Health-related quality-of-life among patients with premature ovarian insufficiency: a systematic review and meta-analysis

Purpose To systematically review studies investigating health-related quality-of-life (HrQoL) in patients with premature ovarian insufficiency (POI), to examine questionnaires used and to conduct a meta-analysis of control studies with normal ovarian function.

Data sources: PubMed, Embase, Web of science, CNKI, and CQVIP, searched from inception until June 2018. The search strategy was a combination of medical (e.g. POI), subjective (e.g. well-being) and methodological (e.g. ques- tionnaires) keywords. PRISMA guidelines were used to assess outcome data quality/validity by one reviewer, verified by a second reviewer. Risk of bias within studies was evaluated. A meta-analysis compared HrQoL in patients and non-patients. Due to measurement differences in the studies, the effect size was calculated as standard mean difference.

We identified 6869 HrQoL studies. Nineteen geographically diverse studies met inclusion criteria, dated from 2006, using 23 questionnaires. The meta-analysis included six studies with 645 POI participants (age 33.3 ± 5.47) and 492 normal-ovarian control subjects (age 32.87 ± 5.61). Medium effect sizes were found for lower overall HrQoL (pooled SMD = − 0.73, 95% CI − 0.94, − 0.51; I 2 = 54%) and physical function (pooled SMD = − 0.54, 95% CI − 0.69, − 0.39; I2 = 55%). Heterogeneity was investigated. Effect sizes varied for sexual function depending on the measure (SMD = − 0.27 to − 0.74), overall HrQoL (SF-36) had the largest effect size (− 0.93) in one study. The effect sizes for psychological and social HrQoL were small.

POI is associated with low-to-medium effect size on HrQoL compared to normal ovarian controls. The greatest effects are found in general HrQoL and most sexual function areas. Condition-specific questionnaires and RCTs are recom- mended for further investigation.

Surveys and questionnaires · Menstruation disturbance · Gynaecology · Women’s health Abbreviations CAMS-R The Cognitive and Affective Mindful- ness Scale V Revised CES-D Epidemiologic Studies Depression Scale DHEA Dehydroepiandrosterone DISF-SR Derogatis Interview for Sexual Func- tion—Female Version DOR Diminished ovarian reserve DSM-IV (SCID) Diagnostic and Statistical Manual of Mental Disorders (fourth edition) FACIT-Sp-12 Functional Assessment of Chronic Ill- ness Therapy—Spiritual Well-Being Scale FACIT-Sp-Ex Functional Assessment of Chronic Ill- ness Therapy—Spiritual Well-Being Scale Expanded Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1113 6-019-02326 -2) contains supplementary material, which is available to authorized users. * B. Y. Liu [email protected] 1 Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China 2 Department of Pediatrics, The Queen Silvia Children’s Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 416 85 Gothenburg, Sweden 3 Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China 20 Quality of Life Research (2020) 29:19–36 1 3 FANLTC Functional Assessment of Non-Life- Threatening Conditions FertiQoL International Fertility Quality of Life Questionnaire FSFI Female Sexual Function Index FSH Follicle-Stimulating Hormone GCS Greene Climacteric Scale HrQoL Health-related quality of life HRT Hormone replacement therapy IHD Ischaemic heart disease LEU Life events scale NOS Newcastle–Ottawa Scale PANAS Positive and Negative Affect Schedule PCOS Polycystic ovarian syndrome PM The Pearlin Mastery Scale POF Premature ovarian failure POI Premature ovarian insufficiency POR Poor ovarian responders PRQ85 Personal Resource Questionnaire 1985 QOL Quality of life SF-36 The 36-Item Short Form Survey from the RAND Medical Outcomes Study SMD Standard Mean Difference SPEQ Sexual Personal Experiences Questionnaire STAI State-Trait Anxiety Inventory TABP/TCBP Type A/C behavior pattern TCM Traditional Chinese Medicine WHOQoL-BREF World Health Organization Quality of Life YMA Young Menopause Assessment

Thanks to medical advances, the living condition of women with premature ovarian insufficiency (POI) has gained more attention in recent years [1 ]. POI is a clinical syndrome defined by loss of ovarian activity before the age of 40, associated with menstrual disturbance, raised gonadotropins and low estradiol [2 ]. Although proper diagnostic accuracy in POI is lacking, the European Soci- ety of Human Reproduction and Embryology (ESHRE) has developed guidelines on management of women with premature ovarian insufficiency [2 ] in which they recom- mend the following diagnostic criteria for POI: (i) oligo/ amenorrhea for at least 4 months, and (ii) an elevated FSH level > 25 IU/l on two occasions > 4 weeks apart. The nomenclature has changed over the years and POI has been referred to as premature ovarian failure, premature menopause, and premature ovarian dysfunction [3 ]. Ear- lier studies often used the term premature ovarian failure (POF) and more recent articles have used POI. It should also be noted that in POI serum follicle-stimulating hor - mone (FSH) levels are often found to exceed the diag- nostic definition in studies of POI and are noted in sev - eral studies to be above 40 IU/L [2 –4]. An earlier study reported the prevalence of POI in women under 30 years old estimated to be 0.1%, while the incidence of meno- pause in women before the age of 40 is approximately 1% [5]. In recent years, studies have investigated the prev - alence of patients with POI in different countries. For example, one article reported a higher prevalence (1.9%; 95% CI 1.7–2.1) of POI in women before the age of 40 in Sweden [6 ] and another article reported 0.91% (95% CI 0.81–1.02%) in Estonia [7 ]. There has been a long-stand- ing confusion over the various terms such as poor ovar - ian responders (POR), premature menopause and dimin- ished ovarian reserve (DOR) [2 , 3, 8, 9]. It is important to distinguish these conditions from POI because women with POI face more challenges than diminished fertil- ity, and have different management needs [2 , 10]. Only 5–10% of women with POI may be able to spontaneously conceive and deliver a child [11]. In addition, women with POI suffer from amenorrhea-related symptoms [12] psychological problems [13, 14], increased risk to car - diovascular health [15, 16] and to bone health [17]. POI is a condition that is influenced by genitourinary and sexual function [18] and neurological dysfunction [19] in both the short- and long-term and can lead to prema- ture death [20]. The best option to relieve symptoms and protect POI patients against serious morbidity related to prolonged estrogen deficiency is hormone replacement therapy (HRT). However, HRT is just a mimic of normal physiological endocrinology, which has no evidence to improve the ovary function [2 ]. Consequently, patients with POI are at risk of poor health quality despite avail- able treatment options. Quality of life (QoL) is a broad multidimensional concept that usually includes subjective evaluations of both positive and negative aspects of life [21]. While, health-related quality of life (HrQoL) focus on the effects of a disease on an individual’s health and its treatment [22– 25] encompassing physical, psychological, and social functioning [23, 26] and presents an avenue for the evaluation of the consequences of experienc- ing premature ovarian insufficiency. This review aimed to investigate studies of women with POI, which have included measures of HrQoL, in order to evaluate effect sizes and in addition to identify the measurement instru- ments used. A meta-analysis was conducted of the studies that reached quality standards and which compared the HrQoL outcomes among patients with POI with a control group consisting of normal ovary function women. 21Quality of Life Research (2020) 29:19–36 1 3

