Clinical management of men with nonobstructive azoospermia - Steps Before Spe...Sandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Lecture 3: Steps Before Sperm Retrieval in Nonobstructive Azoospermia
Clinical management of men with nonobstructive azoospermia - Steps Before Spe...Sandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Lecture 3: Steps Before Sperm Retrieval in Nonobstructive Azoospermia
Clinical management of men with nonobstructive azoospermia - Role of IVF Labo...Sandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Lecture 5: Role of IVF Laboratory in Nonobstructive Azoospermia
Air quality: is it that important? And if so, how to measure and control it?Sandro Esteves
Quality and Risk Management in the IVF Laboratory; Redlara Brasil, Belo Horizonte, 14-15 September 2016
Content:
1.Air quality: is it that important?
2. How to control?
3. How to measure?
Novel concepts in male factor infertility: clinical and laboratory perspectivesSandro Esteves
Presentation Objectives:
1. Update on the WHO reference values for semen parameters, and understand the role of sperm DNA fragmentation testing to decision-making strategies;
2. Learn how to counsel azoospermic men seeking fertility, and the role of gonadotropin therapy in this infertility condition;
3. Understand the benefits of microsurgery to both sperm retrieval and varicocele treatment;
4. Appraise the role of medical and surgical interventions to infertile men undergoing ART.
Public lecture - Stem Cell and Male InfertilitySandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Public Lecture - Stem Cell and Male Infertility
Clinical management of men with nonobstructive azoospermia - Sperm Retrieval ...Sandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Lecture 4: Sperm Retrieval Methods in Nonobstructive Azoospermia
Clinical management of men with nonobstructive azoospermia - Chances of Harve...Sandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Lecture 2: Chances of Harvesting Sperm in Nonobstructive Azoospermia
Clinical management of men with nonobstructive azoospermia - Azoospermia Diff...Sandro Esteves
Reproductive Andrology Workshop III
17-21 January 2016 - Kuwait City - KUWAIT
Organized by: Al Jahra Reproductive Medicine Unit - Ministry of Health
Lecture 1: Azoospermia Differential Diagnosis
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
1. XVIII Annual Ob-Gyn Conference, Kuwait 2013
Ovarian Biomarkers in
Ovulation Induction
Sandro C. Esteves, MD, PhD
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, Brazil
2. Maximize
beneficial effects of
treatment
Central
Paradigm
Individualization of
Controlled Ovarian
Stimulation
(iCOS)
Minimize
complications
and risks
High-quality
Gametes and
Embryos
Optimal
Endometrial Receptivity
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 2
2013 DECEMBER
ANDROFERT
androfert.com.br
3. Know the best
biomarkers
Understand how they
work
How to use biomarkers
in Ovulation Induction
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 3
2013 DECEMBER
ANDROFERT
androfert.com.br
4. Ovarian Biomarkers in Ovulation
Induction
Esteves SC – Kuwait’s XVIII Annual Ob-Gyn Conference, 2013
http://www.androfert.com.br/review
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 4
2013 DECEMBER
ANDROFERT
androfert.com.br
5. Excessive
Ovarian
Response
Avoid over-aggressive stimulation in ‘true’ high
responders
Diminished
Ovarian
Reserve (DOR)
Why Predict Ovarian
Response in OI?
Avoid over-conservative stimulation in ‘true’
DOR
Avoid over-conservative stimulation in ‘false’
high responders
Avoid over-aggressive stimulation in ‘false’
DOR
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 5
2013 DECEMBER
ANDROFERT
androfert.com.br
6. For Patients
Prediction of Ovarian
Response in OI
Realistic Prognosis
• Poor or Negligible Response
• Cycle cancellation
• Egg donation or adoption
• Chances of Pregnancy and Live
Birth
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 6
2013 DECEMBER
ANDROFERT
androfert.com.br
7. Know the Biomarkers
Hormonal Biomarkers
FSH, Clomiphene citrate challenge test,
Inhibin-B, Anti-Mullerian Hormone (AMH)
Functional Biomarkers
Antral Follicle Count (AFC)
Genetic Biomarkers
Single Nucleotide Polymorphisms for FSH, LH,
E2 and AMH receptor genes
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 7
2013 DECEMBER
ANDROFERT
androfert.com.br
8. A Valid Biomarker Should be
Highly Sensitive and Highly Specific
Diminished or Excessive
Ovarian Response
Specificity (D/B+D)
Predictive Value
(PPV=A/A+B; NPV=D/C+D)
Accuracy
(A+D/A+B+C+D)
Esteves, 8
Biomarker Test Result
Sensitivity (A/A+C)
+
-
+
True
Positive
(A)
False
Positive
(B)
-
False
Negative
(C)
True
Negative
(D)
Adapted from: ASRM Practice Committee, Fertil Steril 2012;98:147
10. Biomarkers in OI
In a group of 131 women
undergoing conventional
COS after pituitary downregulation for IVF:
Population
AMH*
ng/mL
Cut-off
Sensitivity
Specificity
Accuracy
Highresponder1
2.1
85%
79%
0.82
Poor
responder2
0.82
76%
86%
0.88
*Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 10
2013 DECEMBER
ANDROFERT
androfert.com.br
11. AMH and AFC are not
accurate for pregnancy
prediction
Evidence
Level
1a
Broer et al. Fertil Steril 2009 ; Broer et al. Hum Reprod Update, 17:46; 2011
Esteves, 11
12. How AMH and
AFC Work
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 12
2013 DECEMBER
ANDROFERT
androfert.com.br
13. AMH
AFC
Esteves, 13
Reflect No. pre-antral and
small antral follicles
(≤4-8mm)
2D-TVUS early follicular phase
2-10 mm (mean diameter)
No. AF at a given time that can
be stimulated by medication
La Marca et al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097;
Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700
.
