Luteal Phase Insufficiency.pptx

Luteal Phase Insufficiency.pptx

• 1.
  Dr Raju Nair Head– Fertility Unit Mitera Hospital, Kottayam Kerala, India Luteal Phase Insufficiency
• 2.
  Dr.Raju Nair Director &HOD Reproductive medicine Mitera Hospital, Kottayam, Kerala Education: MBBS : Government medcial college, Kottayam, ( 94-99) MS( OBG) : Armed forces medcial college ( AFMC), Pune 2004 Reproductive Medicine Fellowship: CMC, Vellore 2007 Member- ESHRE, ASRM,ISAR, FOGSI, IAGE,ACE,IMA,IFS, ASPIRE Reviewer : Cochrane network- sub fertility group Scientific achievements : 11 articles in Indexed Journal 3 national best papers >200 scientific lectures in state and national level ,5 international level scientific lectures Contributed many chapters in Textbook related to ART Academic activities: Course director – Fellowship in Reproductive Medicine, Mitera Hospital, FNB examiner Area of Interest : IVF lab quality control, PCOD, Minimal stimulation ART
• 3.
  • Luteal phasedeficiency (LPD) has been described as a condition in which • endogenous progesterone is not sufficient to maintain a functional secretory endometrium and allow normal embryo implantation and growth
• 5.
  What happens normally… hcg Corpus luteum LHon Granulosa cell P4 Endometrial glands OVULATION
• 6.
  Luteal phase ina natural cycle • Which hormones seem to be crucial during the luteal phase in a natural cycle
• 7.
  The role ofLH in the luteal phase: Crucial • Totally responsible for steroidogenic activity of the corpus luteum (Casper and Yen, 1979) • Upregulation of growth factors, VEGF-A, FGF2 (Sugino et al., 2004; Wang et al., 2002) • Upregulation of cytokines involved in implantation (Licht et al., 2001) • Stimulation of LH receptors in endometrium (Rao, 2001; Tesarik et al., 2003)
• 8.
  The role ofprogesterone • Induces secretory transformation of the endometrium in the luteal phase (Bourgain et al., 1990) • Progesterone deficiency delays endometrial maturation (Dallenbach-Hellweg, 1984) • Removal of CL prior to 7 weeks of gestation leads to pregnancy loss (Csapo, 1972) • Normal pregnancy was sustained when progesterone was given after removal of CL (Csapo, 1973)
• 9.
  What happens normally… •Corpus luteum - Initial support • Once pregnancy begins, corpus luteum rescue and maintenance require a series of well-known endocrine, paracrine and autocrine actions. • luteoplacental shift (onset of placental steroidogenesis) is around the seventh gestational week
• 10.
  Progesterone Production: LutealPlacental Shift Adapted from: Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57.
• 11.
  Luteal phase deficiency(LPD) • A condition of insufficient progesterone exposure to maintain a normal secretory endometrium and allow for normal embryo implantation and growth Obstet Gynecol Clin North Am. 2015 March ; 42(1): 135–151.
• 12.
  Luteal phase deficiency •1970s, the Norfolk group performed several studies on premature onset of menses due to low progesterone concentrations in the luteal phase, which they called luteal phase deficiency (Jones, 1991). • Luteal phase deficiency is defined as a • luteal phase shorter than 11 days • a lag of more than 2 days in endometrial histological development • low mid-luteal progesterone values <10 ng/ml
• 13.
  LPD • Infertility • Firsttrimester Pregnancy loss • Short cycles • Premenstrual spotting • Anorexia • Starvation, and eating disorders • Excessive exercise • Stress • Obesity and polycystic ovary syndrome • Endometriosis • Aging • Inadequately treated 21-hydroxylase deficiency • Thyroid dysfunction • Hyperprolactinemia • ART cycles • Random cycles with or without stimulation Controversy regarding the clinical significance of LPD is due in part to the lack of a reliable test to diagnose this disorder. Luteal phase deficiency has purportedly been associated LPD is only clinically relevant if it is consistently present in most cycles
• 14.
