Animal model for perimenopause and menopause and methods of inducing ovarian failure
a technology of perimenopause and menopause, which is applied in the field of animal models for perimenopause and menopause and methods of inducing ovarian failure, can solve the problems of increasing life expectancy, affecting the incidence of many age-related diseases, and many health risks associated with menopaus
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example 1
[0063]Treatment with VCD reduced (p1 mice (FIG. 1). Primordial follicles were reduced at 80 mg / kg to 12.1% of control, 160 mg / kg (80 mg / kg, 2× daily, and 160 mg / kg 1× daily) 0% of control, 240 mg / kg (80 mg / kg 3× daily) 2.1% of control, 240 mg / kg (240 mg / kg 1× daily) 0% of control, and 320 mg / kg (160 mg / kg 2× daily) 0% of control. Primary follicles were reduced at 80 mg / kg to 38.6% of control, 160 mg / kg (160 1× daily) 2.8% of control, 160 mg / kg (80 mg / kg 2× daily) 11.3% of control, 240 mg / kg (80 mg / kg 3× daily) 5.1% of control, 240 mg / kg (240 mg / kg 1× daily) 0% of control and 320 mg / kg (160 mg / kg 2× daily) 0.6% of control.
[0064]Treatment with VCD (160 mg / kg, i.p.) for=15 days reduced (p<0.05) primary and primordial follicle numbers progressively over time (FIG. 2A). By d46 following commencement of 15d of treatment, all follicle pools were substantially depleted (p<0.05) relative to control. There were no primordial follicles and primary, secondary and antral follicles were 0.5%, 0.7...
example 2
Range Finding Experiment with Alzet Minipumps to Determine the No-Observable-Adverse-Effect-Level (NOAEL) of VCD and Verify Primordial and Primary Follicle Depletion
[0083]We will use B6C3F1 mice because they are the most completely characterized mouse strain using multiple injections of VCD. The 160 mg / kg / d dose injected i.p. for 15d yields the greatest acceleration of follicle depletion via a single injection without adverse effects. We know that if the total VCD dose delivered over 15d (2400 mg / kg) is injected in a single bolus the mice die within hours. Mice can tolerate more VCD per day if it is metered out over the 24 h time period. Our preliminary data indicates that mice tolerate VCD well when dosed 3 times a day @80 mg / kg / d (total 240 mg / kg / d). Three injections a day, per mouse, is labor intense and may be impractical for commercial production.
[0084]VCD is a member of the 4-vinylcyclohexene family of chemicals and appears to be the bioactive compound in rats and mice. It is...
example 3
Using the NOAEL from Example 2 to Define the Kinetics of Follicle Depletion and Increase in Plasma FSH, and Determining if Less VCD is Required When Administered by Continuous Delivery
[0093]Completion of the Example 2 will provide evidence that continuous delivery of VCD by minipump will not cause general toxicity and accomplish follicle depletion similar to 15 daily VCD injections. The VCD NOAEL will be used to analyze the detailed time course of follicle depletion and increased plasma FSH.
[0094]The VCD NOAEL will be used in Alzet minipump model 1002 that delivers the reservoir volume in 14 days. There will be 4 groups of d40 female mice, 6 mice / group, killed at each time point. Groups 1 and 2 will receive 15 daily injections of 50% DMSO vehicle and 50% DMSO with VCD (160 mg / kg, i.p.). Groups 3 and 4 will receive minipumps implanted sc. loaded with 50% DMSO vehicle and 50% DMSO with VCD. Mice will be monitored for 24 h after the implantation to watch for normal feeding and behavior...
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