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Protocol-Hormone therapy in women with premature ovarian failure

Hormone therapy in women with premature ovarian failure

(Protocol)

Gelbaya TA,Vitthala S,Nardo LG,Farquhar C,Seif MMW

This is a reprint of a Cochrane protocol,prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010,Issue1

https://www.doczj.com/doc/3b8134742.html,

T A B L E O F C O N T E N T S HEADER.......................................

1 ABSTRACT......................................

1 BACKGROUND....................................

2 OBJECTIVES..................................... METHODS......................................

2 REFERENCES.....................................

7 APPENDICES..................................... WHAT’S NEW.....................................

11 HISTORY.......................................

12 CONTRIBUTIONS OF AUTHORS............................. DECLARATIONS OF INTEREST..............................

[Intervention Protocol]

Hormone therapy in women with premature ovarian failure

Tarek A Gelbaya2,Srisailesh Vitthala3,Luciano G Nardo4,Cindy Farquhar5,Mourad MW Seif1

1Academic Unit of Obstetrics,Gynaecology&Reproductive Health,University of Manchester@St Mary’s Hospital,Manchester,UK. 2Assisted Conception,University Hospitals of Leicester,Leicester,UK.3Reproductive Medicine/Obstetrics&Gynaecology,St Mary’s Hospital,Manchester,UK.4Reproductive Medicine,St Mary’s Hosiptal,CMMC University Hospitals NHS T rust,Manchester,UK. 5Obstetrics and Gynaecology,University of Auckland,Auckland,New Zealand

Contact address:Mourad MW Seif,Academic Unit of Obstetrics,Gynaecology&Reproductive Health,University of Manchester@ St Mary’s Hospital,Whitworth Park,Manchester,M130JH,UK.linsey.nelson@https://www.doczj.com/doc/3b8134742.html,.mourad.seif@https://www.doczj.com/doc/3b8134742.html,. Editorial group:Cochrane Menstrual Disorders and Subfertility Group.

Publication status and date:Edited(no change to conclusions),published in Issue11,2010.

Citation:Gelbaya TA,Vitthala S,Nardo LG,Farquhar C,Seif MMW.Hormone therapy in women with premature ovarian failure. Cochrane Database of Systematic Reviews2010,Issue1.Art.No.:CD008209.DOI:10.1002/14651858.CD008209.

A B S T R A C T

This is the protocol for a review and there is no abstract.The objectives are as follows:

1.T o investigate the effectiveness of different hormonal regimens on uterine and endometrial development in women with POF.

2.T o investigate adverse effects of different hormonal regimens on women with POF.

B A

C K G R O U N D

Description of the condition

Premature ovarian failure(POF)is an uncommon condition where the ovaries stop functioning and ovulation ceases.It is diagnosed when there is an ovarian sex hormone de?ciency,elevated pituitary gonadotrophins,and cessation of menstruation in women aged beyond two standard deviations below the mean age of menopause for the reference population(Rees2005).A reference age of40 years is frequently used as an arbitrary limit.POF occurs in0.9% to3%of the female population(Coulam1986)of whom2.5% are adolescents(Falsetti1999).

POF may occur as a result of chromosomal and genetic abnormal-ities,for example T urner’s syndrome,or after surgical removal of the ovaries,radiotherapy or chemotherapy.Other causes include autoimmune disease,viral infections and idiopathic POF.T urner’s syndrome is the most common sex chromosome disorder among women,affecting one in2000liveborn girls(Gravholt1996).The main characteristics of T urner’s syndrome include short stature and failure to enter puberty due to inadequate or absent ovar-ian function(Guttmann2001).T oday,more than70%of chil-dren treated for cancer are cured by irradiation and chemother-apy(Mertens2001),with an increasing number of children pre-senting with pubertal failure or POF due to irreversible damage of ovarian or uterine function,or both(Wallace1989;Critchley 2002;Larsen2004).In the majority of cases of POF no apparent cause can be identi?ed(idiopathic POF)(Abdalla1994;Foudila 1999;Hovatta1999;van-Kasteren2000;McDonnell2003;Bodri 2006).

