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 yearsWhen 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
PathophysiologyMost 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.
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
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
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.
Normal menopause vs. POFNormal menopause is an irreversible condition,whereas approximately 50% of women with POFexperience intermittent ovarian function aftertheir periods initially stopSome women will produce estrogen intermittentlyand may ovulate (fluctuating ovarian function )Pregnancies have occurred after the diagnosis ofPOF (5-10%)
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
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
Causes of POF* Etiology unknown, extremelyheterogeneousin more than 90% of cases,apart from● Surgery● Chemotherapy● Radiotherapy● Turner syndrome
CausesCauses of POF in 352 women attending theMiddlesex Hospital , London ,UKn %Idiopathic ( including autoimmune) 204 58Turners Syndrome 82 23Chemotherapy 24 7Familial POF 15 4Pelvic surgery 8 246xy gonadal dysgenesis 7 2Galactosaemia 6 2Pelvic irradiation 6 2Goswami et al 2007Horm Res 2007; 68 : 196-202
Spontaneous POFNo identifiable cause of POFUnexplained early degeneration of the cells of theovaryCommon for woman with spontaneous POF to have afamily history of POF in either her mother or sisterThe American Collage of obstetrics and gynecologynow recommends that women with POF withoutknown cause be screened for FMR1 premutationsobstet Gynecol 2006
Genes and POFVarious genetic mechanisms implicated inpathogenesis of POF includeReduced gene dosageNon-specific chromosome effects that impair meiosisThese can lead to ovarian failure by causingDecrease in the pool of primordial folliclesIncreased atresia of the ovarian follicles due to apoptosisor failure of follicle maturation
Genes and POFIdentify women / families with POF and riskof transmission of a genetic disorderFamilial cases in 15- 20 % of casesChromosomal abnormalities are detected in40- 50 % of women who do not experiencespontaneous pubertyMost common genetic abnormality causingPOF is Turners Syndrome
Autoimmunity and POFPOF may be due to an abnormal self-recognition bythe immune systemautoimmune mechanisms are involved in pathogenesisof up to 30% of cases of POFClinically, autoimmune ovarian failure is broadlydiscussed in two scenarios:In association with autoimmune Addisons diseaseIsolated or associated with other autoimmune diseasesBetterle et al ., 2002
POF and Addisons disease2–10% 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.
POF in absence of Addisons diseaseThyroid autoimmunity is the most common associationThyroid 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)
Autoimmunity and POFPOF is reported to be associated with endocrine and non-endocrine autoimmune disordersEndocrinethyroid, adrenal, hypoparathyroid , diabetes mellitus, and hypophysitisNon-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 hepatitisPOF may be part of the autoimmune polyglandularsyndromes (APS)
Autoimmunity and POFPossible antigenic targets for antibody mediatedautoimmune damage in POFSteroid producing cells (SCA)3ß-hydroxysteroid dehydrogenase (3ß-HSD)autoantibodiesGonadotrophin receptors blocking antibodiesOther ovarian antigens Corpus luteum Zona pellucida and oocyte
Autoimmunity and POFNone 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 unidentifiedTherefore in the clinical work up of POF, screening foran autoimmune etiology is only possible in practice bylooking for coexisting autoimmune diseases
Miscellaneous Causes of POFViral oophoritisMumps oophoritisCigarette smoking and epilepsyEndocrine disruptors, heavy metals,solvents, pesticides, plastics, industrialchemicals
Miscellaneous Causes of POFRadiotherapyEffect of radiotherapy is dependent on dose ,age and onthe radiation therapy fieldComplete ovarian failure occurs with a dose of 20 Gy inwomen under 40 years of age and with only 6 Gy in olderwomenPrepubertal ovary is relatively resistant to gonad toxicitydue to radiotherapy and chemotherapyOvariopexy preserves ovarian function in 60-100% ofpatientsBeerendonk and Breat , 2005
Miscellaneous Causes of POFChemotherapyGonadotoxic effect of chemotherapy is largelydrug and dose-dependent and is related to ageAlkylating agents increase the risk of POF by afactor of 9Teenagers receiving chemotherapy have a 4 timesincreased risk of POFThis risk is increased by a factor of 27 amongwomen aged 21-25 yearsHascalik et al., 2004
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
Miscellaneous Causes of POFPelvic surgery has the potential to damagethe ovary by affecting its blood supply orcausing inflammation in the areaUterine artery embolization may also lead toPOF by compromising the vascular supply tothe ovaryRazayi et al 2004
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%
POF SymptomsGirls 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 symptomsYoung women who develop POF after pubertyfrequently experience symptoms of estrogendeficiency
Consequences of POFEstrogen – deficiency- Symptoms- Long – term effectsBone LossHeart DiseaseInfertilityPsychological needs
ManagementMake and explain the diagnosisTreat symptomsPrevent long – consequencesAddress psychological needsGenetic counseling if appropriateTreat infertilityOffer long – term follow – up and support
Make the diagnosisDiagnosis of POF is often delayed ,even with classic symptoms ofmenopauseAlzubaidi 2002POF is often a fluctuating conditionOvarian dysfunction precedes POF
Make the diagnosisEarly 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
Diagnostic testsElevated 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 madeUltrasoundOvarian biopsyBoth do not alter the managementKhastair 1994 , WHP Monash Uneversity 2007
InvestigationsProlactin, androgensThyroid functionScreen for thyroid and adrenal auto antibodiesKaryotype (early onset POF before age of 30)Genetic screen for FRAXACell surface markers on peripheral blood lymphocytescould result in diagnosis of autoimmune POF before thedevelopment of complete ovarian failure
HRTLong-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.
