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Androgen Gonadotropin Synergy Androgen Gonadotropin Synergy

Androgen Gonadotropin Synergy - PowerPoint Presentation

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Androgen Gonadotropin Synergy - PPT Presentation

David H Barad MD MS Director of Assisted Reproductive Technology Center for Human Reproduction New York NY CHR Grand Rounds May 14 th 2013 Conflict of Interest Dr Barad and Dr Gleicher are listed as coinventors on a number of patents and pending patent applications claiming the ID: 672500

outcome twin pregnancies pregnancy twin outcome pregnancy pregnancies cycles ivf art singleton reporting risks twins 2010 cycle treatment fertility

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Slide1

Androgen Gonadotropin Synergy

David H. Barad, MD MSDirector of Assisted Reproductive TechnologyCenter for Human ReproductionNew York, NY

CHR Grand Rounds

May 14

th

,

2013Slide2

Conflict of Interest

Dr. Barad and Dr. Gleicher are listed as co-inventors on a number of patents and pending patent applications claiming therapeutic benefits from DHEA and other androgens in treatment of infertility and claiming diagnostic and therapeutic benefits from determination of CGG repeat numbers and ovarian FMR1 genotypes and sub-genotypes.Dr. Kushnir has no conflicts of interest.Slide3

Follicles decline with age

The Lancet, Volume 376, Issue 9744, Pages 911 - 921

From

Menkin

J,

Trussel

J, Larsen U.

Science.

1986;233:1389-1394. Reprinted with permission from AAAS.

FertilitySlide4

Ovarian ReserveSlide5

Functional Ovarian Reserve

The Lancet, Volume 376, Issue 9744, Pages 911 - 921Slide6

Androgens decline with AgeSlide7

Rice S et al. JCEM 2007;92:1034-1040

©2007 by Endocrine Society

Primordial Follicle

Transitional Follicle

Primary Follicle

Secondary Follicle

Developing FolliclesSlide8

Rice S et al. JCEM 2007;92:1034-1040

©2007 by Endocrine Society

Androgen, AMH and FSH Receptors

Human Pre-antral FolliclesSlide9

Follicle development in AR KO mice

Molecular Endocrinology 24: 1393–1403, 2010Slide10

Polycystic Ovarian SyndromeSlide11

FSH and Androgen Receptors

Reproductive Biology and Endocrinology 2011, 9:116 doi:10.1186/1477-7827-9-116Slide12

Ovulation InductionSlide13

Follicle Growth

Functional Ovarian Reserve

Functional Ovarian Reserve

Functional Ovarian Reserve

Androgen effect

Androgen plus gonadotropin effectSlide14

Sequential Cycles

85 women with evidence of DFOR 3 consecutive IVF cycles while receiving androgen supplementation with dehyroepiandrosterone (DHEA, 25 mg, TID) for at least 6 weeks prior to the first IVF cycle and ovarian stimulation with 300-450 IU of FSH

68 women with intercycle intervals of < 120 days reflecting concomitant FSH exposure

17 with cycle intervals of ≥120 daysSlide15

Oocyte response to Serial Cycles

Linear trend t = 3.02, DF 51; p = 0.004

< 120 days

> 120 daysSlide16

Oocyte response to Serial Cycles

Linear trend t = 3.02, DF 51; p = 0.004

< 120 days

> 120 daysSlide17

Oocyte response to Serial Cycles

Linear trend t = 3.02, DF 51; p = 0.004

< 120 days

> 120 daysSlide18

Theca Cell Granulosa Cell

Cholesterol

Pregnenolone

17 OH Pregneneolone

Testosterone

Estradiol 17

β

LH

cAMP

cAMP

Protein

Kinase

A

Testosterone

DHEA

FSHSlide19

Federally Mandated IVF Outcome Reporting

(how not

to do it)

Vitaly

A.

Kushnir

M.D.Slide20

Disclosure

I consult for the CDC ART Surveillance TeamThe

Status of Public Reporting of Clinical Outcomes in Assisted Reproductive

Technology

Fertility & Sterility (in press) Slide21

Background

In 1992 President George H.W. Bush signed

The Fertility Clinic Success Rate and Certification Act

(FCSRCA; PL 102-493) into law.