This study followed the Preferred Reporting Items for Sys- tematic Reviews and Meta-analyses (PRISMA) [27] report- ing guideline (Online Resource ESM_1). A submission to the ethics committee of the Clinical Basic Medicine Insti- tute, China Academy of Chinese Medical Sciences was sought. The Ethics committee judged that ethical approval was not required for this research (ref 2019/1). Search strategy and data selection An electronic search of the six databases was undertaken from database inception to June 2018. PubMed/MEDLINE and ‘Web of science’ provided a broad coverage of the bio- medical literature, including reproductive biology and clini- cal medicine. EMBASE was included because it has greater coverage of European and non-English language publica - tions and topics such as alternative medicine. China National Knowledge Infrastructure (CNKI), WanFang database and Chongqing VIP information (CQVIP) were included to ensure that no Asian publications were missed. Searches were conducted without restrictions with respect to publica- tion year, language, type or setting of study or accessibility to full-text articles. A combination of keywords and database specific terms was used (premature ovarian insufficiency OR premature ovarian failure OR diminished ovarian reserve OR poor ovarian response OR premature menopause OR hyper-gonadotropic hypogonadism OR elevated gonado- trophins OR triad of amenorrhea OR estrogen deficiency) AND (well-being OR health outcome OR quality-of-life OR health-related quality of life) AND (questionnaire OR instrument OR patient reported outcome). Strategies differed in the different databases depending upon the information structures. The details of the different search strategies are provided in the online resource materials (online resource ESM_2). The process of article selection is outlined in Fig. 1 with a description of predefined criteria for selection. One author (XT Li) was mainly responsible for screening the titles and abstracts. Articles identified were independently read and discussed with two more authors (HS Yang, PY Li) to ensure an unbiased selection. Some studies of post-men- opause have used instruments such as the MSQOL [28, 29] however this is not a measure of subjective quality-of-life and was therefore not included in this review. No additional articles were identified through the manual search. Stud - ies describing the construction and validity of the HrQoL questionnaires used in the studies were also evaluated. If information on construction and validity was sparse, contact was attempted with the author responsible for the develop- ment of the questionnaire. Criteria to select articles The inclusion criteria for empirical investigation studies of adults with POI was that HrQoL was a primary or second- ary outcome. Studies with participants from hospitals and long-term care facilities or with specific conditions (e.g. Turner syndrome or anorexia) or where abstracts only were found were included in the literature in order to be able to extract data on the questionnaires used but excluded from the meta-analysis. No restrictions were placed on the geo- graphic, soioeconoimic or ethinic backgrounds of any of the participants. There was no restriction in terms of treatment, both randomized and non-randomized trials were included. Exclusion criteria for the systematic review were duplicate publications or reviews, studies that did not include out- comes from a HrQoL questionnaire. Exclusion criteria for the meta-analysis were articles which lacked relevant data for investigation and studies without a normal ovary func- tion control group. Critical appraisal: assessment of bias in the studies The quality of eligible articles was assessed at the study level using the Newcastle–Ottawa Scale (NOS) for nonrand- omized cohort studies [30]. Each article was awarded a ‘star’ or score out of four for selection bias, two for comparability and three for bias in the outcome assessment, with a maxi- mum total score of nine points. The NOS score was used to assess differences in study quality scores > 6 high; 4–6 medium, < 4 low [31]. The scoring system and evaluation is provided in the Online Resource ESM_3. Two authors (XT Li, PY Li) independently evaluated the findings of each study to ensure an unbiased assessment. Meta‑analysis A meta-analysis investigated the outcome of HrQoL in patients with POI compared with a normal ovary func - tion reference population. Review Manager (Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used. The estimated value and 95% confidence interval (95% CI) of the effect size was calculated by Standard Mean Difference (SMD) [ 32]. The SMD is used as a summary statistic in meta-analysis when the studies all assess the same outcome but measure it in a variety of ways [33]. Cohen [34] suggested that d = 0.2 be considered a ‘small’ effect size, 0.5 represents a ‘medium’ effect size and 0.8 a ‘large’ effect size. The size of hetero - geneity among studies after combination was determined via I 2 statistic: 0% to 40%: might not be important; 30% to 22 Quality of Life Research (2020) 29:19–36 1 3 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity [35]. If there was no hetero- geneity among studies, a fixed effects model was applied for meta-analysis; if there was statistical heterogeneity, the sources of heterogeneity were further analyzed, and a random effects model was adopted for meta-analysis. According to the same questionnaires used and same Fig. 1 The article selection process and criteria for selection for the literature review and meta-analysis 23Quality of Life Research (2020) 29:19–36 1 3 specific domain evaluated, the effect sizes were divided into subgroups. This systematic review and meta-analysis were performed and reported according to the PRISMA guidelines. The PRISMA checklist is included as Online Resource_3.