14. Low Inter-cycle Fluctuations (Fanchin et al, Hum Reprod 2005;20:923)
AMH
ICC: 0.89; 95% IC: 0.83–0.94
Can be assessed at any cycle day
with a single measurement
Low Intra-cycle Fluctuations (Hehenkamp et al. JCEM 2006;91:4057)
Max. Variation: 17.4%
Esteves, 14
ICC: 0.55; 95% IC: 0.39–0.71
Max. Variation: 108%
15. Serum Levels:
AMH
Peak at age 25 and decrease with aging
Early marker of diminished ovarian reserve
Non-growing
follicles (NGF)
recruited per
month
Esteves, 15
Kelsey et al. Mol Hum Reprod 2012;18:79
16. AMH
Accurate to Predict Ovarian Response
Cut-off point 3.5 ng/mL* (Nardo et al, Fertil Steril 2009;92:1586)
Ø High sensitivity (88%), specificity (70%)
and accuracy (0.81) to predict excessive response1
Cut-off point 1.4 ng/mL* (Kwee et al, Fertil Steril 2008;90:737)
Ø High sensitivity (76%) and specificity (86%) for DOR2
Caution to apply AMH cut-off points!
Make sure the assay you rely on is the
same used in the reference population
Esteves, 16
*DSL assay; 1>20 oocytes retrieved; 2≤5 oocytes retrieved;
Conversion: ng/mL to pmol/L = value in ng/mL X7.14
17. AMH
ELISA assays with different
performances:
DSL and Immunotech
Beckman-Couter gen II (AB DSL + Curves Im.)
Fully automated ELISA (to be released)
Lack international standardization
and EQC
Sample instability; measured levels
altered by handling
Collection in EDTA
Storage at room temperature (up to 40% increase)
No separation of serum from blood before postage
Esteves, 17
Fleming et al. RBM online 2013;26:130; Nelson SM. Fertil Steril. 2013 Jan 8;
Nelson & La Marca. RBM online 2011;23:411;
18. Moderate to Low Inter-cycle
Fluctuations
AFC
van Disseldorp et al, Hum Reprod 2010;25:221
Esteves, 18
ICC: 0.71 (95% CI: 0.63–0.77);
29% individual cycle
variation
High Inter- and Intra-observer Reproducibility
Scheffer et al. Ultrasound Obstet Gynecol 2002;20:270
19. Accurate to Predict Ovarian Response
Cut-off point of 14
Kwee et al, Fertil Steril 2008;90:737
AFC
High sensitivity (81%) and specificity (89%) to predict
excessive response1
Cut-off point of 4 Bancsi et al, Fertil Steril 2002;77:328
Moderate sensitivity (61%) and High specificity
(88%) and to predict DOR2
Caution to Apply Cut-off Points to Predict No.
of Oocytes to be Retrieved
For any given AFC there is a potential oocyte yield, but it
can be altered by the stimulation strategy
Esteves, 19
1>20
oocytes retrieved in conventional COS; 2≤4 oocytes retrieved
20. Lack of standardization1
• Inclusion criteria for antral follicles
AFC
Ø e.g., 2–5 mm or 2–10 mm
• Method for counting and measuring
follicles
• Variable scanning techniques
• Image optimization
Improved standardization
proposed2
Three-dimensional automated
follicular tracking3
• Reduce intra- and inter-observer variability
• Requires offline analysis
1Nelson SM. Fertil Steril. 2013 Jan 8;
• Costly
2
Esteves, 20
Broekmans et al., Fertil Steril, 2010; 94(3):1044-51;
3Raine-Fenning et al., Fertil Steril 2009;91:1469.
