A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause.

BACKGROUND: The primary determinant of reproductive age in women is the number of ovarian non-growing (primordial, intermediate and primary) follicles (NGFs). To better characterize the decline in NGF number associated with aging, we have employed modern stereology techniques to determine NGF number in women from birth to menopause. METHODS: Normal human ovaries were collected from 122 women (aged 0-51 years) undergoing elective oophorectomy, organ donation or autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. Models to describe the resulting decay curve were constructed and evaluated. RESULTS: NGF decay was best described by a simple power function: log (y) = ax(b) + c, where a, b and c are constants and y = NGF count at age x (R(2) = 0.84, Sums of Squares Error = 28.18 on 119 degrees of freedom). This model implies that follicles decay faster with increasing age. CONCLUSIONS: Unlike previous models of ovarian follicle depletion, our model predicts no sudden change in decay rate, but rather a constantly increasing rate. The model not only agrees well with observed ages of menopause in women, but also is more biologically plausible than previous models. Although the model represents a significant improvement compared with earlier attempts, a considerable percentage of the variation in NGF number between women cannot be explained by age alone.

Estimating human ovarian non-growing follicle number: the application of modern stereology techniques to an old problem.

BACKGROUND Previous published reports on the number of non-growing follicles (NGFs) in the human ovary have employed model-based methods for number estimates. These methods are time-intensive, and require correction factors and assumptions that ultimately limit their accuracy. Here, we describe the modification, application and validation of a modern fractionator/optical disector technique for the estimation of human ovarian NGF number. METHODS Forty-eight pairs of normal human ovaries were collected from women (age 8-51 years) undergoing elective bilateral oophorectomy, organ donation, or from autopsy. After gross pathologic examination, systematic random sampling was utilized to obtain tissue for analysis by the fractionator/optical disector method. The precision of individual NGF counts was determined by calculating the observed coefficient of error (OCE). Intra-observer variability and variation in NGF number between ovaries within a pair were also determined. RESULTS The mean OCE was 16.6% with larger variations observed at lower follicle counts. In recount experiments of the same ovary, NGF number estimates varied by 15-29%, except at very low follicle counts where variation was greater, but absolute differences were small. There was no significant difference in NGF number between ovaries within a pair (Wilcoxon signed rank test, P = 0.81). CONCLUSIONS Modern stereology methods provide an unbiased, efficient method for estimating NGF number in the human ovary. Both ovaries within a pair contain similar numbers of NGFs.

Effect of chromium supplementation on insulin resistance and ovarian and menstrual cyclicity in women with polycystic ovary syndrome.

In women with polycystic ovary syndrome, chromium picolinate (200 microg/d) improves glucose tolerance compared with placebo but does not improve ovulatory frequency or hormonal parameters. This pilot study indicates that future studies in the polycystic ovary syndrome population should examine higher dosages or longer durations of treatment.

Reproductive ageing and ovarian function: is the early follicular phase FSH rise necessary to maintain adequate secretory function in older ovulatory women?

BACKGROUND: Serum FSH elevations and decreases in inhibin B have been consistently demonstrated in the early follicular phase of cycles in women of advanced reproductive age. However, secretory products of the dominant follicle (estradiol and inhibin A) in the serum of older ovulatory women are maintained at levels similar to those of their younger counterparts. The goal of this investigation was to determine if ovarian secretory capacity is dependent on relative FSH levels and if basal measures of ovarian reserve reflect ovarian secretory capacity. METHODS: We administered equivalent low, but effective doses of recombinant FSH for 5 days to a group of older subjects (40-45 years, n=9) and younger controls (20-25 years, n=10) after pituitary suppression with a GnRH agonist. Outcome measures included follicular development as determined by serial transvaginal ultrasound examinations and serum levels of estradiol, inhibin A and inhibin B. RESULTS: Serum levels of estradiol and inhibin A were not statistically different between the two groups, while the number of large follicles formed was greater in the younger subjects. Basal parameters of ovarian reserve were not significantly correlated with ovarian secretory capacity, but did correlate with the number of follicles recruited in response to low-dose FSH. CONCLUSIONS: By providing equivalent serum levels of FSH in older and younger reproductive aged women, this study demonstrates that the secretory capacity of recruited follicles is maintained in older reproductive aged women.

Reproductive aging and variability in the ovarian antral follicle count: application in the clinical setting.

OBJECTIVE: To determine the extent of intercycle and interobserver variability in antral follicle (AF) count and their impact on stimulation quality in IVF. DESIGN: Prospective evaluation of the impact on AF count of GnRH agonist down-regulation and interobserver variability. Retrospective evaluation of intercycle variability in AF count. SETTING: University ART clinic. PATIENT(S): Twenty subjects were used to evaluate the effect of GnRH agonist down-regulation upon AF count; six of whom were used to evaluate interobserver variability. Fifty patients experiencing two or three cycles of IVF within a 1-year interval. INTERVENTION(S): Transvaginal ultrasound exams before and after down-regulation with a GnRH agonist. Videotaped day-3 transvaginal ultrasound exams. MAIN OUTCOME MEASURE(S): [1] Intercycle and interobserver variability in antral follicle count. [2] Oocytes retrieved, peak estradiol, gonadotropin dose, duration of stimulation and cancellation rates. RESULT(S): There is moderate intercycle and interobserver variability in AF counts. GnRH agonist down-regulation does not significantly change AF count. In infertility patients undergoing IVF, paired analysis between the low- and high-AF count cycles did not show a difference in quality of stimulation or cycle cancellation rates. CONCLUSIONS: Within an individual patient, higher AF count in a given cycle was not predictive of better stimulation compared with the case of a lower count cycle.