Induced-hyperandrogenism in female rats: assessing possible modulation of neurobehavioural and neurotransmitter changes following clomiphene/letrozole intervention

Abstract

Hyperandrogenism is the excessive production of androgenic hormones resulting in infertility in a number of women. While letrozole and clomiphene citrate have been used to increase chances of achieving pregnancy, their effects on the brain has been scarcely studied. This study examined the effects of clomiphene and letrozole alone or in combination on neurobehavioural and neurochemical changes in female rats exposed to testosterone. Weaned rats were assigned into eight groups of ten each. Animals were grouped as normal control administered vehicle (normal saline) orally at 10 ml/kg or subcutaneously at 2 ml/kg, three groups administered clomiphene (CLOM) at 100 microgramme/kg, letrozole (LETR) at 5 mg/kg and or a combination of clomiphene and letrozole (CLOM/LETR) orally and saline subcutaneously. There were also four groups Testosterone (Test), Test/CLOM, Test/LETR or Test/CLOM+LETR administered testosterone enantate subcutaneously at 1 mg/100 g. Testosterone or saline was administered from day 1-35, while beginning on day 36, clomiphene, letrozole or saline was administered daily for 10 days. At the end of the dosing period, animals were exposed to different behavioural paradigms. After the behavioural tests, animals were sacrificed, the cerebral cortex was homogenised for the assessment of biochemical assays. The result showed an increase in body weight, food intake, locomotor activity, rearing and self grooming with CLOM, LETR and CLOM/LETR in all treated groups. Decreased spatial working memory and anxiolysis was observed with letrozole and/or clomiphene. Increased oxidative stress, decreased total antioxidant capacity, altered inflammatory cytokines and brain neurotransmitter were observed with letrozole and /or clomiphene. In conclusion, the administration of clomiphene and/or letrozole was associated with significant alterations in brain function, oxidative stress, inflammatory markers and brain neurotransmitter levels.