The Follicle-Deplete Mouse Ovary Produces Androgen1

Abstract

The follicle-depleted postmenopausal ovary is enriched in interstitial cells that produce androgens. This study was designed to cause follicle depletion in mice using the industrial chemical, 4-vinylcyclohexene diepoxide (VCD), and characterize the steroidogenic capacity of cells in the residual ovarian tissue. From a dose-finding study, the optimal daily concentration of VCD was determined to be 160 mg/kg. Female B6C3F(1) immature mice were treated daily with vehicle control or VCD (160 mg kg(-1) day(-1), 15 days, i.p.). Ovaries were removed and processed for histological evaluation. On Day 15 following onset of treatment, primordial follicles were depleted and primary follicles were reduced to about 10% of controls. On Day 46, primary follicles were depleted and secondary and antral follicles were reduced to 0.7% and 2.6% of control, respectively. Seventy-five percent of treated mice displayed disruptions in estrous cyclicity. All treated mice were in persistent diestrus (acyclic) by Day 58. Plasma FSH levels were increased (P < 0.05) relative to controls on Day 37 and had plateaued by Day 100. Relative to age-matched cyclic controls, by Day 127, the significant differences in VCD-treated mice included reduced ovarian and uterine weights, elevated plasma LH and FSH, and reduced plasma progesterone and androstenedione. Furthermore, plasma 17beta-estradiol levels were nondetectable. Unlike controls, immunostaining for LH receptor, and the high density lipoprotein receptor (SR-BI), was diffuse in ovarian sections from VCD-treated animals. Ovaries from Day 120 control and VCD-treated animals were dissociated and dispersed cells were placed in culture. Cultured cells from ovaries of VCD-treated animals produced less LH-stimulated progesterone than control cells. Androstenedione production was nondetectable in cells from cyclic control animals. Conversely, cells from VCD-treated animals produced androstenedione that was doubled in the presence of insulin and LH (1 and 3 ng/ml). Collectively, these data demonstrate that VCD-mediated follicle depletion results in residual ovarian tissue that may be analogous to the follicle-deplete postmenopausal ovary. This may serve as a useful animal model to examine the dynamics of follicle loss in women as ovarian senescence ensues.

Fertility control to mitigate human–wildlife conflicts: a review

“…The epoxide 4-vinylcyclohexene diepoxide (VCD) has ovarian-specific toxicity and follicle-depleting properties (Hoyer et al 2001;Mayer et al 2002). The administration of VCD by injection or ingestion repeatedly over a period of up to 30 days depletes the ovary of follicles leading to ovarian senescence (Mayer et al 2004;Hu et al 2006). Similarly, repeated oral administration of triptolide, a diterpenoid triepoxide, affects the ovarian function by causing follicular atresia (Xu and Zhao 2010;Liu et al 2011).…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…The effects of estrogens on diet-induced atherosclerosis have been studied in atherosclerosis-prone B6 mice as well as in Apoe KO and Ldlr KO mice under hypercholesterolemic conditions (Bourassa et al 1996, Elhage et al 1997a, Hodgin et al 2001, Mayer et al 2005, Tsuda et al 2005, Seli et al 2007, Villablanca et al 2009). In female animals, the study design usually encompassed surgical or pharmacological castration followed by E 2 substitution to assure E 2 concentrations in plasma comparable to those seen in premenopausal women before ovulation (ca.…”

Collaborative work on evaluation of ovarian toxicity 4) Two- or four-week repeated dose study of 4-vinylcyclohexene diepoxide in female rats

“…and, once destroyed, no more can be generated.Therefore, exposure to chemicals that target small follicles can impair reproductive function and cause premature menopause in women (Hooser et al, 1994;Mayer et al, 2002Mayer et al, , 2004. If any deviation from the normal small follicle condition is found on routine histopathological examination, it might be an indication of ovarian toxicity, and more precise histopathological examination, including PCNA immunohistochemistry, should be added.…”

“…Haas et al (2007) reported that VCD-treated female mice can be used to model infertility in perimenopausal women. Chemicals that deplete ovarian follicles are of toxicological concern because the mammalian ova--tion can result in premature ovarian failure (early menopause in women; Hooser et al, 1994;Mayer et al, 2002Mayer et al, , 2004.…”