The document discusses luteal phase support in assisted reproductive technology (ART) cycles. It provides 3 key points:
1. Luteal phase deficiency is common in ART cycles due to multiple factors like multifollicular development and aspiration of granulosa cells, leading to premature luteolysis and defective progesterone secretion.
2. Progesterone supplementation is important for luteal phase support as progesterone prepares the endometrium, decreases uterine contractility, and regulates immunity - all of which are important for embryo implantation and maintenance of early pregnancy.
3. Oral dydrogesterone is recommended for luteal phase support in ART cycles due to its greater bioavailability allowing the use of lower doses, minimal side effects
Since the first formal description of LPD in 1949 as a possible cause of infertility and recurrent miscarriage by Jones. Innumerable investigations have been undertaken in an effort to verify its existence or to characterize its pathophysiology, diagnosis, and treatment. The consensus of the literature is that LPD does exist and that its cause is multifactorial like abnormal folliculogenesis, inadequate LH surge,inadequate secretion of progesterone by the corpus luteum, aberrant end-organ response by the endometrium.
Since the first formal description of LPD in 1949 as a possible cause of infertility and recurrent miscarriage by Jones. Innumerable investigations have been undertaken in an effort to verify its existence or to characterize its pathophysiology, diagnosis, and treatment. The consensus of the literature is that LPD does exist and that its cause is multifactorial like abnormal folliculogenesis, inadequate LH surge,inadequate secretion of progesterone by the corpus luteum, aberrant end-organ response by the endometrium.
Role of progestogens in obstetrics and gynecologyAhmad Saber
The
different progestogens with their overlapping effects on estrogen, androgen, glucocorticoid,
and mineralocorticoid receptors are described in order to allow the clinician to make the most appropriate choice of progestogen.
Significant increase in live birth rate is found when IUI is done with stimulation compared with IUI in natural cycle in women with Unexplained Infertility .
Update on LETROZOLE Current Guidelines for Ovulation Induction Dr. Sharda Jain Lifecare Centre
Update on LETROZOLE Current Guidelines for Ovulation Induction
LET NOT FORGET
WHY
??
LETROZOLE was withdrawn from
Indian market (2012)
“SAFETY ISSUES”
“Could Be Teratogenic In Human”?
Progesterone for luteal phase support in IVF cyclesHesham Al-Inany
Luteal phase support is essential for IVF cycles. Progesterone has many forms and modalities: which to use? this talk is an attempt to answer this question
Strategies for Improving Success Rates in ART PARTLifecare Centre
Strategies for Improving Success Rates in ART
Part - 2
Strategies for Improving Success Rates in ART
Tailoring Controlled Ovarian Stimulation
Strategies for Luteal Phase in ART cycles
Endometrial Receptivity Array
Role of progestogens in obstetrics and gynecologyAhmad Saber
The
different progestogens with their overlapping effects on estrogen, androgen, glucocorticoid,
and mineralocorticoid receptors are described in order to allow the clinician to make the most appropriate choice of progestogen.
Significant increase in live birth rate is found when IUI is done with stimulation compared with IUI in natural cycle in women with Unexplained Infertility .
Update on LETROZOLE Current Guidelines for Ovulation Induction Dr. Sharda Jain Lifecare Centre
Update on LETROZOLE Current Guidelines for Ovulation Induction
LET NOT FORGET
WHY
??
LETROZOLE was withdrawn from
Indian market (2012)
“SAFETY ISSUES”
“Could Be Teratogenic In Human”?