Description of the intervention

Various preparations of hormone therapy(HT)are being pre-scribed for women with POF including the combined oral con-traceptive pill(COCP).In prepubertal girls,the dose and dura-tion of HT to mimic puberty is usually adjusted according to the patient’s height and the Tanner’s stage of development(Hovatta 1999).Thereafter,those young women are usually prescribed a low-dose COCP and they often continue on the same regimen for years.Older women with POF are often prescribed either COCP or a combined HT preparation.Currently the aim of prescribing HT for women with POF is to relieve vasomotor symptoms and reduce the risk of osteoporosis.However,the optimal effective HT regimen to maximize the reproductive potential for young or older age-group women remains unclear.Furthermore,there is a paucity of evidence to support the preferential effectiveness of the differ-ent regimes used.Assisted reproduction using donated oocytes or embryos is the only realistic treatment option for women with POF,with an average clinical pregnancy rate of approximately 40%per cycle started(Foudila1999;Bodri2006).The success rate depends on the uterine and endometrial development,which can be in?uenced by the dose and type of HT as well as the age at which HT was commenced for induction of puberty(McDonnell 2003).We have previously emphasised the role of HT for normal development of the genital tract and its effect on the reproductive potential for women with POF(Meskhi2006).A normal uterine size that is essential for a successful pregnancy outcome has been determined by some investigators as a minimum length of5to8 cm with a sagittal width of1.5to3cm and transverse width of3 to5cm(McDonnell2003).Similarly,an endometrial thickness of 6.5mm or more is necessary for successful implantation(Abdalla 1994).

Hormone replacement therapy has been linked with increased risks of coronary heart disease(Grady2002;Rossouw2007);stroke (Wassertheil-Smoller2003;Hendrix2006);venous thrombosis (Peverill2003;Scarabin2003);and endometrial(Beral2005), breast(Shah2005)and ovarian cancer(Beral2007)in post-menopausal women.Evidence for the risks of HT in women with POF is limited.However,the baseline risk of adverse events in these younger women is lower and the balance of bene?ts and risks may be more favourable than in older women(MHRA2007). In this review,we aim to investigate the effectiveness of different regimens of HT on uterine and endometrial development.Ade-quate uterine and endometrial development is a prerequisite for future reproductive performance in women with POF.We are also going to assess the adverse effects of HT when given to women with POF.

How the intervention might work

The bulk of the human uterus is formed by the myometrium, which consists of smooth muscle cells.The distinct proliferation and differentiation of the smooth muscle cells depend on ovar-ian hormonal secretion(Demas1985;McCarthy1986;Andreyko 1988).The presence of oestrogen receptors in myometrial smooth muscle cells signal the complex interactions between ovarian hor-mones and various growth factors(cytokines,platelet-derived growth factor,?broblast growth factor,epidermal growth factor and insulin-like growth factors)which are responsible for devel-opment and maturation of the uterus.Endometrial epithelial cells are also stimulated by17-beta-oestradiol and epidermal growth factors(Zhang1995).Uterine under development occurs in the absence of sex hormones in women with POF(Hovatta1999). Replacement of sex hormones in women with POF facilitates the achievement of near normal uterine development,which is neces-sary for future successful reproductive performance.

Why it is important to do this review

The currently used HT regimens in women with POF have not been evaluated for their effectiveness in attaining normal uterine growth and function,which are essential for any‘future successful reproductive outcome.There is also a lack of consensus on the optimal type,dosage,and duration of HT and on the potential adverse effects of HT in women with POF.

O B J E C T I V E S

1.T o investigate the effectiveness of different hormonal regimens on uterine and endometrial development in women with POF.

2.T o investigate adverse effects of different hormonal regimens on women with POF.

