As more women are delaying childbirth and more "baby boomers" are
reaching midlife, this surge in advancing maternal age brings the increasing
problem of diminished ovarian reserve (DOR). Ovarian aging has several major
medical consequences including decreased bone mass with risk of fracture, abnormal
uterine bleeding from anovulation, and vasomotor symptoms. Regarding fertility
and DOR, assessing the quantity and quality of eggs is of great importance in
providing realistic expectations to a woman for a successful pregnancy. DOR results
in impaired fertilization of the egg, reduced implantation, and increased miscarriages
due to chromosomal abnormalities.
BACKGROUND
A woman is born with her entire life complement of oocytes, approximately 1-2
million. Through the biologic phenomenon of apoptosis, this amount at birth has
already experienced a rapid decline from 6- 7 million at mid gestation in-utero.
At the time of menarche, the oocyte cohort has diminished to 300,000-400,000.
Each cycle, hundreds of oocytes undergo stimulation with one achieving monthly
ovulation while the rest become atretic. Of the entire oocyte endowment, approximately
1 percent eventually undergoes ovulation. This in contrast to men where puberty
initiates spermatogenesis and new sperm are continuously produced throughout
the remainder of life.
Peak fertility in women occurs before age 30 with a monthly fecundity (pregnancy)
rate of 20-25 percent. Beginning around age 32, this monthly rate declines and
experiences a rapid acceleration during the later 30's and into the 40's. By
age 40, approximately 1 in 3 women experience infertility.
OVARIAN AGE TESTING
Several markers have been used to measure ovarian age. These include menstrual
cycle day three serum FSH (actually days 2-4 are acceptable) and estradiol (less
predictive). In general, these tests are more specific than sensitive; i.e., "normal" results
do not necessarily exclude DOR. AMA results in declining egg quality while elevations
in FSH reflect decreasing egg number. Of importance, an elevated FSH in a woman
below age 30 does not have the poor prognosis as in AMA.
CD3 testing is the simplest screening assessment. Elevated values for FSH and/or
estradiol are poor prognostic indicators for pregnancy particularly with assisted
reproductive technologies, and are laboratory specific due to different assays
(among labs). FSH levels will gradually increase in the early follicular phase
as a result of ovarian follicle decline. Additionally, a shortened follicular
phase occurs in DOR and estradiol levels may become elevated early. Obtaining
both FSH and estradiol levels will allow for more information since an isolated
FSH level may be "falsely" low from negative feedback of a high estradiol
level.
Transvaginal ultrasound with ovarian volume and antral follicle count on CD3
has also been used as screening tests. An ovarian volume of less then 2 cm and/or
a combined antral follicle count of less then 11 is an accurate reflection of
DOR. Lastly, CCCT utilizes the common fertility drug to measure FSH and estradiol
levels. Any elevation in FSH during the CCCT is considered DOR.
THE NEXT GENERATION - ANTIMULLERIAN HORMONE
No biomarker is necessarily predictive of pregnancy but they are more a gauge
of how much stimulation is necessary to induce multi-follicular development.
FSH is the gold standard being readily available but it is an indirect measure
affected by feedback inhibition of estradiol and inhibin. Most confusing is it
that FSH levels may dramatically change on a monthly basis making FSH testing
only valuable if it is elevated.
While Inhibin B is a more direct and earlier reflection of ovarian function produced
by granulose cells, assays lacked consistent results and a standardized cut-off
value. Cycle dependent, FSH is also the last biomarker to be effected by DOR
so elevations reflect more “end-stage” ovarian aging. Both FSH & Inhibin
B reflect the latter stages of follicular development.
AMH reflects primoridial (early) follicles that are FSH independent. A large
glycoprotein, AMH is expressed in the embryo at 8 weeks by the testis Sertoli
cells causing the female reproductive internal system (mullerian) to regress.
Without AMH expression, the mullerian system remains present and the male (wofffian
duct system) regresses. AMH controls the development of early follicles with
more follicles being used up more rapidly as AMH levels decline. First reported
in Fertility & Sterility in 2002 as a much earlier potential marker of ovarian
aging, low levels of AMH predict a lower number of eggs in IVF.
AMH & AFC are most predictive of a poor response to oocyte simulation
and markedly decline with age beginning at 30 with much less change than FSH
levels. AMH is NOT cycle dependent, so it can be conveniently drawn anytime during
the cycle, with recent evidence suggesting even on OCP or GnRH agonists, and
very little inter cycle variability, unlike FSH. Lastly, elevated levels of AMH
are seen more in PCOS patients and are more likely to develop OHSS.
Currently, AMH assays are restricted to a few commercial labs but it should
become more readily available as its clinical use increases.
Mark P. Trolice, M.D., FACOG, FACS is Director of Fertility C.A.R.E. (Center of Assisted Reproduction & Endocrinology in the Orlando, Florida area and Director of Reproductive Endocrinology & Infertility at Arnold Palmer Hospital for Children & Women.
© Mark P. Trolice Copyright 2010
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