Ovarian Aging Mechanisms and Cli

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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
                       Menstrual phase
                          (D 1 – 5)

The functional layer of the endometrium
becomes detached from the uterine wall,
resulting in bleeding (menses).

                            Proliferative phase
                                 (D 6 – 14)


               Follicular development

             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.

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.
                         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.,

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

The cycle starts again with the first day of
menstrual flow.
                                 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
     –   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

• Decrease in inhibin B secretion
    – Stems from reduction in
      folicular cohort size with aging
    – Associated with elevated FSH
         • 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
    – undetectable near menopause

• Represent ovarian quantitative

• Independent of menstrual cycle
     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

•   Clomiphene citrate challenge test
•   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
     –   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
                             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
Development of
Ovarian Follicle
                                                           Inhibin B

Antral Follicle Cohort Size           100

Inhibin B                              60
                                            ER   MR   LR          EMT   LMT   EMP   LMP
                      Fast Follicular Development
                      Dominant Follicle Development

Slow Follicular Development
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
   – 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
• Secreted by granulosa cells of the Primary and Secondary
• Release continues until follicle becomes mid-antral between
• 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
   • 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,
   • 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)

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
     •   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

                            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

                          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

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