M E T H O D S

Criteria for considering studies for this review

T ypes of studies

Only randomised controlled trials(RCTs)will be eligible for in-clusion.Cross-over trials will be excluded because of the long-term effect of HT on the uterine dimensions.

T ypes of participants

All women with premature ovarian failure(POF)due to any cause, including surgically induced POF,will be eligible for inclusion whether the women are trying to conceive or not.POF is de?ned as primary or secondary amenorrhoea(absence of menstruation) associated with high levels of follicle stimulating hormone(>40

IU/L)on two occasions in women less than40years of age.Pri-mary amenorrhoea is de?ned as absence of menstruation by the age16years.Secondary amenorrhoea is de?ned as cessation of menstruation for more than six months.

T ypes of interventions

Different hormonal regimens in women with premature ovarian failure.Different hormonal regimens may be compared with each other,a placebo or with no treatment.Hormonal regimens,using any route,may include the following.

1.Oestradiol:unopposed or as commonly used in hormone replacement therapy preparations,which is in combination with various progestogens in sequential or continuous combined regimens.

2.Conjugated equine oestrogen:unopposed or as commonly used in hormone replacement therapy preparations,which is in combination with various progestogens in sequential or continuous combined regimens.

3.Ethinyl oestradiol:unopposed or as commonly used in oral contraceptives,which is in combination with various progestogenic preparations.

T ypes of outcome measures

Primary outcomes

Uterine volume at ultrasound(to re?ect reproductive potential): calculated by using the formula:volume(ml)=transverse width x sagittal width x length x0.5(Doerr2005).

Secondary outcomes

One or more of the following parameters achieved after hormonal treatment.

1.Endometrial thickness:measured in the longitudinal plane of the uterus,using trans-vaginal or trans-abdominal ultrasound, as the maximal distance(in millimetres)between the myometrial-endometrial junction on either side of the uterine cavity.

2.Endometrial histology:assessed by the presence of secretory endometrium on endometrial biopsy in the stimulated mid-luteal phase.

3.Uterine perfusion:assessed by the pulsatility index,which is the difference between the peak-systolic and the end-diastolic velocities divided by mean velocity,using pulsed Doppler ultrasound.

4.Reproductive outcomes in women with POF who received donated eggs or embryos(fresh or frozen).Reproductive outcomes include pregnancy rate per cycle started or per embryo transfer,clinical pregnancy rate per cycle started or per embryo transfer,and live birth rate per cycle started or per embryo transfer.Pregnancy is de?ned as a positive urine pregnancy test or serum human chorionic gonadotrophin(β-hCG)>25IU/L, performed at least12days following the day of the embryo transfer.Clinical pregnancy is de?ned as the visualization of a gestational sac,by ultrasound scan,at six to seven weeks gestation.

5.Any adverse events reported.

Search methods for identi?cation of studies ?We will search all published and unpublished reports which describe(or might describe)randomised controlled trials of hormonal treatments or therapies in women with POF using the search strategy of the Menstrual Disorders and Subfertility Group(MDSG).

?We will search the Cochrane Menstrual Disorders and Subfertility Group T rials Register for any trials on POF or premature menopause,hormone therapy(HT)or hormone replacement in the title,abstract or keywords sections.

?We will search the Cochrane Central Register of Controlled T rials(CENTRAL)(The Cochrane Library2007);for key words premature ovarian failure and hormone therapy.

?The search will be not restricted by language.

Electronic searches

We will search the electronic databases:CENTRAL(Appendix 3),MEDLINE(Appendix1),EMBASE(Appendix5),CINAHL (Appendix4),PsycINFO(Appendix2),LILACS,Biological Ab-stracts,Science Citation Index,and BIOSIS.