Sponsored by Ron Wyden (D-OR), the statute set out to establish a national public reporting framework for the clinical outcomes of ART programs.Slide22

JAMA. 2011 Sep 14;306(10):1135-6

.Slide23

Implementation

SART

Industry

Voluntary

CDC

Government

StatutorySlide24

Reported Information

Clinic-specific pregnancy & live birth rates stratified by ART modality and maternal age.

Live birth rate per initiated ART cycle, per oocyte retrieval, and per embryo transfer.

Only SART reports total number of initiated cycles

CDC identifies of non-reporting ART programs.Slide25

Reported Information

Program-specific procedural volumes.

Percentage of cycle cancellations.

Average number of embryos transferred

.

Implantation rate

Embryo/gamete cryopreservation capabilities.

Incidence of multiple pregnancies & births.

Aggregated annualized national data.Slide26

Not Reported

Cycles with no immediate outcomes such as

- EMBRYO BANKING

Reports do not

rank

,

rate

, or directly

compare

ART programs in recognition of the differences of their case mix and the variable scope of their practices.

Slide27

Does Public Reporting Improve Clinical Outcomes?

Public reporting of health care outcomes is premised on the tenets of transparency and accountability.

Can public reporting bring about improved clinical outcomes?

Does transparency change behavior of consumers & providers leading to change in quality? Slide28

Investigated Registries

_________________________________________________________________________________________________________ Registry

CDC

SART

Study period (years) 2005-2010 2005-2010

Number of ART clinics

Total 469-484

Reporting (%) 422- 443 (88.2-93.5) 341 (71.9)

Not Reporting (%) 31-57 (6.5-11.8) 133 (28.1)

Number of completed ART cycles 818,927 772,855

Number of started ART cycles 2005-2010 -- 812,400

2005 -- 123,200

2010 -- 146,693Excluded Cycles 2005- 2010 -- 39,545 (4.9%)

2005 -- 4,102

(3.3%)

***

2010 -- 10,821

(7.4%)

***

_________________________________________________________________________________________________________

***

P=<0.001Slide29

ART Cycles Reported and Excluded by SART Slide30

Excluded ART Cycles for 13 Outlier ClinicsSlide31

Pregnancy Rates in Non-Donor Fresh IVF Cycles in Women Under Age 35Slide32

2010 ART Cancellation and Pregnancy Rates

___________________________________________________________________________________________

Outlier Clinics Rest of SART CDC only

13 328 74

____________________________________________________________________________________________

Fresh Cancellation Rate <35 years (%)

Cycle outcome 3.0

***

6.7 8.1

*

Fresh Pregnancy Rate <35 years (%)

Cycle outcome 59.1

***

47.5 45.6Thawed Pregnancy Rate <35 years (%)

Cycle outcome 53.4

*** 37.1 34.2 ____________________________________________________________________________________________ * P=<0.05. *** P=<0.001Slide33

Patient Populations

_________________________________________________________________________________________________

Outlier Clinics Rest of SART CDC only

13 328 74

_________________________________________________________________________________________________

Distribution of Female Patient Population by Age

<38 years (%)

Cycle start

31.2

***

54.5 --

Cycle outcome

51.8***

57.4 60.0***___________________________________________________________________________________________________

***

P=<0.001.OLDER AND POOR PROGNOSIS PATIENT ARE DIRECTED TO EMBRYO BANKING Slide34

Excluded ART Cycles in 13 Outlier Clinics and

Market Share of ART CyclesSlide35

Conclusions

Public reporting creates a health care marketPoor prognosis patients are disproportionately affected

G

overnment agency (CDC) reports provide less transparency than industry group (SART) reports on which it largely relies for data collectionSlide36

Suggested Improvements

Total Reproductive Potential

Better approximates the “true” live birth rate per cycle by including births from fresh and frozen cycles

Prospective reporting

Good Perinatal Outcome

Slide37

Are twins good or bad for America?

