Effect of mitotane on mouse ovarian follicle development and fertility

Abstract

Mitotane (MTT) is an adrenolytic drug used in advanced and adjuvant treatment of adrenocortical carcinoma, in Cushing's disease and in ectopic syndrome. However, knowledge about its effects on the ovary is still scarce. The purpose of this study is to investigate the effect of MTT on the ovary using and models. The study was performed in CD1 mice and in the COV-434 human ovarian granulosa cell line. We examined ovarian morphology, follicle development, steroidogenesis and procreative function in mice and the effect of MTT on cell growth Our results revealed that treatment of CD1 mice with MTT induces a decrease in early antral follicles with a subsequent increase in the secondary follicles, measured by the increased levels of anti-Mullerian Hormone ( < 0.05) and decreased levels of FSH receptor ( < 0.05). Moreover, we observed a significant decrease in ( < 0.01) and ( < 0.001) mRNA level in MTT-treated animals. Ovulation, induced by PMSG/hCG stimulation, was also significantly impaired, with a reduction in the number of ovulated oocytes ( < 0.01) and fewer corpora lutea in treated animals. Likewise, the mating experiment demonstrated a delay in the time of conception as well as fewer pups per litter in MTT-treated mice ( < 0.05). Experiments performed on the COV-434 cell line showed a significant inhibition of growth followed by apoptosis ( < 0.01). In conclusion, our study highlights the key points of ovarian folliculogenesis affected by MTT and demonstrates impairment of the ovulation process with a negative impact on conception, which is nevertheless preserved.

Ovarian cyst formation in women of reproductive age receiving mitotane as part of the treatment of adrenocortical carcinoma: Clinical and experimental observations

“…The observations in the present study that mitotane suppresses steroid production in cultured granulosa cells support this notion. A recent study in mice 20 showing that mitotane induces a decrease in antral follicles, decreases the levels of FSH receptors, and interferes with ovulation adds further support to this concept.…”

Pre- and Postnatal Dietary Exposure to a Pesticide Cocktail Disrupts Ovarian Functions in 8-Week-Old Female Mice

“…Symonds et al found that methoxychlor (insecticide) stimulated the growth of epithelial cells on the surface of the ovary by increasing proliferation (significant increase in PCNA) [ 43 ]. Conversely, experiments by Innocenti et al conducted with mitotane (insecticide-derived drug) on the ovarian tumour cell line COV-434 demonstrated significant growth inhibition (by PCNA labelling) [ 44 ]. We also used an additional, more proliferation-specific marker, Ki67.…”

Trans 10, cis 12-conjugated linoleic acid reduced reproductive ability by disrupting the estrus cycle in female mice

“…The impact of female reproductive health on pregnancy rates and offspring has garnered significant attention. Female reproductive factors, such as ovarian development, oocyte maturation, estrous cycle, and embryo implantation, were influenced primarily by sex hormones, including progesterone, prostaglandin, and estrogen ( Innocenti et al, 2017 ; Bui et al, 2022 ). Sex hormones play crucial roles in the complex and interconnected processes of pregnancy and childbirth ( Zamberlam et al, 2019 ).…”