The key search terms will include:

Keywords CONTAINS“premature ovarian failure”or“ovarian failure”or“anovulation”or“amenorrhea”or“amenorrhoea”or Title CONTAINS“premature ovarian failure”or“ovarian failure”or“anovulation”or“amenorrhea”or“amenorrhoea”

AND

Keywords CONTAINS“HRT”or“Hormone Therapy”or“Hor-mone Substitution”or“estrogen”or“oestrogen”or“estradiol”or oestradiol“or”progestogen“or”progestagen“or”progestin“or ”progesterone“or”norgestrel“or”norethisterone“or”desogestrel“or”gestodene“or”combined oral contraceptive“or”oral contra-ceptive“or Title CONTAINS”HRT“or”Hormone Therapy“or ”Hormone Substitution“or”estrogen“or”oestrogen“or”estra-diol“or oestradiol”or“progestogen”or“progestagen”or“pro-gestin”or“progesterone”or“norgestrel”or“norethisterone”or “desogestrel”or“gestodene”or“combined oral contraceptive”or “oral contraceptive”.

Searching other resources

?We aim to search the Intercollegiate study Institute(ISI) proceedings for conference abstracts,and the International Standard Randomized Controlled T rial Number(ISRCTN)

Register and Meta-register for RCTs(mRCT)for ongoing and achieved randomised controlled trials using the same key words.?We will handsearch the retrieved articles and bibliographies in order to identify other potentially eligible studies or any unpublished data.

?We will check all the references of relevant systematic reviews and RCTs.

Data collection and analysis

Data collection and analysis will be conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins2008).

Selection of studies

T wo of the authors(SV,TG)will independently review the studies in accordance with the mentioned selection criteria as well as the quality of studies.Disagreements will be resolved by consensus and also by the involvement of a third review author(MWS).Particular note will be taken of the baseline characteristics of women in the comparable groups.

Data extraction and management

Data will be extracted from eligible studies using a data extraction form designed and pilot-tested by the authors.See Appendix6for a list of the categories of data that will be collected.Where studies have multiple publications,the main trial report will be used as the reference and additional details supplemented from secondary pa-pers.T wo authors will independently extract the data.Review au-thors will correspond with study investigators if required.If review authors are unavailable to comment,remaining disagreements will be resolved by consensus or by discussion with a third author. Assessment of risk of bias in included studies

The included studies will be assessed for risk of bias using the Cochrane risk of bias assessment tool on:sequence generation; allocation concealment;blinding of participants,providers and outcome assessors;completeness of outcome data;selective out-come reporting;and other potential sources of bias.T wo authors will assess these six domains,with any disagreements resolved by consensus or by discussion with a third author.All judgments will be fully described.The conclusions will be presented in the’Risk of bias’tables and will be incorporated into the interpretation of review?ndings by means of sensitivity analyses(see below). Measures of treatment effect

For dichotomous data(for example endometrial histology),the numbers of events in the control and intervention groups of each study will be used to calculate Peto odds ratios.For continuous data (for example uterine volume or endometrial thickness),weighted mean differences between treatment groups will be calculated if all studies report exactly the same outcomes.If similar outcomes are reported on different scales(for example change in uterine length, change in uterine volume)the standardised mean difference will be calculated.

Unit of analysis issues

There are no unit of analysis issues.

Dealing with missing data

The data will be analysed on an intention-to-treat basis as far as possible and attempts will be made to obtain missing data from the original investigators.Where these are unobtainable,imputation of individual values will be undertaken for the primary outcome only.A change in uterine volume or length will be assumed not to have occurred in participants with unreported outcome.

If studies report suf?cient detail to calculate mean differences but no information on associated standard deviation(SD),the out-come will be assumed to have a standard deviation equal to the highest SD from other studies within the same analysis.

For other outcomes,only the available data will be analysed.Any imputation undertaken will be subjected to sensitivity analysis(see below).

