premature ovarian failure - menopausematters.co.uk · 27th mar 2006 29 west london menopause &...

1

Premature Ovarian FailurePremature Ovarian FailureTherapeutic OptionsTherapeutic Options

2727thth Mar 2006Mar 2006RCOG SSM RCOG SSM

Nick PanayConsultant Gynaecologist

West London Menopause & PMS CentreHonorary Senior Lecturer, Imperial College London

27th Mar 2006 2 West London Menopause & PMS Centre


Definition and pathophysiology

Delivery of treatment – how best to do it

Therapeutic Options– Fertility– HRT– Testosterone– Combined Pill– Alternatives

Conclusions





Therapeutic Options– Fertility– HRT– Testosterone– Combined pill– Alternatives

Conclusions


Premature Ovarian FailurePremature Ovarian FailureDefinitionsDefinitions

Premature Ovarian Failure– Menopause before the age of 40y– Affects 1% of women

Early Menopause– Menopause between 40 – 45y– Up to 20% of women


Premature Ovarian FailurePremature Ovarian FailurePresentationPresentation

Ovarian cycle may cease abruptly (esp if iatrogenic aetiology) or fluctuate leading to– Amenorrhoea or erratic periods

– Climacteric Symptoms

– Raised FSH (or fluctuating levels) ?Inhibin assays

– Reduced Oestradiol (or fluctuating levels)


Premature Ovarian FailurePremature Ovarian FailureConsequencesConsequences

Symptoms – vasomotor, psychological, urogenital

Infertility (< 1% return of fertility after 6/12 amenorrhoea with idiopathic POF)

Bone loss

Heart disease


Premature Ovarian FailurePremature Ovarian FailureConsequencesConsequences

• Fertility in Premature Ovarian Failure

• Success of oocyte donation (dependent on donor age) suggests that

endometrium remains healthy & receptive • Navot Fertil Steril 1994

• Large doses of HRT in donor cycles may mask underlying defects in

receptivity, perfusion & hormone receptor no in endo. of atrophic uterus

• Yaron Fertil Steril 1993; Meldrum Fertil Steril 1993; Goswamy Hum Reprod


Premature Ovarian FailurePremature Ovarian FailureOsteoporosisOsteoporosis

Rate of bone loss is the same as following natural menopause but consequences are more severe as longer life expectancy

Dimitrios et al Maturitas 2003 – 514 women studied in total– Women with POF exhibited lower BMD compared

with normally menopaused women @ ages 45-55


Premature Ovarian FailurePremature Ovarian FailureOsteoporosisOsteoporosis

Van der Voort et al Ost Int 2003– 4725 postmenopausal women (2757 natural

menopause) filled in questionnaires

– Those with early menopause had significantly higher fracture rates OR 1.5 (CI 1.2-1.8)

27th Mar 2006

Premature Ovarian FailurePremature Ovarian FailureCoronary artery diseaseCoronary artery disease

Related to number of years past menopause rather than ageDavies, Br J Cardiol 1997

27th Mar 2006

Hormonal changes at menopause and risk of Hormonal changes at menopause and risk of coronary eventcoronary event

Age of menopause and Coronary Heart Disease risk : Nurse’s Health Study

Significant correlation between younger age of menopause & CHD in non HRT users

Hu et al Arch Int Med 1999; Grodstein 2006

27th Mar 2006

Cardiovascular disease risk in premature Cardiovascular disease risk in premature ovarian failureovarian failure

– Endothelial dysfunction due to hypo-estrogenic state

– 6 months HRT restored endothelial dysfunction

• Kalantaridou J Clin Endoc Metab 2004






Conclusions


Premature Ovarian FailurePremature Ovarian FailureOptimising Hormone TherapyOptimising Hormone Therapy

Multidisciplinary collaborationMultidisciplinary collaboration

Menopause / Reproductive medicine collaboration

Specialist GP’s & Nurses– Menopause nurse specialists– Gynae oncology nurse specialist (Macmillan) – GPSI in menopause

Other specialists– Haematology / Gynae Oncology– Dietician– Psychologist / Councellors– Physios






Conclusions


Fertility Options after POFFertility Options after POF• Realistic options:

• Oocyte Donation• Embryo Donation• Surrogacy

• Potential Future Options:

• Cloning with somatic cell nuclear transfer to enucleated oocytes

• Stem Cell technology - UK 10 years; USA 2 years!