  Detecting Luteal PhaseInsufficiency • Serum progesterone level: <3 ng/ml • Mid-luteal phase: At least 6.5 ng/ml and preferably 10 ng/ml or more • Blood levels range from 2 to 40 ng/ml within a brief time period • Random serum progesterone levels are difficult to interpret beyond documenting ovulation • Endometrial biopsy is no longer the gold standard for assessment of endometrial maturation There is no consensus on minimum serum progesterone concentration that defines luteal function Indian J Endocrinol Metab. 2013 Jan;17(1):44-9.
• 15.
  • IF DIAGNOSISIS NOT POSSIBLE, IS TREATMENT FOR LUTEAL INADEQUACY EVER APPROPRIATE?
• 16.
  TREATMENT FOR LUTEAL INADEQUACY • Thefirst approach to treatment of potential luteal inadequacy is the correction of any underlying condition. • hypothalamic dysfunction, thyroid dysfunction,or hyperprolactinemia • Rest are all empiric • to promote endometrial maturation • to enhance endometrial receptivity • to support implantation and development of an early pregnancy. • Strategies • supplemental progesterone • progesterone plus estrogen • human chorionic gonadotropin (hCG)
• 17.
  LPD: Prevalence • 5-10%pregnant women have prevalence of LPD • 25-40% women with ‘Recurrent pregnancy lose’ have prevalence of LPD • 15-20% women with ‘Unexplained infertility’ have prevalence of LPD
• 18.
  The luteal phasein stimulated cycles
• 19.
  Luteal phase defectin all stimulated cycles • Schematic representation of changes in luteal phase length and progesterone profile induced by ovarian hyperstimulation for IVF (Macklon et al., 2006)
• 20.
  Why in ARTCycles…. • Suppression of endogenous luteinizing hormone secretion during the luteal phase as a result of persistent pituitary suppression by GnRH agonists. • Supraphysiological levels of both estradiol and progesterone in the early luteal phase may lead to advanced development of the endometrium, hence asynchrony between the embryo and the endometrium and decreased pregnancy rates in IVF cycles. • Duration of ovarian steroid production is shorter in stimulated cycles compared with that of natural cycles. Early menses may prevent successful implantation due to abrupt decreases in serum concentrations of estradiol and progesterone in ART cycles compared with those of natural cycles. • The aspiration of the granulosa cells that surround the oocyte can interfere with the production of progesterone. • LH levels are lowered by high steroid levels, These steroid levels are high because of the multiple corpora lutea,which produce more steroids than in a natural cycle. This causes a negative feedback on the pituitary gland and lowers the LH levels. In this way the length of the luteal phase is shortened (known as premature luteolysis) and the chances of pregnancy are reduced.
• 21.
  Etiology of lutealphase deficiency • Follicular phase events • Luteal phase events • Luteal rescue events
• 22.
  Follicular Phase Events Trophicalterations • Inadequate FSH stimulation • Increased inhibin • Alterations in LH secretion Intrinsic ovarian defects • Defective granulosa cells • Decreased inhibin levels • Decreased follicular phase diameter • Decreased primordial follicles Intrinsic endometrial defects • Inadequate estrogen priming
• 23.
  Luteal Phase Events Trophicalterations • Alterations in LH secretion • Decreased LH surge and luteal levels • Systemic factors • Factors acting upon corpus luteum Intrinsic corpus luteum defects • Specific cellular defects • Large and small cell abnormalities Intrinsic secretory endometrial defect • Deficient number of progesterone receptors
• 24.
  Luteal Rescue Events Trophicalterations • Defective hCG stimulus Intrinsic corpus luteum defects in early pregnancy • Defective progesterone synthesis Intrinsic endometrial defects
• 25.
  Progesterone deficiency and failureof embryo implantation
• 26.
  Progesterone deficiency inARTs • Progesterone important for early embryonic development • Deficient progesterone responsible for • Implantation failure • Miscarriages and • unsuccessful ARTs • In ART procedures, iatrogenically low progesterone environment is created Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2012 Nov;98(5):1112-1117. Shah and Nagarajan. Indian J Endocrinol Metab. 2013 JanFeb;17(1): 44–49.
• 27.
  Implantation failure • Lutealphase progesterone deficiency – one of the reasons of implantation failure • Progesterone insufficiency interferes with secretory transformation of endometrium • Up-regulation of pro-inflammatory cytokines is a risk factor • Pro-inflammatory cytokines- IFN-γ and TNF-α • Down-regulation of anti-inflammatory IL-4, IL-6 and IL-10
• 28.
