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Ovarian Aging: Mechanisms and Clinical Consequences F. J. Broekmans, M. R. Soules, and B. C. Fauser B. Alves, B. Davis, W. Frank, A. Navarrette, and J. Thorson Menstrual Cycle Series of cyclic changes in the endometrium in response to changes in levels of ovarian hormones. Usual cycle lengths from 19 to 60 days. 28 days is the most common. Broekmans, F. J. et al. Endocr Rev 2009;30:465-493 https://courses.stu.qmul.ac.uk/smd/kb/microanatomy/humandev/index.htm Menstrual phase (D 1 – 5) The functional layer of the endometrium becomes detached from the uterine wall, resulting in bleeding (menses). http://embryology.med.unsw.edu.au Proliferative phase (D 6 – 14) GnRH FSH LH Follicular development http://embryology.med.unsw.edu.au Increasing levels of estrogen Endometrium begins to Stimulation of proliferate and thicken, progesterone receptors tubular glands and spiral synthesis in endometrial arteries form. cells. Late Proliferative (Ovulatory D13-14) The glands are long and tortuous due to active growth. Stroma is gradually becoming oedematous. Estimation of day of ovulation: changing ratio of urinary concentrations of oestrone-3-glucuronide and pregnanediol-3-glucuronide, measured in daily urine specimens. http://embryology.med.unsw.edu.au Fertile window: five days before ovulation and the day of ovulation itself. On average, at least 10% of women with regular cycles were in their fertile window on any given day of their cycle between days 6 and 21 (Wilcox et al., 2000). (Wilcox et al., 2000). Secretory phase (D 15 – 22) Rising levels of progesterone Enlargement of glands which begin secreting mucus and glycogen in preparation for implantation of the fertilized ovum. Increased fluid (oedema) in the stroma. http://embryology.med.unsw.edu.au Late secretory – Premenstrual (D 23 – 28) If fertilization does not occur, the corpus luteum degenerates, progesterone levels fall and the endometrium degenerates. Withdrawal of LH results in luteolysis (Fraser et al., 1986) Uterine glands are wide, tortuous and saccular. Spiral arteries begin contracting, capillary beds they supply in the stroma begin to seeping blood into the endometrium which then into the uterine cavity at menses. The cycle starts again with the first day of menstrual flow. http://embryology.med.unsw.edu.au Ovarian Reserve • Capacity of the ovary to provide eggs – Capable of fertilization – Result in healthy / successful pregnancy • Important in the treatment of infertility • Each month one ovulatory egg is released • Almost 99% of ovarian follicles undergo atresia – Hormonally controlled apoptotic process – Depends on granulosa cell apoptosis – Cannot be assessed using trans vaginal ultrasound (TVS) • As maternal age advances, number of eggs that can be successfully recruited for a possible pregnancy declines • Women with poor ovarian reserve are unlikely to conceive with ART Need for noninvasive assessment of potentially useful oocytes Clinical Ovarian Reserve Testing (ORT) • All current ORT involves follicle cohort size – AFC and ovarian volume via TVS • AFC: total number of antral follicles 2–10mm present in both ovaries – Endocrine markers • Anti-Müllerian hormone / inhibin B / FSH (indirect) ORT Usability Criteria • Accuracy of the test: correctly predicts tested outcome – Ovarian response and pregnancy after IVF – Receiver operator characteristic (ROC) curve • Clinical value of the test – How abnormal ORT would effectively change infertile couple options • Ratio of false-positives ORT: Inhibin B • Inhibin A and inhibin B are granulosa cell products • Inhibin B secreted predominantly during follicular phase – May influence folliculogenesis – Primarily produced by FSH- sensitive cohort of antral follicles • Decrease in inhibin B secretion – Stems from reduction in folicular cohort size with aging – Associated with elevated FSH levels • Also decreased oocyte quality and fertility potential • Likely a better indicator of ovarian activity than reserve ORT: Anti-Müllerian hormone (AMH) • As number of antral follicles decrease with age, Anti- Müllerian hormone (AMH) serum levels also become diminished – undetectable near menopause • Represent ovarian quantitative reserve • Independent of menstrual cycle phase ORT: Follicle Stim. Hormone ( FSH) • Measured basally or by challenge • FSH indirect measure of OR – Pituitary FSH release changes with altered feedback from inhibin B and estradiol • Clomiphene citrate challenge test (CCCT) • FSH measured before and after the administration period (cycle day 5-9) • Properly responsive ovaries – Clomiphene-dependent rise in FSH suppressed by the release of estradiol and inhibin B from developing follicles • FSH suppression absent – Suggests decreased ovarian reserve ORT Accuracy (Baseline Tests) • Most tests adequately predict poor ovarian hyperstimulation response – AFC and AMH best • Ovarian volume and inhibin B – Areas under the (ROC) curve insufficient to be usable tests • Multivariate approaches: no improvement over AFC – Tests express same quantitative aspect of