Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LH-RH) in the rhesus monkey

Although luteinizing hormone-releasing hormone (LH-RH) agonists have been administered successfully by other than systemic routes (oral, intranasal (i.n.) and vaginal), there is no evidence that inhibitory analogues may be used in any form other than injectable. In the present study, we compared the effect of two routes of administration: (1) subcutaneous (s.c.), 0.5, 0.2 and 1 mg; and (2) i.n., 0.2, 1 and 5 mg of an LH-RH antagonist, ORG 30276 ([N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10]-LH-RH) on gonadotropin levels in oophorectomized monkeys. One hour after s.c. administration, FSH and LH values exhibited a dose-dependent fall that lasted for up to 12h. After s.c. administration, the maximum inhibition of serum FSH and LH was 29 and 41% (0.2 mg dose) and 41 and 58% (1 mg dose), respectively. After i.n. administration, maximum inhibition of serum FSH and LH was 19 and 40% (1 mg) and 32 and 53% (5 mg), respectively. These decreases were dose-related and lasted for up to 12h. Analysis of the data revealed that the bioavailability of the i.n. route versus the s.c. route ranged from 16 to 26%. This high effectiveness of the i.n. route in terms of bioavailability is markedly greater than that previously reported for LH-RH agonists (1%) and is probably due to a resistance to enzymatic hydrolysis in the nasal mucosa. These results show for the first time that antagonists of LH-RH can be administered by routes other than parenteral, increasing their potential clinical use in conditions in which inhibition of gonadotropins is desired, as in contraception and in therapy for endometriosis, precocious puberty, and hormone-dependent neoplasms. Resumé Bien que des agonistes de l'hormone de libération de la lutéinostimuline (LH-RH) aient été administrés avec succès par des voies autres que systémiques (orale, intranasale (i.n.) et vaginale), il n'existe aucune preuve que des analogues inhibiteurs puissent être utilisés sous une forme autre qu'injectable. Dans la présente étude, nous avons comparé les effets de deux voies d'administration (1. sous-cutanée (s.c.) (0,5, 0,2 et 1 mg) et 2. i.n. (0,2, 1 et 5 mg)) d'un antagoniste de la LH-RH, le ORG30276 ((N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10)-LH-RH) sur les taux de gonadotropine chez des singes oophorectomisés. Une heure après administration s.c., les valeur de la FSH et de la LH présentaient une baisse dépendant de la dose, qui durait jusqu'à 12 heures. Après administration s.c., l'inhibition maxima de la FSH et de la LH du sérum était de 29% et 41% (dose 0,2 mg) et de 41% et 58% (dose 1 mg), respectivement. Après administration i.n., l'inhibition maxima de la FSH et de la LH du sérum était de 19% et 40% (1 mg) et de 32% et 53% (5 mg), respectivement. Ces diminutions étaient liées à la dose et duraient jusqu'à 12 h. L'analyse des résultats à révélé que la biodisponibilité de la voie i.n. par rapport à la voie s.c. allait de 16% à 26%. Cette efficacité élevée de la voie i.n. exprimée par la biodisponibilité est nettement plus élevée que celle précédemment indiquée pour les agonistes de la LH-RH (1%) et elle est probablement dûe à une résistance à l'hydrolyse enzymatique dans la muqueuse nasale. Ces résultats montrent pour la première fois que des antagonistes de la LH-RH peuvent être administrés par des voies autres que parentérales, ce qui améliore leur potentiel d'utilisation clinique dans des conditions dans lesquelles une inhibition de gonadtropines est désirée, comme dans la contraception et le traitement de l'endométriose, de la puberté précoce et des néoplasmes hormonodépendants. Resumen Aunque los agonistas de la hormona liberadora de hormona luteinizante (LHRH) en han sido utilizados exitosamente de otras maneras, además de sistémicas (tales como oral, intranasal (i.n.) y vaginal), no existe evidencia que análogos inhibitorios puedan ser usados en otra forma que la inyectable. En el presente estudio hemos comparado el efecto en dos formas de administración: (1) subcutánea (s.c.) (0,5, 0,2 y 1 mg); y (2) i.n. (0,2, 1 y 5 mg) de un antagonista a LHRH, el ORG30276 ([N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10]-LHRH) en los niveles de gonadotropinas en monas ooforectomizadas. Una hora después de la administración subcutánea, los valores de la hormona folículo estimulante (FSH) y de la hormona luteinizante (LH), exhibieron una caída dependiente del dosaje que duró hasta 12 horas. Luego de la administración s.c. la máxima inhibición de FSH y de LH en suero, fué respectivamente 29% y 41% (dosis de 0,2 mg) y 41% y 58% (dosis de 1 mg). Luego de una administración i.n., la máxima inhibición de FSH y de LH en suero fué respectivamente 19% y 40% (1 mg) y 32% y 53% (5 mg). Estas disminuciones estuvieron relacionadas con el dosaje y duraron hasta 12 horas. El análisis de los datos reveló que la disponibilidad biológica de la administración i.n. versus la s.c. varió de 16% a 26%. Esta efectividad alta de la administración i.n. en términos de disponibilidad es acentuadamente mayor que la previamente notada para los agonistas LHRH (1%) y posiblemente sea debido a la resistencia a hidrólisis enzimática en la mucosa nasal. Estos resultados indican por primera vez que los antagonistas de la LHRH pueden ser administrados por rutas distintas a la parenteral, aumentando su potencial uso clínico en condiciones en las que se desee la inhibición de las gonadotropinas, tal como en la anticoncepción y en el tratamiento de la endometriosis, pubertad precoz y neoplasmas hormono-dependientes. Similar content being viewed by others

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Current status of antagonistic analogs of LH-RH as a contraceptive method in the female. In:Research Frontiers in Fertility Regulation, Vol. 2, no. 5. Program for Applied Research on Fertility Regulation, Northwestern University, Chicago Author information Authors and Affiliations Rights and permissions About this article Cite this article Asch, R.H., Balmaceda, J.P., De Castro, M.N. et al. Comparison of the subcutaneous and intranasal administration of an LH-RH antagonist ([N-Ac-d-p-Cl-Phe1,2,d-Trp3,d-Arg6,d-Ala10]-LH-RH) in the rhesus monkey. Adv Contracept 1, 109–117 (1985). https://doi.org/10.1007/BF01849792 Received: Accepted: Issue date: DOI: https://doi.org/10.1007/BF01849792