Thirty-four studies matched the inclusion criteria and were included for review. Fifteen articles were related to treatment evaluation while 19 articles examined elements of HrQoL (Tables  1, 2). In five of these studies only the abstracts were available for examination [36– 40]. These articles were all published between 2006 and 2018. Eighteen articles were cross-sectional studies [36– 53] two of which included case–controls [43, 51]. One article reported only case–con- trol data [54]. Nine articles described HrQoL among patients with the nomenclature of POI [36, 39, 40, 42, 47, 49, 51–53] and ten articles described HrQoL among patients with the previous nomenclature of POF [37 , 38, 41, 43–46, 48, 50, 54]. Thirteen articles had control groups [39–46, 48, 49, 51, 53, 54] and nine of these had a control group of women with normal ovarian function [41–46, 51, 53, 54], six of these had sufficient information to be included in the meta-analysis [41–45, 54]. None of the studies used proxy-reports from family members as part of the evaluation. Reported stud- ies had varying sample sizes; the largest sample size was 340 women [46]. The studies were geographically diverse including China [41, 44–46], UK [37, 38, 50], America [36, 39, 40, 42, 49, 51–53], Brazil [43, 54], Australia [48] and multi-national studies [47] (Fig.  1 and Tables  1, 2). Domains of HrQoL examined The definition of HrQoL used in the studies is derived from the domains of the questionnaires used to measure HrQoL. Among the 19 articles examining HrQoL, seven studies included a measure of overall HrQoL as measured by either a generic questionnaire (SF-36, WHOQoL-BREF) [37, 43, 44, 50, 54] or measured in relation to fertility or sexual function [42, 45, 50, 54]. Nine studies focused on psychiatric aspects including depression and meaning in life [36, 38–40, 49–53]. Four articles used the POI related symptom questionnaires [38, 47, 48] Only one of these [50] used a condition specific instrument designed for POI (Young Menopause Assess- ment (YMA) [50]). One study evaluated the aspect of social function: perceived social support [53]. The reduced HrQoL among patients with POI was mentioned in all 19 articles. A summary of the studies is found in Tables  1, 2. Overall HrQoL Three articles described factors correlated with lower HrQoL in POI populations: one article reported that orgasm and sexual satisfaction were correlated with all QOL domains [54]; a second article analysed charac- ter traits of POI patients [45], which showed that older patients, with primary infertility and who had had chil- dren had lower HrQoL scores than patients who were of younger age, secondary infertility or had previously given birth. In one article [ 44] different Traditional Chinese Medicine (TCM) syndromes were considered as summa- ries of symptoms of the pathogenesis of disease develop- ment [55]. These syndromes included insufficiencies of liver and kidney or asthenia of both the spleen and kidney. It was noted that patients with deficiency of liver and kid- ney had the lowest overall QOL scores (Table  3). Physical function and symptoms Physical health of the women with POI was consistently reported to be significantly lower than controls. A number of physical function symptoms were explored including experience of physical pain [43] sexual function [42, 54] arousal, lubrication, orgasm and satisfaction, and sexual behaviour/experiences [42, 50, 54]. In addition, meno- pause symptoms such as vasomotor symptoms, mood swings and mental fog, hair loss, dry eyes, cold intoler - ance, joint clicking, tingling in limbs and low blood pres- sure were found at a high rate in patients with POI [47]. Psychological function and psychosocial aspects Women with spontaneous POI were reported to score adversely on all measures of psychological functioning [43, 51] with higher negative feelings such as “blue mood” [56], despair, anxiety, and depression or had a negative impact on their self-image and confidence [50 ]. This population also had a high rate of mental health medication use and counsel- ling [51] and a risk for depression [49]. Some articles ana- lysed the factors related to these negative feelings. Adverse affective symptoms were associated with a lower perceived level of control [39]. One article reported illness uncertainty and lack of purpose in life as a significant independent factor associated with anxiety [51]. Scores on the Spiritual Well- Being scale were also associate with POI and were found to reduce with increased age [52]. 