21. How to Use AMH
and AFC in OI
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 21
2013 DECEMBER
ANDROFERT
androfert.com.br
22. Evidence
Level
2b
Biomarkers for iCOS in High
Responders
AMH (ng/mL) >2.1¶
GnRH Agonist
Low-starting FSH dose (150 UI)
(n=148)
GnRH
Antagonist
(n=34)
Days of Stimulation
13 (12-14)
9 (8-11)*
No. Oocytes retrieved (n)
14 (10-19)
10 (8.5-13.5)*
OHSS requiring hospitalization
20 (13.9%)
0 (0%)*
4 (2.7%)
1 (2.9%)
40.1%
63.6%*
Cancellation
CPR per transfer
*P ≤ 0.01
Esteves, 22
¶DSL assay; Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to
controlled ovarian stimulation for assisted conception. Hum Reprod. 2009; 24(4):867-75.
23. Evidence
Level
GnRH Antagonists in High
Responders
1a
9 RCT; 966 PCOS women
GnRH Antagonist X Agonist
Weight Mean Difference (WMD)1;
Relative Risk (RR)2
Duration of OS
-0.74 (95% CI: -1.12; -0.36)1
Gonadotropin dose
-0.28 (95% CI: -0.43; -0.13)1
Oocytes retrieved
0.01 (95% CI: -0.24; 0.26)1
Risk of OHSS (Moderate & Severe)
20% vs 32%
0.59 (95% CI: 0.45-0.76)2
Clinical PR
1.01 (95% CI: 0.88; 1.15)2
Miscarriage rate
0.79 (95% CI: 0.49; 1.28)2
~40% reduction in moderate/severe OHSS by using
antagonists rather than agonists
Esteves, 23
Pundir J et al. RBM Online 2012; 24:6-22.
24. GnRH Antagonist Protocol with
Long-acting recFSH vs recFSH
4 RCT; 2377 pts.
Clinical PR, Miscarriage, LBR
Risk of OHSS
Cancellation
OR [95% CI]
Not different
1.29 (0.78; 2.26)
5.67 (1.07; 30.13)*
*p=0.04; risk of OHSS
Mahmoud Youssef et al. van Fertil Steril 2012; 97(4): 876-85; Pouwer AW et al.
Cochrane Database Syst Rev 2012; 6: CD009577.
Esteves, 24
25. Biomarkers for iCOS in Poor
Responders
Up to 45% of Infertility Patients in ART
Older patients (≥35 years)
Poor responders
Slow/Hypo-responders
Deeply suppressed endogenous LH
Marrs et al. Reprod Biomed Online 2004;8:175;Mochtar MH, Cochrane Database, 2007; Alviggi,
et al. RBMOnline 2009; De Placido et al. Clin Endocrinol (Oxf) 2004;60:637
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26. Ovarian Aging
Impaired Oocyte Quality
Reduced Fertilization Rate
Reduced Embryo Quality
Increased Miscarriage Rates
Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002
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27. Normal
LH “Window” Concept
• Normal androgen and estrogen biosynthesis
• Normal follicular growth and development
• Normal oocyte maturation
Reduced
ovarian
paracrine
activity
Androgen
secretory
capacity
reduced
Decreased
numbers of
functional
LH receptors
Reduced LH
bioactivity
Hurwitz & Santoro
2004
• Piltonen et al.,
2003
• Vihko et al. 1996
• Mitchell et al. 1995;
Marama et al 1984
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28. Level
1a
LH Supplementation in DOR
Regimen
Mochtar et al, 2007
3 RCT (N=310)
Poor responders
Bosdou et al, 2012
7 RCT (N= 603)
Poor responders
Outcome
Effect on Pregnancy
r-hFSH+rLH
vs.
r-hFSH alone*
OPR
OR: 1.85
r-hFSH+rLH
vs.
r-hFSH alone*
CPR
LBR
(only 1 RCT)
Hill et al, 2012
7 RCT (N=902)
Women advanced age ≥35
yrs.
r-hFSH+rLH
vs.
r-hFSH alone
CPR
(95% CI: 1.10; 3.11)
RD: +6%,
(95% CI: -0.3; +13.0)
RD: +19%
(95% CI: +1.0; +36.0%)
OR: 1.37
(95% CI: 1.03; 1.83)
*long GnRH-a protocol; OR=odds-ratio; RD=risk difference
Esteves, 28
Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al,
Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.
29. Rationale of LH supplementation
Action of LH at the follicular level in a dose dependent
manner increases androgen production;
Androgens are later aromatized to estrogens and may help
restore the follicular milieu;
LH has also a direct positive effect on final follicular
maturation;
Altogether, positive effect in oocyte quality and, therefore,
embryo quality and implantation.
