The ERA trial: findings and implications for the future

Nair, Girish V.; Herrington, David M.

doi:10.1080/13697130008500132

Cited by 19 publications

(3 citation statements)

References 23 publications

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“…Because follicle depletion occurs over time, this may serve as an approach for studying the dynamics of follicle loss in women as ovarian senescence ensues (perimenopause). Recent clinical findings have demonstrated a need to find better ways of evaluating the risks versus benefits of long-term steroid hormone replacement [47][48][49]. Such an approach may be worthwhile for studies designed as a comparison for women who have undergone menopause by the natural process.…”

Section: Discussionmentioning

confidence: 99%

The Follicle-Deplete Mouse Ovary Produces Androgen1

Mayer

Devine

Dyer

et al. 2004

Biology of Reproduction

165

215

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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.

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Section: Discussionmentioning

confidence: 99%

The Follicle-Deplete Mouse Ovary Produces Androgen1

Mayer

Devine

Dyer

et al. 2004

Biology of Reproduction

165

215

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“…However, we still lack a clear understanding of POF, such as the causes and the dynamics of follicle depletion. It is important to develop animal models for studying POF, because there is an urgent need to examine the dynamics of follicle loss and the endocrine profiles that can help to evaluate the risks versus benefits of some therapies (like long-term steroid hormone replacement) for this disease (BarrettConnor and Stuenkel, 1999;Nair and Herrington, 2000;Rossouw et al, 2002). Additionally, animal models are especially useful in some research that is impossible or unethical to perform in humans.…”

Section: Discussionmentioning

confidence: 99%

Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide

Jiang

Zhao

et al. 2013

J. Zhejiang Univ. Sci. B

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Busulfan/cyclophosphamide (Bu/Cy) conditioning regimen has been widely used to treat cancer patients, while their effects on major internal organs in females are not fully understood. We treated female mice with Bu/Cy, and examined the histopathology of major internal organs on Day 30 after the treatment. The results show that Bu/Cy treatment affected the ovaries most extensively, while it had less effect on the spleen, lungs, and kidneys, and no effect on the heart, liver, stomach, and pancreas. To better understand the effect of Bu/Cy on the ovaries, we counted follicles, and determined the levels of ovarian steroids. The Bu/Cy-treated mice showed a reduction of primordial and primary follicles (P<0.01) on Day 30 and a marked loss of follicles at all developmental stages (P<0.01) on Day 60. Plasma levels of estradiol and progesterone in Bu/Cy-treated mice decreased by 43.9% and 61.4%, respectively. Thus, there was a gradual process of follicle loss and low estradiol in Bu/Cy-treated mice; this is a profile similar to what is found in women with premature ovarian failure (POF). The Bu/Cy-treated mice may serve as a useful animal model to study the dynamics of follicle loss in women undergoing POF.

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“…However, the field has been rejuvenated by a number of governmental initiatives, controversial outcomes of several large clinical trials (Hulley et al, 1998;Nair and Herrington, 2000;, the growing public interest in "safer," more "bioidentical" hormones, and the interest in personalized, sex-based medicine (pharmacogenomics). Furthermore, validation of controversial mechanisms of action of sex steroids, identification of novel effects of estrogen such as a regulator of mitochondrial function, and development of new theories of treatment efficacy based on further analyses of data from various observational and clinical trials (Salpeter et al, 2004(Salpeter et al, , 2006Grodstein et al, 2006;Hsia et al, 2006b;Clarkson, 2007; support the possibility that hormonal therapies may be viable options to prevent some chronic conditions of aging.…”

Section: Introductionmentioning

confidence: 99%