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%)
HRT typeWith the oral and transdermal routes there is achoice between continuous or sequentialdeliveryContinuous regimen avoids menstrual flow butbreak through bleeding may be more commonSequential regimen ensures monthly menstrualbleed, which may be a psychological benefit tosome young women (and absurd to others!).
HRT typeOral estrogen Conjugated equine estrogen 17ß –oestradiolHave consistent and comparable effects on hot flasheHave similar short-term adverse effectsNelson, 2004.
HRT typeTransdermal 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
HRT typeHormone 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
HRT typeSome young women with POF find the combinedoral contraceptive pills a more acceptable optionProvides a fixed combination of estrogen andprogesterone with a ‘pill free week’ which contrastsfrom the greater flexibility with the HRT alternativesThe pill-free week amounts to 3 months ofestrogen deficiency each yearNelson , 2004
OCP vs. HRTSynthetic • PhysiologicalMore potent • May be safer for long timePill – free week • Continuous estrogenLike peer-group • Stigma of HRTReminder of infertility • Notcontraceptive
HRT dosageAn 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
HRT dosageStandard HRT doses may be suboptimalIn young women HRT may not be enoughExpectation for sexual function can be higher Vaginal moisturisers Topical estrogenMonitor 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
Choice of progesteroneProgestins vary from the more potent such asnorethisterone to the weaker such asdydrogesterone The route may be oral, transdermal or uterineWith the oral and transdermal routes there is achoice between continuous or sequential (for10-14 days each month)
Choice of progesteroneUterine delivery with the levonorgestrelintrauterine device (Mirena) has theadvantage of avoiding the adverse effectsof oral progestins highlighted in thestudies of older womenChlebowski et al. 2003
TestosteroneAndrogen level decrease in POF(half of testosterone supply from ovaries )Hartman 1997Reduced libido, sexual function , ? Energy ? BMDWorse in oophorectomised womenTransdermal testosterone administration anddehydroepiandrosterone treatment are two of theoptions for androgen replacement in these womens/e excess hair growth and acneBraunstein 2005, shifren 2007
Alternative to HRTEfficacy 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
lifestyle Smoking increase risk of POFChang 2007Exercise , especially weight bearing ,Improves bone massWallace 2000Diet , calcium and vitamin DJackson 2006Alcohol and caffeine
Long- term risks of POFLife expectancy reducedRocca et al lancet oncol 2006Cohort 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
Long- term risks of POF (2)May clinic cohort study – bilateraloophorectomy1950 -1987 followed to 2006Premature deathCardiovascular diseaseCognitive impairment , dementia , parkinsonismOsteoporosis and fractureDecrease psychological wellbeingDecrease sexual functionShuster et al Menopause int2008
Osteoporosis preventionHRT prevents bone lossHRT improves BMD in POFLittle evidence on alternative in POF Bisphosphonates used in breast cancer Calcium and vitamin DDavis 1990, Van der Voort 2003
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
Women’s Health Initiative (WHI)JAMA 2002;288:321-333Two parallel RCTStudy 18506 women received HRT(0.625mg CEE+2.5mg MPA)8102 received placeboStudy 2Oestrogen alone Vs placeboWomen with menopausal symptoms or osteoporosisneeding HRT not recruited into study.
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.
HRT durationUntil 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”
Fertility“ The sudden switch fromfertile women to irrevocablyinfertile women was thebiggest blow of all”
Spontaneous pregnancyPregnancy rate 5 – 10 %Can occur on HRTMiscarriage rate ? 20 %Van Kasteren 1999Prognostic factors : Recent diagnosis – short period of amenorrhea Fluctuating FSH Ovarian activity on ultrasound POF due to autoimmunity or chemotherapy
Fertility treatmentTreatment strategies unproven: Stimulation after FSH suppression Corticosteroids All were reported to be equally ineffectiveReview in 194 patients, 3 pregnanciesRecovery of ovarian function may occur afterregression of the autoimmune statusVan Kasteren 1999
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 ?
Egg donationGood success rates ( up to 50 %)Donated oocytes has been used to achievepregnancy in women with POF since 1987Wide variation in availabilityRecipient needs HRT to prepare uterusDonor undergoes IVF stimulation cycle
Risks to egg donorRisks of stimulation OHSS (hormone – dependant conditions )PregnancyRisks of egg collection Bleeding Infection
SurrogacyMay be required after gynecologicalcancer or uterine irradiation IVF with “full “ surrogacy (donated eggs) Insemination (surrogate is egg donor)
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
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:
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
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).
Egg freezingPregnancy rate 10 – 20 % per transfer withconventional freezingHigher with vitrificationno long – term safety data? 500 births in totalTur- Kaspa ASRM 2007
Ovarian tissue freezingStill experimentalCycle – independentPossible in pre-pubertal patient4 live births reportedDonnez et al,2004Future ? IVM ? Whole ovary graft
PsychologyPOF 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 diagnosisCrises arise some years after the originaldiagnosis, for instance when a near relativeachieves a pregnancy
PerspectiveGenome scanning for familial casesGenome scanning for sporadic casesCandidate genes from animal models ?
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.
POF Recommendations Improve awareness. Multi- disciplinary clinical services. Incorporate psychology & associate with“late effects “ service in cancer centers. Multicentre research collaboration. ? Guidelines.