Progesterone for luteal phase support in IVF cyclesHesham Al-Inany
Luteal phase support is essential for IVF cycles. Progesterone has many forms and modalities: which to use? this talk is an attempt to answer this question
Strategies for Improving Success Rates in ART PARTLifecare Centre
Strategies for Improving Success Rates in ART
Part - 2
Strategies for Improving Success Rates in ART
Tailoring Controlled Ovarian Stimulation
Strategies for Luteal Phase in ART cycles
Endometrial Receptivity Array
LUTEAL PHASE SUPPORT CHOOSING THE RIGHT PROGESTERONEDr. Girija Wagh
Increasing maternal age, need for assited reproduction also has increased the need for appropriate luteal phase support During the luteal phase of the menstrual cycle, progesterone plays a crucial role in preparing the uterine lining for potential embryo implantation. In assisted reproductive technologies (ART) and fertility treatments, optimizing luteal phase support is essential for successful outcomesAdministering exogenous (external) progesterone during the luteal phase is associated with significantly higher pregnancy rates compared to placebo or no treatmentWomen undergoing ART are appropriate candidates for luteal phase supportchoosing the right progesterone for luteal phase support is critical for optimizing fertility treatments. Collaboration among specialists ensures better outcomes for patients
Role of adjuvants in poor ovarian responders , undergoing infertility treatment , in terms of Intra uterine inseminations ( IUI ) to In Vitro Fertilization ( IVF )
Similar to Luteal phase support in ART Cases Dr Sharda Jain (20)
The Newer Concepts In Endometriosis Management : Dr Sharda JainLifecare Centre
The Newer Concepts In
Endometriosis Management
ENDOMETRIOSIS IS ENIGMA
DIAGNOSTIC DELEMMA
DEBILITATING DISEASE QOL
PROGRESSIVE DISEASE
RECURRENCE IS BIG PROBLEM
NO FINAL VERDICT ON CAUSE
NO PERMANENT CURE
The exact prevalence of endometriosis is unknown, but estimates 10% in the general female population in India but up to 50% in infertile women
The Newer Concepts for Reduced Surgery to preserve fertility in Endometrios...Lifecare Centre
The Newer Concepts for Reduced Surgery to preserve fertility in Endometriosis
ENDOMETRIOSIS IS ENIGMA
DIAGNOSTIC DILEMMA
DEBILITATING DISEASE QOL
PROGRESSIVE DISEASE
RECURRENCE IS BIG PROBLEM
NO FINAL VERDICT ON CAUSE
NO PERMANENT CURE
The exact prevalence of endometriosis is unknown, but estimates 10% in the general female population in India but up to 50% in infertile women
Anemia Free India Gynaecologist to focuss on *12gm Haemoglobin at Delivery I...Lifecare Centre
Important Highlights
Prophylactic Iron and Folic Acid Supplementation in all six target age groups.
Intensified year-round Behaviour Change Communication (BCC) Campaign for:(a) improving compliance to IFA and deworming, (b) enhancing appropriate infant and young child feeding practices, (c) encouraging increase in intake of iron-rich food through diet and/or fortified foods (d) ensuring delayed cord clamping .
Testing and treatment of anaemia, using digital methods and point of care treatment, with special focus on pregnant women and school-going adolescents.
Addressing non-nutritional causes of anaemia
in endemic pockets with special focus on malaria, hemoglobinopathies and fluorosis
How to optimize success rates in ART? : Dr Sharda JainLifecare Centre
How to optimize success rates in ART? : Dr Sharda Jain
How to improve success rates in ART?
The big debate कार्य में आनंद
Evolution of In-vitro Fertilization (IVF)
Factors Influencing IVF Success Ist Part
Strategies for Improving Success Rates in ART Second Part
Innovations & Breakthroughs in IVF Part Three
OPEN DEBATE
SOCIALEGG FREEZING : Dr Poorva Bhargav and Dr Sharda JainLifecare Centre
SOCIALEGG FREEZING : Dr Poorva Bhargav and Dr Sharda Jain
Introduction
Social egg freezing (oocyte cryopreservation for non-medical reasons) has evolved as a proactive option for women looking to extend their reproductive possibilities past their peak childbearing years
It is the process of saving or protecting eggs, or reproductive tissues so that a person can use them to have biological children in future
CMV UPDATE Few solid facts about cytomegalovirus (CMV) Infection & New devel...Lifecare Centre
CMV UPDATE Few solid facts about cytomegalovirus (CMV) Infection & New development from France for Indian Gynaecologists & public to know :Dr Sharda Jain
CMV is a common herpesvirus that can infect people of all ages, including pregnant women.
CMV is not the same as HSV (herpes simplex virus), although they belong to the same viral family.
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
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
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
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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!
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
4. Luteal Phase Defect: A Well-Established
Reason for Infertility
1. Mesen TB, et al. Obstet Gynecol Clin North Am. 2015;42(1):135–51. 2. Griesinger G, et al. Fertil Steril. 2018;109(5):756–62.
CL: Corpus lutea; HPA: Hypothalamic–pituitary axis; IVF: In vitro fertilization; LH: Luteinizing hormone; LP: Luteal phase.
