Premature ovarian failure


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pathophysiology of ovarian failure

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Premature ovarian failure

  1. 1. ByProf .Refaat AlshimyAlAzhar University20092009
  2. 2. Premature ovarian failure (POF(Premature ovarian failure (POF) , sometimes calledpremature ovarian insufficiency, occurs when the ovaries(the twin female organs that produce and release an eggeach monthly cycle ) stop working before a women turns40 yearsWhen they stop working , women do not ovulate orproduce normal amounts of the hormone estrogen,Puts them at risk for serious conditions such asosteoporosis and heart disease , as well as infertilityGonway ,2000Definition
  3. 3. PathophysiologyMost women experience the natural loss ofovarian function, the event we callmenopause, between the age of 45 and 55years ,with little variation in this figurebetween different countries and differentethnic groups .This age range reflects theindividual variation in biological ageing ofthe ovaries between different women.
  4. 4. A constant number of restingprimordial follicles enter thegrowth phase at any given time,independent of pituitarygonadotropinsLater stages of maturation requireFSH and LHFollicles either mature to ovulationor become atresicOvarian Structure
  5. 5. Ovaries have about 2 million primordial follicles at birth(Ovarian reserve!):each containing a primary oocyteBy puberty:number drops to about 250,000 - 400,000400 oocytes ovulated duringthe reproductive yearsIn the absence of LH/FSH, folliclesundergo atresiaOnce follicles are depleted,ovarian hormone productiondeclines
  6. 6.  Johnson et al. (2004) have challenged the conceptthat each woman is endowed with anirreplenishable number of gametes in the ovary. They came to a conclusion that ovarian germ cellsare a dynamic population and undergo constantrenewal. Such a novel concept that challenges the centraldogma in reproductive sciences is likely to stir aflurry of debate and to be followed by furtherstudies exploring the issue.
  7. 7. Age-related rise and fluctuation in FSH
  8. 8. Normal menopause vs. POFNormal menopause is an irreversible condition,whereas approximately 50% of women with POFexperience intermittent ovarian function aftertheir periods initially stopSome women will produce estrogen intermittentlyand may ovulate (fluctuating ovarian function )Pregnancies have occurred after the diagnosis ofPOF (5-10%)
  9. 9. Primary ovarian failure:A women never ovulates and never experiencesnatural menstruationSecondary ovarian failure:Menstruation occurs for months to years , butthen stops prematurely as ovaries have failedTypes
  10. 10. Prevalence* 1% of women under the age of 40* 0.1% of women under 30* 0.01% of women under 20 10- 28 % of women with 1ary amenorrhea 4 – 18 % of women with 2Ry amenorrhea 4 – 31 % of all cases with POF are familialTaylor, 2001
  11. 11. Causes of POF* Etiology unknown, extremelyheterogeneousin more than 90% of cases,apart from● Surgery● Chemotherapy● Radiotherapy● Turner syndrome
  12. 12. CausesCauses of POF in 352 women attending theMiddlesex Hospital , London ,UKn %Idiopathic ( including autoimmune) 204 58Turners Syndrome 82 23Chemotherapy 24 7Familial POF 15 4Pelvic surgery 8 246xy gonadal dysgenesis 7 2Galactosaemia 6 2Pelvic irradiation 6 2Goswami et al 2007Horm Res 2007; 68 : 196-202
  13. 13. Spontaneous POFNo identifiable cause of POFUnexplained early degeneration of the cells of theovaryCommon for woman with spontaneous POF to have afamily history of POF in either her mother or sisterThe American Collage of obstetrics and gynecologynow recommends that women with POF withoutknown cause be screened for FMR1 premutationsobstet Gynecol 2006
  14. 14. Genes and POFVarious genetic mechanisms implicated inpathogenesis of POF includeReduced gene dosageNon-specific chromosome effects that impair meiosisThese can lead to ovarian failure by causingDecrease in the pool of primordial folliclesIncreased atresia of the ovarian follicles due to apoptosisor failure of follicle maturation