Assessment of heterogeneity

The authors will consider whether the clinical and methodological characteristics of the included studies are suf?ciently similar for meta-analysis to provide a meaningful summary.Statistical hetero-geneity will be assessed by the I2statistic.An I2statistic greater than 50%will be taken to indicate substantial heterogeneity(Higgins 2008).If substantial heterogeneity is detected,possible explana-tions will be explored in sensitivity analyses(see below). Assessment of reporting biases

In view of the dif?culty in detecting and correcting for publication bias and other reporting biases,the authors will aim to minimize their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data.If there are10or more studies in an analysis,a funnel plot will be used to explore the possibility of small study effects(a tendency for the intervention effect to be more bene?cial in smaller studies). Data synthesis

The data from primary studies will be combined using a?xed-effect model in the following comparisons.

1.Oestradiol,unopposed or in combination with various pro-gestogens in a sequential or a continuous combined regimens ver-sus placebo or no treatment,strati?ed by mode of administration and dose:

(i)low dose oral;

(ii)high dose oral;

(iii)low dose subcutaneous;

(iv)high dose subcutaneous.

2.Oestradiol versus alternative oestrogen therapy,strati?ed by:

(i)conjugated equine oestrogen;

(ii)ethinyl oestradiol.

3.Oestradiol(low dose)versus oestradiol(high dose),strati?ed by mode of administration:

(i)oral;

(ii)subcutaneous.

4.Oestradiol(oral)versus oestradiol(subcutaneous),strati?ed by:

(i)low dose;

(ii)high dose.

An increase in the odds of a particular outcome,which may be bene?cial(for example increase in uterine volume)or detrimental (for example adverse effects),will be displayed graphically in the meta-analyses to the right of the centre line and a decrease in the odds of an outcome will be to the left of the centre line. Subgroup analysis and investigation of heterogeneity Where data are available,subgroup analyses will be conducted to determine the evidence within the following subgroups.

1.Pregnancy and live birth rates of women with POF undergoing donated oocyte or embryo replacement.

2.Studies on young adolescents with an average age less than20 years.

Sensitivity analysis

Sensitivity analyses will be conducted for the primary outcome to determine whether the conclusions are robust with the arbitrary decisions made regarding the eligibility and analysis.These analy-ses will include consideration of whether conclusions would have differed if:

1.eligibility was restricted to studies without high risk of bias;

2.studies with outlying results had been excluded;

3.alternative imputation strategies had been adopted;

4.a random-effects model had been adopted.

T rials that used a different de?nition for POF will be included and the quality of all the de?nitions will be assessed by a sensitivity analysis.

Time line

Completion of the review is expected within one year of publica-tion of the protocol on The Cochrane Library.New searches for RCTs will be performed every two years thereafter and the review updated accordingly.

R E F E R E N C E S

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?Indicates the major publication for the study

A P P E N D I C E S

Appendix1.MEDLINE

1exp Ovarian Failure,Premature/

2ovar$fail$.tw.

3POF.tw.

4exp anovulation/or exp menopause,premature/

5anovulation.tw.

6prematur$menopaus$.tw.

7exp Amenorrhea/(8581)

8gonadotropin$resistant ovar$syndrome$.tw.

9puberty failure.tw.

10Amenorrhea.tw.

11or/1-10

12exp hormone replacement therapy/or exp estrogen replacement therapy/

13hormone therap$.tw.

14estrogen therap$.tw.

15oestrogen therap$.tw.

16(oestradiol or estradiol).tw.

17exp contraceptives,oral/or exp contraceptives,oral,combined/or exp ethinyl estradiol-norgestrel combination/or exp contraceptives, oral,hormonal/or exp contraceptives,oral,sequential/or exp contraceptives,oral,synthetic/

18oral contraceptive$.tw.

19contracept$pill$.tw.

20exp progesterone/or exp algestone/or exp20-alpha-dihydroprogesterone/or hydroxyprogesterones/or exp17-alpha-hydroxypro-gesterone/or exp medroxyprogesterone/or exp medroxyprogesterone17-acetate/

21hormon$substitution.tw.

