Health-related quality of life in adult Mediterranean women with polycystic ovary syndrome attending to a tertiary hospital: a case-control study.

Previous studies evaluating health-related quality of Life (HRQoL) in women with polycystic ovary syndrome (PCOS) present some methodological limitations. Moreover, differences in the HRQoL between different PCOS phenotypes have never been analyzed. Therefore, the aim of our study was to compare the HRQoL between women with PCOS and its phenotypes- and controls attending to a tertiary hospital. This is a case-control study carried out in the Department of Obstetrics and Gynecology at “ Virgen de la Arrixaca ” University Hospital (Murcia, Spain). A group of 117 women with PCOS and 153 controls were studied between 2014 and 2016. Controls were women without PCOS attending the gynecological outpatient clinic for routine examinations. Cases were women attending the same setting and diagnosed with PCOS. PCOS diagnose was performed following the Rotterdam Criteria and women were further classified by anovulatory or ovulatory phenotypic subtype. Women underwent physical and gynecological exams and completed health questionnaires including the Short Form-12v2. Eight scales and two component summary scores [Physical (PCS) and Mental (MCS), respectively] were calculated.


Conclusions
HRQoL was significantly decreased in adult Mediterranean women with PCOS and its anovulatory phenotype compared to controls attending the outpatient clinic of a tertiary hospital. These results may have implications for the clinical practice and suggest the need for specific interventions in women with PCOS.

Background
Polycystic ovary syndrome (PCOS) is one of the most common chronic endocrinopathies affecting between 5 and 10% of reproductive age women (National Institute of Health 2012). Clinical manifestations of this syndrome such as obesity, infertility, hirsutism, biochemical and hormonal disturbances has been widely described (Amiri et al. 2019). Yet, these symptoms are often related to a deterioration in the woman's self-esteem and selfimage and may affect their health-related quality of life (HRQoL), particularly in relationship with psychosocial domains (Barry et al. 2011;Afifi et al. 2017;Rzońca et al. 2018).
HRQoL is a multidimensional concept widely used in medical research, but its usage in routine medical practice is increasing. It is defined as "individual´s perception of their own life in the context of their cultures and believes, and their personal goals and concerns" (Skevington et al. 2004;AlJamal et al. 2018). Over the past years, there has been a growing tendency to incorporate assessment of HRQoL in clinical studies and routine clinical management of PCOS.
Consequently, several investigations conducted over the world have shown associations between HRQoL and the presence of PCOS (Coffey and Mason 2003;Hahn et al. 2005; Barnard et al. 2007;Li et al. 2011;Ozcan Dag et al. 2017;Rzońca et al. 2018;Amiri et al. 2019). Women with PCOS may be at a higher risk of low HRQoL (Elsenbruch et al. 2006;Veltman-verhulst et al. 2012;Bazarganipour et al. 2013Bazarganipour et al. , 2014Taghavi et al. 2015;Cooney et al. 2017). However, several of the previous studies have focused on series of cases or evaluated the effect of an intervention (lifestyle or medical treatments) on HRQoL of women with PCOS (Sarwer et al. 2013;Dokras et al. 2016) without adequate control. Therefore, the interpretation and generalization from these studies is challenging, due to relatively small sample sizes, heterogeneities between study populations, tools evaluating HRQoL, or the inadequate control of confounding. The impact of potential confounders such as age, body mass index (BMI), educational level or even professional activity upon HRQoL in PCOS women is uncertain as they may not have been properly evaluated (Aliasghari et al. 2017;Rzońca et al. 2018). Besides, there are differences in PCOS symptoms presented across geographical locations and between differing race or ethnic groups (Carmina et al. 1992;Wolf et al. 2018 Therefore, the goal of this work was to compare the HRQoL of adult Mediterranean women with PCOS -and its phenotypes-and controls. We hypothesize that women with PCOS, especially those with anovulatory phenotype, would show worse HRQoL compared to women without PCOS.