  15. 15. Genes and POFIdentify women / families with POF and riskof transmission of a genetic disorderFamilial cases in 15- 20 % of casesChromosomal abnormalities are detected in40- 50 % of women who do not experiencespontaneous pubertyMost common genetic abnormality causingPOF is Turners Syndrome
  16. 16. Early follicular loss :Turners Syndrome
  17. 17. X chromosome deletionRossetti et al 2004Inherited deletion of X chromosome in motherand two daughtersMother menopause at 43 yearsDaughters menopause at 17 and 22 yearsRole of environment
  18. 18. Genes Implicated in POFGene Gene locusX chromosome BMP15 Xp11.2Genes FMR1 Xq27.3FMR2 Xq28POF1b Xq21.1 – q23.3Autosomal FSH receptor 2p21 – p16Genes LH receptor 2p21Inhibin A 2q33 – q36FOX1.2 3q22 – q23GALT 9p13FSH beta variant 11p13EIF2b2,4 and 5 14q24.3, 2p23.3,3q27POLG 15q25NOGGIN 17q22LH-B 19q13.32AIRE 21q22.3_______________________________________________________________________
  19. 19. Autoimmunity and POFPOF may be due to an abnormal self-recognition bythe immune systemautoimmune mechanisms are involved in pathogenesisof up to 30% of cases of POFClinically, autoimmune ovarian failure is broadlydiscussed in two scenarios:In association with autoimmune Addisons diseaseIsolated or associated with other autoimmune diseasesBetterle et al ., 2002
  20. 20. POF and Addisons disease2–10% of POF cases are known to beassociated with adrenal autoimmunity.POF precede Addisons disease by 8–14 years.Sharing of auto antigens between ovary andadrenal glands, particularly the side-chaincleavage enzyme may explain the associationof ovarian failure and Addisons disease.
  21. 21. POF in absence of Addisons diseaseThyroid autoimmunity is the most common associationThyroid autoimmunity 20 - 40 % ( Belvisi et al. 2006 )Insulin-dependent diabetes mellitus (IDDM)Myasthenia gravis has also been reported(Ryan and Jones, 2004)Women with SLE, anti-ovarian antibodies were detectedin 84% (Moncayo-Naveda et al., 1989)
  22. 22. Autoimmunity and POFPOF is reported to be associated with endocrine and non-endocrine autoimmune disordersEndocrinethyroid, adrenal, hypoparathyroid , diabetes mellitus, and hypophysitisNon-endocrinechronic candidiasis, idiopathic thrombocytopenic purpura, vitiligo,alopecia, autoimmune haemolytic anaemia, pernicious anaemia,systemic lupus erythematosus, rheumatoid arthritis, Crohns disease,Sjögrens syndrome, myasthenia gravis, primary biliary cirrhosis andchronic active hepatitisPOF may be part of the autoimmune polyglandularsyndromes (APS)
  23. 23. Autoimmunity and POFPossible antigenic targets for antibody mediatedautoimmune damage in POFSteroid producing cells (SCA)3ß-hydroxysteroid dehydrogenase (3ß-HSD)autoantibodiesGonadotrophin receptors blocking antibodiesOther ovarian antigens Corpus luteum Zona pellucida and oocyte
  24. 24. Autoimmunity and POFNone of these antibody assays has been validated toconfirm a clinical diagnosis of autoimmune POF ???1- Serological marker of autoimmunity may not be presentdespite the disease being autoimmune in nature due todecline in the quantity of auto antigen2- Many auto antigens of organ-specific autoimmune diseaseslike POF may be still unidentifiedTherefore in the clinical work up of POF, screening foran autoimmune etiology is only possible in practice bylooking for coexisting autoimmune diseases
  25. 25. Miscellaneous Causes of POFViral oophoritisMumps oophoritisCigarette smoking and epilepsyEndocrine disruptors, heavy metals,solvents, pesticides, plastics, industrialchemicals
  26. 26. Miscellaneous Causes of POFRadiotherapyEffect of radiotherapy is dependent on dose ,age and onthe radiation therapy fieldComplete ovarian failure occurs with a dose of 20 Gy inwomen under 40 years of age and with only 6 Gy in olderwomenPrepubertal ovary is relatively resistant to gonad toxicitydue to radiotherapy and chemotherapyOvariopexy preserves ovarian function in 60-100% ofpatientsBeerendonk and Breat , 2005
  27. 27. Miscellaneous Causes of POFChemotherapyGonadotoxic effect of chemotherapy is largelydrug and dose-dependent and is related to ageAlkylating agents increase the risk of POF by afactor of 9Teenagers receiving chemotherapy have a 4 timesincreased risk of POFThis risk is increased by a factor of 27 amongwomen aged 21-25 yearsHascalik et al., 2004