  Progesterone link withimmune system Progesterone stimulates the production of progesterone-induced blocking factor (PIBF) and induces via the cytokines a T-helper 2 response Progesterone is essential for the maintenance of pregnancy. It is produced by the corpus luteum until week 7–9, when the placenta takes over this function Progesterone CD-8 + T cell PIBF Norwitz ER, et al. N Engl J Med 2001; 345(19): 1400-1408. Szekeres-Bartho J, Wegmann TG. J Reprod Immunol 1996; 31(1-2): 81-95. Szekeres-Bartho J. Int Rev Immunol 2002; 21(6): 471-495.
• 29.
  Th1-Th2 Paradigm T helpercells = sub-group of lymphocytes • Th1 cells Pro-inflammatory cytokines IL-2, TNFα, TNFβ, IFNγ Cell-mediated immunity • Th2 cell Anti-inflammatory cytokines IL-4, IL-5, IL-6, IL-10, IL-13 Humoral immunity Th1 Th2 Cytokines T Cell Immunology. Available from: http://www.bdbiosciences.com/research/tcell/about/helper.jsp. (last accessed February 2014). Raghupathy R, et al. BJOG 2005; 112(8): 1096-1101.
• 30.
  Decreased survival ofembryo due to hyper immunity Progesterone PIBF Normally Progressing Pregnancy Progesterone PIBF Miscarriage Mifepristone Progesterone PIBF +anti-PIBF Miscarriage Adapted from: Szekeres-Bartho J, et al. Int Immunopharmacol 2001; 1(6): 1037-1048.
• 31.
  Role of Humanchorionic gonadotropin • Human chorionic gonadotropin (HCG) acts as indirect support of luteal support • HCG stimulates corpus luteum • Increases the concentration of estrogen and progesterone – rescues failing corpora lutea • Administration of HCG icreases placental protein 14, integrin and relaxin • HCG insufficiency may lead to miscarriage Hutchinson-Williams et al. Fertil Steril. 1990;53:495–501. Anthoy et al. Fertil Steril. 1993;59:187–91. Ghosh et al. Hum Reprod. 1997;12:914–20.
• 32.
  Role of HCGin human pregnancy Adapted from: Polese et al. Front. Endocrinol. 2014; 5:106.
• 33.
  Luteal Phase supportby Exogenous Progesterone
• 34.
  What is Evidence-Based Medicine? •“The integration of individual clinical expertise with the best available clinical evidence from systematic research.” • David L Sackett, W Scott Richardson, William Rosenberg, R Brian Haynes Evidence Based Medicine-- How to Practice and Teach EBM, 1996 14 March 2023 34
• 35.
  • There isa worldwide controversy concerning the • Requirement of luteal phase support • Type of hormones used for LPS • Dose and duration • When to start • When to stop
• 36.
  • Strategies • supplementalprogesterone • progesterone plus estrogen • human chorionic gonadotropin (hCG)
• 37.
  Normal cycle • Roleof luteal phase support • Normo ovulatory patient • PCOD • Prevent miscarriage • No treatment for luteal phase insufficiency has been shown to improve pregnancy outcomes in natural, unstimulated cycles.
• 38.
  non-ART cycle • Useof supplemental progesterone, in a non-ART cycle beyond the time of expected menses (i.e., 2 weeks after ovulation), is not proven beneficial.
• 42.
  Etiology of lutealphase defect • Oocyte retrieval? • Removal of granulosa cells • hCG? • Suppressing LH • GnRH agonist? GnRH antagonist? • Combination of these factors?
• 43.
  Progesterone • Why? • What? •When? • How? • Dose?
• 44.
  Dr BN Chakraborthy 2005
• 45.
  2011
• 46.
  Cocherane 2011- Interventionreview of different progesterone regimens • Comparison has 32 studies included with 9,839 women participants • Investigated difference between different progesterone regimens: • Intramuscular (IM) versus oral • IM versus vaginal or rectal administration • Vaginal or rectal versus oral administration • Low dose vaginal versus high dose vaginal progesterone • Short protocol versus long protocol regimen • Micronized progesterone versus oral progesterone Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154.
• 47.