Study population
This was a case-control study conducted from September 2014 to May 2016 at the Department of Obstetrics and Gynecology of the University Clinical Hospital "Virgen de la Arrixaca" in the Murcia Region (southeastern Spain). The study conception and design have been previously described elsewhere (Sánchez-Ferrer et al. 2017). All women, aged from 18 to 40 years old, were excluded from the study if they: had endocrine disorders (e.g. Cushing's syndrome, congenital adrenal hyperplasia, androgen-secreting tumors, hyperprolactinemia and hyper-and hypothyroidism) or were taking any hormonal medication (including contraception) during the 3 months prior to the study; were pregnant or lactating; had been exposed to oncological treatment; or had genitourinary prolapse. Cases (n = 117) were women attending the gynecology unit of the hospital, and included newly diagnosed cases as well as prevalent ones. Diagnosis of PCOS was established following the Rotterdam criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004) which included a complete medical history with a modified Ferriman-Galwey (mF-G) score (Ferriman and Gallwey 1961), transvaginal ultrasound (TVUS) and serum sexual hormones. Diagnosis of PCOS required completion of at least two of the following three criteria: (i) hyperandrogenism either biochemical (total testosterone level ≥ 2.6 nmol/l) or clinical (mF-G score ≥ 12) (Afifi et al. 2017) with or without acne or androgenic alopecia; (ii) oligo-and/or anovulation (menstrual cycles > 35 days or amenorrhea > 3 months); (iii) polycystic ovarian morphology (POM) on TVUS (≥ 12 follicles measuring 2-9 mm in diameter, mean of both ovaries) (Conway et al. 2014).
On the other hand, controls (n = 153) were women without PCOS (or other major gynecological conditions, e.g. endometriosis) attending the gynecological outpatient clinic for routine gynecological exams. The same procedures were performed in both cases and controls: anamnesis and questionnaires, physical examination including weight and height measured using a digital scale (Tanita SC 330-S, Amsterdam, The Netherlands). Uterine and ovarian morphology were evaluated with TVUS with Voluson E8® and 4-9 MHz transducer (General Electric Healthcare, USA) and blood draw between days 2.5 of the menstrual cycle. Written informed consent was obtained from all subjects. This study was Health-related quality of life measurement The Short Form (SF)-12v2 Health Survey is a validated shorter version of the SF-36 generic questionnaire that encompasses 12 items, evaluating physical and mental health from the participant's point of view (4 weeks recall period) (Ware J Jr et al. 1996;Gandek et al. 1998;Razavi and Gandek 1998;Vilagut et al. 2008). The questionnaire generates eight scales: physical functioning, role physical, bodily pain, general health, role emotional, vitality, social functioning and mental health. All raw scale scores were converted to a 0-100 scale, with higher scores representing higher levels of HRQoL. Additionally, the subscales were also transformed to normative-based scores according to the SF-12v2 recommendations to give a mean of 50 and a standard deviation of 10, using a representative sample of the 1998 US general population (Ware J Jr et al. 1996;Gandek et al. 1998;Razavi and Gandek 1998). This transformation allows to obtain two summary measures: Physical and Mental Component Summary (PCS and MCS, respectively) that may be directly compared with other scales and scores. As the mean score is set to 50, scores ≥50 or < 50 indicate better or worse physical or mental health than the 1998 US general population. Scores bounds are set at 48 (0.2 SD) for a small effect on HRQoL, 45 (0.5 SD) for a moderate influence and, f ≤42 (0.8 SD) for a large effect on HRQoL (Cohen 1988;Contopoulos-Ioannidis et al. 2009).

