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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.
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03/04/2014
AMH BEYOND IVF: RAISING THE BAR IN REPRODUCTIVE HEALTH DIAGNOSTICS
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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
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AMH: Direct Measure of Ovarian Reserve
Antonio Lamarca chart
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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?
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Primary Research Areas
Click icon to add picture
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• AFP• I-hCG• Unconjugated
Estriol (UE3)• PAPP-A• PAPP-A2
Coming soon! • IGFs / BPs
• Activin B • Activin AB
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Predictability of AMH
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Predictability of AMH
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AMH is not cycle-day dependent
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FSH indirect, cycle day dependent
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FSH is a Surrogate Marker of Ovarian Reserve
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Simple utility of direct ovarian markers
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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.
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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.
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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.
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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
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Polycystic Ovary MorphologyAntral 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 2-8 mm follicles and/or an ovarian volume of >10ml
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Health conditions associated with PCOSWomen 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)
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Elevated AMHin PCOSFIG. 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 25th-75th 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
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AMH in PCOSAnti-Müllerian hormone (AMH) before and 5 years after in anovulatory and ovulatory group and control subjects
Fertility and SterilityVolume 98, Issue 4 , Pages 1043-1046, October 2012
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Literature Suggested Patient Stratification
AMH (pmol/L)
AMH (ng/mL)
Status DxAFC
(approx)Tx
50 7.00PCOS
50 Antagonist Control Agonist Trigger
40 5.60 40
30 4.20 3020 2.80 2415 2.10 1810 1.40 12
7 0.98 105 0.70 Reduced
ResponseSub-
fertility7
Flare agonist
1 0.14Neglible Infertility
2 Flare Agonist / Tertiary actions
Normal Response
High ResponseAntagonist Control hCG
Agonist Trigger
Fertility Long Down-regulation Agonist Control
Optimal Fertility
• 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.
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Differences between commercial assays Feature DRG International, Inc. Other Commercially Available AssayCapture Ab specific for a linear epitope on the pro
region not impacted by cleavagedirected 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
Detection Ab specific for a linear epitope on the mature region not impacted by cleavage
directed against the mature region and a conformational epitope, which appears to be impacted by changes in sample conditions and cleavage, or both
Specificity Human specific Antibodies derived against rec human AMH, but have significant cross-reactivity with many species (especially bovine, chicken, rat, mouse, pig, etc.)
Calibration (Ag) rec human AMH, mammalian (CHO cell)-derived
Bovine serum AMH
Interference None known Complements, and heterophilic antibodies (animal IgG, especially bovine)
Dilution Dilutes linearly from >75ng/mL to Limit of Detection
Do not dilute. Company reports to not dilute over 10 ng/mL because the samples will over recover. Affects PCOS and neonatal gender determinations.
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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
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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 wide-physiological range of AMH makes the DRG International, Inc. assay useful for broader applications in gynecological assessment of patients.
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