Decreased Bone Mineral Density in Rats Rendered Follicle-Deplete by an Ovotoxic Chemical Correlates with Changes in Follicle-Stimulating Hormone and Inhibin A

Abstract

Bone loss during perimenopause, an estrogen-sufficient period, correlates with elevated serum follicle-stimulating hormone (FSH) and decreased inhibins A and B. Utilizing a recently described ovotoxin-induced animal model of perimenopause characterized by a prolonged estrogen-replete period of elevated FSH, we examined longitudinal changes in bone mineral density (BMD) and their association with FSH. Additionally, serum inhibin levels were assessed to determine whether elevated FSH occurred secondary to decreased ovarian inhibin production and, if so, whether inhibins also correlated with BMD. BMD of the distal femur was assessed using dual-energy X-ray absorptiometry (DXA) over 19 months in Sprague-Dawley rats treated at 1 month with vehicle or 4-vinylcyclohexene diepoxide (VCD, 80 or 160 mg/kg daily). Serum FSH, inhibins A and B, and 17-ß estradiol (E2) were assayed and estrus cyclicity was assessed. VCD caused dose-dependent increases in FSH that exceeded values occurring with natural senescence, hastening the onset and prolonging the duration of persistent estrus, an acyclic but E2-replete period. VCD decreased serum inhibins A and B, which were inversely correlated with FSH (r2 = 0.30 and 0.12, respectively). In VCD rats, significant decreases in BMD (5–13%) occurred during periods of increased FSH and decreased inhibins, while BMD was unchanged in controls. In skeletally mature rats, FSH (r2 = 0.13) and inhibin A (r2 = 0.15) correlated with BMD, while inhibin B and E2 did not. Thus, for the first time, both the hormonal milieu of perimenopause and the association of dynamic perimenopausal changes in FSH and inhibin A with decreased BMD have been reproduced in an animal model.

COMPROMISED FERTILITY IN FREE FEEDING OF WILD-CAUGHT NORWAY RATS (RATTUS NORVEGICUS) WITH A LIQUID BAIT CONTAINING 4-VINYLCYCLOHEXENE DIEPOXIDE AND TRIPTOLIDE

“…Males and females were housed individually for 15 consecutive days (days 1-15). On day 16 of access to bait, control females and males, and treated females and males were housed as individual pairs for mating (treatment-paired, randomly assigned, breeding cycle 1) with continued access to bait (days [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Females and males were separated for 2 wk (rest cycle days 36-50) to allow pups to be born and counted.…”

“…20 VCD has also been shown to cause ovarian failure in rats, following repeated dosing. 12,18,21 Evidence has been provided that daily dosing of mice and rats with VCD, or the parent product 4-vinyl cyclohexene, does not produce generalized toxicity or effects in other tissues. 22,23,27 Therefore, use of VCD as a method of sterilization (ovarian failure) in female rat pests might hold promise as a nontoxic method of population control.…”

The Relationship between Follicle-stimulating Hormone and Bone Health: Alternative Explanation for Bone Loss beyond Oestrogen?

“…Distal femoral BMD was lower in VCD-treated rats starting from two months and 11 months after treatment of 160 and 80 mg/kg/day VCD was initiated 29 . This corresponded to the changes in their hormonal milieu, whereby FSH increased consistently two months after treatment initiation in VCD-treated rats 29 . Their oestrogen level was similar with the untreated rats 29 .…”

“…Lukefahr et al (2012) used 4-vinylcyclohexene diepoxide (VCD) to establish a hormonal milieu similar with premenopausal women (high FSH, normal oestrogen) in rats 29 . Distal femoral BMD was lower in VCD-treated rats starting from two months and 11 months after treatment of 160 and 80 mg/kg/day VCD was initiated 29 .…”

“…Lukefahr et al (2012) used 4-vinylcyclohexene diepoxide (VCD) to establish a hormonal milieu similar with premenopausal women (high FSH, normal oestrogen) in rats 29 . Distal femoral BMD was lower in VCD-treated rats starting from two months and 11 months after treatment of 160 and 80 mg/kg/day VCD was initiated 29 . This corresponded to the changes in their hormonal milieu, whereby FSH increased consistently two months after treatment initiation in VCD-treated rats 29 .…”