22progest$.tw.

23exp Estradiol/

24exp“Estrogens,Conjugated(USP)”/

25conjugated equine oestrogen$.tw.

26conjugated equine estrogen$.tw.

27or/12-26

2827and11

29randomized controlled trial.pt.

30controlled clinical trial.pt.

31randomized.ab.

32placebo.ab.

33cross-over studies/

34(crossover or cross-over or cross over).tw.

35clinical trials as topic.sh.

36randomly.ab.

37trial.ti.

38or/29-37

39humans.sh.

4038and39

4128and40

42from41keep1-564

Appendix2.PsycINFO

1exp Ovarian Failure,Premature/

2ovar$fail$.tw.

3POF.tw.(20)

4exp anovulation/or exp menopause,premature/

5anovulation.tw.

6prematur$menopaus$.tw.

7exp Amenorrhea/

8gonadotropin$resistant ovar$syndrome$.tw.

9puberty failure.tw.

10Amenorrhea.tw.

11or/1-10(586)

12exp hormone replacement therapy/or exp estrogen replacement therapy/

13hormone therap$.tw.

14estrogen therap$.tw.

15oestrogen therap$.tw.

16(oestradiol or estradiol).tw.

18oral contraceptive$.tw.

19contracept$pill$.tw.

20exp progesterone/or exp algestone/or exp20-alpha-dihydroprogesterone/or hydroxyprogesterones/or exp17-alpha-hydroxypro-gesterone/or exp medroxyprogesterone/or exp medroxyprogesterone17-acetate/

21hormon$substitution.tw.

22progest$.tw.

23exp Estradiol/

24exp“Estrogens,Conjugated(USP)”/

25conjugated equine oestrogen$.tw.

26conjugated equine estrogen$.tw.

27or/12-26

2827and11

29from28keep1-56

Appendix3.CENTRAL

1exp Ovarian Failure,Premature/

2ovar$fail$.tw.

3POF.tw.

4exp anovulation/or exp menopause,premature/

5anovulation.tw.

6prematur$menopaus$.tw.

7exp Amenorrhea/

8gonadotropin$resistant ovar$syndrome$.tw.

9puberty failure.tw.

10Amenorrhea.tw.

11or/1-10

12exp hormone replacement therapy/or exp estrogen replacement therapy/

13hormone therap$.tw.

14estrogen therap$.tw.

15oestrogen therap$.tw.

16(oestradiol or estradiol).tw.

18oral contraceptive$.tw.

19contracept$pill$.tw.

20exp progesterone/or exp algestone/or exp20-alpha-dihydroprogesterone/or hydroxyprogesterones/or exp17-alpha-hydroxypro-gesterone/or exp medroxyprogesterone/or exp medroxyprogesterone17-acetate/

21hormon$substitution.tw.

22progest$.tw.

23exp Estradiol/

24exp“Estrogens,Conjugated(USP)”/

25conjugated equine oestrogen$.tw.

26conjugated equine estrogen$.tw.

27or/12-26

2827and11

29from28keep1-407

Appendix4.CINHAL

1exp Ovarian Failure,Premature/

2ovar$fail$.tw.

3POF.tw.

4exp anovulation/or exp menopause,premature/

5anovulation.tw.

6prematur$menopaus$.tw.

7exp Amenorrhea/

8gonadotropin$resistant ovar$syndrome$.tw.

9puberty failure.tw.

10Amenorrhea.tw.

11or/1-10

12exp hormone replacement therapy/or exp estrogen replacement therapy/

13hormone therap$.tw.

14estrogen therap$.tw.

15oestrogen therap$.tw.

16(oestradiol or estradiol).tw.

18oral contraceptive$.tw.

19contracept$pill$.tw.

20exp progesterone/or exp algestone/or exp20-alpha-dihydroprogesterone/or hydroxyprogesterones/or exp17-alpha-hydroxypro-gesterone/or exp medroxyprogesterone/or exp medroxyprogesterone17-acetate/

21hormon$substitution.tw.

