BMJ Open. Protocol for Systematic Review: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms

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1 Protocol for Systematic Review: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Journal: BMJ Open Manuscript ID bmjopen-0-00 Article Type: Protocol Date Submitted by the Author: -Dec-0 Complete List of Authors: abdi, fatemeh;. Ph.D Student, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Kazemi, Farideh;. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran. roozbeh, nasibeh;. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. <b>primary Subject Heading</b>: Obstetrics and gynaecology Secondary Subject Heading: Pharmacology and therapeutics, Obstetrics and gynaecology Keywords: Reproductive medicine < GYNAECOLOGY, Pharmacology < TROPICAL MEDICINE, Clinical trials < THERAPEUTICS BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

2 Page of BMJ Open Protocol for Systematic Review: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Fatemeh Abdi, Farideh Kazemi, Nasibeh Roozbeh *. Ph.D Student, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran.. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran.. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Abstract Introduction:Menopause is a critical stage in every woman's life. Menopause can be a distressing time for women with many experiencing vasomotor symptoms. Phytoestrogens potentially exert various favorable effects in postmenopausal women, especially alleviating vasomotor symptoms. The plant of Hop( Humulus lupulus L.) contains -prenylnaringenin (- PN) as the most powerful phytoestrogen known to date. Hop is eight times stronger than other herbal estrogens. Evidence from experimental studies suggests that hop may be a biologically treatment for menopausal symptoms. Methods and analysis: the aim of the proposed study is a comprehensive systematic survey of the effects of hop in the management of menopausal vasomotor symptoms. The present article explains the protocol for conducting such a research. Ethics and Dissemination: Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The findings of our project BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

3 Page of can help reproductive health researchers when designing a study. The expected dissemination actions are effective treatment in designing strategies that aim to develop women s health. Keywords: hop, menopause, vasomotor symptoms, menopause symptoms. Introduction Menopause, sometimes called a second puberty, is a critical stage in every woman's life(). During this period, women undergo substantial biological and psychosocial changes. Certain characteristics of this evolutionary process affect quality of life and put women at risk of developing various disease(, ). Following recent medical advances and the consequent increase in life expectancy (LE), the number of menopausal women is on a rapid rise. According to the World Health Organization, the population of women aged over 0 will exceed one billion in 00 (). Despite the mentioned improvement in LE, menopause age has remained relatively constant, i.e. post-menopausal years constitute about one-third of women's lives(). Therefore, menopause is an ongoing major health issue().postmenopausal women experience a variety of symptoms including hot flashes, night sweats, sleep disorders, anxiety, irritability, and mood swings(). Due to the high incidence rate and considerable negative effects of menopausal symptoms (, ), most women tend to seek appropriate treatments. Hormone therapy (HT), containing estrogen alone or together with progestogens, is often recommended for management of menopausal symptoms().however, the Women's Health Initiative (WHI) suggested an increased risk of breast cancer, thromboembolic events, stroke, and coronary heart diseases in recipients of HT(0, ). Hormpne replacement therapy is also believed to cause a gradual reduction in the cytotoxicity of natural killer(nk) cells and thus weaken the immune system. In fact, a two times higher incidence of breast cancer was reported in women receiving HT for nine years(). Herbal medicine, especially those containing estrogen, potentially exert various favorable effects in postmenopausal women, especially alleviating vasomotor symptoms(). Phytoestrogens are plant derivatives whose structural similarity to estrogens makes them capable of exerting both estrogenic and anti estrogenic effects().since phytoestrogens can produce stronger estrogenic effects in the absence of adequate estrogen, they can compensate for the reduced levels of endogenous β-estradiol during menopause. Substantial amounts of -PN, the strongest known phytoestrogen capable of binding to both estrogen receptors in human body, are found in hop. As BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

4 Page of BMJ Open a member of the Cannabaceae family, H. lupulus contains volatile oils and estrogenic, resinbased, and polyphylic compounds. Due to its potent phytoestrogenic compounds and humulene, tannin, beta-myrcene, pectin, potassium, and flavonoid contents along with its ability to decrease sexual desire and to create estrogenic, sedative, hypnotic, antipyretic, anti-inflammatory, and antiseptic effects(, ), hop has found wide medicinal and industrial applications. The presence of estrogenic compounds, such as isoxanthohumol, progesteronic xanthohumol, and - PN, in hop have also made it an appropriate herbal medicine for treatment of menopausal symptoms().heyerick et al. examined the efficacy of a hop extract enriched in - prenylnaringenin on relief of menopausal symptoms.they showed daily intake of a hop extract, have favorable effects on vasomotor symptoms(). Rosic et al. noticed significant improvements in the physical, psychological, and genitourinary symptoms of menopause following the administration of phytoestrogens(). In this regard in another study observed that hop effectively reduced the vasomotor symptoms(0).likewise, a clinical trial by Alizadeh Caharandabi et al. showed hop to significantly reduce the early menopausal symptoms(). Numerous scales, including the Greene Climacteric Scale and Cooperman's index, have been developed to determine the incidence and severity of menopausal symptoms(, ).However, to the best of our knowledge, no systematic review has evaluated the effects of hop in the management of menopausal vasomotor symptoms. Therefore, the results of this study can potentially help to select appropriate treatment options for menopause..objectives This systematic review will aim to clarify whether Humulus lupulus is more effective than placebo in reducing the menopausal vasomotor symptoms. Our secondary objective will be to answer the following two questions: - Does response to treatment with Humulus lupulus depend on the dosage or duration of treatment? - What are the side effects of Humulus lupulus in comparison to placebo?.methods Criteria for considering studies for this review.. Types of studies BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

5 Page of All controlled cluster randomized and randomized crossover clinical trials conducted during will be included. Case reports will be excluded... Types of Participants The studies will be selected if their participants: aged 0-0 years and experienced at least one menopausal vasomotor symptom; were recruited based on the Greene Climacteric Scale, Cooperman's index, Menopause Rating Scale (MRS), or visual analogue scale (VAS); were assessed using the Greene Climacteric Scale, Cooperman's index, MRS, or VAS to determine the effects of the intervention; used hop and placebo for at least four weeks; and Completed the whole course of the intervention... Types of Interventions The studies will be reviewed if: Hop is used in the intervention (no time limits are imposed); The effects of hop are compared to those of placebo; Placebo is used for symptom relief. Studies without a control group will be excluded. No time limits will be imposed on the treatment period... Primary Outcome The primary outcome will be the rate of response to treatment in the intervention and placebo groups... Secondary Outcomes The side effects of hop and the mean scores of the Greene Climacteric Scale, Cooperman's index, MRS, and VAS in the studied clinical trials will be evaluated as secondary outcomes. All outcomes will be examined during a period of six months (short-term outcomes). BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

