Ovarian aging and the activation of the primordial follicle reserve in the long-lived Ames dwarf and the short-lived bGH transgenic mice

Abstract

The aim of this study was to evaluate the effect of growth hormone (GH) in the maintenance of the ovarian primordial follicle reserve. Ovaries from 16 mo old GH-deficient Ames Dwarf (df/df) and Normal (N/df) mice were used. A subgroup of df/df and N mice received GH or saline injections for six weeks starting at 14 mo of age. In addition, ovaries from 12 mo old mice overexpressing bovine GH (bGH) and controls were used. df/df mice had higher number of primordial and total follicles than N/df mice (p<0.05), while GH treatment decreased follicle counts in both genotypes (p<0.05). In addition, bGH mice had lower number of primordial and total follicles than the controls (p<0.05). pFoxO3a levels were higher in mice treated with GH and in bGH mice (p<0.05) when comparing with age match controls. These results indicate that increased circulating GH is associated with a reduced ovarian primordial follicle reserve and increased pFoxO3a content in oocytes.

Changes of Ovarian microRNA Profile in Long-Living Ames Dwarf Mice during Aging

“…Of these, only three miRNAs were commonly regulated with age between N and df/df mice, indicating a very divergent profile of ovarian miRNAs as both mice genotypes age. It was previously demonstrated that the size of the primordial follicle reserve decreases by approximately 90% from the ages of 0.5 to 1.5 years in N female mice [12], and we demonstrated before that the ovarian reserve of primordial follicles in df/df mice is three times larger than in N mice [19, 20]. Therefore, our finding indicates that changes in the ovarian reserve with aging are reflected in changes in the ovarian miRNA profile of N and df/df mice.…”

“…Although female df/df mice have normal ovarian cyclicity and can maintain pregnancy under hormonal stimulation, they have delayed puberty [16]. We previously reported that Forkhead Box O3a (Foxo3a) phosphorylation, one of the main pathways implicated in irreversible primordial follicle activation [17, 18], is reduced in oocytes enclosed in primordial follicles from df/df mice, preventing primordial follicle activation [19, 20]. As a result df/df mice have a delayed ovarian aging and an increased number of primordial follicles compared to old Normal (N) mice [19, 20].…”

“…We previously reported that Forkhead Box O3a (Foxo3a) phosphorylation, one of the main pathways implicated in irreversible primordial follicle activation [17, 18], is reduced in oocytes enclosed in primordial follicles from df/df mice, preventing primordial follicle activation [19, 20]. As a result df/df mice have a delayed ovarian aging and an increased number of primordial follicles compared to old Normal (N) mice [19, 20]. Activation of primordial follicle growth is also impaired in GH receptor disrupted mice [21] and mice subjected to caloric restriction [22], also culminating in delayed ovarian aging and a greater number of primordial follicles in the quiescent stage.…”

“…Activation of primordial follicle growth is also impaired in GH receptor disrupted mice [21] and mice subjected to caloric restriction [22], also culminating in delayed ovarian aging and a greater number of primordial follicles in the quiescent stage. On the other hand, transgenic mice overexpressing GH have increased activation of Foxo3a and accelerated loss of primordial follicles [19], evidencing the role of GH/IGF-I in this process.…”

“…However, very little is known about the miRNA profile associated with ovarian aging, since most mouse models for ovarian aging (knockouts for PTEN and FoxO3 for example) have complete ovarian failure early after puberty [17, 29]. df/df mice can maintain the ovarian reserve for a longer period than N mice [19, 20], which allows for comparison of expression profiles at different stages of life, making it a very valuable model of ovarian aging. Therefore, the aim of the current work is to evaluate the ovarian miRNA profile in young and aged df/df and N mice in order to establish miRNAs potentially involved in ovarian aging.…”