22progest$.tw.

23exp Estradiol/

24exp“Estrogens,Conjugated(USP)”/

25conjugated equine oestrogen$.tw.

26conjugated equine estrogen$.tw.

27or/12-26

2827and11

29exp clinical trials/

30Clinical trial.pt.

31(clinic$adj trial$1).tw.

32((singl$or doubl$or trebl$or tripl$)adj(blind$3or mask$3)).tw.

33Randomi?ed control$trial$.tw.

34Random assignment/

35Random$allocat$.tw.

36Placebo$.tw.

37Placebos/

38Quantitative studies/

39Allocat$random$.tw.

40or/29-39

4128and40

42from41keep1-48

Appendix5.EMBASE

1exp ovary insuf?ciency/or exp anovulation/or exp premature ovarian failure/ 2(ovar$insuf?cien$or ovar$failure).tw.

3POF.tw.

4anovulation.tw.

5exp Early Menopause/

6prematur$menopaus$.tw.

7exp amenorrhea/or exp primary amenorrhea/or exp secondary amenorrhea/ 8gonadotropin$resistant ovar$syndrome$.tw.

9puberty failure.tw.

10Amenorrhea.tw.

11or/1-10

12exp hormonal therapy/or exp hormone substitution/or exp steroid therapy/ 13hormone therap$.tw.

14estrogen therap$.tw.

15oestrogen therap$.tw.

16(oestradiol or estradiol).tw.

17exp Oral Contraceptive Agent/

18oral contraceptive$.tw.

19contracept$pill$.tw.

20exp Progesterone/

21hormon$substitution.tw.

22progest$.tw.

23exp Estradiol/

24exp Conjugated Estrogen/

25conjugated equine estrogen$.tw.

26Estradiol.tw.

27or/12-26

2827and11

29Controlled study/or randomized controlled trial/

30double blind procedure/

31single blind procedure/

32crossover procedure/

33drug comparison/

34placebo/

35random$.ti,ab,hw,tn,mf.

36latin square.ti,ab,hw,tn,mf.

37crossover.ti,ab,hw,tn,mf.

38cross-over.ti,ab,hw,tn,mf.

39placebo$.ti,ab,hw,tn,mf.

40((doubl$or singl$or tripl$or trebl$)adj5(blind$or mask$)).ti,ab,hw,tn,mf.

41(comparative adj5trial$).ti,ab,hw,tn,mf.

42(clinical adj5trial$).ti,ab,hw,tn,mf.

43or/29-42

44nonhuman/

45animal/not(human/and animal/)

46or/44-45

4743not46

4828and47

49limit48to yr=“2006-2008”

50from49keep1-478

Appendix6.List of the categories of data that will be collected

Study characterstics

?Method of randomisation

?Allocation concealment

?Study design:single centre,multicentre;single phase,cross-over

?Number of participants randomised,excluded and analysed

?Number of participants lost in follow up or dropped out of the study

?Duration,timing and location of the study

?Source of funding or sources of interest con?ict

Baseline characterstics of the studies

?Etiology of POF

?Diagnosis of POF based on clinical features and results of investigations

?Age of diagnosis of POF

?Age of commencement of HT

?Dose and duration of HT

?Main outcome reported after HT

?Prior hormonal treatment

Interventions

Different regimens of HT mentioned above.

Outcomes

Primary and secondary outcomes as mentioned earlier.

Data will be extracted independently by two authors in accordance with the Cochrane guidelines.Additional information regarding the methodology and/or actual study will be sought from the authors which might meet inclusion criteria.Disagreements will be registered and resolved by agreement of the investigators.

W H A T’S N E W

Last assessed as up-to-date:3May2009.

Date Event

20September2010Amended

12 Hormone therapy in women with premature ovarian failure(Protocol)