Individualized stimulation protocols maximize benefits and minimize risks in OI/IUI cycles. Biomarkers like AMH and AFC can help predict ovarian response. For CC stimulation, 50mg daily for 5 days is typically used for up to 3 cycles before considering injectables. Low-dose step-up gonadotropin stimulation starting at 37.5-50IU is effective with fewer risks than conventional protocols. Recombinant hormones provide similar outcomes to urinary products but with less impurities. Adding recombinant LH may benefit some patients, like those with low LH levels.
DOC2 - No significant risk levels 4 MI - CaliforniaToxiColaOrg
Esta es la propuesta que está presentando la Oficina de Riesgos Ambientales en la Salud de la Agencia de Protección Ambiental de California para establecer un nivel máximo de ingesta diaria de 4-Metilidimadazol (compuesto cancerígeno que se encuentra en el Caramelo IV utilizado en las bebidas de Cola) que no signifique riesgo a la salud. La propuesta de la autoridad en California es que no se consuma más de 16 microgramos de este compuesto en todo un día. Como se ve en el DOC3, la cantidad de 4-Metilidimadazol que se encuentra en una lata de bebida de cola puede ser 8 veces más de este límite.
In ART, GnRH antagonists are effective in preventing a premature LH surge and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol.
DOC2 - No significant risk levels 4 MI - CaliforniaToxiColaOrg
Esta es la propuesta que está presentando la Oficina de Riesgos Ambientales en la Salud de la Agencia de Protección Ambiental de California para establecer un nivel máximo de ingesta diaria de 4-Metilidimadazol (compuesto cancerígeno que se encuentra en el Caramelo IV utilizado en las bebidas de Cola) que no signifique riesgo a la salud. La propuesta de la autoridad en California es que no se consuma más de 16 microgramos de este compuesto en todo un día. Como se ve en el DOC3, la cantidad de 4-Metilidimadazol que se encuentra en una lata de bebida de cola puede ser 8 veces más de este límite.
In ART, GnRH antagonists are effective in preventing a premature LH surge and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol.
Improving Success by Tailoring Infertility Treatments - We are all individualsSandro Esteves
Aula ministrada pelo Dr. Sandro Esteves no 5th. Dubai International Obs-Gyne & Fertility Conference & eXHIBITION DIOFCE 2010, em 05 de novembro de 2010.
Workshop on Management of poor prognosis patientsMatheus Roque
In this presentation, it was discussed new concepts in stratification of low prognosis patients. It was also discussed the differences between LH and hCG, and how they can have an influence during COS.
Which type of Gonadotrophins should we use for ovarian stimulation in IVF?Hesham Al-Inany
There are many types of gonadotropins: some are recombinant , others are urinary derived. some contain LH like activity , others do not. which to use?? many research with conflicting results but the final word came from Cochrane mega- systematic review. This talk will illustrate this issue
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.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
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.
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
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
1. Is There a Best Stimulation
Protocol in OI/IUI Cycles?
Sandro Esteves, M.D., Ph.D.
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, BRAZIL
ASPIRE III, Istanbul, September 2013
2. Esteves, 2
Is There a Best Stimulation
Protocol in OI/IUI Cycles?
Review this Lecture at:
http://www.androfert.com.br/review
ASPIREIII,Istanbul
September2013
3. Esteves, 3
Level Type of evidence
1a Meta-analysis of randomized trials
1b At least one randomized trial
2a Well-designed controlled study without
randomization
2b At least one other type of well-designed quasi-
experimental study
3 Well-designed non-experimental studies
(comparative and correlation studies, case series)
4 Expert committee reports or opinions or clinical
experience of respected authorities
Adapted from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009)
Level of
Evidence
OI and IUI population
Grade A recommendation
6. Esteves, 6
Singleton
live birth at
term
Maximize
Beneficial
Effects
1Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; 2Cantineau et al.,
Cochrane Database Syst Rev. 2007; 18:CD005356;
3Aboulghar. Fertil Steril. 2012;97:523-6.
Multiple
Pregnancy2
10-40%
Cycle
Cancellation1
2-8%
Risk of OHSS
OHSS3
Severe 2%
Moderate 3-6%
Minimize Complications
and Risks
7. Age, BMI, Race
Genetic profile
Cause
Duration
Health
Nutrition
Esteves, 7
8. Reproductive Hormones Report - GCC Countries (Feb 2011)
Bologna criteria: Ferraretti et al. Hum Reprod 2011.