6 Page of BMJ Open Search Strategies for identification of studies The following resources will be searched: The Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (via Pubmed, from 000 to the president); EMBASE (via Scopus, from 000 to the present); PsycINFO; Scopus; ProQuest; and Google scholar. Our key terms for preliminary analysis of previous research will be hop, menopause, vasomotor symptoms, and phytoestrogen which will be combined using Boolean operators AND and OR. Further relevant keywords and Boolean operators will also be selected for a change of strategy in each particular database. No particular language criterion will be defined either directly during the database search or indirectly during the evaluation of studies' reference lists... Database of Ongoing Clinical Trials The search for ongoing clinical trials will be performed in the following databases: and Searching Other Resources Hand searches will be conducted in key journals. Government reports, theses and dissertations, papers published by research committees, and abstracts of papers presented at different conferences and seminars will be evaluated... Data Collection and Analysis BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

7 Page of Selection of Relevant Studies The first stage of this systematic review will involve the evaluation of the titles, abstracts, and eligibility of studies (by F.K.). In the second stage, the full text of the papers will be independently assessed by two co-authors (F.A.and N.R.) to confirm their eligibility. Areas of disagreement will be discussed until a consensus is reached. In cases where the disagreement cannot be resolved, the viewpoints of an external observer will be used. Authors of papers with available abstracts whose results are published on posters will be ed and requested to send the full text..0. Data Extraction and Management Two co-authors (F.A. and N.R.) will independently extract data from the full texts of previously published papers and will design a form accordingly. Data will be collected as follows: - Research information (the first author, geographic location, year of publication, beginning and end dates, research design, sample size, duration of follow-up); - Characteristics of the participants (age, gender, and number of participants, inclusion and exclusion criteria, menopausal symptoms, keywords definitions, and measurement tools); - Intervention and comparison of the details (group size, blinding procedure, dose and type of intervention, dose based on body weight, factors determining the duration of treatment, treatment withdrawal, and sample loss); - Outcome measures (explanations on the administered measurement tools, and methods evaluating outcomes, side effects, and serious side effects). The third author (F.R.) will review the collected data. Cases of disagreement between the authors will be resolved based on the opinions of an external observer... Quality Assessment of Studies The risk of bias will be independently determined by two external observers using the Cochrane Risk of Bias Tool. The quality of the papers will be assessed based on the CONSORT checklist which contains items scored as zero or one. (Appendix: ) BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

8 Page of BMJ Open Only studies which scored over on the CONSORT checklist will be included. Like previous stages, points of disagreement will be resolved based on the viewpoints of an external observer. Data synthesis Quantitative data will, where possible, be pooled in statistical meta-analysis using STATA software. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their % confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. We will also consider subgroup meta-analysis such as year of publication and region. Ethics and Dissemination: Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The findings of our project can help reproductive health researchers when evaluating the discomforts of research procedures described in study protocols or when designing a study. Information on experiences of postmenopausal women involved in previous studies may also help in future research. The expected dissemination actions are effective treatment in designing strategies that aim to develop women s health. Contributors: FA and NR conceived the research questionnaire and drafted the aspects of the study protocol. NR was responsible for drafting this paper and all authors read, provided important revisions and approved the final version of the manuscript. Acknowledgements To Dr Keshtkar for his help in developing this protocol. Funding: This work has not supported by any organization yet. Competing interests: None declared. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

9 Page of References. Yazdkhasti M, Simbar M, Abdi F. Empowerment and Coping Strategies in Menopause Women: A Review. Iranian Red Crescent Medical Journal. 0;().. Nosek M, Kennedy HP, Gudmundsdottir M. Distress During the Menopause Transition. Sage Open. 0;():0.. Harris MT. Menopause: the need for a paradigm shift from disease to women's health. 0.. Rubinstein. The meanings of menopause: identifying the bio-psycho-social predictors of the propensity for treatment at menopause.: University of Cambridge.; 0.. Al-Safi ZA, Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertility and sterility. 0;0():0-.. Rotem M, Kushnir T, Levine R, Ehrenfeld M. A Psycho Educational Program for Improving Women's Attitudes and Coping With Menopause Symptoms. Journal of Obstetric, Gynecologic, & Neonatal Nursing. 00;():-0.. Crowe B. The Effects of Yoga Participation on Symptoms Associated with Menopause: A Mixed Methods Study. 0.. Golyan Tehrani SM, M. Khaledian, E. Study of quality of life and its patterns in different stage of menopause for women in tehran. Hayat. 00;(-):-.. Reid R, Blake J, Abramson B, Khan A, Senikas V, Fortier M. Menopause and osteoporosis update 00. J Obstet Gynaecol Can. 00;( Suppl ):S Theroux R. Women's decision making during the menopausal transition. Journal of the American Academy of Nurse Practitioners. 00;():-.. Gurney EP, Nachtigall MJ, Nachtigall LE, Naftolin F. The Women's Health Initiative trial and related studies: 0 years later: A clinician's view. The Journal of Steroid Biochemistry and Molecular Biology. 0;:-.. Mascitelli L, Goldstein MR. Menopause, estrogen, statins, and the immune system. Maturitas. 0;():; author reply.. Teekachunhatean S, Mattawanon N, Khunamornpong S. Short-Term Isoflavone Intervention in the Treatment of Severe Vasomotor Symptoms after Surgical Menopause: A Case Report and Literature Review. Case reports in obstetrics and gynecology. 0;0:0.. Moreira AC, Silva AM, Santos MS, Sardão VA. Phytoestrogens as alternative hormone replacement therapy in menopause: What is real, what is unknown. The Journal of steroid biochemistry and molecular biology. 0;:-.. Van Cleemput M, Cattoor K, De Bosscher K, Haegeman G, De Keukeleire D, Heyerick A. Hop (Humulus lupulus)-derived bitter acids as multipotent bioactive compounds. Journal of natural products. 00;():0-0.. Depypere HT, Comhaire FH. Herbal preparations for the menopause: beyond isoflavones and black cohosh. Maturitas. 0;():-.. Hosseini E. Effect of Aalcoholic Extract of Hop Flowers on Serum Level Pituitary-Thyroid Hormones in Adult Male Rats.. Journal of Birjand University of Medical Sciences 0;():-.. Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 00;():-. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

10 Page of BMJ Open Rosic S, Kendic S, Rosic M. Phytoestrogens impact on menopausal symptomatology. Materia socio-medica. 0;():. 0. Aghamiri V, Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Nazemiyeh H. The effect of Hop (Humulus lupulus L.) on early menopausal symptoms and hot flashes: A randomized placebocontrolled trial. Complementary therapies in clinical practice. 0.. Mohammad-Alizadeh-Charandabi S, Mirghafourvand M, Aghamiri V, Nazemiyeh H, Soltanpoor S. Efficacy of hop (Humuluslupulus L.) on early menopausal symptoms in perimenopausal women: A randomized double blind placebo-controlled trial. Scientific Journal of Kurdistan University of Medical Sciences. 0;():-.. Tao M, Shao H, Li C, Teng Y. Correlation between the modified Kupperman Index and the Menopause Rating Scale in Chinese women. Patient preference and adherence. 0;:. Corresponding Author: Nasibeh Roozbeh PhD student of reproductive health, Child and Mother care center,hormozgan University of Medical Sciences, Bandar Abbas, Iran Tel: +0, 00 nasibe@yahoo.com, fatemeh.abdi@yahoo.com BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