  28. 28. Sonmezer, M. et al. Oncologist 2006;11:422-434Alkylating agents areextremely gonadotoxicbecause they are notcell cycle-specific andcan damage restingprimordial follicles,whereas cycle-specificagents such as MTXand 5-FU do not haveany effect on ovarianreserveDegree of gonadal failure associatedwith chemotherapeutic agents
  29. 29. Miscellaneous Causes of POFPelvic surgery has the potential to damagethe ovary by affecting its blood supply orcausing inflammation in the areaUterine artery embolization may also lead toPOF by compromising the vascular supply tothe ovaryRazayi et al 2004
  30. 30. PresentationAmenorrheaOligomenorrhoea / menstrual dysfunctionInfertilityEstrogen – deficiency symptomsPubertal delay / primary amenorrhea
  31. 31. POF-SymptomsBaber ,Abdalla and Studd (1991)Vasomotor 76%Loss of libido 31%sexual enjoyment reduced 37%Most Distressing symptomLoss of fertility 54%Feeling Older 27%
  32. 32. POF SymptomsGirls who have POF before puberty do notexperience the classic symptoms of estrogendeficiency as exposure of the body to adultlevels of estrogen and subsequent estrogenloss appear to be necessary for thedevelopment of symptomsYoung women who develop POF after pubertyfrequently experience symptoms of estrogendeficiency
  33. 33. Consequences of POFEstrogen – deficiency- Symptoms- Long – term effectsBone LossHeart DiseaseInfertilityPsychological needs
  34. 34. What are the Impacts of Estrogen Decline?
  35. 35. ManagementMake and explain the diagnosisTreat symptomsPrevent long – consequencesAddress psychological needsGenetic counseling if appropriateTreat infertilityOffer long – term follow – up and support
  36. 36. Make the diagnosisDiagnosis of POF is often delayed ,even with classic symptoms ofmenopauseAlzubaidi 2002POF is often a fluctuating conditionOvarian dysfunction precedes POF
  37. 37. Make the diagnosisEarly diagnosis of familial POF will providethe opportunity to predict the likelihood ofearly menopause, and allow other reproductivechoices to be made, such as freezing embryosor having children earlier.Because POF has cumulative effects overtime, it is important for clinicians to make atimely diagnosis and begin appropriatestrategies for management
  38. 38. Diagnostic testsElevated FSH levels in menopausal rang (usuallyabove 40 IU/I), PLUS a low estrogen level ( usuallybelow 20 picogram /ml ) must be detected on atleast two separate occasions each at least onemonth apart for a firm diagnosis to be madeUltrasoundOvarian biopsyBoth do not alter the managementKhastair 1994 , WHP Monash Uneversity 2007
  39. 39. InvestigationsProlactin, androgensThyroid functionScreen for thyroid and adrenal auto antibodiesKaryotype (early onset POF before age of 30)Genetic screen for FRAXACell surface markers on peripheral blood lymphocytescould result in diagnosis of autoimmune POF before thedevelopment of complete ovarian failure
  40. 40. HRTWhich type?What dose?What duration?
  41. 41. HRTLong-term HRT is needed for relief ofmenopausal symptoms.Prevent long-term health sequel of estrogendeficiency, such as osteoporosis and possiblycoronary heart disease.WOMEN with premature ovarian failure shouldbe informed that standard hormone therapy doesnot provide effective contraception.
  42. 42. Choice of HRT for women with POFUK Soc Paediatric Endocrinology 42 questionnaires (28 responses)COCP 18 (64%)Oral HRT (sequential) 5 (18%)Transdermal HRT (sequential) 3 (11%)Ethinyloestradiol (sequential) 2 (7%)
  43. 43. HRT typeWith the oral and transdermal routes there is achoice between continuous or sequentialdeliveryContinuous regimen avoids menstrual flow butbreak through bleeding may be more commonSequential regimen ensures monthly menstrualbleed, which may be a psychological benefit tosome young women (and absurd to others!).
  44. 44. HRT typeOral estrogen Conjugated equine estrogen 17ß –oestradiolHave consistent and comparable effects on hot flasheHave similar short-term adverse effectsNelson, 2004.