24 Quality of Life Research (2020) 29:19–36 1 3 Table 1 Presentation of details of studies included in the systematic review and included in the meta-analysis Author, year [Ref]/ country Title Type of study Objective of the study Questionnaire [ref]/ type of questionnaire Sample size/observation group (age range) and population Control group (size), mean (SD) and population NOS Pang et al. 2007 [41]/ China Investigations of person- ality characteristics and mental health status in patients with premature ovarian failure Cross-sectional study Analysis of personal- ity characteristics and mental health status of patients with premature ovarian failure TABP/TCBP [57–59]/Behaviour pattern N = 80 no description of age range Hospital-based PCOS N = 80, Normal N = 81 no description of age range Population-based 7 High Kalantaridou et al. 2008 [42]/USA Sexual function in young women with spontane- ous 46, XX primary ovarian insufficiency Cross-sectional study To assess sexual function in women with sponta- neous 46, XX primary ovarian insufficiency after at least 3 months of a standardized hormone replacement regimen DISF-SR-Female Version/[60, 61]/ sexual function N = 143 32 ± 5.5 years Hospital-based Women of healthy, non- pregnant, and regularly menstruating N = 70 28.5 ± 7.3 years Population-based 7 High Benetti-Pinto et al. 2011 [43]/Brazil Quality of life in women with premature ovarian failure Cross-sectional and Case–control study Evaluate quality-of- life in women with a diagnosis of premature ovarian failure (POF) WHOQoL- BREF-100/[62–64]/ Generic QoL N = 58 22–39 years 44.8%, 40–51 years 55.2% Hospital-based Women with normal ovar- ian function N = 58 22–39 years 53.4% 40–51 years 46.6% Hospital-based 7 High Ji 2013 [44]/China Clinical study on the relationship between syndrome types dif- ferentiation of TCM and quality-of-life in premature ovarian failure Cross-sectional study To understand the qual- ity-of-life in patients with premature ovarian failure and to explore the correlation between TCM syndrome types and quality of life SF-36/[65–67]/ Generic QoL N = 114 34.5 ± 3.66 years Hospital-based Women with normal ovar- ian function N = 90 34.6 ± 3.2 years Hospital-based 7 High Yang et al. 2017 [45]/ China Study on quality of fertility in patients with premature ovarian failure Cross-sectional study Investigation of repro- ductive quality-of-life in patients with prema- ture ovarian failure FertiQoL/[68, 69]/ Fertility specific N = 170 31.2 ± 5.8 years Hospital-based women with normal ovar- ian function N = 113 30.5 ± 5.3 years Hospital-based 7 High Yela et al. 2018 [54]/ Brazil Influence of sexual function on the social relations and quality of life of women with premature ovarian insufficiency Case–control study To evaluate the impact of sexual function (SF) in the quality-of-life of women with premature ovarian insufficiency (POI) 1. FSFI/[70–72]/ Sexual function 2. WHOQoL-BREF [62–64]/Generic QoL N = 80 38.4 ± 7.3 years Hospital-based women matched by age (± 2 years) and present- ing preserved gonadal function free of chronic diseases N = 80 38.1 ± 7.3 years Hospital-based 7 High 25Quality of Life Research (2020) 29:19–36 1 3Table 2 Studies included in the systematic review not included in the meta-analysis due to insufficient data or non-normal ovarian function control group Author, year [ref], country Title Type of study Objective of the study Questionnaire Sample size/observation group (age range) and population Control group(size) and population NOS Pang 2006 [46], China a The demonstration study of the relationship between the social/ psychology factors in patients with POF Cross-sectional study To study the relationship between premature ovarian failure and psychosocial factors such as emotional state, personality char- acteristics and negative life events 1. TABP/TCBP (reported 2007) 2. STAI 3. Life Events Scale N = 80 33.3 ± 5.33 years Hospital-based PCOS N = 60 25.6 ± 4.7 years, Normal N = 200 33.53 ± 5.29 years Population-based Insufficient data reported 8 High Davis et al. 2010 [51], USA The psychosocial transi- tion associated with spontaneous 46, XX primary ovarian insuf- ficiency: illness uncer- tainty, stigma, goal flexibility, and purpose in life as factors in emotional health Cross-sectional and case–control study To examine factors asso- ciated with emotional well-being in women with spontaneous primary ovarian insuf- ficiency 1. CES-D 2. STAI 3. PANAS 4. Purpose in Life N = 99 32.4 ± 5.2 years Hospital-based Healthy control women of similar age N = 60 31.0 ± 6.9 years Population-based Insufficient data reported 7 High Orshan et al. 2009 [53], USA Women with spontane- ous 46, XX primary ovarian insufficiency (hypergonadotropic hypogonadism) have lower perceived social support than control women Cross-sectional study To test the hypoth- esis that women with spontaneous POI differ from controls regard- ing perceived social support and to inves- tigate the relationship with self-esteem 1. PRQ85 2. Rosenberg’s Self Esteem Questionnaire N = 154 32.2 ± 4.9 years Hospital-based Control women: healthy, free of chronic dis- ease, not pregnant, and regularly menstruating N = 63 29.9 ± 7.0 years Population-based Insufficient data reported 7 High Gibson-Helm et al. 2014 [48], Aus Symptoms, health behavior and under- standing of menopause therapy in women with premature menopause Cross-sectional study To explore symptoms, understanding of menopausal therapies, medication use and health-related behavior in women with and without