Transcript Folie 1

1
DRG INTERNATIONAL,
INC.
Where medical needs meet innovation
Note: Unless otherwise stated in our catalog or other
company documentation accompanying DRG
International, Inc. product(s), these assay kits are
intended for research use only (RUO) in the United
States.
2
AMH BEYOND IVF: RAISING
THE BAR IN REPRODUCTIVE
HEALTH DIAGNOSTICS
03/04/2014
3
What is AMH?
• 140 kDa glycoprotein
• produced during normal
embryogenesis by the Sertoli
cells of the embryonic testis
• causes involution of the
Müllerian duct in developing
males. It inhibits female
gonadogenesis by inducing
apoptosis of target gonadal cells
• TGF-β super family hormone
with paracrine control functions
in folliculogenesis
4
AMH: Direct
Measure of
Ovarian
Reserve
Antonio Lamarca chart
5
Research on
AMH, including
potential clinical
utility, is
increasing rapidly
IVF / Ovarian response and
OHSS
POF
POA
POI
Oncofertility
Ovarian surgery
Gonadotoxicity
Menopause
PCOS
Granulosa cell tumors
Hypogonadotropic
hypogonadism
Non-obstructive
azoospermia
Neonatal gender
determination
What’s next?
6
Primary
Research Areas
Reproductive function and
pregnancy complications
• Comprehensive line of
assays to TGF-beta
superfamily hormones
that play key roles in
folliculogenesis
• Classical and novel
maternal screening
markers for chromosomal
anomalies, preeclampsia,
IUGR, and gestational
diabetes
Reproductive
Function
•
•
•
•
•
•
AMH
Inhibin A
Inhibin B
Total Inhibin
Follistatin
Activin A
Pregnancy
•
•
•
•
Inhibin A
Coming soon!
AFP
I-hCG
• IGFs / BPs
Unconjugated • Activin B
Estriol (UE3) • Activin AB
• PAPP-A
• PAPP-A2
7
8
Predictability of AMH
9
Predictability of AMH
10
AMH is not cycle-day dependent
11
FSH indirect, cycle day dependent
12
FSH is a Surrogate Marker of Ovarian
Reserve
13
Simple utility of direct ovarian markers
14
Introduction to PCOS
• Polycystic ovary syndrome (PCOS) is one of the most
•
•
•
•
common endocrine disorders among females.
PCOS affects 6-12% of women of reproductive age.
In a population like India, that number represents >50 million
females with PCOS in varying degrees of severity, largely
influenced by obesity.
PCOS is comprised of a number of different medical conditions
which can sometimes make definitive diagnosis difficult.
The one common finding that determines PCOS is polycystic
ovaries. This makes AMH an important biochemical feature of
PCOS.
15
Learning
Objectives
After this session
participants will be
able to:
1. explain polycystic
ovary syndrome,
2. explain the most
common criteria
for diagnosing
PCOS,
3. discuss AMH as a
marker of PCOS,
and
4. describe the
benefits of
assessing AMH
for the diagnosis
of PCOS.
16
What is Polycystic Ovary Syndrome
(PCOS)
• A condition in which a woman has an imbalance of female (and male)
sex hormones.
• menstrual cycle changes,
• cysts in the ovaries,
• difficulty getting pregnant / infertility, and
• other health changes.
• Ovaries unable to release mature, competent oocyte.
• PCOS is typically diagnosed in women in their 20s or 30s; it also
affects teenage girls. The symptoms often begin when a girl's periods
start.
• Enlarged ovaries containing numerous small cysts can be detected by
ultrasound, but polycystic ovaries alone do not confirm the diagnosis
though.
17
Symptoms
• Most common includes changes
in the menstrual cycle:
amenorrhea or irregular periods
(MCL and heaviness)
• PCOS can cause virilization
•
•
•
•
Body hair on chest, belly, and face
Decreased breast size
Enlargement of the clitoris (rare)
Thinning of the hair on the head,
i.e., male-pattern baldness
• Voice gets deeper
• Skin changes:
• Acne that gets worse
• Dark or thick skin markings and
creases around the armpits, groin,
neck, and breasts
• Obese
18
Polycystic
Ovary
Morphology
Antral follicles can be seen
lining the periphery of the
ovary, appearing as a 'string
of pearls' on ultrasound
examination.
In PCOS, these antral
follicles are in a state of
arrested development due to
a disruption of normal
folliculogenesis. These
follicles 2-8mm in size
produce the highest
concentrations of AMH.