Statistical analyses
Descriptive statistics are presented using raw data. Continuous variables were compared using unpaired Student T tests, and categorical variables with chi-squared. Analysis of covariance was employed to calculate adjusted crude (0-100) and norm-based scales and component summaries differences between cases and controls. Multiple logistic regression was used to explore associations between cases and controls and norm-based scales and summary measures' score with a cut-off of above/below 50 using odds ratios (OR) and 95% confidence intervals (95%CI). In both cases, several relevant covariates were considered (age, BMI, infertility problems, educational level and current employment) as potential confounders. From previous publications, we aimed to detect a difference of at least 3 points (with a standard deviation of about 7 points) in the global scores (PCS or MCS) between cases and controls. For an of alpha error of 0.05 and 80% statistical power to detect differences, a minimum of 90 women would be required in each group. All tests were two-tailed at 0.05 significance level. Analyses were conducted with IBM SPSS 25.0 (IBM Corporation, Armonk, New York, USA).

Results
Overall, PCOS women were younger, had higher BMI, more infertility problems, and showed lower educational and current occupation level than controls. Regarding marital status and other lifestyle factors both groups were comparable (Table 1).        Mean score is set to 50, therefore scores ≥50 or < 50 indicate better or worse physical or mental health than the mean US population, respectively. a T-student test was use.

Discussion
HRQoL of women with PCOS -and especially, anovulatory PCOS-was significantly decreased compared to controls. Overall, these results suggest that PCOS may play an important role and have a potential effect on HRQoL in these Mediterranean women. To the best of our knowledge, this is the first study evaluating phenotypic subtypes of PCOS in relation to HRQoL.
It is known that PCOS have a significant negative impact on women's HRQoL. Several authors have reported that PCOS women show worse HRQoL compared to women without the disorder (Coffey and Mason 2003;Hahn et al. 2005;Barnard et al. 2007;Li et al. 2011). Moreover, problems with sexual satisfaction and increased psychological disturbances have been reported as well (Hahn et al. 2005). A recent meta-analysis concluded that having PCOS significantly reduced HRQoL in adolescent girls (Kaczmarek et al. 2016).
In our study, patients with PCOS had significantly lower scores in several subscales and in the PCS, which is somewhat consistent with the previously published literature on the matter (Benson et al. 2009;Ozcan Dag et al. 2017;Panico et al. 2017). Benson et al. (2009) carried out a nation-wide survey in Germany using the SF-12 scale in a cohort of women with PCOS and observed that women with PCOS were at higher risk of common psychiatric disorders such as anxiety, depression or both, and that these disorders were related to lower HRQoL in these women (Benson et al. 2009 Dag et al. 2017) in both PCS and MCS (Shishehgar et al. 2016). Lastly, Panico et al. (2017) reported worse HRQoL in women with PCOS compared to controls in the subscales of vitality and role emotional, although no differences for body pain were found, using the SF-36 questionnaire. However, they also reported significant differences regarding mental health and social and physical functioning, which were not found in our study population. On the other hand, changes in role physical and general health found in our study population were not observed by Panico et al. (2017). The discrepancies between those findings and our study might be attributed to differences in the results that are reported in the studies. In those studies only crude results are shown, and no further adjustments are made by potential confounders such as BMI, age, current occupation or educational level. An alternative explanation, though unlikely explanation that would require further study, might be that there are true specific differences in the HRQoL of PCOS women in Southern Spain.
In a meta-analysis of Li et al. (2011), five studies using SF-36 were included to evaluate the impact of PCOS on specific HRQoL domains. They concluded that women with PCOS obtained lower scores in all the analysed domains compared to controls and that the most affected one was the emotional role. These findings are in agreement with ours, since the emotional role domain was one of most affected one in both, cases and controls.
It is important to bear in mind that our participants were enrolled in a tertiary care center, therefore results may vary from other kind of populations (secondary care, patient's associations, etc.

Conclusions
Our results support the hypothesis that HRQoL is significantly decreased in adult Mediterranean women with PCOS and its anovulatory phenotype compared to controls. If confirmed, these results may have important implications for prevention, clinical practice and intervention in women with this condition. PCOS is a chronic and highly prevalent disorder in reproductive age women, therefore it may be important to assess HRQoL as a way of measuring their progression alongside the treatment in a follow-up.

Abbreviations
Body mass index (BMI)

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. substantial intellectual contributions and approved the final version of the manuscript.  SuppTable1.PNG