premature menopause GCS N = 25 36 ± 8.0 years Population-based Premenopausal women N = 23, 29 ± 13 years and women with medically induced premature meno- pause (MIPM)N = 29 38 ± 4.0 years Population-based 6 Medium 26 Quality of Life Research (2020) 29:19–36 1 3 Social function Marital relationship and social support were reported to be significantly lower in POI patients [45]. Social relationships were found to have a negative influence of sexual function such as arousal, orgasm, satisfaction and pain [53, 54]. How- ever, other articles reported no significant differences found with respect to the social relationships or support [43, 46]. Questionnaires In total, twenty-three different questionnaires had been used in the nineteen articles identified for review (Table  4). The most frequently used questionnaires were the two generic HrQoL: World Health Organization Quality of Life (WHO- QoL-BREF) [62– 64], and the 36-Item Short Form Survey from the RAND Medical Outcomes Study (SF-36) [65–67] which were used in five studies. Between 1 and 4 question- naires were used in each study, 50% of the studies only used one questionnaire. Those studies that used four concentrated on the psychological aspects of the condition and were mainly from the same research group at NIH in the US and reported in Abstract form. Other studies combined generic questionnaires with condition specific issues e.g. sexual or menopause specific questionnaires. Only one study [50] used a POI specific questionnaire (Young Menopause Assessment (YMA) [Unpublished]. This was used in combination with a sexual function questionnaire (Sexual Personal Experiences Questionnaire (SPEQ) [73]) a psychological questionnaire (Rosenberg’s Self Esteem Questionnaire [ 74–77]) and a generic questionnaire (SF-36 Short Form Survey from the RAND Medical Outcomes Study (SF-36) [65– 67]). All the HrQoL instruments used are described in Table  4, a more detailed summary of the six questionnaires used in the stud- ies included in the meta-analysis can be found as Online Resource ESM_5. Synthesis of results and risk of bias (results of meta‑analysis) Six studies were included in the meta-analysis [41– 45, 54] (Fig.  2) with 645 POI participants and 492 normal-ovarian controls. Where data on average age was available the POI group had a pooled mean age of 33.3 ± 5.47; and the control group a pooled mean age of 32.87 ± 5.61. At the overall HrQoL level (Fig.  2a) four studies [42, 44, 45, 54] had lower level of HrQoL recorded in the POI group (pooled SMD = − 0.73, 95% CI − 0.94, − 0.51; I2 = 54%) as compared to a normal ovarian control group. The pooled Table 2 (continued) Author, year [ref], country Title Type of study Objective of the study Questionnaire Sample size/observation group (age range) and population Control group(size) and population NOS Schmidt et al. 2011 [49], USA Depression in Women with Spontaneous 46, XX Primary Ovarian Insufficiency Cross-sectional study To characterize the prev- alence of psychiatric disorders and the onset timing of clinically significant depression relative to POI and the onset of menstrual irregularity in women with POI [DSM-IV] (SCID) N = 174 31.6 ± 5.3 years Hospital-based Turner syndrome N = 100 no description of age range Hospital-based 3 Low a English translations of the Chinese abstracts are included as Online Resources ESM_4 27Quality of Life Research (2020) 29:19–36 1 3 Table 3 Studies included in the systematic review not included in the meta-analysis due to insufficient data and no control group Author/year, country Title Type of study Objective of the study Questionnaire Sample size/Observation group (age range) and population Control group(size) and population Allshouse et al. 2014 [47], USA + International Evidence for prolonged and unique amenorrhea-related symptoms in women with POF/POI Cross-sectional study Aims to describe POF/POI symptoms experienced by women from members of a POF/POI-specific support group 1. Menopause-specific QoL + 10 symptoms 2. CAMS-R N = 160 39.3 ± 7.3 years Population-based No control group Singer et al. 2011 [50], UK The silent grief: psychosocial aspects of premature ovar- ian failure Cross-sectional study To investigate experiences of diagnosis, perception of cause, treatment, concerns, a self-esteem, sexual func- tioning and HrQoL 1. Rosenberg’s Self Esteem 2. SF 36; 3. YMA; 4. SPEQ N = 136 38.7 ± 7.03 years Hospital-based No control group Ventura et al. 2007 [52], USA Functional well-being is posi- tively correlated with spir- itual well-being in women who have spontaneous premature ovarian failure Cross-sectional study To examine the relation- ship between spiritual well-being and functional well-being in women who have spontaneous POF 1. FANLTC 2. FACIT-Sp-12 N = 137 32 years Hospital-based No control group Sterling et al. 2009 [36], USA A study of the relational aspects of spiritual well- being and functional well-being in women with spontaneous 46, XX POI Cross-sectional study To analyze the relational aspects of spirituality and functional