Luteal phase defect2
High number of CL
during the early LP2
Supraphysiologic
levels of steroids2
Negative
feedback
actions at
the HPA2
Inhibition of LH
release2
Stimulated IVF cycles2
• Insufficient progesterone exposure
• Inability to maintain a normal secretory
endometrium to allow normal embryo
implantation and growth1
• Infertility1
• Recurrent
pregnancy loss1
…Caring hearts, healing hands
5. Why Is Luteal Phase Deficient in ART Cycles?
ART: Assisted reproductive treatment; LH: Luteinizing hormone
FOGSI FOCUS-Emerging Trends in Infertility. Available at: https://www.fogsi.org/wp-content/uploads/fogsi-focus/2018/fogsi-focus-infertility-2018.pdf. Last accessed on 25 January 2021.
The success rate of ART technique depends on numerous factors,
one of which is the quality of the luteal phase.
Multiple factors: Multifollicular development, use of analogues, aspiration of the
granulosa cells that surround the oocyte, supraphysiological steroid levels that
lead to negative feedback of the hypothalamic–pituitary–ovarian (HPO) axis.
Multiple
factors
Inhibition of
LH release
Premature luteolysis
and defective
progesterone secretion
…Caring hearts, healing hands
6. Characteristics of Luteal Phase Deficiency
Pirard C, et al. Int J Endocrinol. 2015;2015:727569.
1. Low progesterone levels
2. Delayed endometrial secretory
transformation
3. Shortened luteal phase of <10 days
Reduced embryo
implantation
Lower pregnancy rates
Increased
miscarriage rates
…Caring hearts, healing hands
8. Preparation of the endometrium for implantation (secretory
changes)1
1. Schindler AE. First trimester endocrinology: consequences for diagnosis and treatment of pregnancy
failure. Gynecol Endocrinol 2004;18(1):51–57;
2. 2. Chang K, Zhang L. Review article: steroid hormones and uterine vascular adaptation to pregnancy.
Reprod Sci. 2008;15(4):336–348.c
Decreases contractility of uterine smooth muscle2
9. Mediates -
(i) Uterine blood flow
(ii) Uterine endothelial adaptation to pregnancy [increased
NO production]2
1. Schindler AE. First trimester endocrinology: consequences for diagnosis and treatment of pregnancy failure. Gynecol Endocrinol
2004;18(1):51–57;
2. 2. Chang K, Zhang L. Review article: steroid hormones and uterine vascular adaptation to pregnancy. Reprod Sci. 2008;15(4):336–
348.c
Regulation of cellular immunity1
11. Luteal Phase Support Algorithm in ART Cycles
Data on file (2). Last accessed on 27 January 2021.
ART: Assisted reproductive treatment; hCG: Human chorionic
gonadotropin; IM: Intramuscular; GnRH: Gonadotropin-releasing
hormone; IU: International unit; OR: Oocyte retrieval; mg:
Milligram; SC: Subcutaneous.
…Caring hearts, healing hands
12. When to Start Progesterone?
Administration of progesterone before oocyte retrieval (OR) is associated with a
lower progesterone due to premature secretory changes in the endometrium, and
therefore implantation rate.1
Decrease in pregnancy rates by 24% was seen when luteal phase support (LPS) was
delayed until 6 days after OR compared to 3 days after OR.2
No difference was found when LPS was started at OR
compared to within 24–48 hours after OR.3
1. Sohn SH, et al. Fertil Steril. 1999;71(1):11–4. 2. Williams SC, et al. Fertil Steril. 2001;76(6):1140–3. 3. Yanushpolsky EH. Semin Reprod Med. 2015;33(2):118–27.
Progesterone can be initiated at OR and there is an acceptable window of time, 24 to 48
hours after oocyte retrieval for initiation of progesterone supplementation with optimal
cycle results3
…Caring hearts, healing hands
13. Optimal Period for Luteal Phase Support
Usually given till 8–10 weeks,
when the placenta takes over
the function of producing
hormones
Up to 12 weeks
No benefit after
first ultrasound
But according to ASRM
guidelines, there is no proven
role in adding progesterone or
hCG for luteal support once a
pregnancy has been established.
In all HRT cycles, the LPS
should be given till luteal
placental shift at around
10–12 weeks.
ASRM: American Society for Reproductive Medicine; hCG: Human chorionic gonadotropin; HRT: Hormone replacement therapy; LPS: Luteal phase support.
