Clomiphene/letrozole administration can modulate neurobehavioural and neurochemical indices in hyperandrogenic female rats

 Olofinnade Anthony Tope¹, Onaolapo Olakunle James², Onaolapo Adejoke Yetunde³.

1. Department of Pharmacology,Therapeutics and Toxicology, Faculty of Basic Clinical Sciences, College of
   Medicine, Lagos State University, Ikeja, Lagos State. anthony.olofinnade@lasucom.edu.ng
2. Behavioural Neuroscience and Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Ladoke
   Akintola University of Technology, Ogbomoso, Oyo State, Nigeria, orcid.org/0000-0003-2142-6046
3. Behavioural Neuroscience and Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of
   Technology, Ogbomoso, Oyo State, Nigeria, orcid.org/0000-0001-7126-7050

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 successfully 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 rata exposed to testosterone. Eighty 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 µg/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 enanthate subcutaneously at 1 mg/100 g in addition to respective treatment. Testosterone or saline was administered daily day 1-35, beginning on day 36 clomiphene, letrozole or distilled water was administered daily for 10 days. At the end of the experimental period, animals were exposed to different behavioural paradigms. Twenty-four hours after the last behavioural test, animals were sacrificed by cervical dislocation, the brain was dissected, sectioned and homogenised for the assessment of inflammatory cytokines (interleukin 10 and TNF-α), lipid peroxidation, total antioxidant capacity and brain neurotransmitter levels. Results showed alterations in body weight, feed intake, and open -field behaviours with testosterone control and with clomiphene or letrozole administered alone or with testosterone. Memory, anxiety-related behaviours and oxidative stress increased with testosterone, but decreased with letrozole and/or clomiphene. In conclusion, the administration of clomiphene and/or letrozole was associated with alterations in brain function, oxidative stress, inflammatory markers and neurotransmitter levels

KEYWORDS: Hyperandrogenism, Neurotransmitters, Ovulation, Oxidative stress, Polycystic ovary syndrome