well-being in women with spontaneous 46, XX sPOI 1. FACIT-Sp-Ex 2. FANLTC N = 140 No description of age range Source unreported No control group Abstract only Islam et al. 2011 [37], UK The impact of premature ovarian failure on quality of life: results from the UK 1958 Birth Cohort Cross-sectional study To assess the prevalence and quality-of-life impact of premature ovarian failure in a large population based sample SF-36 N = 370 No description of age range Population-based No control group Abstract only Nicopoullos et al. 2009 [38], UK Effect of age and aetiology of premature ovarian failure on symptoms at presentation data from the west London POF database Cross-sectional study To assess the effect of age at diagnosis and aetiology on presentation Symptom questionnaire(no details) N = 239 No description of age range Hospital-based No control group Abstract only Covington et al. 2009 [39], USA Perceived mastery and emo- tional well-being in women with 46, XX primary ovar- ian insufficiency Cross-sectional study To compare mastery in women with 46, XX sPOI to controls and assess asso- ciated affective symptoms 1. Pearlin Mastery Scale 2. CES-D; 3. STAI; 4. PANAS N = 100 No description of age range Source unreported Control women N = 60 no description of age range Source unreported Abstract only Vanderhoof et al. 2009 [40], USA Spirituality and emotional well-being in women with spontaneous 46, XX pri- mary ovarian insufficiency (SPOI) Cross-sectional study To compare spirituality and religiousness of women with sPOI to controls, and assess the association with affective symptoms 1 Spirituality and Religion 2. CES-D; 3. STAI; 4. PANAS N = 100 No description of age range Source unreported Control women N = 60 no description of age range Source unreported Abstract only 28 Quality of Life Research (2020) 29:19–36 1 3 Table 4 Questionnaires used in the studies included in the systematic review Focus of scale Instrument Instrument description Study Study origin Generic HrQoL World Health Organization Quality of Life (WHO- QoL-BREF) [62–64]a Last 4 weeks/5 point Likert. 4 domains: Social, Emo- tional, Physical, Environmental (28 items) Benetti-Pinto 2011 [43] Yela 2018 [54] São Paulo, Brazil São Paulo, Brazil SF-36 RAND Medical Outcomes Study [65–67] a Last 4 weeks/5 point Likert. 8 domains: Physical, Role limitations, Bodily pain, Social, General men- tal health, Role limitations/emotional, Vitality, Gen health. (36 items) Singer 2011 [50] Islam 2011 [37] Ji 2013 [44] b London, UK London, UK GuangZhou, China Functional well-being Functional Assessment of Non-Life-Threatening Con- ditions (FANLTC) [78] Last 7 days/5 point Likert 4 domains: Physical, Social/ Family, Emotional, Functional (25 items) Ventura 2007 [52] Sterling 2009 [36] NICH, USA NIH, USA Psychological aspects of HrQoL The Cognitive and Affective Mindfulness Scale V Revised (CAMS-R) [79] No time scale/4 point Likert. 1 domain: Mindfulness (10 items) Allshouse 2014 [47] Colorado, USA The Pearlin Mastery Scale (PM) [80, 81] No time scale/7 point Likert. 1 domain: Mastery (7 items) Covington 2009 [39] Arizona, USA Epidemiologic Studies Depression Scale (CES-D) [82–84] Last 7 days/4 point Likert 1 domain: Depression (20 items) Covington 2009 [39] Vanderhoof 2009 [40] Davis 2010 [51] NIH, USA NIH, USA NIH, USA State-Trait Anxiety Inventory (STAI) [85–88] At the moment/4 point Likert. 2 domains: State and Trait Anxiety (40 items) Pang 2006 [46] Covington2009 [39] Vanderhoof2009 [40] Davis 2010 [51] GuangZhou, China NIH, USA NIH, USA NIH, USA Positive and Negative Affect Schedule (PANAS) [ [89–91] Time scale appropriate to the study/5 point Likert. 1 domain: Positive/negative affect (40 items) Davis 2010 [51] Covington2009 [39] Vanderhoof 2009 [40] NIH, USA NIH, USA NIH, USA Type A behavior pattern TABP/TCBP [57–59] a Current time/dichotomous. 3 domains: Time urgency, Hostility, Competitive drive (60 items) Pang 2007 [51] Pang 2006 [46] GuangZhou, China GuangZhou, China Rosenberg’s Self Esteem Questionnaire [74–77] Current time/4 point Likert. 1 domain: Self worth (10 itmes) Singer 2011 [50] Orshan 2009 [53] London, UK NICH, USA Purpose in Life subscale from the Positive Mental Well-Being Inventory [92, 93] Current time/7 point Unmarked Semantic Differential Scale. 1 domain: Meaning and purpose (20 items) Davis 2010 [51] NIH, USA Functional Assessment of Chronic Illness Therapy— Spiritual Well-Being Scale (FACIT-Sp-12) [94] Last 7 days/5 point Likert. 3 domains: Spiritual well- being (peace, meaning, faith) (12 items) Ventura 2007 [52] NICH, USA Functional Assessment of Chronic Illness Therapy— Spiritual Well-Being Scale Expanded (FACIT-Sp- Ex) [94] Last 7 days/5 point Likert. 3 domains: Spiritual well- being (peace, meaning, faith) (23 items) Sterling 2009 [36] NIH, USA Brief Multidimensional Measure of Religiousness/ Spirituality [95, 96] Current time/6-point scale. 9 domains: Daily spiritual experiences, Meaning, Values/Beliefs, Forgiveness, Religious practice, Spiritual coping, Religious sup- port, Religious History, Commitment (40 items) Vanderhoof 2009 [40] NIH, USA Life events Life events scale(LES) [97] No time limit/. 