Data on file (2). Last accessed on 27 January 2021.
…Caring hearts, healing hands
14. Why Is Luteal Phase Deficient in ART Cycles?
02
03
04
Oral dydrogesterone
Potent oral progestin with
improved bioavailability
Oral micronized progesterone
Low bioavailability and adverse
effects, such as drowsiness,
dizziness, and headaches
Intramuscular
progesterone
Injection-site pain
and abscesses
Micronized vaginal
progesterone
Associated with
administration-related side
effects, such as vaginal
irritation and discharge
01
02
02
03
04
02
03
04
Griesinger G, et al. Hum Reprod. 2018;33(12):2212–2221.
…Caring hearts, healing hands
15.
16. Bioavailability
1. Stanczyk FZ, et al. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev 2013;34(2):171–208; 2. Paulson RJ, et al. Progesterone
Pharmacokinetics and Pharmacodynamics With 3 Dosages and 2 Regimens of an Effervescent Micronized Progesterone Vaginal Insert. J Clin Endocrinol Metab 2014;99(11):4241–4249. 3. Schindler AE, Campagnoli C, Druckmann R, et
al. Classification and pharmacology of progestins. Maturitas 2008;61(1-2):171-180.
28% oral
dydrogesterone1
4–8% vaginal
progesterone2
100, 200,
300 mg
oral
progesterone3
<5% oral
progesterone1
Dydrogesterone has ~5.6 times better oral bioavailability than oral progesterone1-3
17. In a recent phase III RCT, the daily dose of oral dydrogesterone used was 20 times lower than micronized vaginal
progesterone capsules4,5 and showed similar clinical benefits with a well established safety profile4
Approved daily dosing for luteal support in ART
30 mg oral
Dydrogesterone1
1. Abbott Laboratories. Company Core Data Sheet. Dydrogesterone. 5 July 2017; 2. Merck Serono Ltd. Crinone 8% vaginal progesterone gel. SPC UK. March 2015; 3. Besins Healthcare (UK) Ltd. Utrogestan vaginal
200 mg capsules. SPC UK. 29 June 2017; 4. Tournaye H, et al. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for
luteal support in in vitro fertilization. Hum Reprod 2017; 32(5):1019-1027; 5. Sukhikh G., et al. Lotus I: a phase III randomized controlled trial of oral dydrogesterone verses micronized vaginal progesterone for luteal support
in in vitro fertilization, with focus on the Russian subpopulation. Akusherstvo I Ginekologiya/Obstetrics and Gynecology 2017;7: http://dx.doi.org/10.18565/aig.2017.7.
600 mg
vaginal
progesterone capsules3
90 mg
vaginal
progesterone gel2
18. Progesterone: Routes of Administration
Transvaginally
•600–800 mg daily in
divided doses
•Vaginal gel 8%
90 mg/day
Embryo transfer in natural and
modified natural cycle
Cleavage stage
• Embryo transfer 2/3 days after
ovulation or 3/4 days after LH peak
Blastocyst stage
• 5 days after ovulation or 6 days
after LH peak
HRT cycle-timing of ET stringent
after initiation of progesterone
administration
• First day of progesterone adminis-
tration should be considered day 0
• Progesterone + 2 for 4 cell
• Progesterone + 3 for 8 cell
• Progesterone + 5 for blastocyst
Oral dydrogesterone
• 10 mg TID
IM
• 50–100 mg/day
Administration of progesterone
Data on file (2). Last accessed on 27 January 2021.
ET: Embryo transfer; HRT: Hormone replacement therapy; IM: Intramuscular; LH: Luteinizing hormone; mg: Milligram; TID: Thrice in a
day.
…Caring hearts, healing hands
19. Oral Dydrogesterone: Better and Convenient Option
Approved in threatened and recurrent miscarriage and other
progesterone deficiencies1
Greater bioavailability2
Effective at lower dose and causes endometrial
transformation2
Minimizes the activation of receptors other than progesterone
receptor, and thus minimizes unwanted effects2
Shifts cytokine balance from T-helper (Th)1 toward Th2
cytokine production that is conducive to the success of
pregnancy3
Suppression of T-cell and killer-cell activity6
Induces nitric oxide synthesis that improves endometrial
receptivity and pregnancy outcomes3,4
Increases progesterone-induced blocking factor production
thereby improving pregnancy success rates5
1. Prescribing information of Duphaston®. Available at: https://data.health.gov.il/drugs/alonim/Duphaston_dr_1410193172635.pdf. Last accessed on 25 January 2021. 2. Schindler AE, et al. Maturitas. 2003;46(Suppl 1):S7–S16. 3.