PCO defined by one or both
ovaries having 12 or more 28 mm follicles and/or an
ovarian volume of >10ml
19
Health
conditions
associated with
PCOS
Women with PCOS are
more likely to develop:
Infertility
Insulin resistance
Type 2 diabetes
Weight gain and
obesity
Metabolic
Syndrome
High blood
pressure
High cholesterol
Cardiovascular
diseases
Inflammation
Endometrial
cancer
Breast cancer
(slightly
increased risk)
20
Elevated
AMH
in PCOS
FIG. 1. Box-and-whisker
plots showing the values
of serum AMH (1ng/ml
7.14 pmol/liter) and 2- to
5-mm follicle number in
patients with PCOS (n
59) and in controls (n 45).
Horizontal small bars
represent the 10–90th
percentile range, and the
boxes indicate the 25th75th percentile range. The
horizontal line in each box
corresponds to the
median.
PASCAL PIGNYET.AL The
Journal of Clinical
Endocrinology &
Metabolism 88(12):5957–
5962
21
AMH in PCOS
Anti-Müllerian hormone
(AMH) before and 5
years after in
anovulatory and
ovulatory group and
control subjects
Fertility and Sterility
Volume 98, Issue 4 ,
Pages 1043-1046,
October 2012
22
Literature
Suggested
Patient
Stratification
AMH AMH
(pmol/L) (ng/mL)
7.00
50
Status
PCOS
• Individualization of
treatment based on
subjective ovarian
response categories
• Treatment strategies
should be designed to
minimize risk while
maximizing oocyte yield
• The suggested AMH /
antral follicle count (AFC)
thresholds are based on
the correlation of AMH
and AFC and the
associated response
obtained from literature.
• These are not
population specific, and
this should be an
important
consideration.
Adapted from: Nelson. Biomarkers of
ovarian response. Fertil Steril 2013.
40
30
20
15
10
7
5
1
5.60
Dx
High Response
AFC
(approx)
50
Tx
Antagonist Control
Agonist Trigger
40
Optimal
Fertility
4.20
2.80
Fertility
2.10
1.40 Normal Response
0.98
SubReduced
0.70
fertility
Response
0.14
Infertility
Neglible
Antagonist Control hCG
Agonist Trigger
30
24
18
Long Down-regulation
12
Agonist Control
10
7
Flare agonist
2 Flare Agonist / Tertiary
actions
23
Differences between commercial assays
Feature
Capture Ab
DRG International, Inc.
specific for a linear epitope on the pro
region not impacted by cleavage
Detection Ab
specific for a linear epitope on the mature directed against the mature region and a
region not impacted by cleavage
conformational epitope, which appears to be
impacted by changes in sample conditions and
cleavage, or both
Specificity
Human specific
Calibration (Ag)
rec human AMH, mammalian (CHO cell)- Bovine serum AMH
derived
None known
Complements, and heterophilic antibodies
(animal IgG, especially bovine)
Dilutes linearly from >75ng/mL to Limit of Do not dilute. Company reports to not dilute over
Detection
10 ng/mL because the samples will over recover.
Affects PCOS and neonatal gender
determinations.
Interference
Dilution
Other Commercially Available Assay
directed against the mature (or is it Pro?) region,
which appears to be a conformational epitope
impacted by different sample collection and
handling conditions and/or naturally occurring
protein processing
Antibodies derived against rec human AMH, but
have significant cross-reactivity with many
species (especially bovine, chicken, rat, mouse,
pig, etc.)
24
Summary of PCOS
• Polycystic ovary syndrome affects between 6 and 12% of all women of reproductive age
worldwide. Some geographies report as high as 18% prevalence!
• Over 70% of PCO / PCOS women are undiagnosed!
• PCOS can be treated, if diagnosed. Periodic checks, repeat diagnostic testing is
prescribed.
• According to the Revised Rotterdam Criteria (most common criteria used for assessment
of PCOS) a patient must demonstrate two out of the three listed criteria:
• Oligo- or amenorrhea
• hyperandrogenism, and
• evidence of polycystic ovary (usually determined by ultrasound).
• Common finding that determines PCOS is polycystic ovaries, which makes AMH an
important biochemical feature of PCOS.
• Because AMH is produced by the granulosa cells of ovary, elevated AMH levels indicate a
polycystic ovary even when an accurate antral follicle count cannot be obtained, and in
the absence of hyperandrogenism and/or anovulation.
• AMH is consistently >2x greater in PCOS than in non-PCO age-matched controls
25
Conclusion
• The DRG International, Inc. assay
methods offer clear analytical and
clinical performance advantages over
other commercially available assays.
• The DRG International, Inc. assay
addresses the challenges raised
regarding the reliability of AMH testing
due to interferences and lab-to-lab
variability presumably due to sample
handling.
• The increased sensitivity and
accuracy throughout the widephysiological range of AMH makes the
DRG International, Inc. assay useful
for broader applications in
gynecological assessment of patients.