11 Page 0 of Appendix: 0 BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

12 Page of BMJ Open Appendix: BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

13 Page of BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

14 Protocol for Systematic Review and meta-analysis: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Journal: BMJ Open Manuscript ID bmjopen-0-00.r Article Type: Protocol Date Submitted by the Author: 0-Feb-0 Complete List of Authors: abdi, fatemeh;. Ph.D Student, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Kazemi, Farideh;. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran. roozbeh, nasibeh;. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. <b>primary Subject Heading</b>: Obstetrics and gynaecology Secondary Subject Heading: Pharmacology and therapeutics, Obstetrics and gynaecology Keywords: Reproductive medicine < GYNAECOLOGY, Pharmacology < TROPICAL MEDICINE, Clinical trials < THERAPEUTICS, hop, Humulus,menopause, vasomotor, Hot Flashes BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

15 Page of BMJ Open Protocol for Systematic Review and meta-analysis: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Fatemeh Abdi, Farideh Kazemi, Nasibeh Roozbeh *. Ph.D Student, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran.. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran.. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Article summary Strengths and limitations of this study: Systematic review and meta-analysis will offer highest level of evidence for informed decisions. So far, no meta-analysis has been done on this topic. One difficult step of this study is to collect all the raw data of eligible trials by systematic search, which may be the limitation of this meta-analysis. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

16 Page of Abstract Introduction: Menopause is a critical stage in every woman's life. Menopause can be a distressing time for women with many experiencing vasomotor symptoms(vms). Phytoestrogens potentially exert various favorable effects in postmenopausal women, especially alleviating VMS. The plant of Hop( Humulus lupulus L.) contains -prenylnaringenin (-PN) as the most powerful phytoestrogen known to date. Hop is eight times stronger than any other herbal estrogens. The aim of the proposed study is a comprehensive systematic and metaanalysis survey of the effects of hop in the management of menopausal vasomotor symptoms. Methods: Only randomized controlled clinical trials conducted between will be included in this review. This includes cluster and crossover, blinded and non blinded designs. Quasi experimental and observational studies, as well as case reports will be excluded. The studies will be selected if their participants. Aged 0-0 years with elevated FSH or menstrual irregularities or both and who reported a minimum of some hot flashes or night sweats that caused discomfort. The primary outcome will be the rate of response to treatment, such as changes in frequency and intensity of symptoms in the intervention and placebo groups. Our key words will be Hop, Humulus, menopause, vasomotor, Hot Flashes, phytoestrogen. Qualitative papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review. Any disagreements, will be resolved through a third reviewer.the risk of bias will be independently determined using the Cochrane Risk of Bias Tool. The quality of the papers will be assessed based on the CONSORT checklist. Ethics and Dissemination: Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The results of our project can help reproductive health researchers when designing a study. Keywords: Hop, Humulus, menopause, vasomotor, Hot Flashes BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

17 Page of BMJ Open Introduction Menopause, sometimes called a second puberty, is a critical stage in every woman's life(). During this period, women undergo substantial biological and psychosocial changes. process may put some women at risk of experiencing severe symptoms that could greatly affect quality of life (, ). Following recent medical advances and the consequent increase in life expectancy (LE), the number of menopausal women is on a rapid rise. According to the World Health Organization, the population of women aged over 0 will exceed one billion in 00 (). Despite the mentioned improvement in LE, menopause age has remained relatively constant, i.e. postmenopausal years constitute about one-third of women's lives(). Therefore, menopause has the potential to be an ongoing major health issue ().Postmenopausal women experience a variety of symptoms including hot flashes, night sweats, sleep disorders, anxiety, irritability, and mood swings(). Due to considerable negative effects of menopausal symptoms (, ), most women tend to seek appropriate treatments. Hormone therapy (HT), containing estrogen alone or together with progestogens, is often recommended for management of menopausal symptoms().however, the Women's Health Initiative (WHI) suggested an increased risk of breast cancer, thromboembolic events, stroke, and coronary heart diseases in recipients of HT(0, ). Hormpne replacement therapy is also believed to cause a gradual reduction in the cytotoxicity of natural killer(nk) cells and thus weaken the immune system. In fact, a two times higher incidence of breast cancer was reported in women receiving HT for nine years(). Herbal medicine, especially those containing estrogen, potentially exert various favorable effects in postmenopausal women, especially alleviating vasomotor symptoms(). Phytoestrogens are plant derivatives whose structural similarity to estrogens makes them capable of exerting both estrogenic and anti estrogenic effects().since phytoestrogens can produce stronger estrogenic effects in the absence of adequate estrogen, they can compensate for the reduced levels of endogenous β-estradiol during menopause. Substantial amounts of -PN, the strongest known phytoestrogen capable of binding to both estrogen receptors in human body, are found in hop. As a member of the Cannabaceae family, H. lupulus contains volatile oils and estrogenic, resinbased, and polyphylic compounds. Due to its potent phytoestrogenic compounds and humulene, tannin, beta-myrcene, pectin, potassium, and flavonoid contents along with its ability to decrease sexual desire and to create estrogenic, sedative, hypnotic, antipyretic, anti-inflammatory, and antiseptic effects(, ), hop has found wide medicinal and industrial applications. The BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

18 Page of presence of estrogenic compounds, such as isoxanthohumol, progesteronic xanthohumol, and - PN, in hop have also made it an appropriate herbal medicine for treatment of menopausal symptoms().heyerick et al. examined the efficacy of a hop extract enriched in - prenylnaringenin on relief of menopausal symptoms.they showed daily intake of a hop extract, have favorable effects on vasomotor symptoms(). Rosic et al. noticed significant improvements in the physical, psychological, and genitourinary symptoms of menopause following the administration of phytoestrogens(). In this regard in another study observed that hop effectively reduced the vasomotor symptoms(0).likewise, a clinical trial by Alizadeh Caharandabi et al. showed hop to significantly reduce the early menopausal symptoms(). Numerous scales, including the Greene Climacteric Scale and Cooperman's index, have been developed to determine the incidence and severity of menopausal symptoms(, ).However, to the best of our knowledge, no systematic review has evaluated the effects of hop in the management of menopausal vasomotor symptoms. Therefore, the results of this study can potentially help to select appropriate treatment options for menopause..objectives This systematic review will aim to clarify whether Humulus lupulus is more effective than placebo in reducing the menopausal vasomotor symptoms. Our secondary objective will be to answer the following two questions: - Does response to treatment with Humulus lupulus depend on the dosage or duration of treatment? - What are the side effects of Humulus lupulus in comparison to placebo?.methods Criteria for considering studies for this review.. Types of studies Only randomized controlled clinical trials conducted between will be included in this review. This includes cluster and crossover, blinded and non blinded designs. Quasi experimental (studies without controls) and observational studies, as well as case reports will be excluded, studies conducted in various languages will be included. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