Raghupathy R, et al. Am J Reprod Immunol. 2015;74(5):419–426. 4. Abdel-Razik M, et al. J Reprod Infertil. 2014;15(3):142–146. 5. Kalinka J, et al. Am J Reprod Immunol. 2005;53(4):166–171. 6. Faust Z, et al. Am J Reprod
Immunol. 1999;42(2):71–75.
…Caring hearts, healing hands
21. ESHRE Guidelines for Ovarian Stimulation in IVF/ICSI
2019 ESHRE guidelines for ovarian stimulation in IVF/ICSI cycles
Dydrogesterone is probably recommended for
luteal phase support.
Similar ongoing pregnancy
Compared to progesterone, dydrogesterone has:
Similar safety and tolerability
Better patient preference
ESHRE, 2019. Available at: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Ovarian-Stimulation-in-IVF-ICSI. Accessed on: 18 August 2020.
ESHRE: European Society of Human Reproduction and Embryology; IVF: In vitro fertilization; ICSI: Intracytoplasmic sperm injection.
…Caring hearts, healing hands
22. RANZCOG: Australian and New Zealand Guidelines
Dydrogesterone is the best option for luteal phase support in women
undergoing ART treatment.
Exogenous progesterone is associated with significantly higher
PR than placebo or no treatment, with better results obtained with
synthetic progesterone (dydrogesterone) than MP.
Progesterone support of the luteal phase and in the first trimester. Guidelines issued by: The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Available at:
https://ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Progesterone-support-of-the.pdf?ext=.pdf. Accessed on: 17 August 2020.
ART: Assisted reproductive technology; MP: Micronized progesterone; PR: Pregnancy rate; RANZCOG: The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.
…Caring hearts, healing hands
23. Griesinger G. PLoS One. 2020;15(11):e0241044.
Key Findings of Griesinger et al.
One-step Meta-analysis of Individual Participant Data
Significantly higher pregnancy
rate than MVP capsules and gels.
Significantly higher live birth
rate than MVP capsules and
gels.
Well-established safety profile
with no significant maternal or
fetal safety concerns.
Oral dydrogesterone was associated with
MVP: Micronized vaginal progesterone.
…Caring hearts, healing hands
24. Immunomodulating Effects of Dydrogesterone
and Positive Outcomes
Patki A, et al. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
Th: T helper; IFNγ: Interferon gama; TNFα: Tumor necrosis factor-alpha.
Dydrogesterone
inhibits Th1
cytokines, IFN-γ and
TNFα production.
Harmful cytokine
Embryo/fetus
T-helper 1 cell response activated
Tumor necrosis factor- , interleukin-2
Abortion of fetus
Natural killer cells
Immunological reactions during recurrent pregnancy loss
Lymphokine-activated killer cells
…Caring hearts, healing hands
25. Dydrogesterone Induces PIBF Production
Patki A, et al. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
PIBF: Progesterone induced blocking factor.
Immunological reactions during successful pregnancy
Dydrogesterone
induces PIBF
production.
Progesterone receptor activation
Progesterone-induced blocking factor
Blocks cascade reaction, shift to T-helper type 2
Embryo-protective immunomodulation
Protection of embryo/fetus
…Caring hearts, healing hands
26. IND2179865 8th April 2021 For the use of registered medical practitioner only
…Caring hearts, healing hands
Editor's Notes
This section helps in understanding the importance of luteal phase support in assisted reproductive treatment cycles.
Luteal phase deficiency (LPD) is a condition of insufficient progesterone exposure to maintain a normal secretory endometrium and allow for normal embryo implantation and growth. Luteal phase defect is a major cause of infertility and recurrent pregnancy loss.1 The main etiology of the LPD observed in stimulated in vitro fertilisation (IVF) cycles is the supraphysiologic levels of steroids secreted by a high number of corpora lutea during the early luteal phase, which directly inhibits luteinizing hormone release via negative feedback actions at the level of the hypothalamic–pituitary axis.2
References
Mesen TB, Young SL. Progesterone and the luteal phase: A requisite to reproduction. Obstet Gynecol Clin North Am. 2015;42(1):135–51.