OR • Predictive ability for pregnancy (1 IVF cycle) marginal for all tests • Very small proportions of nonpregnant cases correctly predicted • False-positives persisted even with extreme cutoffs for an abnormal test ORT Clinical Value • Predictions effectively change management remains unanswered • Dosage modification doesn’t significantly increase cohort size • Poor responders show little improvement with management modification • For ART, value of ORT for outcome prediction has been overestimated – No effective treatment for diminished OR – Predictive value of female age only modestly improved by AFC and AMH – True impact of routine ORT remains to be evaluated • Genetic factors most potential as long-term predictors of early or delayed reproductive aging Hormones and Development of Ovarian Follicles as it Pertains to Ovarian Aging Normal Development of Ovarian Follicle Inhibin B 140 120 Antral Follicle Cohort Size 100 Ng/ml 80 Inhibin B 60 40 20 0 ER MR LR EMT LMT EMP LMP Fast Follicular Development FSH Dominant Follicle Development Slow Follicular Development FSH Dominant Follicle Development Inhibin and Anti-Müllerian Hormone Role in Ovarian Aging and Detection Inhibin A & B • Dimeric polypeptides • Granulosa cell products – B secreted during follicular phase by antral follicles, may have effects on folliculogenesis – A decreases FSH secretion from the pituitary • In regards to ovarian aging, focus more on Inhibin B Inhibin B and Ovarian Aging • Due to its secretion site, Inhibin B is used as an assessment of the small antral cohort and hence ovarian age • Low IB has been associated with increased FSH levels and decreased oocyte quality and fertility • RECENT STUDIES HAVE REVEALED SOME DOUBT IN THESE PREVIOUS THEORIES… – There is no gradual decline of IB in relation to increasing female age (Broekmans, 2009) • Considered a late marker of decreased follicular numbers • IB could be used as a better gauge of ovarian function rather than follicle reserve numbers – Due to direct link with growing follicles – Influenced by the waxing and waning of ovarian function • IB changes with the menstrual cycle and peaks at two times: early- midfollicular phase and at ovulation (Sowers, 2008) • Samples would need to be taken during the early follicular phase to provide the maximum amount of information related to ovarian aging (Sowers, 2008) Anti-Müllerian Hormone • Dimeric glycoprotein, also known as Müllerian Inhibiting Substance • Secreted by granulosa cells of the Primary and Secondary follicles • Release continues until follicle becomes mid-antral between 2-6mm • Has both autocrine and paracrine functions involved in follicle development, however has been detected in serum • One of the earliest markers of ovarian age – Due to the fact that this reflects the transition of primordial follicles into growing follicles (Sowers, 2008) AMH and Ovarian Aging • Research has shown that AMH may be secreted into serum via small antral follicles • As the number of antral follicles decreased, there was a decrease in circulating AMF…being nearly undetectable at the time of menopause • Use as a marker for follicle numbers and hypergonadotropism (Broekmans, 2009) due to its role in regulation of primordial follicle recruitment and that AMH is produced at nearly all follicle stages (Sowers, 2008) • May also be able to be used as a marker independent of phase of menstrual cycle • In a study involving AMH, Inhibin B, and FSH, AMH was found to be the most reliable due to the fact that it resulted in a linear decline starting 5yrs. pre-FMP (Final Menstrual Period) (Sowers, 2008) References Broekmans, F.J., M.R. Soules, B.C. Fauser 2009 Ovarian Aging: Mechanisms and Clinical Consequences. Endocrine Reviews 30(5):465-493 Sowers, M.R., A.D. Eyvazzadeh, D. McConnell, M. Yosef, et al 2008 Anti-Mullerian Hormone and Inhibin B in the Definition of Ovarian Aging and the MenopauseTransition. J Clin Endocrinol Metab 93(9):3478-3483 Aging & Ovarian Function • Increasing age & decreasing fecundity • Reproductive aging varies considerably – Largely based on age-related changes in ovarian function • Decreased follicle number • Diminished oocyte quality • Menstrual cycle irregularity • Altered endocrine signaling – Genetic component • Far from being understood F. J. Broekmans et al., 2009 Aging & Ovarian Function • Aging • Reduced cohort size • Decrease in inhibin B • Elevated FSH levels • Decreased oocyte quality & potential fertility F. J. Broekmans et al., 2009 Aging & Ovarian Function • Decline in AFC • Altered feedback – Reduced inhibin B – Steady rise in FSH – Reduced inhibin A and estradiol – Gradually declining AMH F. J. Broekmans et al., 2009 Aging & Ovarian Function • Loss of oocyte quality – Increase in meiotic nondisjunction • Increasing rate of aneuploidy – Germ cell formation – Accumulated damage – Quality of granulosa cells F. J. Broekmans et al., 2009 Ovarian Aging: Mechanisms and Clinical Consequences F. J. Broekmans, M. R. Soules, and B. C. Fauser B. Alves, B. Davis, W. Frank, A. Navarrette, and J. Thorson
"Ovarian Aging Mechanisms and Cli"