19 Page of BMJ Open Types of Participants The studies will be selected if their participants: Aged 0-0 years with elevated FSH or menstrual irregularities or both and who reported a minimum of some hot flashes or night sweats that caused discomfort. were recruited based on the Greene Climacteric Scale, Cooperman's index, Menopause Rating Scale (MRS), or visual analogue scale (VAS); were assessed using the Greene Climacteric Scale, Cooperman's index, MRS, or VAS to determine the effects of the intervention; used hop and placebo for at least four weeks; and At least 0% of participants completed the whole course of the intervention.. Types of Interventions The studies will be reviewed if: Hop is used in the intervention (no time limits are imposed); The effects of hop are compared to those of placebo; Placebo is used for symptom relief. Studies whit scored over on the CONSORT checklist will be included. No time limits will be imposed on the treatment period. (Appendix: )().. Primary Outcome The primary outcome will be the rate of response to treatment, such as changes in frequency and intensity of symptoms in the intervention and placebo groups. Treatment outcome measurements based on the Greene Climacteric Scale, Cooperman's index, Menopause Rating Scale (MRS), or visual analogue scale (VAS). BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

20 Page of Secondary Outcomes The side effects of hop and the mean scores of the Greene Climacteric Scale, Cooperman's index, MRS, and VAS in the studied clinical trials will be evaluated as secondary outcomes. All outcomes will be examined during a period of six months (short-term outcomes). The number of hot flashes is one of the items in Green climacteric scale.it will be assessed as secondary outcome... Search Strategies for identification of studies The following resources will be searched: The Cochrane Central Register of Controlled Trials.. MEDLINE (via Pubmed, from 000 to the president); EMBASE (via Scopus, from 000 to the present); PsycINFO; Scopus; ProQuest; and Google scholar. Our key terms for preliminary analysis of previous research will be Hop, Humulus, menopause, vasomotor, Hot Flashes, phytoestrogen which will be combined using Boolean operators AND and OR. Further relevant keywords and Boolean operators will also be selected for a change of strategy in each particular database. No particular language criterion will be defined either directly during the database search or indirectly during the evaluation of studies' reference lists... Database of Ongoing Clinical Trials The search for ongoing clinical trials will be performed in the following databases: and BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

21 Page of BMJ Open Searching Other Resources Hand searches will be conducted in key journals. Government reports, theses and dissertations, papers published by research committees, and abstracts of papers presented at different conferences and seminars will be evaluated... Data Collection and Analysis Selection of Relevant Studies The first stage of this systematic review will involve the evaluation of the titles, abstracts, and eligibility of studies (by F.K.). In the second stage, the full text of the papers will be independently assessed by two co-authors (F.A.and N.R.) to confirm their eligibility. Areas of disagreement will be discussed until a consensus is reached. In cases where the disagreement cannot be resolved, the viewpoints of an external observer will be used. Authors of papers with available abstracts whose results are published on posters will be ed and requested to send the full text..0. Data Extraction and Management Two co-authors (F.A. and N.R.) will independently extract data from the full texts of previously published papers and will design a form accordingly. Data will be collected as follows (Appendix: )() - Research information (the first author, geographic location, year of publication, beginning and end dates, research design, sample size, duration of follow-up); - Characteristics of the participants (age, gender, and number of participants, inclusion and exclusion criteria, menopausal symptoms, keywords definitions, and measurement tools); - Intervention and comparison of the details (group size, blinding procedure, dose and type of intervention, dose based on body weight, factors determining the duration of treatment, treatment withdrawal, and sample loss); - Outcome measures (explanations on the administered measurement tools, and methods evaluating outcomes, side effects, and serious side effects). BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

22 Page of The third author (F.R.) will review the collected data. Cases of disagreement between the authors will be resolved based on the opinions of an external observer... Quality Assessment of Studies The risk of bias will be independently determined by two external observers using the Cochrane Risk of Bias Tool (Appendix: )() the quality of the papers will be assessed based on the CONSORT checklist which contains items scored as zero or one. Only studies which scored over on the CONSORT checklist will be included. Like previous stages, points of disagreement will be resolved based on the viewpoints of an external observer. Data synthesis Quantitative data will, where possible, be pooled in statistical meta-analysis using Rev Man software. Two models of meta-analysis were conducted for outcomes: the fixed-effect model and the random-effect model. A fixed-effect model using the Mantel Haenszel method assumes that studies are sampled from populations with the same effect size, making an adjustment to the study weights according to the in-study variance. A random-effect model assumes that studies are taken from populations with various effect sizes and calculates study weights both from instudy and between-study variances, considering the extent of variation, or heterogeneity. The random-effect model is more appropriate when heterogeneity is present. For each model, we estimated the between-study heterogeneity in all of the eligible comparisons using the chisquare-based Q statistic. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their % confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. We will also consider subgroup meta-analysis such as menopausal status including premenopause and postmenopause. Ethics and Dissemination: Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The results of our project can help reproductive health researchers when evaluating the discomforts of research procedures described in study protocols or when designing a study. Information on experiences of BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

23 Page of BMJ Open menopausal women involved in previous studies may also help in future research. The expected dissemination actions are effective treatment in designing strategies that aim to develop women s health. Contributors: FA and NR conceived the research questionnaire and drafted the aspects of the study protocol. NR was responsible for drafting this paper and all authors read, provided important revisions and approved the final version of the manuscript. Acknowledgements To Dr Keshtkar for his help in developing this protocol. Funding: This work has not supported by any organization yet. Competing interests: None declared. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