  45. 45. HRT typeTransdermal estrogen Avoids first-pass liver metabolism Has rapid onset and termination of action Attainment of therapeutic hormone levels withlow daily doses Appears to be free of an excess risk of thrombosis
  46. 46. HRT typeHormone Implants Higher Circulating oestradiol More effective Symptom control Better skeletal effects Better effects on uterus? Placement of 25-50mg oestradiol pellets usually inthe lower abdomen or buttocks in a minor officeprocedure
  47. 47. HRT typeSome young women with POF find the combinedoral contraceptive pills a more acceptable optionProvides a fixed combination of estrogen andprogesterone with a ‘pill free week’ which contrastsfrom the greater flexibility with the HRT alternativesThe pill-free week amounts to 3 months ofestrogen deficiency each yearNelson , 2004
  48. 48. OCP vs. HRTSynthetic • PhysiologicalMore potent • May be safer for long timePill – free week • Continuous estrogenLike peer-group • Stigma of HRTReminder of infertility • Notcontraceptive
  49. 49. HRT dosageAn HRT regimen should be based onthe individual preferences of eachpatient who should be encouraged toundertake a trial and error approachthrough the wide variety of productsavailable
  50. 50. HRT dosageStandard HRT doses may be suboptimalIn young women HRT may not be enoughExpectation for sexual function can be higher Vaginal moisturisers Topical estrogenMonitor by symptoms and BMD- Oestradial levels useful only for implants to determine the timeof re-dosing, which is about every 6 months for most women
  51. 51. Choice of progesteroneProgestins vary from the more potent such asnorethisterone to the weaker such asdydrogesterone The route may be oral, transdermal or uterineWith the oral and transdermal routes there is achoice between continuous or sequential (for10-14 days each month)
  52. 52. Choice of progesteroneUterine delivery with the levonorgestrelintrauterine device (Mirena) has theadvantage of avoiding the adverse effectsof oral progestins highlighted in thestudies of older womenChlebowski et al. 2003
  53. 53. TestosteroneAndrogen level decrease in POF(half of testosterone supply from ovaries )Hartman 1997Reduced libido, sexual function , ? Energy ? BMDWorse in oophorectomised womenTransdermal testosterone administration anddehydroepiandrosterone treatment are two of theoptions for androgen replacement in these womens/e excess hair growth and acneBraunstein 2005, shifren 2007
  54. 54. Alternative to HRTEfficacy lower than HRT: Serotonin and noradrenalin re- uptake inhibitors Clonidine Gabapentin• Efficacy unproven: Progesterone transdermal cream Phyto-oestrogens ( soy, red clover)• Safety unproven: Herbal preparatione.g. black cohosh , dong quiPanay and rees RCOG 2006
  55. 55. lifestyle Smoking increase risk of POFChang 2007Exercise , especially weight bearing ,Improves bone massWallace 2000Diet , calcium and vitamin DJackson 2006Alcohol and caffeine
  56. 56. Long- term risks of POFLife expectancy reducedRocca et al lancet oncol 2006Cohort of > 12, 000 women 2 years less life expectancy if menopause < 40 Increase mortality ischemic heart disease Reduced uterine and ovarian cancerOsseward et al Epidemiology 2005 .16 : 556
  57. 57. Long- term risks of POF (2)May clinic cohort study – bilateraloophorectomy1950 -1987 followed to 2006Premature deathCardiovascular diseaseCognitive impairment , dementia , parkinsonismOsteoporosis and fractureDecrease psychological wellbeingDecrease sexual functionShuster et al Menopause int2008
  58. 58. Osteoporosis preventionHRT prevents bone lossHRT improves BMD in POFLittle evidence on alternative in POF Bisphosphonates used in breast cancer Calcium and vitamin DDavis 1990, Van der Voort 2003
  59. 59. Cardiac disease Vascular endothelial dysfunctionassociated with oestrogen – deficiency Improved by HRT Kalantaridou 2004 , Osberg 2007 Increased risk of ischemic heart diseasefollowing BSO Atsma 2006, Allison 2008 Lack of long – term data on HRT for POF
  60. 60. Women’s Health Initiative (WHI)JAMA 2002;288:321-333Two parallel RCTStudy 18506 women received HRT(0.625mg CEE+2.5mg MPA)8102 received placeboStudy 2Oestrogen alone Vs placeboWomen with menopausal symptoms or osteoporosisneeding HRT not recruited into study.
  61. 61. Benefits and risks WHI Women studies arenot applicable to young women No data are available to evaluate the impact oftreatment on risk factors, such as the developmentof breast cancer or of cardiovascular events inyoung women with POF and extrapolation fromstudies in older women may not always beappropriate.