Griesinger G, Blockeel C, Tournaye H. Oral dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Fertil Steril. 2018;109(5):756–62.
Luteal phase is defective in hyper-stimulated cycles especially in assisted reproductive technology cycles because the pulsatile secretion of luteinizing hormone (LH) is responsible for the function of a normal corpus luteum which is disrupted during controlled ovarian stimulation. Multiple factors are responsible for LH release inhibition:
Multifollicular development leads to insufficient luteal phase
Use of analogues to suppress LH surge
Removal of large number of granulosa cells during pick up
Supraphysiological steroid levels lead to negative feedback of the hypothalamic–pituitary–ovarian axis and as a result luteal phase insufficiency.
Reference
FOGSI FOCUS-Emerging Trends in Infertility. Available at: https://www.fogsi.org/wp-content/uploads/fogsi-focus/2018/fogsi-focus-infertility-2018.pdf. Last accessed on 25 January 2021.
Luteal phase deficiency is characterized by low progesterone levels, delayed endometrial secretory transformation, and a shortened luteal phase of less than ten days, resulting in reduced embryo implantation, lower pregnancy rates, and increased miscarriage rates.
Reference
Pirard C, Loumaye E, Laurent P, et al. Contribution to more patient-friendly ART treatment: Efficacy of continuous low-dose GnRH agonist as the only luteal support—Results of a prospective, randomized, comparative study. Int J Endocrinol. 2015;2015:727569.
Various medications along with their routes of administration and doses are shown on the screen.
Reference
Data on file (2). Last accessed on 27 January 2021.
The optimal timing of progesterone initiation within the in vitro fertilization (IVF) cycle is detailed in this slide. Endogenous production of progesterone starts at the peak of follicular phase, so the initiation of progesterone too early may have detrimental effects, i.e. premature secretory changes in the endometrium and therefore implantation rate.1 Initiation of progesterone on the day of human chorionic gonadotropin trigger or on the day of oocyte retrieval (OR) is considered to be optimum.1,2,3 Starting progesterone very late is also considered to be equally detrimental i.e. decrease in pregnancy rates by 24% was seen when luteal phase support was delayed until six days after OR compared to three days after OR.2 No significant difference was found in the pregnancy rates, whether the progesterone was started on the day of trigger, day of oocyte retrieval, or on the day of embryo transfer compared to within 24–48 hours after OR.3 Progesterone can be initiated at the time of OR and there is an acceptable window of time, 24 to 48 hours after OR for initiation of progesterone supplementation with optimal cycle results.3
References
1. Sohn SH, Penzias AS, Emmi AM, et al. Administration of progesterone before oocyte retrieval negatively affects the implantation rate. Fertil Steril. 1999;71(1):11–4.
2. Williams SC, Oehninger S, Gibbons WE, et al. Delaying the initiation of progesterone supplementation results in decreased pregnancy rates after in vitro fertilization: a randomized, prospective study. Fertil Steril. 2001;76(6):1140–3.
3. Yanushpolsky EH. Luteal phase support in in vitro fertilization. Semin Reprod Med. 2015;33(2):118–27.
The optimal period of luteal phase support is clearly discussed on the slide.
Reference
Data on file (2). Last accessed on 27 January 2021.
Multiple routes of progesterone administration for luteal phase support have been explored; however, no single formulation or regimen has been identified as superior with regard to efficacy.
Progesterone for luteal phase support can be administered orally, intramuscularly, and vaginally, with each route having different bioavailability and tolerability profiles. Oral dydrogesterone is a potent oral progestin with improved bioavailability. In comparison, oral micronized progesterone is associated with low bioavailability and may lead to adverse events, such as drowsiness, dizziness, and headaches; while intramuscular progesterone is associated with injection-site pain and abscesses.
Although micronized vaginal progesterone is preferred over oral and intramuscular progesterone at most assisted reproductive technology centers, it is associated with its own administration-related side effects, such as vaginal irritation and discharge. Micronized vaginal progesterone is usually administered as a gel or as capsules, with both formulations having similar efficacy for luteal phase support.
Reference
Griesinger G, Blockeel C, Sukhikh GT, et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: A randomized clinical trial. Hum Reprod. 2018;33(12):2212–2221.
Various routes of administration of progesterone are clearly detailed on the screen.
Reference
Data on file (2). Last accessed on 27 January 2021.
