Endocrinologia

Gn-RH (Gonadotropin Releasing Hormone), analoghi, antagonisti, recettori

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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:

  1. leuprorelina (Lupron, Eligard)
  2. buserelina (Suprefact, Suprecor)
  3. nafarelina (Synarel)
  4. istrelina (Supprelin LA, Vantas)
  5. goserelina (Zoladex)
  6. deslorelina (Suprelorin, Ovuplant)
  7. triptorelina (Gonapeptyl, Decapeptyl)

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

Gn-RH1 recettore

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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