OocyteOocyte DonationDonationTypical Pregnancy RatesTypical Pregnancy Rates

539 Cycles with fresh ET198 Pregnancies

37% per cycle

191 cases frozen ET34 pregnancies

18% per cycle


OocyteOocyte Donation Donation -- problemsproblems

Donor difficultiesDemand far greater than availability of donorsTime and commitment for donorInvasive treatmentNon Payment

Maternal DifficultiesHealth Long term sequelae of maternal illnessTreatment physically and emotionally tiring


Obstetric outcome in Egg Donation Obstetric outcome in Egg Donation PregnanciesPregnancies

Higher incidence ofMiscarriage

Pregnancy Induced Hypertension

Growth Restriction


Options for women at risk of ovarian failureOptions for women at risk of ovarian failure

Surgery– Ovarian transposition

– Ovarian Tissue CryopreservationTransplantationIn Vitro maturation

IVF– Embryo Cryopreservation

– Oocyte Cryopreservation


Ovarian tissue CryopreservationOvarian tissue Cryopreservation

Increasingly done world wide in spite of still being an experimental technique

9 cases in literature so far of successful transplantation withtemporary reproductive function


Ovarian Ovarian AutotransplantAutotransplant

Oktay & Karlikaya ’00 CP 1 othotopic TRadford ’01 CP 1 othotopic TOktay ’01 CP 2 heterotopic TCallejo et al ’01 fresh 3 heterotopic T

“ CP 1 heterotopic TOktay ’04 CP 1 heterotopic T


Ovarian tissue Ovarian tissue CryopreservationCryopreservation

Potential to restore normal ovarian function and natural fertility

Can be used for girls who are both pre and post menarche

Little delay in commencing chemo / irradiation


IVFIVFEmbryo CryopreservationEmbryo Cryopreservation

Most successful, tried and tested (can be frozen for 5-10 years) but problems

Risks of IVF e.g. high estrogen levels

Need partner in stable relationship

Time restraints ; “ Funding “

Ethical issues in event of death of patient


IVFIVFOocyteOocyte CryopreservationCryopreservation

– Ideal for Single women– Avoids legal, regulatory and social dilemma

– But, Overall low success ratesLive birth rate 2% per oocyte


Effect of cooling on Effect of cooling on oocytesoocytes






Conclusions



Therapeutic Options – HRT

– Impact of Adverse Media on HRT use in POF

– “Minimising side effects – maximising benefits” RoutesSequential v Continuous CombinedDosageProgestogens



Impact of Alarmist Media on HRT use for Premature Menopause

Ng C., Reddy N., Panay N. 2004 ESHRE Berlin

Conclusions

– All aware of adverse publicity

– Majority continuing with HRT BUT 37% (1/3) were contemplating stopping HRT because of breast cancer fears

– Less than half realised that risks did not apply to their age group



Therapeutic Options – HRT

– Impact of Adverse Media on HRT use in POF

– “Minimising side effects – maximising benefits” RoutesSequential v Continuous CombinedDosageProgestogensRisks


Choice of HRT for post pubertal women with Choice of HRT for post pubertal women with premature ovarian failure premature ovarian failure Bath et al 2001 Bath et al 2001 ClinClin EndocrinolEndocrinol

UK Soc Paediatric Endocrinology 42 questionnaires (28 responses)

COCP 18 (64%) Loestrin (20-30) 12(67%)

Oral HRT (sequential) 5 (18%) Prempak C 5 (100%)

Transdermal HRT (sequential) 3 (11%) Estracombi 2 (66%)

Ethinyloestradiol (sequential) 2 (7%)

– Two respondents had no preferred HRT preparation!

– “No consensus for prescribing in POF to optimise skeletal & cardiovascular health”



Route / Type – Conclusion

In the absence of better prospective randomised data…

GIVE WOMEN WHAT THEY WANT

…………particularly if you want them to use it!


Sequential v Continuous CombinedSequential v Continuous Combined

Sequential – Pros

“More normal to have periods”Endometrial Generation Pre Fertility TreatmentLess Unscheduled Bleeding

– ConsPossible risk of endometrial hyperplasia (Sturdee 2000)“Why should I bleed if I don’t have to?”More side effects in progestogen phase


Sequential v Continuous CombinedSequential v Continuous Combined

Continuous Combined– Pros

No risk of endometrial hyperplasia (?protective)Less Progestogen overall

– ConsPossible risk of endometrial atrophy/necrosis pre IVFUnscheduled bleeding Un-physiological


Dosage of HRTDosage of HRTOestrogenic side effectsOestrogenic side effects

Management– Start with standard dose oestrogen in most cases –

benefits still maintained

– 0.625mg CEE /1.0mg E2 / 50mcg patch / 25-50mg implant

– Warn re possibility of SE’s initially & reassure



Exceptions to starting standard dose oestrogen– Very symptomatic premature ovarian failure

– Severe osteoporosis

– Predominance of psychological problems (mental tonic effect of higher doses)



Management– Liaise with gynae onc / oncologists re time to start

– Immediately if curative procedure (after histol)

– Delay (1 year disease free interval) if advanced oestrogen sensitive tumour e.g. endometrial carcinoma


ProgestogenProgestogen?use at all?use at all


ProgestogenProgestogen –– the dilemmathe dilemma10 years use E2 alone in non - hysterectomised women

– Excess 5:1000 breast cancer cases – Excess 10:1000 endometrial cancer cases– Total 15:1000 cases

10 years use E2: Prog: – 19:1000 breast cancer cases – No Excess endometrial cancer cases with ccHRT– Total 19:1000 cases

– BUT…..