24 Page 0 of References -Yazdkhasti M, Simbar M, Abdi F. Empowerment and Coping Strategies in Menopause Women: A Review. Iranian Red Crescent Medical Journal. 0;() : e. -Nosek M, Kennedy HP, Gudmundsdottir M. Distress During the Menopause Transition. Sage Open. 0;():0. - Harris MT. Menopause: the need for a paradigm shift from disease to women's health. PhD thesis, Southern Cross University, Lismore, NSW.0. -Rubinstein, Helena. The meanings of menopause: identifying the bio-psycho-social predictors of the propensity for treatment at menopause.lucy Cavendish College, The University of Cambridge. 0.. Al-Safi ZA, Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertility and sterility. 0;0():0-.. Rotem M, Kushnir T, Levine R, Ehrenfeld M. A Psycho Educational Program for Improving Women's Attitudes and Coping With Menopause Symptoms. Journal of Obstetric, Gynecologic, & Neonatal Nursing. 00;():-0. -Crowe, Brandi. The Effects of Yoga Participation on Symptoms Associated with Menopause: A Mixed Methods Study.Clemson University. 0. All Dissertations. Paper.. Golyan Tehrani SM, M. Khaledian, E. Study of quality of life and its patterns in different stage of menopause for women in tehran. Hayat. 00;(-):-.. Reid R, Blake J, Abramson B, Khan A, Senikas V, Fortier M. Menopause and osteoporosis update 00. J Obstet Gynaecol Can. 00;( Suppl ):S Theroux R. Women's decision making during the menopausal transition. Journal of the American Academy of Nurse Practitioners. 00;():-.. Gurney EP, Nachtigall MJ, Nachtigall LE, Naftolin F. The Women's Health Initiative trial and related studies: 0 years later: A clinician's view. The Journal of Steroid Biochemistry and Molecular Biology. 0;:-. - Mascitelli L, Goldstein MR. Menopause, estrogen, statins, and the immune system. Maturitas. 0;():. - Teekachunhatean S, Mattawanon N, Khunamornpong S. Short-Term Isoflavone Intervention in the Treatment of Severe Vasomotor Symptoms after Surgical Menopause: A Case Report and Literature Review. Case reports in obstetrics and gynecology. 0;0:0.. Moreira AC, Silva AM, Santos MS, Sardão VA. Phytoestrogens as alternative hormone replacement therapy in menopause: What is real, what is unknown. The Journal of steroid biochemistry and molecular biology. 0;:-.. Van Cleemput M, Cattoor K, De Bosscher K, Haegeman G, De Keukeleire D, Heyerick A. Hop (Humulus lupulus)-derived bitter acids as multipotent bioactive compounds. Journal of natural products. 00;():0-0.. Depypere HT, Comhaire FH. Herbal preparations for the menopause: beyond isoflavones and black cohosh. Maturitas. 0;():-.. Hosseini E. Effect of Aalcoholic Extract of Hop Flowers on Serum Level Pituitary-Thyroid Hormones in Adult Male Rats.. Journal of Birjand University of Medical Sciences 0;():-.. Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 00;():-.. Rosic S, Kendic S, Rosic M. Phytoestrogens impact on menopausal symptomatology. Materia socio-medica. 0;():. 0 BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

25 Page of BMJ Open Aghamiri V, Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Nazemiyeh H. The effect of Hop (Humulus lupulus L.) on early menopausal symptoms and hot flashes: A randomized placebo-controlled trial. Complementary therapies in clinical practice. 0:-.. Mohammad-Alizadeh-Charandabi S, Mirghafourvand M, Aghamiri V, Nazemiyeh H, Soltanpoor S. Efficacy of hop (Humuluslupulus L.) on early menopausal symptoms in perimenopausal women: A randomized double blind placebo-controlled trial. Scientific Journal of Kurdistan University of Medical Sciences. 0;():-.. Tao M, Shao H, Li C, Teng Y. Correlation between the modified Kupperman Index and the Menopause Rating Scale in Chinese women. Patient preference and adherence. 0;:.. Cochrane Handbook for Systematic Reviews of Interventions Version..0. In: Higgins JPT, Green S, Eds. The Cochrane Collaboration; 0.. Cochrane Group.Data collection form for intervention reviews: RCTs only Version, April 0. Julian P T Higgins senior statistician, Douglas G Altman director, Peter C Gøtzsche director,et.al.the Cochrane Collaboration s tool for assessing risk of bias in randomised trials. BMJ 0;. Corresponding Author: Nasibeh Roozbeh PhD student of reproductive health, Child and Mother care center,hormozgan University of Medical Sciences, Bandar Abbas, Iran Tel: +0, 00 nasibe@yahoo.com, fatemeh.abdi@yahoo.com BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

26 Page of BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

27 Page of BMJ Open Appendix:. Cochrane Handbook for Systematic Reviews of Interventions Version..0. In: Higgins JPT, Green S, Eds. The Cochrane Collaboration; 0. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

28 Page of Appendix: BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

29 Page of BMJ Open Cochrane Group.Data collection form for intervention reviews: RCTs only Version, April 0. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

30 Page of Appendix:. Julian P T Higgins senior statistician, Douglas G Altman director, Peter C Gøtzsche director,et.al.the Cochrane Collaboration s tool for assessing risk of bias in randomised trials. BMJ 0; BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

31 Page of BMJ Open PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 0 checklist: recommended items to address in a systematic review protocol* Section and topic Item No Checklist item ADMINISTRATIVE INFORMATION Title: Identification a Identify the report as a protocol of a systematic review Update b If the protocol is for an update of a previous systematic review, identify as such Registration If registered, provide the name of the registry (such as PROSPERO) and registration number Authors: Contact a Provide name, institutional affiliation, address of all protocol authors; provide physical mailing address of corresponding author Contributions b Describe contributions of protocol authors and identify the guarantor of the review Amendments If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments Support: Sources a Indicate sources of financial or other support for the review Sponsor b Provide name for the review funder and/or sponsor Role of sponsor or funder INTRODUCTION c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol Rationale Describe the rationale for the review in the context of what is already known Objectives Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO) METHODS Eligibility criteria Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years considered, language, publication status) to be used as criteria for eligibility for the review Information sources Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature sources) with planned dates of coverage Search strategy 0 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated Study records: Data management a Describe the mechanism(s) that will be used to manage records and data throughout the review Selection process b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is, screening, eligibility and inclusion in meta-analysis) Data collection process c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators Data items List and define all variables for which data will be sought (such as PICO items, BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

32 Page of funding sources), any pre-planned data assumptions and simplifications Outcomes and prioritization List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale Risk of bias in individual studies Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis Data synthesis a Describe criteria under which study data will be quantitatively synthesised b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining data from studies, including any planned exploration of consistency (such as I, Kendall s τ) c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) d If quantitative synthesis is not appropriate, describe the type of summary planned Meta-bias(es) Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies) Confidence in cumulative evidence Describe how the strength of the body of evidence will be assessed (such as GRADE) * It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the PRISMA-P Group and is distributed under a Creative Commons Attribution Licence.0. From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 0: elaboration and explanation. BMJ. 0 Jan ;(jan0 ):g. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

33 Protocol for Systematic Review and meta-analysis: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Journal: BMJ Open Manuscript ID bmjopen-0-00.r Article Type: Protocol Date Submitted by the Author: 0-Mar-0 Complete List of Authors: abdi, fatemeh;. Ph.D Student, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Kazemi, Farideh;. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran. roozbeh, nasibeh;. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. <b>primary Subject Heading</b>: Obstetrics and gynaecology Secondary Subject Heading: Pharmacology and therapeutics, Obstetrics and gynaecology Keywords: Reproductive medicine < GYNAECOLOGY, Pharmacology < TROPICAL MEDICINE, Clinical trials < THERAPEUTICS, hop, Humulus,menopause, vasomotor, Hot Flashes, night sweats BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

