Effectiveness of a monoclonal antibody against human chorionic gonadotropin (hCG) to prevent reproductive and metabolic dysfunctions in transgenic females mice.

RATNER LD ; CALANDRA RS ; MARCIAL LÓPEZ A ; NAND K ; RULLI SB ; GUPTA J ; TALWAR G

Geneva

Congreso; ESHRE 33rd Annual Meeting; 2017

European Society of Human Reproduction and Embryology

Study question: Is the monoclonal antibody against human chorionic gonadotropin(hCG) effective in preventing the phenotypic alterations of transgenicmice hypersecreting hCG?Summary answer: The treatment was more effective in reversing the phenotypeof transgenic female mice when it was administered at the juvenil stage ascompared to adulthoodWhat is known already: hCG is involved in many functions during placentationand fetal development. Its levels are increased during pregnancy and postmenopause,and in pathological conditions, such as trophoblastic and nontrophoblastictumors. Our previous studies demonstrated that transgenicfemale mice overexpressing the hCGβ-subunit (hCGβ+ mice) are infertile,exhibit increased levels of hCG, prolactin, progesterone and testosterone.Later in life, they develop prolactinomas and mammary gland tumors. In addition,these animals present insulin resistance and glucose intolerance. A monoclonalantibody developed by Dr. Talwar?s group has high affinity for the hCGβ-subunit, without cross-reaction with pituitary hormones.Study design, size, duration: hCGβ+ females were injected i.p. with themonoclonal antibody (300 μg/mouse/dose) at 5 weeks (hCGβ+ mAB5w:every other day for one week, followed by one dose weekly; n = 10) and 16weeks of age (hCGβ+ mAB16w: one dose weekly; n = 4) during two months.These were compared with females hCGβ+ injected with vehicle as controls(n = 5). Fertility studies, body weight, carbohydrate metabolism and the presenceof tumors at 3-6 months of age were conducted.Participants/materials, setting, methods: For fertility studies, hCGβ+treated females were mated with wild type males two days after the last injection.Body weight was registered for 12 days. Blood glucose was measured infasted female mice at 0, 30, 60 and 90 min after glucose administration (2 g/kg;i.p) for intraperitoneal glucose tolerance test (IGTT). The same procedure wasused for insulin tolerance test (ITT; 0,75 IU/kg of insulin).Main results and the role of chance: The effectiveness of the treatmentwould depend on the stage in which it is administered. During the juvenil stage,(hCGβ+ mAB5w) female mice normalized the estrous cycle and recovered fertility,but not at adulthood (hCGβ+ mAB16w). No differences in body weight betweenthe groups were observed. The glucose tolerance test was normalized in both treatedgroups (p<0.05). All groups maintained the insulin resistance (p<0.05).Pituitary tumor development was prevented in the hCGβ+ mAB5w group.Limitations, reasons for caution: Complementary studies will be neededfor a better understanding of the mechanisms involved during the treatmentwith the monoclonal antibody against hCG. Other doses should be tested inorder to get all the phenotypic alterations normalized.Wider implications of the findings: This treatment was able to immunoneutralizethe effects of hCG, which could be a useful tool for therapies relatedwith cancer and reproduction/infertility.