Аннотация
Для стимуляции овариального стероидогенеза и контролируемой индукции овуляции в клинике применяют препараты гонадотропинов – хорионического гонадотропина человека (ХГЧ) и лютеинизирующего гормона (ЛГ), которые, однако, имеют ряд побочных эффектов, таких как снижение чувствительности яичников к эндогенному ЛГ и синдром гиперстимуляции яичников. Альтернативой ХГЧ и ЛГ могут стать аллостерические агонисты рецептора ЛГ/ХГЧ, в том числе разработанное нами тиено-[2,3-d]-пиримидиновое производное TP03. Целью работы было изучить влияние TP03 (40 мкг/кг, в/б) и взятого для сравнения ХГЧ (30 МЕ/крысу, п/к) на овариальный стероидогенез у половозрелых самок крыс, находящихся в фазе позднего проэструса, в том числе обработанных антагонистом гонадолиберина Оргалутраном (100 мкг/кг, п/к, за 3 ч до введения TP03 или ХГЧ). В крови крыс оценивали уровни эстрадиола, прогестерона и ЛГ, в яичниках – экспрессию генов стероидогенеза (Star, Cyp11a1, Hsd3b, Cyp17a1, Hsd17b, Cyp19a1) и рецептора ЛГ/ХГЧ (Lhcgr). Через 3 ч после введения TP03 и ХГЧ повышали уровень прогестерона в крови, стимулировали экспрессию генов холестерин-транспортирующего белка StAR, цитохрома P450c17 и ароматазы (цитохрома P450c19), и этот эффект выявлялся как у контрольных крыс с нормальным уровнем ЛГ, так и у Оргалутран-обработанных крыс с пониженным уровнем ЛГ. Эффекты TP03 были сопоставимы с таковыми ХГЧ, но в отличие от ХГЧ аллостерический агонист не снижал функционирования гипоталамо-гипофизарно-гонадной оси, на что указывает отсутствие его влияния на уровень ЛГ в крови и экспрессию рецепторов ЛГ/ХГЧ. Полученные данные свидетельствует о способности TP03 эффективно стимулировать овариальный стероидогенез и указывают на перспективность разработки на его основе лекарственных форм для контролируемой индукции овуляции.
Литература
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