34 Page of BMJ Open Protocol for Systematic Review and meta-analysis: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Fatemeh Abdi, Farideh Kazemi, Nasibeh Roozbeh *. Ph.D Studeant, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran.. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran.. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Corresponding Author: Nasibeh Roozbeh PhD student of reproductive health, Child and Mother care center,hormozgan University of Medical Sciences, Bandar Abbas, Iran Tel: +0, 00 nasibe@yahoo.com, fatemeh.abdi@yahoo.com BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

35 Page of Abstract Introduction: Menopause is a critical stage in every woman's life. It can cause a distressing time for women by creating various vasomotor symptoms (VMS). Phytoestrogens can potentially exert various favorable effects and alleviate VMS in postmenopausal women. Hop (Humulus lupulus L.) contains -prenylnaringenin (-PN), the most potent phytoestrogen known to date. Hop is eight times stronger than any other herbal estrogens. This study aims to conduct a comprehensive systematic review and a meta-analysis survey of the effects of hop in the management of VMS in postmenopausal women. Methods: Only randomized controlled clinical trials, with cluster randomization and crossover, blinded, and non-blinded designs, conducted between will be included in this review. Quasi-experimental and observational studies as well as case reports will be excluded. The studies will be selected if their participants aged 0-0 years, had elevated follicle-stimulating hormone (FSH) levels and/or menstrual irregularities, and experienced discomforting VMS (at least hot flashes or night sweats). The primary outcome will be the rate of response to treatment, such as changes in frequency and intensity of symptoms in the intervention and placebo groups. Hop, Humulus, menopause, vasomotor, hot flashes, phytoestrogen, and night sweats will be used as search key words. Prior to their inclusion in the review, the selected papers will be assessed by two independent reviewers for methodological validity. Any disagreements will be resolved through a third reviewer. The risk of bias will be independently determined using the Cochrane Risk of Bias Tool. The quality of the papers will be assessed based on the CONSORT checklist. Ethics and Dissemination: Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The results of our project can help reproductive health researchers design more relevant studies. Keywords: Hop, Humulus, menopause, vasomotor, hot flashes, night sweats BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

36 Page of BMJ Open Article summary Strengths and limitations of this study: Systematic reviews and meta-analyses will provide the highest level of evidence for informed decisions. To the best of our knowledge, no meta-analysis has been conducted on this topic. Hop (Humulus lupulus L.) contains phytoestrogens and can thus reduce the risk of cardiovascular diseases, breast and endometrial cancer, and osteoporosis, relieve menopausal symptoms, especially hot flashes, and improve memory performance and sleep patterns without the side effects of hormone therapy. One limitation of this study is that the authors are only fluent in Persian and English. Therefore, a translator will be required when the papers are published in other languages. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

37 Page of Introduction Menopause, sometimes called a second puberty, is a critical stage in every woman's life(). Certain characteristics of this multidimensional evolutionary process affect women's quality of life and put them at high risk of developing various health conditions (, ). Following recent medical advances and the consequent increase in life expectancy (LE), the number of menopausal women is on a rapid rise. According to the World Health Organization, the population of women aged over 0 will exceed one billion in 00 (). Despite the mentioned improvement in LE, menopause age has remained relatively constant, i.e. post-menopausal years constitute about one-third of women's lives (). Therefore, menopause can potentially be a major health issue (). Postmenopausal women experience a variety of symptoms including hot flashes, night sweats, sleep disorders, anxiety, irritability, and mood swings (). Due to considerable negative effects of menopausal symptoms (, ), most women tend to seek appropriate treatments. Hormone therapy (HT), using estrogen either alone or in combination with progestogens, is often recommended for the management of menopausal symptoms (). However, the Women's Health Initiative (WHI) has reported increased risk of breast cancer, thromboembolic events, stroke, and coronary heart diseases following HT (0, ). Hormone replacement therapy is also believed to cause a gradual reduction in the cytotoxicity of natural killer (NK) cells and thus weaken the immune system. In fact, a two times higher incidence of breast cancer was seen in women receiving HT for nine years (). Herbal medicines, especially those containing estrogen, can have various favorable effects and alleviate vasomotor symptoms in postmenopausal women (). Phytoestrogens are plant derivatives whose structural similarity to estrogens makes them capable of exerting both estrogenic and anti-estrogenic effects (). Since phytoestrogens can produce stronger estrogenic effects in the absence of adequate estrogen, they can compensate for the reduced levels of endogenous β-estradiol during menopause. Substantial amounts of -prenylnaringenin (-PN), the strongest known phytoestrogen capable of binding to both estrogen receptors in human body, are found in Humulus lupulus (commonly known as hop). As a member of the Cannabaceae family, H. lupulus contains volatile oils and estrogenic, resin-based, and polyphylic compounds. Due to its potent phytoestrogenic compounds and humulene, tannin, beta-myrcene, pectin, potassium, and flavonoid contents along with its ability to create estrogenic, sedative, hypnotic, antipyretic, anti-inflammatory, and antiseptic effects (, ), H. lupulus has found wide BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

38 Page of BMJ Open medicinal and industrial applications.the presence of estrogenic compounds, such as isoxanthohumol, progesteronic xanthohumol, and -PN, in hop have also made it an appropriate herbal medicine for treatment of menopausal symptoms().heyerick et al. Have examined the efficacy of a hop extract enriched in -prenylnaringenin on relief of menopausal symptoms.they showed that daily intake of a hop extract, has favorable effects on vasomotor symptoms (). Rosic et al. have been noticed significant improvements in the physical, psychological, and genitourinary symptoms of menopause following the administration of phytoestrogens(). In this regard another study has observed that hop effectively reduced the vasomotor symptoms(0).likewise, a clinical trial by Alizadeh Caharandabi et al. showed significantly hop can reduces the early menopausal symptoms(). Numerous scales, including the Greene Climacteric Scale and Cooperman's index, have been developed to determine the incidence and severity of menopausal symptoms(, ).However, based on our knowledge and understanding, no systematic review has evaluated the effects of hop in the management of menopausal vasomotor symptoms. Therefore, the results of this study can potentially help to select appropriate treatment options for menopause. The aim of this study is to conduct a comprehensive systematic and meta-analysis survey of the effects of hop in the management of menopausal vasomotor symptoms..objectives This systematic review will aim to clarify whether Humulus lupulus is more effective than placebo in reducing the menopausal vasomotor symptoms. Our secondary objective shall be to answer the following two questions: - Does response to treatment with Humulus lupulus depend on the dosage or duration of treatment? - What are the side effects of Humulus lupulus compare to placebo? BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