ProgestogenProgestogen –– the dilemmathe dilemma

Increased morbidity & mortality due to bleeding problems leading to increased intervention– Endometrial sampling– Scans– Hysteroscopy– Hysterectomy

?Local or tissue selective progestogen (in future SERMS / SPRMS e.g. asoprisnil)


Avoiding Major Adverse Events Avoiding Major Adverse Events Local delivery of Local delivery of progestogenprogestogen

LNG IUS (Mirena) -20mcg

MLS (Menopause Levo. System) - 10mcg

BUT STILL SIG. SYSTEMIC EFFECTS!


Avoiding Major Adverse Events Avoiding Major Adverse Events Local delivery of Local delivery of progestogenprogestogen

Mirena data

Backman et al 2005 Obstet GynecolFinnish Cancer Registry17, 360 Mirena Users : 30-54ys

No difference in breast cancer rates compared to average Finnish breast cancer rates


Avoiding Major Adverse EventsAvoiding Major Adverse EventsCHOICE: CHOICE: MammographicMammographic density Digitized quantificationdensity Digitized quantification

Buenos Aires IMS 2005Buenos Aires IMS 2005

0

5

10

15

20

25

30

Placebo ALD 0.1 ALD 0.25

Mean b

reast

density

(%

)

Screening Week 24 No significant difference between groups


HRT RisksHRT RisksPrevious Gynaecological MalignancyPrevious Gynaecological Malignancy

Cervical (squamous)

Endometrium

Ovaries

Vagina / Vulva



Cervical Cancer (squamous)– Not Oestrogen sensitive– No evidence of excess risk

Cervical Cancer (adenocarcinoma)– No evidence– But, more cautious approach



Endometrial Cancer – 3 retrospective studies

– Stage 1 & 2 & 3 Endometrial Cancer

– Matched Control Study

– 2/75 (1%) recurrences in HRT group v 11/75 (14%) in non users (83 v 69 month observation period)

– Hormone users had a statistically longer disease free interval than non users

• Suriano et al Obstet Gynecol 2001



Ovaries– “HRT does not seem to have a noteworthy

effect on the progression of epithelial carcinoma of the ovary”

– 31 patients with 55 month follow up

Bebar et al Eur J Gynecol Oncol 2000



Vagina / Vulva (squamous)

No evidence

Vaginal Adenocarcinoma

No evidence






Conclusions


HRT: Maximising Efficacy HRT: Maximising Efficacy Minimising ProblemsMinimising Problems

TestosteroneTestosterone

Management

– Always consider testosterone as well as oestrogen replacement

– Especially in women with low energy / libido / depressed mood

– 50% loss of testosterone with POF esp surgical


HRT: Maximising Efficacy HRT: Maximising Efficacy Minimising ProblemsMinimising Problems

TestosteroneTestosteroneManagement– Implants (25 - 100mg) only licensed preparation for use in

women

– However, trial data and limited experience exists for use of tailor made doses of

Methyltestosterone (oral)Gel (Testogel)Patch (Phase III trials)Injection (Sustanon)Sublingual


Testosterone gelTestosterone gel

Unlicensed for women5ml gel 50mg sachet0.5 – 1.0ml / dayAbdo / inner thighsFAI up to 6.5%


Testosterone Patch Testosterone Patch –– Improves sexual activity Improves sexual activity and desire in surgically menopausal womenand desire in surgically menopausal women

Simon et al Abstract AMS 2004– 562 oophorectomised women : “Hypo Sexual Desire Disorder”– Oral / transdermal estradiol– 300mcg /day patch v placebo 24 weeks

Results– 74% increase in frequency of total sexual activity

2.13 v 0.98 episodes / 4 weeks (p=0.003)

– 56% increase in sexual desire score11.85 v 6.90 points (p=0.006)

27th Mar 2006

Effect on mood: Effect on mood: LivialLivial®® versus placeboversus placebo

LivialPlaceboCross-over

Weeks

Mea

n w

eekl

y su

msc

ore

(16

item

s)

0 1 5 10 15 20 25 30

40

50

60

70

Tax et al., Maturitas






Conclusions



Combined pill– “Use of ethinylestradiol has been driven by

practicalities rather than science”

• Conway et al (1996)



Combined pillPros: – Convenient

– “Peer Friendly”

– Free



Combined PillCons– Un-physiological

– Difficult to monitor – what is correct dose anyway?