Esteves, 8
Up to
68%
Infertile Patients (WHO II)
with PCO in Clinical Practice
Up to 45% Patients
Aged ≥35 have Poor
Response to
Stimulation
9. Esteves, 9
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
Reflect No. Pre-antral and Small Antral
Follicles (≤4-8mm)
Low inter and intra-cycle variation
AMHAFC
2D-TVUS at early follicular phase
2-10 mm (mean diameter)
Reflect No. AF at a given time that can be
stimulated by medication
Relatively low inter-cycle variation
11. 1Nardo et al. Fertil Steril 2009; 2Checa et al. Fertil Steril 2010
Esteves, 11
AMH
(ng/mL)
AFC False
Result
Risk
OHSS1,2 >3.5 >16 ~15%
pmol/L X1000/140
Level
2a
12. Esteves, 12
Individualized approaches maximize treatment
beneficial effects and minimize complications
and risks.
Biomarkers, AMH and AFC, are useful to predict
ovarian response and to define an
individualized stimulation.
14. Pituitary
GnRH
FSH/LH
estrogen
Hypothalamus
Ovary
ClomipheneCitrate
Esteves, 14
Similar to estrogen
Extended binding depletes ER levels1
Ovulatory women
Increase GnRH pulse frequency2
PCOS
Increase GnRH amplitude3
1Clark & Markaverich. Pharmacol Ther 1982;15:467; 2Kerin JF et al. J Clin Endocrinol Metab
1985;61:265; 3Kettel et al. Fertil Steril 1993;59:532; 4Ibrahim et al. Arch Gynecol Obstet.
2012;286:1581; 5Annapurna et al. Int J Fertil Womens Med 1997;42:215.
Negative Effect on
Endometrium4 and
Cervical Mucus5
15. ClomipheneCitrate
Esteves, 15
How to Use?
Dose: 50 mg/d for 5 days
UltrasoundMenses
Start day
CC
2 3 4 5 76 8 9 10 11 12 131
Adapted form the ASRM Practice Committee. Fertil Steril 2003;5:1302–8
Ultrasound
16. Points to ConsiderClomipheneCitrate
Esteves, 16
PCOS: >75% of anovulatory infertility
~25% CC-resistant (mainly obese & hyperandrogenic)
~15% who ovulate have thin endometrium/poor mucus
Ultrasound monitoring
1. Dose can be adjusted, if necessary, in subsequent
cycles.
2. Allows endometrial evaluation.
In IUI, endometrial appearance/thickness more important than
follicle size for hCG administration
3. Assessment for the risk of OHSS.
17. 50 mg/d 100 mg/d 150 mg/d
OvulationOvulation
2 – 3 cycles with the same dose
Ovulation
No
Ovulation
No
Ovulation
No
Ovulation
No pregnancySuboptimal Endometrium
(thickness <7mm)
Injectable
Gonadotropins
ClomipheneCitrate
Esteves, 17
Hypogonadotropic
Hypogonadism
Adapted from the ASRM Practice Committee. Fertil Steril 2003;5:1302–8
How Many Cycles and How?
19. Esteves, 19
Low Dose Step-up StimulationGonadotropins
Starting dose: 37.5 - 50 IU (rec-hFSH)
Step-up (by 37.5 IU) if no follicles >10mm after 7 days
Step-up every 7 days until dominant follicle appear
hCG ≥18mm and endometrium ≥7mm
2 3 4 5 76 8 9 10 11 12 131
Ultrasound
Menses
Start day
14 15
20. Gonadotropins
N = 968 Cycles
>70% ovulatory cycles
>85% monofollicular development
Threshold to produce a dominant follicle:
37.5 to 75 IU (~75%)
Average stimulation duration: 15 days
CPR after 6 cycles: ~60%
No OHSS; ~10-15% cancellation
(multifollicular development)
Low Dose Step-up Stimulation in PCO
Esteves, 20
21. Points to Consider
Esteves, 21
Gonadotropins
Be patient!
It may take 10 days or more for a dominant follicle to
appear during the first treatment cycle with low-dose
gonadotropin.
TVUS scan before starting:
if endometrium thickness >8 mm, we use progestin
(medroxyprogesterone acetate, 5-10 mg/d) to induce a
withdrawal bleed.
24. Esteves, 24
Injectable gonadotropins when…
3 CC ovulatory cycles but no pregnancy
Suboptimal endometrium thickness (< 7mm) after CC-OI
No response with CC 150 mg/d
WHO I (hypo-hypo) anovulation
Yields higher PR than CC without increased
risks.
Low-dose (37.5 to 50 IU) step-up (every 7d)
stimulation is the best protocol.