Grandrounds, CHR-NYMay 14th, 2013

Norbert Gleicher, MD

Medical Director and Chief

Scientist

,

Center for Human Reproduction – New York

President, Foundation for Reproductive

MedicineSlide38

The Issue

Assuming we can really produce at will singletons and twins, which is the “better” outcome for women who don’t mind twins, and have no medical contraindications for twins?SET, in comparison to 2-ET, reduces pregnancy chances, thereby causing potential medical harm to patients.Not even the most accomplished R.E. can ever guarantee a second consecutive successful pregnancy. Therefore, splitting up potential pregnancy chances into 2 consecutive chances is, ethically, a very questionable proposition.

McLemon

et al., BMJ 2010

Gelbaya

et al., F&S 2010Slide39

We often accept treatment harm IF COMPENSATED BY POTENTIAL TREATMENT BENEFITS!ARE THERE SUCH BENEFITS FROM SET?Slide40

Twin pregnancies carry higher risk than singleton pregnancies!

How do we know?Obstetrical outcome studies!Slide41

Obstetrical Outcomes

Compare: Outcome of one new born (SINGLETON) to outcome of two newborns (TWINS)Slide42

OBSTETRICS:Retrospective

Compares 1 to 2 newborns (1 singleton to 1 twin pregnancy)INFERTILITY:ProspectiveCompares 2 to 2 newborns

(2 singletons to 1 twin pregnancy)Slide43

Twin pregnancy, contrary to consensus, is a desirable outcome in infertility

Norbert Gleicher,

MD, David

H

Barad, MD, MS

Objective

:

To determine whether the worldwide consensus that twin pregnancy after fertility treatment represents an adverse outcome to be avoided is correct.

Design

:

Literature search via

PubMed

and MEDLINE, going back to 1990.

Setting

: Academically affiliated, private fertility center.

Patient(s)

:

Mothers and offspring in singleton and twin pregnancies.Intervention(s): None.

Main Outcome Measure(s)

:

M

aternal and

perinatal

/neonatal risks as well as cost considerations for singleton versus twin pregnancies.

Result(s)

:

Most risk assessments of twin pregnancies after fertility treatment have used spontaneous conceptions data, which reflect different treatment paradigms and outcome benefits from pregnancies after fertility treatments. In vitro fertilization (IVF) twins demonstrate approximately 40% lower outcome risks than spontaneous twin conceptions. Most risk assessments in the literature are calculated with pregnancy as the primary outcome, but in a fertility-treatment paradigm where patients want more than one child the statistically correct risk assessment should refer to born children as the primary reference. If published data are corrected accordingly to achieve statistical commonality of outcome (i.e., one child in singleton versus two children in twins), twin pregnancies no longer demonstrate a significantly increased risk profile and/or cost for mothers or individual offspring.

Conclusion(s)

:

For infertile patients who want more than one child, twin deliveries represent a favorable and cost-effective treatment outcome that should be encouraged, in contrast to the current medical consensus.

Gleicher et al. Fertil Steril

2009;91(6):2426-31.Slide44

Errors Imported by Obstetrical Paradigm

Non-comparable outcome 1 vs 2 newborns;Excessive perinatal risks for IVF twins (ca. 40%)

(

Helmerhorst

et al 2004

)

Too low

perinatal

risks for IVF singleton (Helmerhorst et al 2004)Slide45

Helmerhorst et al 2004 (BMJ 328:261)

Systematic review of 17 matched and 8 non-matched studies, comparing singleton and twin pregnancy outcomes between natural and ART conceptionsSingleton pregnancies after ART

had significantly

worse

perinatal

outcome

Twin

pregnancies after ART had 40% lower perinatal mortalitySlide46

Conclusions

When risk/cost in a prospective infertility paradigm are statistically correctly compared between 2 singleton and 1 twin delivery, twins no longer carry excessive risk/costSlide47

Lemazou et al. Obtaining two children with IVF: a comparison between one twin and two consecutive single pregnancies. J

Gynecol Biol Reprod 2011 (Paris)

Retrospective study of couples desirous of 2 children

115 IVF twin pregnancies

115 consecutive singleton x 2

205 singleton delivery without secondSlide48

“A twin pregnancy after IVF represents a reasonable option to accomplish a parental desire of having two children.”