1 domain: Life events (48 items) Pang 2006 [46] GuangZhou, China 29Quality of Life Research (2020) 29:19–36 1 3 a Six questionnaires included in the meta-analysis are further summarized in Table S5 b Ji gives a measure of overall HrQoL derived from the SF-36 but does not explain how this is calculated c Singer refers to the measure as the Sexual Personal Experiences Questionnaire but gives a reference to the Dennerstein Short Personal Experiences Questionnaire Table 4 (continued) Focus of scale Instrument Instrument description Study Study origin Sexual function Female Sexual Function Index (FSFI) [70–72]a Last 4 weeks/5 point Likert. 6 domains: Desire, Arousal, Lubrication, Orgasm, Satisfaction, Pain (19 items) Yela 2018 [54] São Paulo, Brazil Derogatis Interview for Sexual Function (DISF-SR— Female Version) [60, 61]a Current time/9 and 5 point scales. 4 domains: Sexual cognition and fantasy; Sexual arousal; Sexual behaviour and experience; orgasm; Sexual drive and relationship (25 items) Kalantaridou 2008 [42] NIH, USA Short Personal Experiences Questionnaire (SPEQ) [73] Current time/8 domains: Desire, Arousal, Orgasm, Enjoyment, Satisfied by frequency, Frequency of intercourse, Frequency of fantasies, Dyspareunia (9 items) Singer 2011 [50] b London, UK Disease or symptom-specific Fertility Quality of Life Questionnaire(FertiQoL) [68, 69]a Current time/5 point Likert. 4 domains: Emotional, Mind–body, Relational; Social. (36 items) Yang 2017 [45] Henan, China Menopause-specific Quality of Life questionnaire [28, 29, 98] 4 Weeks/7 point Likert 5 domains: Physical; Vasomo- tor; Psychosocial; Sexual; working life (30 items) Allshouse 2014 [47] Colorado, USA Greene Climacteric Scale (GCS) [99–101] Symptoms checklist (21) Gibson-Helm 2014 [48] Monash, Australia POI specific Young Menopause Assessment (YMA) [50] 3 Domains: Description of POF; Treatment; informa- tion and support (3 items 6) (Designed for this study referred to as developed in a pilot study—unpub- lished) Singer 2011 [50] c London, UK Perceived social support Personal Resource Questionnaire 1985, part 2 (PRQ85) [102] Current time/7-point scale. 5 domains: Valued individual; part of a group; intimacy; nurturance; info emotional and material help + description and satisfaction with resources (25 items) Orshan 2009 [53] NICH, USA 30 Quality of Life Research (2020) 29:19–36 1 3 Fig. 2 a Patients with POI compared with normal ovarian reference populations: overall health related quality-of-life (HrQoL). b Patients with POI compared with normal ovarian reference populations: phys- ical functioning. c Patients with POI compared with normal ovarian

populations: mental health. d Patients with POI compared with normal ovarian reference populations: social functioning 31Quality of Life Research (2020) 29:19–36 1 3 heterogeneity can be considered moderate. To address the heterogeneity, a subgroup analysis (2 studies included) was performed to separately examine the measures of sexual functioning (Fig.  2a3) (SMD = − 0.78, 95% CI − 1.00, − 0.55; I 2 = 0%) the effect size was medium to large and there was no indication of heterogeneity. The largest effect size (large) was found for ‘overall HrQoL’ as measured by the SF-36 (− 0.93, 95% CI − 1.22, − 0.64). In regard to the physical functioning aspects of HrQoL (Fig.  2b), this was measured by four studies using nine different indicators. The results again showed moderate pooled effect size and moderate heterogeneity (pooled SMD = − 0.54, 95% CI − 0.69, − 0.39; I 2 = 55%) as com- pared to a normal ovarian control group. The sexual function (2 studies included) measures explained the heterogeneity where these alone demonstrated substantial heterogeneity (I 2 = 64%) but with a medium effect size (SMD = 0–0.52, 95% CI − 0.70, − 0.34; I2 = 64%). The largest effect size (moderate) was found for ‘Lubrication’ as measured by the FSFI (− 0.74, 95% CI − 1.06, − 0.42). In the mental health area (Fig.  2c1, 2), the studies agreed that there was a lower level of mental health in the POI group than was found in the controls however the pooled effect size was small [1. SMD = − 0.43, 95% CI − 0.54, − 0.32; I 2 = 0% (higher score = better Fig. 2c1); 2. SMD = 0.72, 95% CI 0.50, 0.95; I2 = 0% (lower score = better Fig.  2c2)]. The largest effect size (moderate) was found for ‘Optimism’ as measured by the TABP/TABC (− 0.64, 95% CI − 0.95, − 0.32). The social functioning domain (Fig. 2d) was addressed by five of the six studies, the pooled effect size was small with no heterogeneity (pooled SMD = − 0.27, 95% CI − 0.38, − 0.15; I 2 = 0%). The largest effect size (moderate) was found for ‘Drive and relationship’ in the DISF (− 0.48, 95% CI − 0.78, − 0.17). Ji [44] has calculated a total QoL score for the SF-36. There is not information on how this was calculated. For

on this issue see by Lins and Martins Carvalho (2016) https ://doi.org/10.1177/20503 12116 67172 5.