– Pill free week can lead to symptom resurgence

– ?Risks of long term ethinylestradiol v “natural hormone replacement



Combined Pill v HRT– Guttmann et al 2001 Clin Endocrinol

– 0.625mg v 30mcg EE in 17 adult women with Turner’s Syndrome

– 6 month cross over study :Hormones, Lipids, Bone Turnover etc

– FSH most suppressed by EE, BUT HRT was superior at minimising hyperinsulinaemia & bone turnover






Conclusions


Why not HRT?Why not HRT?

Woman does not want

Medical contraindication

Media terror

Alternatives better


LifestyleLifestyleRegular Exercise– CVS & Bone Health

Well balanced diet– Complex carbohydrates– Oily fish

Moderating Smoking / Alcohol / Caffeine

Phytoestrogen rich diet– Soy, legumes, pulses etc


Alternatives to HRTAlternatives to HRTPharmaceutical Alternatives

– SNRIs• e.g. Venlafaxine 37.5mg bd, approx 50% symptom reduction in RCTs• Nausea / poor tolerance

– Progestogens• e.g. Megestrol acetate 30-50% symptom reduction• ?Breast cancer risk

Complementary Medicines– Phytoestrogens

• e.g. Red Clover Isoflavones, Soy, Legumes• Approx. 50-60% symptom reduction in some RCT’s

– Black Cohosh• ?CNS effect on vasomotor symptoms• Hepatotoxicity reported in a few cases


PhytoestrogensPhytoestrogens

Use for osteoporosis prevention not confirmed though may be reduction in bone turnover

Surrogate marker studies for CVD– ⇓ cholesterol, LDL, TGs

? Effect on breast cancer

27th Mar 2006

SSelectiveelective ooEEstrogenstrogen RReceptoreceptor MModulatorodulator

Agonist

Bone CVS

Antagonist

Breast Uterus


HRT: Current ControversiesRaloxifene : Not an HRT alternative!

HRT: Current ControversiesHRT: Current ControversiesRaloxifeneRaloxifene : : Not an HRT alternative!Not an HRT alternative!

Side effects Placebo Active – 1.Leg cramps 1.9% 5.9%

– 2.Flushes 18.3% 24.6%

Thromboembolic disease risks similar to HRT RR 2.16(95% CI 1.11-4.21)

Wyeth Bazedoxifene / HRT trial ongoing


TiboloneTibolone: STEAR: STEAR (selective tissue estrogenic activity (selective tissue estrogenic activity regulator)regulator)

Tibolone and active metabolites

ReceptorE2 receptor activation

Pre-receptorEffect on Metabolism local enzymes

Bone, Vagina, ?Brain

Tissue stimulation

Less activeestrogenic compounds

Breast

No tissue stimulation

∆ -isomer4

Endometrium

rrrr


THEBES THEBES Endometrial Histology Results Oct 2005Endometrial Histology Results Oct 2005

Tibolone (1.25 + 2.5)

CEE + MPA

Subjects as treated 1598 1626

Women-years 2402 2415

Hyperplasia 0 (0.0%) 2 (0.1%)Endometrial cancer* 0 (0.0%) 1* (0.1%)

Polyps at year 1 33 (2.6%) 40 (3.1%)

Polyps at year 2 24 (2.5%) 25 (2.5%)


ANGELS (Activators of non genomic ANGELS (Activators of non genomic estrogenestrogen like signalling) like signalling) EstrenEstren

Ligand dependent i.e. oestradiol, genomic pathway is major route to osteoblast activation

Estren stimulates non genomic pathways to suppress osteoblast apoptosis – bone strengthening in mice (UAMS 2002)

Avoids stimulation of ligand dependent genomic pathways in endometriumand breast

Tobias J Osteoporosis Review 2003; 11 1-5.





Therapeutic Options

– Fertility– HRT– Testosterone– Combined pill– Alternatives

Conclusions


Premature Ovarian FailurePremature Ovarian FailureFuture ObjectivesFuture Objectives

Multidisciplinary Working Group to:

– Identify clinics seeing POF patients

– Develop National Register of POF patients

– Establish National Guidelines for Mx of POF

– Propose future research : particularly to determine optimum therapeutic regimens


Premature Ovarian FailurePremature Ovarian FailureConclusionsConclusions

HRT is for quality of life AND for primary prevention in POF

HRT & Alternatives – research urgently required!

Future RegimensSelective targeting of desired organs/tissues with

receptor selective agents


“Longevity has no meaning withoutQuality of Life”


Thank you for your Thank you for your attention!attention!

77

Postmenopausal HealthJoint RCOG/BMS Special Skills Meeting

premature ovarian failure - menopausematters.co.uk · 27th mar 2006 29 west london menopause &...

Documents