva le proteine G eterotrimeriche. Quaranta interazioni non covalenti che collegano residui topologicamente equivalenti in diverse eliche transmembrana (TM) sono conservate in strutture di classe A GPCR, indipendentemente dallo stato di attivazione. I contatti interhelici indipendenti dalla conformazione rappresentano una struttura proteica conservata dei recettori e la loro importanza nella struttura dei recettori del GnRH è supportata dalla ridotta espressione dei recettori con mutazioni dei residui nella rete.
Le mutazioni del recettore GnRH associate a ritardo della pubertà e ipogonadismo
ipogonadotropico congenito, Questo ruolo centrale nella regolazione della riproduzione ha reso il GnRH-r un bersaglio per il trattamento dell’infertilità e dell’iperplasia steroidea-dipendente, tra cui fibromi uterini, endometriosi e cancro prostatico, dove la produzione di steroidi gonadici può essere ridotta dalla somministrazione di antagonisti del GnRH o da alte dosi di Agonisti del GnRH, che riducono l’espressione del recettore.
La metà delle circa 250 interazioni intramolecolari nei GPCR differiscono tra le strutture inattive e attive. I contatti interelastici specifici per la conformazione dipendono dagli amminoacidi che cambiano partner durante l’attivazione. Conservati contatti specifici di conformazione inattiva impediscono l’attivazione del recettore stabilizzando la prossimità delle eliche TM 3 e 6 e un sito di legame alle proteine G chiuso (60-90).
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- White CD, Coetsee M, Morgan K, Flanagan CA, Millar RP, Lu ZL. A crucial role for Galphaq/11, but not Galphai/o or Galphas, in gonadotropin-releasing hormone receptor-mediated cell growth inhibition. Mol Endocrinol (2008) 22(11):2520–30.
- Grosse R, Schmid A, Schoneberg T, Herrlich A, Muhn P, Schultz G, et al. Gonadotropin-releasing hormone receptor initiates multiple signaling pathways by exclusively coupling to G(q/11) proteins. J Biol Chem (2000) 275(13):9193–200.
- Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev (2004) 25(2):235–75.
- Munk C, Isberg V, Mordalski S, Harpsoe K, Rataj K, Hauser AS, et al. GPCRdb: the G protein-coupled receptor database – an introduction. Br J Pharmacol (2016) 173(14):2195–207.
- Isberg V, de Graaf C, Bortolato A, Cherezov V, Katritch V, Marshall FH, et al. Generic GPCR residue numbers – aligning topology maps while minding the gaps. Trends Pharmacol Sci (2015) 36(1):22–31.
- Mahoney JP, Sunahara RK. Mechanistic insights into GPCR-G protein interactions. Curr Opin Struct Biol (2016) 41:247–54.10.1016/j.sbi.2016.11.005
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- Tesmer JJ. Hitchhiking on the heptahelical highway: structure and function of 7TM receptor complexes. Nat Rev Mol Cell Biol (2016) 17(7):439–50.
- Cvicek V, Goddard WA, III, Abrol R. Structure-based sequence alignment of the transmembrane domains of all human GPCRs: phylogenetic, structural and functional implications. PLoS Comput Biol(2016) 12(3):
- Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM. Molecular signatures of G-protein-coupled receptors. Nature (2013) 494(7436):185–94.10.1038/nature11896
- Ballesteros JA, Weinstein W. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci(1995) 25:366–428.10.1016/S1043-9471(05)80049-7
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- Flanagan CA, Zhou W, Chi L, Yuen T, Rodic V, Robertson D, et al. The functional microdomain in transmembrane helices 2 and 7 regulates expression, activation, and coupling pathways of the gonadotropin-releasing hormone receptor. J Biol Chem (1999) 274(41):28880–6.
- Katritch V, Fenalti G, Abola EE, Roth BL, Cherezov V, Stevens RC. Allosteric sodium: a key co-factor in class A GPCR signaling. Trends Biochem Sci (2014) 39(5):233–44.
- Zhou W, Flanagan C, Ballesteros JA, Konvicka K, Davidson JS, Weinstein H, et al. A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor. Mol Pharmacol (1994) 45(2):165–70.
- Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S. Action of molecular switches in GPCRs-theoretical and experimental studies. Curr Med Chem (2012) 19(8):1090–109.
- Carpenter B, Nehme R, Warne T, Leslie AG, Tate CG. Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature (2016) 536(7614):104–7.
- Goncalves JA, South K, Ahuja S, Zaitseva E, Opefi CA, Eilers M, et al. Highly conserved tyrosine stabilizes the active state of rhodopsin. Proc Natl Acad Sci U S A (2010) 107(46):19861–6.
- Ballesteros J, Kitanovic S, Guarnieri F, Davies P, Fromme BJ, Konvicka K, et al. Functional microdomains in G-protein-coupled receptors. The conserved arginine-cage motif in the gonadotropin-releasing hormone receptor. J Biol Chem (1998) 273(17):10445–53.
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