Nineteen studies reported the empirical measurement of HrQoL among patients with POI. Reports of the impact of POI on different aspects of HrQoL differed between stud - ies. However, impaired physical, psychological and gen- eral health was reported across all areas of HrQoL. There were no articles prior to 2006 and studies used a variety of HrQoL instruments both generic and condition specific although only one measure was specially designed for POI [50]. Although subjective experiences of patients with POI have received more attention from the medical profession in the past decade, relevant and valid evaluation instruments have not been developed, and long-term follow-up studies of HrQoL have not been carried out. The six controlled studies included in the meta-analysis demonstrated that overall HrQoL in patients with POI/POF is lower than individuals with normal ovarian functioning with low to medium pooled effect sizes [41– 45, 54]. The moderate heterogeneity in the general measure of HrQoL appears to be due to the different concept being measured under the term HrQoL. It may also come from the different Fig. 2 (continued) 32 Quality of Life Research (2020) 29:19–36 1 3 socioeconomic groups being included in the various studies. Information on socioeconomic status was sparsely reported and it was not possible for us to make an assessment of the influence of this moderator. The finding that studies concerning HrQoL in relation to POI were not found prior to 2006 may be related to fact that the definition of POI had not been standardized. Recent guidelines from the European Society of Human Reproduc- tion and Embryology, published in 2015 [2 ], coincide with the beginning of investigations into HrQoL in POI. However, some variation in diagnostic criteria is evident. Some studies used broader age intervals, and the levels of Follicle-Stimu- lating Hormone (FSH), which is a very important indicator of POI diagnosis [2 ], were vague. This may lead to hetero- geneity of the results. The factors measured in the six studies in the meta-anal- ysis varied and included: fertility, sexual function, anxiety, depression, menopausal symptoms. Although all the meas- urements were cross-sectional, the concepts measures could all be considered to have long-term effects and would vary according to, for example, diagnostic age, marriage con- dition or education. In one study [45], an association was investigated between personal character traits and the impact of POI this highlighted the patient’s response to the stress of a POI diagnosis and of living with the condition. Geographical diversity is apparent from our review. It is noted that studies were found in five countries and included one multi-national study [47]. Studies taking a cross-cultural perspective were not conducted. This highlights the possibil- ity of cultural bias in the results [103]. The sparsity of these studies may be due to the lack of a single agreed and vali- dated condition specific instrument translated into multiple language. In addition, despite substantial clinical studies on the use of traditional medicine with this condition, there is a lack of controlled studies that can be used as evidence of treatment effects. The large number of instruments used (23) in 19 stud - ies with a very low repetition rate, indicates that there is no common view concerning instruments. In some studies, the generic instruments were used to address a comprehen- sive array of domains of QoL, however, this focus may have limited the sensitivity to detect subtle aspects of POI. It is interesting to speculate on what we did not find, which was the patient perspective. The instrument designed for POI by Singer [50] for their study was based on ‘clinical expe- rience’ and covered the areas of ‘About your POF/young menopause’, ‘Treatment’, and ‘Information and Support’. For many patients, there are concerns about the implica- tions of the treatment and of possible long-term side effects which might be more meaningful to the patient [104, 105] and yet these aspects were not investigated. Some studies choose questionnaires that are specific for similar conditions such as menopause or infertility, however, even though the symptoms may be similar, the patients’ experiences and requirements may not be the same [47, 48, 54]. It also must be considered that these questionnaires may not be sensi- tive to all patients with POI. Although the majority of the questionnaires used to measure HrQoL in these studies had good psychometric properties, none of them had evidence to confirm the sensitivity and specificity of the instruments in relation to POI. There were ten studies [36, 39, 40, 46, 47, 50–54] that used a combination of questionnaires to capture more comprehensive information. However, mood, symp- tom, and fertility questions specific for women with POI were lacking [47, 50]. Strengths and limitations Some limitations of the study need to be taken into consid- eration. It is possible that some studies have been missed due to the use of different terms for POI or in languages that were not included in the databases we examined. There were some studies that were only published as Abstracts and although we tried to contact these researchers we were una- ble to obtain more information. Our study has the strength of including both European and Asian databases. Those databases that were searched are those that have the highest likelihood of finding studies of HrQoL and POI.

and future recommendations This literature review and meta-analysis gives new informa- tion on HrQoL in patients with POI. In this review, the mag- nitude of the subjective effects is found to vary with effect sizes between low and medium. The largest effect sizes were found in the area of sexual function and general HrQoL. Cross-cultural approaches and international collaboration were found in only one study. Additional studies are recom- mended to make a stratified comparison of patients, larger sample sizes to identify real changes in outcomes and long- term follow-ups need to be done in order to have sufficient information for evidence based clinical practice decisions. Future research should focus on developing condition spe- cific and sensitive assessments of the effect of POI based on the patient perspective. This can be achieved through focus groups with the aim of achieving a broader understanding of the outcome domains that are relevant to this population. Funding This study was funded by National Key R&D Projects: Inter- national Cooperation Research on Evaluation of the Effect of Acupunc- ture on Superiority Diseases (Grant Number 2017YFC1703600) and National 13th Five-Year Plan: Evaluation of the Effect of Acupuncture on Ovarian Function (Grant Number 2017YFC1703603). 33Quality of Life Research (2020) 29:19–36 1 3 Compliance with ethical standards Ethical approval We will report this review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. A submission to the ethics committee of the Clinical Basic Medicine Institute, China Academy of Chinese Medical Sciences con- sidered that an ethics review was not required (ref 2019/1). Open Access This article is distributed under the terms of the Crea- tive Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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