Ovarian Reserve in Women with BRCA Mutation

Ovarian Reserve in women with BRCA
mutations
Norbert Gleicher, MD
Medical Director and Chief Scientist, Center for Human Reproduction – NY
President, Foundation for Reproductive Medicine
Conflict Statement


Dr. Gleicher is listed as co-inventor on a number of pending
patent applications claiming diagnostic and therapeutic benefits
from determination of CGG repeat numbers and ovarian FMR1
genotypes and sub-genotypes.
Dr. Gleicher is co-inventor of three awarded U.S. patents,
claiming therapeutic benefits for supplementation of DHEA in
women with diminished ovarian reserve, a topic discussed in
this talk. Other patent applications in regards to DHEA and other
fertility-related claims, with no relationship to this talk, are
pending. Dr. Gleicher receives royalties from, and owns shares in
Fertility Nutraceuticals, LLC, a distributor of a DHEA product.
Objectives
To better understand the genetic control
of ovarian reserve (OR)
 To understand effects of BRCA mutations
on OR
 To understand the possible interplay of
different genes on OR

Natural Pregnancy Rates and
Age
Menkin J, Trussel J, Larsen U. Science. 1986;233:1389-1394. Reprinted with permission from AAAS.
Ovarian Reserve
“Ovarian reserve is a term that is used to determine
the capacity of the ovary to provide eggs that are
capable of fertilization resulting in a healthy and
successful pregnancy”
From Wikipedia, the free encyclopedia
Ovarian Reserve
AMH inhibits recruitment and growth
La Marca & Volpe: Clinical Endocrinology (2006) 64, 603–610
ROC Curve Defining Maximal
Ppoint of Inflection in AMH
ROC curve of anti-Müllerian hormone
and live births involving 507 IVF cycles in
295 women with DOR. Star indicates
point of maximal inflection,
representing, as the set in table
demonstrates, an AMH value of 1.05
ng/mL. Not shown here are ROC curves
at age 30 to 35, 36 to 40 and >40 years,
all demonstrating the same point of
maximal inflection between lower and
higher live births. The value of 1.05
ng/mL thus represents a uniform cut off
between lower and higher live birth
chance, independent of age.
Gleicher et al, Fertil Steril 2010
Functional Ovarian Reserve
Androgens, cortisol and
androgen/cortisol ratios

DOR is an
androgen
deficiency state
Box and whisker plots of serum androgen levels, serum
cortisol levels and the ratio of total testosterone
concentration over serum cortisol levels for controls,
POA/OPOI, and physicologic DOR. The mean is depicted
with a dashed line, the median with a solid line, and the
normal range for serum androgens with a grey
background. (a) Comparison of serum androgen levels:
an asterisk denotes significant differences in mean
between groups. (b) Shows distribution of serum
cortisol levels. (c) Shows the ratio of TT over cortisol
levels.
Gleicher et al, Hum Reprod 2013; 28: 1084-91
We, therefore, now consider DOR to
be an androgen deficiency syndrome.
Which suggests an adrenal
contribution to the occurrence of
DOR.
Genetic Control of Functional
Ovarian Reserve
Genetic control of functional
ovarian reserve
Original tendency towards explosive
recruitment
 Most controlling genes hold back
recruitment

 AIRE
Gene
 FMR1 Gene
 BRCA1 Gene
Some BRCA1/2 mutations are
associated with increased cancer risks.
BRCA
Oktay et al. Association of BRCA1 mutation with occult primary ovarian
insufficiency: a possible explanation for the link between infertility and
breast/ovarian cancer risks. J Clin Oncol. 2010; 28: 240-4.
Odds ratios (ORs) of low ovarian response in women with BRCA mutations. (*) Only
mutations with proven clinical significance for breast and ovarian cancer risk are included.
BRCA continued
Titus et al. Impairment of BRCA1-related DNA doublestrand break repair leads to ovarian aging in mice and
humans. Science Translat Med. 2013; 5: 172ra21.
 Impaired ataxia-telangiectasia mutated (ATM)-mediated
DNA double-strand break repairs (DSB)
 DSBs accumulate with age in primordial follicles
 Expression of key DNA DSB repair genes (BRCA1, MRE11,
Rad51, ATM), but not BRCA2, declines with age in
oocytes.
BRCA continued
Titus et al. Impairment of BRCA1-related DNA doublestrand break repair leads to ovarian aging in mice and
humans. Science Translat Med. 2013; 5: 172ra21.
 BRCA1-deficient mice demonstrate impaired
reproductive capacity, primordial follicle counts lower,
and DSBs increased with age in comparison to wildtypes.
 Oocyte-specific knockdown of BRCA1, MRE11, Rad51,
ATM expression increased DSbs and reduced survival,
while BRCA1 overexpression enhanced both.
 FOR (AMH) was impaired in young women with
FMR1
Gleicher et al, PloS One 2012; 7: e44753.
Distribution on both FMR1 alleles, of CGG n in BRCA1/2
mutation carriers as well as U.S. controls in form of
scattergrams. Horizontal and vertical parallel lines in
scattergrams define the norm distribution area (CGG n=2634), with areas below and above representing low and high,
sub-genotypes, respectively; a represents higher and lower
count allele, respectively, for individual patients. Only the
lower count allele varied significantly between the two
groups (Mann-Whitney U test, P<0.001). Scattergrams, as
well as a, demonstrate graphically the significant shift
towards low FMR1 sub-genotypes, especially on the lower
count allele of BRCA1/2 mutation carriers. In a - - represents mean; ______ represents median.
This finding has been disputed by others:




Ricci et al. Eur J Hum Genet. 2014; 22: 280-2.
Dagan et al. Eur J Hum Genet. 2014; 22: 277-9.
Brandão et al. Hum Reprod. 2013; 28: 2308-11.
Gleicher et al. Eur J Hum Genet. 2014; 22: 155-6.
PRINCIPAL COLLABORATORS:
CHR SCIENTISTS:
David H Barad, MD, MS
Vitaly A. Kushnir, MD
Yan-Guang Wu, PhD
Yao Yu, PhD
Ho-Joon Lee, PhD
Emanuela Lazzaroni, MS
VISITING CHR SCIENTISTS:
Andrea Weghofer, MD, PhD, MBA, MS, Medical
University Vienna
Aritro Sen, PhD, Rochester University School of
Medicine & Dentistry & CHR

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