CHR SPRING RESEARCH
UPDATE
Norbert Gleicher, MD
David H. Barad, MD, MS
GENETICALLY PROGRAMMED (PREMATURE)
OVARIAN AGING:
THE FMR1 GENE.
DISTRIBUTION OF CGG TRIPLE REPEAT EXPANSIONS ON THE
FMR1 IN THE WHOLE STUDY POPULATION OF INFERTILE
WOMEN IN COMPARISON WITH A GENERAL POPULATION
The figure demonstrates the
distributions of CGG triple
repeat counts on allele-1
(interrupted line) and allele-2
(solid line) against the shaded
background distribution curve
reported by Fu et al for a general
population. Infertile women
demonstrate a mild shift for
allele-1and much clearer shift for
allele-2 towards higher triple
repeats.
LOGISTIC REGRESSIONS IN GROUPS A AND C
The figure represents logistic
regressions, demonstrating
predicted relative risk (RR) of
having AMH of less than 0.8
ng/ml over CGG repeat counts,
stratified by age. Blue dots (and
blue line) represent women ≥ 38
years of age; Red dots (and green
line) represent age < 38 years. The
black line reflects women of all
ages. RR of diminished ovarian
reserve, as reflected by AMH,
progressively increases in the
presence of CGG counts below
and above 30 repeats. For every 5
repeat decrease in CGG count
below 30, the relative risk of low
AMH increases by 60%. For every
5 repeat increase in CGG repeat
count above 30 the relative risk of
low AMH is increased by 40%.
TRIPLE CGG COUNTS BY BOX AND WHISKER PLOT
FOR ENTIRE PATIENT POPULATION
TRIPLE CGG COUNTS BY
BOX AND WHISKER PLOTS
FOR INDIVIDUAL
RACIAL/ETHNIC GROUPS
HETEROZYGOUS VS. HOMOZYGOUS
Normal CGG range: 26-32
Median CGG count: 30
BOX AND WHISKER PLOT,
DEFINING NORMAL AMH
LEVELS AND OUTLIERS
The figure reflects AMH levels in egg donors and infertility patients
based on zygosity in women under age 38 years, when
physiological diminution of ovarian reserve due to advancing age
affects ovarian function only to a lesser degree. * Denotes one allele
in normal count range (26-33) and one allele outside of normal
range. ** Denotes both alleles outside of normal range. A reflects
egg donors and B infertility patients. The bold horizontal line
within each box reflects the median value.
AMH values in egg donors did not vary statistically, though they
seem to mildly trend upwards from normal to heterozygous and
homozygous. Amongst infertility patients results differed
significantly between the three patient groups (p=0.032).
Specifically, homozygous women demonstrated significantly lower
AMH levels than normal patients (p=0.009) and a strong trend
towards lower levels in comparison to heterozygous women
(p=0.063).
LINEAR REGRESSION OF ASSOCIATION BETWEEN
AMH LEVELS AND AGE BASED ON FMR1 STATUS
The figure represents egg donors and infertility patients at
all ages. Normal females at young ages have the highest,
and women with homozygous CGG count abnormalities
the lowest AMH levels. AMH levels, however, decline in
normal women more rapidly than in heterozygous and
homozygous patients. At approximately 35 years of age
AMH levels in heterozygous women start to exceed those
of normal women. AMH levels in homozygous women
track those of normal women almost till age 50, when they
start exceeding the latter.
AMH LEVELS IN BINNED AGE GROUPS BASED
ON FMR1 STATUS
The figure represents egg donors and infertility
patients of all ages. Under age 30years AMH levels
significantly differ amongst all three patient groups
(p=0.009). Specifically, AMH in normal women is
significantly higher between normal women and
homozygous females (p<0.001) and between
heterozygous and homozygous patients (p=0.002). By
age 34.99, these statistical differences no longer are
present.
Count
20
18
16
14
12
10
8
6
4
2
0
Eggs
Embryos
D
H
E
A
1
2
3
4
5
6
Treatment Cycle
7
8
9
Barad et al. Obstet Gynecol 2007: 109; 1404-10.
PREVIOUSLY REPORTED
REPRODUCTIVE BENEFITS OF DHEA
 Improves egg/embryo numbers
 Improves egg/embryo quality
 Improves spontaneous pregnancy rates
 Improves IVF pregnancy rates
 Improves time to conception
 Improves cumulative pregnancy rates
Carson et al. Hum Reprod 2000
Barad and Gleicher, Fertil Steril 2005
Barad and Gleicher, Hum Reprod 2006
Barad et al, J Assist Reprod Genet 2007
SURVIVAL FUNCTION FOR CUMULATIVE FAILURE TO
CONCEIVE STRATIFIED BY AGE
Cumulative Failure to Conceive
1.2
1.0
.8
AGE
.6
• >=42
.4
• 38 ->42
• <38
.2
0
2
4
Months Since Starting DHEA
6
8
Cumulative Pregnancy
PREMATURE OVARIAN AGING
Diminished Ovarian Reserve
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
DHEA
0.1
DHEA
0.1
Control
0.0
0
2
4
6
8
Months from Initial Visit
Control
0.0
10
0
2
4
6
8
10
Months from Initial Visit
Cumulative pregnancy rate based on Cox regression of time from initial visit to clinical pregnancy
or censor by DHEA use stratified by ovarian reserve and adjusted for ART treatment,
race/ethnicity, age and baseline FSH (HR 3.8; 95% CI 1.2-11.8; p<0.05)
Barad et al. J Assist Reprod Genet 2007: 24; 629-634.
Comparison of Miscarriage Rates between
DHEA Supplemented Infertility Patients
and 2004 National US IVF Outcome Data.
0.6
0.5
0.4
National
0.3
DHEA
0.2
0.1
0
<35
35-37
38-40
41-42
>42
AMH INHIBITS RECRUITMENT AND
GROWTH
La Marca & Volpe: Clinical Endocrinology (2006) 64,
603–610
AMH IS STABLE ACROSS THE MENSTRUAL
CYCLE
AMH / FSH AND AGE NOMOGRAM
RETRIEVALS (BY YEAR AND AGE)
AMH BY AGE CATEGORY
PERCENT RETRIEVALS BY AGE AND YEAR
RETRIEVALS PER YEAR %BY AGE