  Intervention result Comments HCGvs Placebo No effect P4 vs Placebo Beneficial 1.02 – 8.56 ( OR) P4 Vs Hcg Same OHSS high P4 Vs P4 +E2 Same P4 Vs P4 + GnRh a Benefit 1.03 -1.67
• 48.
  Cochrae-2011: Micronized vaginalversus Dydroprogesterone • Four studies with 698 events in 2388 participants reported • A significantly better outcome of pregnancy is seen with dydrogesterone • Outcome: Pregnancy outcome rates Van der Linden et al. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD009154. Treatment A- Micronized Treatment B – synthetic
• 49.
  Dydrogesterone in LPS •2011, Cochrane Review showed a significant effect in favour of progesterone for luteal phase support, favouring synthetic progesterone over micronized progesterone. • Dydrogesterone, is an oral progestin with improved bioavailability compared with oral micronized progesterone.1 • In one randomized, controlled trial, pregnancy rates were higher in women undergoing IVF using oral dydrogesterone for luteal support versus vaginal micronized progesterone (41.0 vs 29.4%,P≤.01).2 Steroids. 2003; 68(10–13):927–9. ;Gynecol Endocrinol. 2007; 23(Suppl 1):68–72.
• 51.
  Dydrogesterone in LPS Conclusions:Oral dydrogesterone seems to be as effective as vaginal progesterone for LPS in ART cycles, and appears to be better tolerated
• 52.
  Lotus I andLotus II study • Lotus I and Lotus II demonstrate that oral dydrogesterone is as efficacious as MVP (capsules or gel) for luteal phase support in fresh-cycle IVF, with a similar safety profile Dydrogesterone has the potential to induce a paradigm shift for luteal phase support in the estimated 1.5 million women undergoing IVF each year Gynecological Endocrinology. 2016 Feb 1;32(2):97-106.
• 54.
  Dydrogesterone in LPS CONCLUSION: Sincethe outcomes of dydrogesterone are comparable to those of intramuscular and vaginal progesterone, it is a reasonable option to provide luteal phase support for women who are uncomfortable with injections or vaginal insertions.
• 55.
  Despite oral administrationand first pass through the liver, dydrogesterone was well tolerated and may become the new standard for LPS in fresh embryo transfer IVF cycles
• 56.
  Advantages of Dydrogesteroneover oral progesterone for LPS 1.Pandya M, Gopeenathan P, Gopinath et al. Evaluating the clinical efficacy and safety of progestogens in the management of threatened and recurrent miscarriage in early pregnancy- A review of the literature. Indian Journal of Obstetrics and Gynecology Research. 2016;3(2):157–66. 2.Data on file for dydroboon. Dydrogesterone • Bioavailability is 5.6 times better than oral micronized progesterone1 • Receptor affinity is 1.5 times better than oral micronized progesterone1 • Low doses are required due to its high potency2 Oral micronized progesterone • Low bioavailability is attributed to its significant first-pass effect1 • Less receptor affinity1 • High doses are required resulting in side effects, such as drowsiness, nausea, and headaches1
• 57.
  Advantages of Dydrogesteronefrom patients’ perspective 1. Griesinger G, Blockeel C, Tournaye H. Oral Dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Fertil Steril. 2018 May;109(5):756-762. 2. Salehpour S, Tamimi M, Saharkhiz N. Comparison of oral Dydrogesterone with suppository vaginal progesterone for luteal-phase support in in vitro fertilization (IVF): A randomized clinical trial. Iran J Reprod Med. 2013 Nov;11(11):913-8. 01 Preferred route by majority patients 02 Higher patient satisfaction 03 Easiest and most acceptable route of administration 04 Stable form 05 Effective 06 Better tolerability 07 Low side effects/ good safety profile 08 Excellent patient compliance 09 No androgenic effects on fetus/ no side effects for mother
• 58.
  Summary LPS, Luteal phasesupport; IVF, In vitro fertilization; IUI, Intrauterine insemination Progesterone is essential for establishing and maintaining early pregnancy Absence of exogenous hormonal support for LPS after IVF is associated with significant reduction in success rate Progesterone is critical to support the luteal phase following IVF and widely used in IUI cycles Dydrogesterone, an active metabolite of progesterone has a good bioavailability Several trials have demonstrated the efficacy of Dydrogesterone in IVF and IUI
• 59.
  Thank You