39 Page of Methods Criteria for considering studies for this review.. Types of studies Only randomized controlled clinical trials conducted between which will be include in this review. This includes cluster and crossover, blinded and non-blinded designs. Quasi experimental (studies without controls) and observational studies, as well as case reports will be excluded. There are no language restrictions in using and entering articles to this study. Because, if the language used in the articles was other than Persian or English, we will ask for a translator to translate this articles... Types of Participants The studies will be selected if their participants: Aged 0-0 years with elevated FSH or menstrual irregularities or both and those who reported a minimum of some hot flashes or night sweats that caused discomfort. were recruited based on the Greene Climacteric Scale, Cooperman's index, Menopause Rating Scale (MRS), or visual analogue scale (VAS); were assessed using the Greene Climacteric Scale, Cooperman's index, MRS, or VAS to determine the effects of the intervention; used hop and placebo for at least four weeks; and At least 0% of participants completed the whole course of the intervention.. Types of Interventions The studies will be reviewed if: Hop is used in the intervention (no time limits are imposed); The effects of hop are compared to those of placebo; Placebo is used for symptom relief. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

40 Page of BMJ Open Studies whit scored over on the CONSORT checklist will be included. No time limits will be imposed on the treatment period. (Appendix: )().. Primary Outcome The primary outcome will be the rate of response to treatment, such as changes in frequency and intensity of symptoms in the intervention and placebo groups. Treatment outcome measurements will be based on the Greene Climacteric Scale, Cooperman's index, Menopause Rating Scale (MRS), or visual analogue scale (VAS)... Secondary Outcomes The side effects of hop and the mean scores of the Greene Climacteric Scale, Cooperman's index, MRS, and VAS in the studied clinical trials will be evaluated as secondary outcomes. All outcomes will be examined during a period of six months (short-term outcomes). The number of hot flashes is one of the items in Green climacteric scale which it will be assessed as secondary outcome... Search Strategies for identification of studies The following resources will be searched: The Cochrane Central Register of Controlled Trials MEDLINE (via Pubmed, from 000 to the president) EMBASE (via Scopus, from 000 to the present) PsycINFO Scopus ProQuest Google scholar CINAHL(via EBSCO) BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

41 Page of Our key terms for preliminary analysis of previous research will be Hop, Humulus, menopause, vasomotor, Hot Flashes, phytoestrogen, Night sweats, which will be combined using Boolean operators AND and OR. Further relevant keywords and Boolean operators will also be selected for a change of strategy in each particular database. No particular language criterion will be defined either directly during the database search or indirectly during the evaluation of studies' reference lists... Database of Ongoing Clinical Trials The search for ongoing clinical trials will be performed in the following databases: and Searching Other Resources Hand searches will be conducted in key journals. Government reports, theses and dissertations, papers published by research committees, and abstracts of papers presented at different conferences and seminars will be evaluated... Data Collection and Analysis Selection of Relevant Studies The first stage of this systematic review will involve the evaluation of the titles, abstracts, and eligibility of studies (by F.K.). In the second stage, the full text of the papers will be independently assessed by two co-authors (F.A.and N.R.) to confirm their eligibility. Areas of disagreement will be discussed until a consensus is reached. In cases where the disagreement cannot be resolved, the viewpoints of an external observer will be used. Authors of papers with available abstracts whose results are published on posters will be ed and requested to send the full text. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

42 Page of BMJ Open Data Extraction and Management Two co-authors (F.A. and N.R.) will independently extract data from the full texts of papers that is published previously and will design a form accordingly. Data will be collected as follows (Appendix: ) () - Research information (the first author, geographic location, year of publication, beginning and end dates, research design, sample size, duration of follow-up); - Characteristics of the participants (age, gender, and number of participants, inclusion and exclusion criteria, menopausal symptoms, keywords definitions, and measurement tools); - Intervention and comparison of the details (number of groups, blinding procedure, dose and type of intervention, dose based on body weight, factors determining the duration of treatment, treatment withdrawal, and sample loss); - Outcome measures (explanations on the administered measurement tools, and methods evaluating outcomes, side effects, and serious side effects). The third author (F.R.) will review the collected data. Cases of disagreement between the authors will be resolved based on the opinions of an external observer... Quality Assessment of Studies The risk of bias will be independently determined by two external observers using the Cochrane Risk of Bias Tool (Appendix: ) (). The quality of the papers will be assessed based on the CONSORT checklist which contains items scored as zero or one. Only studies which scored over on the CONSORT checklist will be included. Like previous stages, points of disagreement will be resolved based on the viewpoints of an external observer. Data synthesis Quantitative data will, where possible, be pooled in statistical meta-analysis using Rev Man software. Two models of meta-analysis were conducted for outcomes: the fixed-effect model and the random-effect model. A fixed-effect model using the Mantel Haenszel method assumes that studies are sampled from populations with the same effect size, making an adjustment to the study weights according to the in-study variance. A random-effect model assumes that studies BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

43 Page 0 of are taken from populations with various effect sizes and calculates study weights both from instudy and between-study variances, considering the extent of variation, or heterogeneity. The random-effect model is more appropriate when heterogeneity is present. For each model, we estimated the between-study heterogeneity in all of the eligible comparisons using the chisquare-based Q statistic. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their % confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. We will also consider subgroup meta-analysis such as menopausal status including pre-menopause and post-menopause. Ethics and Dissemination: Results will be disseminated through traditional academic literature. Dissemination of results will occur by peer-reviewed publications. The results of our project can help reproductive health researchers when evaluating the discomforts of research procedures described in study protocols or when designing a study. Information on experiences of menopausal women involved in previous studies may also help in future research. The expected dissemination actions are effective treatment in designing strategies that aim to develop women s health and healthcare providers when offering treatment for women with vasomotor symptoms Contributors: FA and NR conceived the research questionnaire and drafted the aspects of the study protocol. NR was responsible for drafting this paper and all authors read, provided important revisions and approved the final version of the manuscript. Acknowledgements To Dr Keshtkar for his help in developing this protocol. Funding: This work has not supported by any organization yet. Competing interests: None declared 0 BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