  62. 62. HRT durationUntil expected age ofmenopause“In women who have experienced a premature menopause(due to ovarian failure , surgery , or other causes ) HRTmay be used for treatment of menopausal symptoms andfor prevention of osteoporosis until the age of 50 years.After this age , therapy for prevention of osteoporosisshould be reviewed and HRT considered a second choice”
  63. 63. Fertility“ The sudden switch fromfertile women to irrevocablyinfertile women was thebiggest blow of all”
  64. 64. Spontaneous pregnancyPregnancy rate 5 – 10 %Can occur on HRTMiscarriage rate ? 20 %Van Kasteren 1999Prognostic factors : Recent diagnosis – short period of amenorrhea Fluctuating FSH Ovarian activity on ultrasound POF due to autoimmunity or chemotherapy
  65. 65. Fertility treatmentTreatment strategies unproven: Stimulation after FSH suppression Corticosteroids All were reported to be equally ineffectiveReview in 194 patients, 3 pregnanciesRecovery of ovarian function may occur afterregression of the autoimmune statusVan Kasteren 1999
  66. 66. Fertility horizons Germ cells in BM – unproven “Bone marrow transplantation generates immatureoocytes and rescues long – term fertility in apreclinical mouse model of chemotherapy- inducedPOF”Johnson& Tilly 2005 , Lee 2007 Cloning ? Artificial gametes ?
  67. 67. Egg donationGood success rates ( up to 50 %)Donated oocytes has been used to achievepregnancy in women with POF since 1987Wide variation in availabilityRecipient needs HRT to prepare uterusDonor undergoes IVF stimulation cycle
  68. 68. Risks to egg donorRisks of stimulation OHSS (hormone – dependant conditions )PregnancyRisks of egg collection Bleeding Infection
  69. 69. Pregnancy risksMultiple birthPre- eclampsiaTurner syndromeCancer survivors : Cardiac / renal toxicity of chemotherapy Uterine irradiation : misc. , IUGR, pre- term
  70. 70. SurrogacyMay be required after gynecologicalcancer or uterine irradiation IVF with “full “ surrogacy (donated eggs) Insemination (surrogate is egg donor)
  71. 71. Prevention of POF Lower hysterectomy rate Fertility- preserving surgery for cancer Less gonad toxic chemotherapy regimens ? Hormonal protection ( GnRH-a ) Embryo , egg and tissue freezing
  72. 72. 18 women, 15-40 yrs, Hodgkin’s or non-Hodgkin’s lymphomasChemotherapy + LHRH-ahistorical matched control group of 18 women (17-40 yrs)treated with chemotherapy aloneCOMPARED TO:
  73. 73. ASCO Recommendations on FertilityPreservation in Cancer Patients(Expert Panel, J Clin Oncol 2006) At this time, since there is insufficientevidence regarding the safety and effectiveness ofGnRH analogs and other means of ovariansuppression on female fertility preservation, womeninterested in ovarian suppression for this purposeare encouraged to partecipate in clinical trials
  74. 74. Embryo CryopreservationIt is the only establishedmethod for fertility preservationSurvival rates per thawed embryos are inthe range of 35%–90%, implantation rates are inthe range of 8%–30%, and cumulative pregnancyrates exceed 60%(Sonmezer et al, 2004).
  75. 75. Egg freezingPregnancy rate 10 – 20 % per transfer withconventional freezingHigher with vitrificationno long – term safety data? 500 births in totalTur- Kaspa ASRM 2007
  76. 76. Ovarian tissue freezingStill experimentalCycle – independentPossible in pre-pubertal patient4 live births reportedDonnez et al,2004Future ? IVM ? Whole ovary graft
  77. 77. PsychologyPOF is an extremely devastating life experience Women with POF report High levels of depression Low levels of self-esteem with negative effects on sexuality Moderate to severe stress at the time of diagnosisCrises arise some years after the originaldiagnosis, for instance when a near relativeachieves a pregnancy
  78. 78. PerspectiveGenome scanning for familial casesGenome scanning for sporadic casesCandidate genes from animal models ?
  79. 79. Genesof menopauseNew contraceptive targetsNew infertility treatment
  80. 80. Conclusions POF is a complex condition that requires specialistservices. The diagnostic workup is aimed at determining theetiology where possible and is followed by a screenfor syndromic conditions. Estrogen replacement and fertility options need tobe reassessed at intervals and clinicians have to bevigilant for psychological sequelae. Encourage HRT at least until 51 yrs. No increased risk of breast cancer.
  81. 81. POF Recommendations Improve awareness. Multi- disciplinary clinical services. Incorporate psychology & associate with“late effects “ service in cancer centers. Multicentre research collaboration. ? Guidelines.