Several factors suggest that oral dydrogesterone is the better and convenient option for luteal phase support in assisted reproductive treatment. These include:
Approved in threatened and recurrent miscarriage and other progesterone deficiencies1
Greater bioavailability2
Effective at lower dose and causes endometrial transformation2
Minimizes the activation of receptors other than progesterone receptor, and thus minimizes unwanted effects2
Shifts cytokine balance from T-helper (Th)1 toward Th2 cytokine production that is conducive to the success of pregnancy3
Induces nitric oxide synthesis that improves endometrial receptivity and pregnancy outcomes.3,4
Increases progesterone-induced blocking factor production, thereby improving pregnancy success rates.5
Suppression of T-cell and killer-cell activity6
References
Prescribing information of Duphaston®. Available at: https://data.health.gov.il/drugs/alonim/Duphaston_dr_1410193172635.pdf. Last accessed on 25 January 2021.
Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2003;46 Suppl 1:S7–S16.
Raghupathy R, Al-Azemi M. Modulation of Cytokine Production by the Dydrogesterone Metabolite Dihydrodydrogesterone. Am J Reprod Immunol. 2015;74(5):419–426.
Abdel-Razik M, El-Berry S, Mostafa A. The Effects of Nitric Oxide Donors on Uterine Artery and Sub-endometrial Blood Flow in Patients with Unexplained Recurrent Abortion. J Reprod Infertil. 2014;15(3):142–146.
Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone-induced blocking factor concentrations in women with threatened abortion. Am J Reprod Immunol. 2005;53(4):166–171.
Faust Z, Laskarin G, Rukavina D. Progesterone‐Induced Blocking Factor Inhibits Degranulation of Natural Killer Cells. Am J Reprod Immunol. 1999;42(2):71–75.
This section discusses the guidelines and recommendations as well as evidence supporting the use of dydrogesterone for luteal support.
According to European Society of Human Reproduction and Embryology (ESHRE) guidelines (2019), dydrogesterone is probably recommended for luteal phase support. As compared to progesterone, dydrogesterone has similar ongoing pregnancy rate and similar safety and tolerability profile. Additionally, patients prefer the oral administration route of dydrogesterone over the vaginal route of progesterone. However, these safety data are considered insufficient to make a firm statement and there is a lack of long-term offspring health studies.
Reference
ESHRE (2019). Ovarian stimulation for IVF/ICSI. Guideline of the European Society of Human Reproduction and Embryology. Available at: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Ovarian-Stimulation-in-IVF-ICSI. Accessed on: 18 August 2020.
According to the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG), Australian and New Zealand Guidelines for Luteal Phase Support in Assisted Reproductive Technology (ART), exogenous progesterone is associated with a significantly higher pregnancy rate than placebo or no treatment with better results obtained with synthetic progesterone (dydrogesterone) than micronized progesterone. Currently, dydrogesterone is the best option for luteal phase support in women undergoing ART treatment.
Reference
Progesterone support of the luteal phase and in the first trimester. Guidelines issued by: The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Available at: https://ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Progesterone-support-of-the.pdf?ext=.pdf. Accessed on: 17 August 2020.
Let us summarize the key findings of Griesinger et al. one-step meta-analysis of individual population data.
Oral dydrogesterone was associated with
Significantly higher pregnancy rate than micronized vaginal progesterone (MVP).
Significantly higher live birth rate than MVP
Well-established safety profile with no significant maternal or fetal safety concerns.
Reference
Griesinger G, Blockeel C, Kahler E, et al. Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis. PLoS One. 2020;15(11):e0241044.
Progesterone acts via its own receptor to produce a mediator protein known as progesterone-induced blocking factor (PIBF). It favors the development of human T helper (Th) cells producing Th2-type cytokines and promotes the production of interleukin (IL)-4, while inhibiting embryotoxic Th1 cytokine production.
In women with recurrent spontaneous abortion, dydrogesterone inhibits the production of the Th1 cytokines, interferon-gama, and tumor necrosis factor-alpha (TNFα) from lymphocytes and upregulates production of the Th2 cytokines IL-4 and IL-6, thereby inducing a Th1 to Th2 cytokine shift.
Reference
Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
Dydrogesterone also induces progesterone-induced blocking factor (PIBF) production. Thus, apart from progestogenic properties, dydrogesterone has been shown to have immunomodulating effects, which favor a successful pregnancy.
Reference
Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