Lemazou et al. 2010 Cont.Slide49

The irrational attraction of elective single-embryo transfer (

eSET

)

Norbert Gleicher,

MD

Abstract

: In this issue of the journal,

Niinimäki

et al., colleagues from a pioneering Finnish center in the development of elective single-embryo transfer (

eSET

), propose the expansion of

eSET

to suitable women at ages of 40-44 years. This paper offer not only a critique of their proposal but also of

eSET

in general.

Gleicher

N. Hum

Reprod 2013;28(2):294-297.

human

reproduction

INVITED COMMENTARYSlide50

Sazonova et al., Fertil Steril 2013

Patient selection biasesHigher maternal risks: Abruption (OR 1.30) CS (OR 4.19) PROM (OR 0.12)

Previa

(OR -0.37)

Preeclampsia =

Gestational DM =

Maternal mortality =Slide51

Mistaken advocacy against twin pregnancies following IVF

Norbert Gleicher,

MD; David

H

Barad, MD, MS

Purpose

:

A recent publication by Swedish colleagues in Fertility & Sterility for the first time, statistically correctly, attempted to assess risks of twin IVF pregnancies in comparison to two consecutive singleton IVF pregnancies. Historic comparisons have been statistically incorrect, comparing risks of one twin to one singleton pregnancy. We here analyze data and conclusions presented in this Swedish study.

Methods

: We reviewed the manuscript by

Sazonova

et al. (Fertil Steril 2013)..

Results

: Based on incorrect statistical methodology, twins after in vitro fertilization (IVF) have come under attack as “adverse” outcomes. Above noted study recently, for the first time, correctly compared one twin to two consecutive singleton pregnancies. Investigators, however, in our opinion interpreted their own data incorrectly by claiming “dramatically” higher maternal and neonatal risks in twin pregnancies. Our interpretation of reported data, indeed, in contrast suggests surprisingly

minor differences in observed twin risks. Moreover, such minor risk increases do not offer adequate compensatory benefits for significantly lower pregnancy chances in first IVF cycles with

eSET

in comparison to two-embryo transfers (2-ET)

.

Conclusions

: As significantly higher maternal and neonatal risks of twin IVF pregnancies represent the principal rationale for

eSET

, the Swedish study actually suggests that

eSET

offers neither patient-friendly nor cost-effective treatment options for IVF, except where patients object to twins or have medical contraindications. The need for a second pregnancy to achieve equal outcome (2 children), resulting

treatment delays, increased efforts and costs, in absence of any guarantees that a second successful singleton pregnancy/delivery will ever be accomplished, invalidates

eSET

as a routine procedure.

Gleicher

and Barad, J Assist

Reprod

Genet 2013;30(4):575-579.

ASSISTED REPRODUCTION TECHNOLOGIESSlide52

Higher neonatal risks:Respiratory complications (OR 4.42)Jaundice (OR 5.13)

Perinatal mortality =Apgar < 7/5 minutes =Mortality in 1st year =Congenital abnormalities =Slide53

March of Dimes Stakeholder Workshop, June 20-21, 2012 in collaboration with Hastings InstituteSlide54

There is hope!Slide55

PRINCIPAL COLLABORATORS:

David H Barad, MD, MS, CHR

Vitaly A Kushnir, MD, CHR

Andrea Weghofer, MD, PhD, MBA, MS, Medical University Vienna

Ho-Joon Lee, PhD, CHR

Aya Shohat-Tal, PhD, CHR

Yan-

Guang

Wu, PhD CHR

Yao Yu, PhD, CHREmanuela Lazzaroni, MS, CHR

Aritro Sen, PhD, Rochester University School of Medicine & Dentistry & CHRSlide56