Autoimmune Targeted Disruption of the Pituitary-Ovarian Axis Causes Premature Ovarian Failure

Abstract

Premature ovarian failure (POF) is characterized by amenorrhea and high serum levels of follicle-stimulating hormone (FSH). POF causes female infertility and represents a substantial women’s health risk affecting 1% of women by age 40. Although ovarian autoimmunity has been associated with POF, the identity of ovarian Ags recognized is unknown. In this study, we show that autoimmune-targeted disruption of the pituitary-ovarian axis leads to POF. Immunization of SWXJ female mice with the p215–234 peptide derived from mouse inhibin-α activates CD4+ T cells and induces experimental autoimmune oophoritis with a unique biphasic phenotype characterized by an early stage of enhanced fertility followed by a delayed stage of POF. Affected mice show high serum levels of inhibin-α-neutralizing Abs that prevent inhibin-mediated down-regulation of activin-induced pituitary FSH release. The loss of activin/FSH down-regulation leads to prolonged metestrus-diestrus, superovulation, increased numbers of mature follicles, increased offspring, accelerated depletion of primordial follicles, and ultimately premature infertility. Thus, inhibin-α-targeted experimental autoimmune oophoritis is initiated by CD4+ Th1 T cells that stimulate B cells to produce inhibin-α-neutralizing Abs directly capable of mediating POF and transferring disease into naive recipients. Our inhibin-α autoimmune model of POF shows how premature infertility may develop in the context of elevated FSH levels thereby closely mimicking the hallmark features of human POF.

Functional analysis of the human inhibin subunit variant A257T and its potential role in premature ovarian failure

“…Experiments where ewes and glits are immunized against inhibin result in increased ovulation rates with increased FSH release (Forage et al, 1987;Brown et al, 1990;O'Shea et al, 1993). In a mouse model, immunization against inhibin resulted in an autoimmune oophoritis and early ovarian failure (Altuntas et al, 2006). The proinflammatory phenotype in these mice was characterized by elevated production of interferon-g and IL-2.…”

“…This study provides evidence that the suppression of inhibin and the resulting elevation of FSH levels cause ovarian stimulation, an earlier depletion of follicles and an accelerated rate of ovarian failure. The disparity in the ovarian phenotype between the FSH overexpressing mouse model (McTavish et al, 2007) and the inhibin immunized mice (Altuntas et al, 2006) may reflect an important role of inhibin in follicular maturation processes.…”

The Use of Rheum Palmatum L. In the Treatment of Acute Respiratory Distress Syndrome: A Meta-Analysis of Randomized, Controlled Trials

“…Fixed-effect or random-effect model used in the analysis depended on the absence or presence of significance heterogeneity which was evaluated by the Chi-square and I-square (I 2 ) tests. Measurement data with the same unit were summarized by using weight mean difference (WMD) with 95% CI, and the Measurement data with different unit were summarized by using standardized mean difference (SMD) with 95% CI (Altuntas et al, 2006).…”

Autoimmunity to Steroid-Producing Cells

“…In a second, delayed phase, the activation of CD4+ T-cells resulted in a lymphocytic infiltration of the ovary that occurred in parallel with a progressive decrease in fertility and ovarian function (Altuntas et al, 2006). However, it is still unclear to what extent these animal models are similar to human autoimmune POI.…”

“…Immunization of mice with a peptide of inhibin alpha chain induced an initial increase in fertility, mediated by high serum levels of inhibin alpha neutralizing antibodies, that prevented inhibin-mediated downregulation of activin-induced FSH release (Altuntas et al, 2006). In a second, delayed phase, the activation of CD4+ T-cells resulted in a lymphocytic infiltration of the ovary that occurred in parallel with a progressive decrease in fertility and ovarian function (Altuntas et al, 2006).…”