Esteves, 29
30. Sources of LH Activity
Purity
(LH content)
hCG
content
(IU/vial)
LH activity
(IU/vial)
Specific activity
(LH/mg protein)
Rec-hLH
>99%
0
75
22,000 IU
hMG-HP*
3%
~70
75*
≥ 60 IU
*derives from hCG
Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.
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31. Sources of LH Activity
Sources of LH Activity
Beta unit
hCG
Longer in hCG;
(Higher
receptor
affinity)
Carboxyl
terminal
segment
Absent in LH and
present in hCG
(Longer Half-life)
LH
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32. hMG
Grondal et al. 2009:
r-FSH
Sources of LH Activity
GCs gene expression in pts. treated with
hMG and rec-hFSH
q Lower expression of LH/hCG receptor
gene and other genes involved in
steroids biosynthesis in hMG group
Down-regulation of receptors owed to
constant ligand exposure to hCG
(Menon et al. 2004)
CYP11A activity decreased by 2.4 fold
Lower steroids synthesis and P levels
q Higher potency of rec-hFSH inducing
more LH/hCG receptors
Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Menon KM et al. Biol Reprod 2004; 70:861-866
Esteves, 32
33. Sources of LH Activity
Matched case-control study; N=4,719 IVF pts.
35
30
25
P=0.02
31
26
20
15
25
19
14
10
14
5
Duration of
Stimulation
(days)
Mean No.
oocytes
retrieved
IR (%)
CPR per
transfer (%)
0
Fixed 2:1 r-hFSH
(150IU)/r-hLH
(75IU)
HMG
rec-hFSH + HMG
Buhler KF, Fisher R. Gynecol Endocrinol 2011;1-6.
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34. Individualization of OI with AMH
AMH cut-off points used to individualize COS in 118
women undergoing IVF;
Outcome compared with a group of 131 women who
received conventional stimulation
High
Responders
AMH >2.1
Poor
Responders
AMH ≤ 0.82
Esteves, 34
rec-hFSH FbM 112.5 to 150 IU daily +
GnRH antagonist
rec-hFSH FbM + 75 IU rec-hLH
+ GnRH antagonist
• Total daily dose: 262.5 to 375 IU
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
37. Take Home Messages
AMH and AFC are currently the best biomarkers
to predict ovarian response to COS.
AMH and AFC are direct biomarkers of ovarian
reserve. Both markers have similar accuracy to
predict who is at risk of excessive and poor
response in COS.
After identifying ‘Who is Who’, mild stimulation and
GnRH antagonists in pts. at risk of excessive
response, and rec-hLH supplementation in DOR,
maximize treatment benefits and minimize risks.
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39. iCOS Using AMH
Excessive1
Oocytes retrieved
OHSS
Pregnancy
Poor2
Oocytes retrieved
Cancellation
Pregnancy/ET
1Excessive
Esteves, 39
iCOS
(n=118)
P
value
39.3%
Response to COS
Conventional COS
(n=131)
14.3%
18.5 ± 6.7
14.3%
57.1%
14.7± 6.2
4.8%*
55.6%
0.03
0.04
0.38
0.92
72.0%
3.5 ± 3.1
45.0%
20.0%
46.6%
4.8 ± 3.5
23.3%
26.8%
0.02
0.03
0.06
0.51
response: >20 oocytes retrieved; 2Poor response: <5 oocytes retrieved;
*Pts. received GnRH-a trigger + embryo vitrification; No severe OHSS reported
40. Progesterone Rise
What we have learned…
Number of oocytes
Estradiol levels on hCG day
FSH dose
Rec-hFSH vs. hMG
positively
associated
with P levels
P levels not associated with oocyte and embryo
quality, nor with fertilization and cleavage rates
Bosch et al. 2008, 2010; Xu et al, 2012;
Kolibianakis et al 2012; Venetis et al. 2012; Griesinger et al 2013
Esteves, 40
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42. Progesterone thresholds
affecting PR controversial
Bosch et al. 2010 (N=4,032)
Irrespective of GnRH analogue;
CUT-OFF = 1.5 ng/mL
Xu et al, 2012 (N=11,055)
GnRH agonist
Ovarian
response
Number of
oocytes
Serum P
threshold
(ng/mL)
Poor
≤4
1.5
Intermediate
5-19
1.75
High
≥20
■ Fresh
■ FET
2.25
Esteves, 42
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43. Effect of progesterone levels on day of
hCG administration on pregnancy
Griesinger et al, 2013 (6 RCT, N=1866; Antagonist cycles)
P4 cut-off: 1.5 ng/mL
P4 rise related to
ovarian response:
Low-responder: 4.5%
High-responder: 19%
Overall: 8.4%
OPR not impaired in
high responders with P
elevation
Ongoing PR: OR = 0.55 (0.37–0.81)
Griesinger et al. Fertil Steril 2013
Esteves, 43
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