27. Bassett et al. Reprod Biomed Online 2005;10:169–177.
Purity
(protein
content)
Mean specific
activity
(IU/mg protein)
LH
activity
(IU/vial)
Injected
protein per
75 IU (mcg)
hMG < 5% ~100 75 ~750
hMG-HP < 70% 2,000–2,500 75 ~33
rec-hFSH* > 99% 13,645 0 6.1
Esteves, 27
RecombinantvsUrinary
*Follitropin alfa
28. Esteves, 28
Level
1a
Matorras et al. Fertil Steril. 2011;95(6):1937-42
3 RCT; “equal dose group”
Higher PR with rec-hFSH (16.4% vs 12.3%)
RR: 1.39 (95% CI: 1.00-1.96)
Meta-analysis Rec-hFSH vs HP-uFSH in IUI
6 RCT; (N=713 pts; 1,581 cycles)
Similar PR: 14.5% vs 14.9% with rec-FSH dose 50%
lower (RR: 0.970; 95% CI: 0.68-1.37)
Recombinantvs
Urinary
29. Esteves, 29
68%
25%
Folitropin alfa
prefilled ready-to-
use pen
Needle-free
reconstitution,
conventional
syringe
Easy of use 58%
Dosing mechanism 43%
Less chance of error 26%
Reasons
Weiss N. RBMonline 2007;15:31-7
Level
2a
• Allowed injections
at home
• Improved pts.
satisfaction (QOL)
30. ; Bassett et al. Reprod Biomed Online 2005;10:169–177;
Driebergen et al. Curr Med Res Opin 2003;19:41–46.
Steelman-Pohley
Bioassay
High
variability
Rat ovary
weight
gain
Esteves, 30
Gonadotropin injected sc
1x 3days
Sacrifice day 4
and collect Ovaries
Ovaries are weighed and
data processed
UrinaryProducts
31. Bassett et al. Reprod Biomed Online 2005;10:169–177;
Driebergen et al. Curr Med Res Opin 2003;19:41–46.
FbM: Novel analitycal
method
Protein content in
solution by mass
1.6% batch-to-batch
variability
Follitropin alfa
Esteves, 31
Size Exclusion High
Performance Liquid
Chromatography
(SE- HPLC)
37.5
62.5
50
RecombinantProducts
32. hCG for Triggering
Ovulation
Urinary
lyophilized vials
(5,000-10,000 IU)
IM
Recombinant
choriogonadotropin
alfa
pre-filled syringes
(250 mcg ≅ 6,750 IU)
SC
Recommended Dose: 5,000 IU (or 250 mcg rec-hCG)
ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; Tsoumpou et al. Reprod
Biomed Online. 2009;19:52-8
Recombinantvs
Urinary
33. Esteves, 33
When: 19–30 mm (~25 mm)1
2D TVUS
Mean Diameter of Dominant Follicle Size
23-28 mm (988 IUIs with CC & Letrozole)2
≥16 mm (620 IUIs with gonadotropins)3
hCG for Triggering
Ovulation
1ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20;
2Palatnik et al, Fertil Steril 2012;97:1089–94;
3da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012;164:156-60.
34. Clinical Efficacy
LH Surge
RCT N Odds-ratio
Live birth 6 1,019 OR: 1.04 (95% CI 0.79 to 1.37)
Miscarriage 7 1,106 OR: 0.69 (95% CI: 0.41 to 1.18)
Severe OHSS 3 549 OR: 1.49 (95% CI: 0.54 to 4.1)
Side Effects 3 374 OR: 0.39 (95% CI: 0.25 to 0.61)
Level
1a
Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719.Esteves, 34
Recombinantvs
Urinary
35. Esteves, 35
Better safety, purity and potency with
recombinants.
Similar PRs using 50% less dose with rec-hFSH;
Higher PR with the same dosage.
SC self-injection and individualized stimulation
using small dose adjustments with Pen
injectors.
Better tolerability with rec-hCG.
38. Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265.Esteves, 38
• Normal androgen and estrogen biosynthesis
• Normal follicular growth and development
• Normal oocyte maturation
Normal
• Suppression of GC proliferation
• Follicular atresia (non-dominant follicles)
• Premature luteinization
• Oocyte development compromised
High
• Insufficient androgen (and estrogen) synthesis
• Follicular maturation impaired
• Inadequate endometrial proliferation
Low
39. WHO group I (LH levels <1.2 UI/L)
Level
1b
Esteves, 39
LHinOI/IUI
Similar follicular development HMG vs FSH + rec-hLH;
Higher cumulative PR after 3 cycles in FSH + rec-hLH
(56% vs 23%; p=0.01)
Carone et al., 2012
Higher follicular
development pts.