44 Page of BMJ Open References -Yazdkhasti M, Simbar M, Abdi F. Empowerment and Coping Strategies in Menopause Women: A Review. Iranian Red Crescent Medical Journal. 0;() : e. -.Nosek M, Kennedy HP, Gudmundsdottir M. Distress During the Menopause Transition.A Rich Contextual Analysis of Midlife Women s Narratives. Sage Open. 0;():0. - Harris MT. Menopause: the need for a paradigm shift from disease to women's health. PhD thesis, Southern Cross University, Lismore, NSW.0. -Rubinstein, Helena. The meanings of menopause: identifying the bio-psycho-social predictors of the propensity for treatment at menopause.lucy Cavendish College, The University of Cambridge. 0.. Al-Safi ZA, Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertility and sterility. 0;0():0-.. Rotem M, Kushnir T, Levine R, Ehrenfeld M. A Psycho Educational Program for Improving Women's Attitudes and Coping With Menopause Symptoms. Journal of Obstetric, Gynecologic, & Neonatal Nursing. 00;():-0. -Crowe, Brandi. The Effects of Yoga Participation on Symptoms Associated with Menopause: A Mixed Methods Study.Clemson University. 0. All Dissertations. Paper.. Golyan Tehrani SM, M. Khaledian, E. Study of quality of life and its patterns in different stage of menopause for women in tehran. Hayat. 00;(-):-.. Reid R, Blake J, Abramson B, Khan A, Senikas V, Fortier M. Menopause and osteoporosis update 00. J Obstet Gynaecol Can. 00;( Suppl ):S Theroux R. Women's decision making during the menopausal transition. Journal of the American Academy of Nurse Practitioners. 00;():-.. Gurney EP, Nachtigall MJ, Nachtigall LE, Naftolin F. The Women's Health Initiative trial and related studies: 0 years later: A clinician's view. The Journal of Steroid Biochemistry and Molecular Biology. 0;:-. - Mascitelli L, Goldstein MR. Menopause, estrogen, statins, and the immune system. Maturitas. 0;():. - Teekachunhatean S, Mattawanon N, Khunamornpong S. Short-Term Isoflavone Intervention in the Treatment of Severe Vasomotor Symptoms after Surgical Menopause: A Case Report and Literature Review. Case reports in obstetrics and gynecology. 0;0:0.. Moreira AC, Silva AM, Santos MS, Sardão VA. Phytoestrogens as alternative hormone replacement therapy in menopause: What is real, what is unknown. The Journal of steroid biochemistry and molecular biology. 0;:-.. Van Cleemput M, Cattoor K, De Bosscher K, Haegeman G, De Keukeleire D, Heyerick A. Hop (Humulus lupulus)-derived bitter acids as multipotent bioactive compounds. Journal of natural products. 00;():0-0.. Depypere HT, Comhaire FH. Herbal preparations for the menopause: beyond isoflavones and black cohosh. Maturitas. 0;():-.. Hosseini E. Effect of Aalcoholic Extract of Hop Flowers on Serum Level Pituitary-Thyroid Hormones in Adult Male Rats.. Journal of Birjand University of Medical Sciences 0;():-.. Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 00;():-.. Rosic S, Kendic S, Rosic M. Phytoestrogens impact on menopausal symptomatology. Materia socio-medica. 0;():. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

45 Page of Aghamiri V, Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Nazemiyeh H. The effect of Hop (Humulus lupulus L.) on early menopausal symptoms and hot flashes: A randomized placebo-controlled trial. Complementary therapies in clinical practice. 0:-.. Mohammad-Alizadeh-Charandabi S, Mirghafourvand M, Aghamiri V, Nazemiyeh H, Soltanpoor S. Efficacy of hop (Humuluslupulus L.) on early menopausal symptoms in perimenopausal women: A randomized double blind placebo-controlled trial. Scientific Journal of Kurdistan University of Medical Sciences. 0;():-.. Tao M, Shao H, Li C, Teng Y. Correlation between the modified Kupperman Index and the Menopause Rating Scale in Chinese women. Patient preference and adherence. 0;:.. Cochrane Handbook for Systematic Reviews of Interventions Version..0. In: Higgins JPT, Green S, Eds. The Cochrane Collaboration; 0.. Cochrane Group.Data collection form for intervention reviews: RCTs only Version, April 0. Julian P T Higgins senior statistician, Douglas G Altman director, Peter C Gøtzsche director,et.al.the Cochrane Collaboration s tool for assessing risk of bias in randomised trials. BMJ 0;. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

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47 Page of Appendix:. Cochrane Handbook for Systematic Reviews of Interventions Version..0. In: Higgins JPT, Green S, Eds. The Cochrane Collaboration; 0. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

48 Page of BMJ Open Appendix: BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

49 Page of Cochrane Group.Data collection form for intervention reviews: RCTs only Version, April 0. BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

50 Page of BMJ Open Appendix:. Julian P T Higgins senior statistician, Douglas G Altman director, Peter C Gøtzsche director,et.al.the Cochrane Collaboration s tool for assessing risk of bias in randomised trials. BMJ 0; BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

51 Page of PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 0 checklist: recommended items to address in a systematic review protocol* Section and topic Item No ADMINISTRATIVE INFORMATION Checklist item Title: Identification a Identify the report as a protocol of a systematic review Update b If the protocol is for an update of a previous systematic review, identify as such Registration If registered, provide the name of the registry (such as PROSPERO) and registration number n/a Authors: Contact a Provide name, institutional affiliation, address of all protocol authors; provide physical mailing address of corresponding author Contributions b Describe contributions of protocol authors and identify the guarantor of the review Amendments If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments Support: Sources a Indicate sources of financial or other support for the review Sponsor b Provide name for the review funder and/or sponsor Role of sponsor or funder INTRODUCTION c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol Reported on page n/a Funding Statement Rationale Describe the rationale for the review in the context of what is already known, Objectives Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO) METHODS Eligibility criteria Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years considered, language, publication status) to be used as criteria for eligibility for the review Information sources Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature sources) with planned dates of coverage Search strategy 0 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated Study records: Data a Describe the mechanism(s) that will be used to manage records and data throughout the management review Selection process Data collection process b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is, screening, eligibility and inclusion in metaanalysis) c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators Data items List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and simplifications,,,, BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

52 Page of BMJ Open Outcomes and prioritization Risk of bias in individual studies Data synthesis List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis a Describe criteria under which study data will be quantitatively synthesised b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining data from studies, including any planned exploration of consistency (such as I, Kendall s τ) c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, metaregression) d If quantitative synthesis is not appropriate, describe the type of summary planned Meta-bias(es) Specify any planned assessment of meta-bias(es) (such as publication bias across studies,, selective reporting within studies) Confidence in cumulative evidence Describe how the strength of the body of evidence will be assessed (such as GRADE) * It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the PRISMA-P Group and is distributed under a Creative Commons Attribution Licence.0. From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 0: elaboration and explanation. BMJ. 0 Jan ;(jan0 ):g. Appendix:, BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.

53 Protocol for Systematic Review and meta-analysis: Hop (Humulus Lupulus L.) for Menopausal Vasomotor Symptoms Journal: BMJ Open Manuscript ID bmjopen-0-00.r Article Type: Protocol Date Submitted by the Author: -Mar-0 Complete List of Authors: abdi, fatemeh;. Ph.D Student, Students Research Committee, Nursing and Midwifery Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Kazemi, Farideh;. PhD Candidate,Department of Midwifery and Reproductive Health, Nursing and Midwifery Faculty,Shahid Beheshti University of Medical Sciences, Tehran, Iran. roozbeh, nasibeh;. PhD student of reproductive health, Child and Mother care center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. ramezani tehrani, fahimeh; Professor, Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran <b>primary Subject Heading</b>: Obstetrics and gynaecology Secondary Subject Heading: Pharmacology and therapeutics, Obstetrics and gynaecology Keywords: Reproductive medicine < GYNAECOLOGY, Pharmacology < TROPICAL MEDICINE, Clinical trials < THERAPEUTICS, hop, Humulus,menopause, vasomotor, Hot Flashes, night sweats BMJ Open: first published as 0./bmjopen-0-00 on April 0. Downloaded from on 0 June 0 by guest. Protected by copyright.