receiving LH
(67% vs 20%; p=0.02)
Shoham et al., 2008
40. Level
1b
Esteves, 40
Clomiphene-resistant
Fewer intermediate-sized follicles and OHSS in LH-supl.
vs FSH group; similar ovulation rate. Plateau, 2006
Previous Excessive Response
Higher monofollicular development in LH group
(32% vs 13%; p=0.04). Hughes et al., 2005
IUI
Higher monofollicular development in LH group w/o
intermediate-size (42% vs 11%; p=0.03);
Lower cycle cancellation due to risk of OHSS (-7%
difference). Segnella et al., 2011
WHO group IILHinOI/IUI
41. Esteves, 41
• ~80% normogonadotropic women
undergoing Ovarian Stimulation1,2
Normal
• 15-20% of NG women have less
sensitive ovaries
• Older patients (≥35 years)3
• Poor responders4
• Slow/Hypo-responders5
• Deeply suppressed endogenous LH
levels (hypo-hypo; endometriosis treated with
GnRH-a)6
Low
1Tarlatzis et al. Hum Reprod 2006;21:90; 2Esteves et al. Reprod Biol Endocrinol 2009;7:111;
3Marrs et al. Reprod Biomed Online 2004;8:175;4Mochtar MH, Cochrane Database, 2007;
5Alviggi, et al. RBMOnline 2009; 6De Placido et al. Clin Endocrinol (Oxf) 2004;60:637
LHinOI/IUI
42. Reduced
ovarian
paracrine
activity
Hurwitz &
Santoro 2004
LH
receptor
poly-
morphisms
Alviggi et al.,
2006
Androgen
secretory
capacity
reduced
• Piltonen et al.,
2003
Decreased
numbers of
functional
LH
receptors
• Vihko et al. 1996
Reduced
LH
bioactivity
while
imnuno-
reactivity
unchanged
• Mitchell et al.
1995; Marama et
al 1984
Action of LH at the follicular level increases androgen
production for its later aromatization to estrogens;
May restore the follicular milieu with positive impact on
oocyte quality.
LHinOI/IUI
43. Mochtar et al,
2007
3 RCT (N=310)
r-hFSH+rLH vs.
r-hFSH alone*
OPR
OR 1.85
(95% CI: 1.10; 3.11)
Bosdou et al,
2012
7 RCT (N= 603)
r-hFSH+rLH vs.
r-hFSH alone*
CPR
LBR
(only 1 RCT)
RD: +6%,
(95% CI: -0.3; +13.0)
RD: +19%
(95% CI: +1.0; +36.0%)
Hill et al, 2012
7 RCT (N=902)
r-hFSH+rLH vs.
r-hFSH alone CPR
OR 1.37
(95% CI: 1.03; 1.83)
*long GnRH-a protocol; OR=odds-ratio; RD=risk difference
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.Esteves, 43
44. Esteves, 44
PCOS w/previous excessive response
Add 75 IU LH activity from D1 (min. 7 days)
Hypo-hypo
Add 75 IU LH activity from D1
Poor responders
1:1 or 2:1 FSH/LH ratio from stimulation D1
Add 75 IU LH activity starting on D6
2 3 4 5 76 8 9 10 11 12 131
Ultrasound
Menses
14 15
LHinOI/IUI
45. *derives from hCG
Beta unit Carboxyl terminal segment
Longer in hCG; higher
receptor affinity
Absent in LH and present in
hCG (Longer Half-life)
Purity
(LH
content)
hCG
content
(IU/vial)
LH
activity
(IU/vial)
Specific
activity
(LH/mg
protein)
>99% 0 75 22,000 IU
3% ~70 75* ≥ 60 IU
Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.Esteves, 45
Rec-hLH
hMG-HP*
46. HMG: lower expression of LH/hCG
receptor and other genes involved
in steroids biosynthesis in GC
Down-regulation due to constant
ligand exposure of receptors to hCG
Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. Biol
Reprod 2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Esteves, 46
Level
2a
47. Esteves, 47
Mandatory in anovulation WHO I (~75 IU).
WHO II CC-resistent and hyper-responders
Higher monofollicular growth and Lower cancellation
Diminished Ovarian Reserve
May restore follicular millieu and optimize oocyte quality
LH activity is different in HMG and rec-hLH
May influence oocyte and corpus luteum competence.
48. Esteves, 48
Yes, we should individualize the
stimulation protocol.
CC can be your first line, but move to
gonadotropins after 3 ovulatory cycles.
Low dose step-up when using
gonadotropins.
Better safety and pt. tolerability
Higher purity, potency and efficacy
with recombinants.
LH supplementation has a role in
selected patients.