Evaluation the Impact of Prescribed Metformin on Health-related quality of Life: A Cross- sectional Study

doi:10.21203/rs.3.rs-2820500/v1

Introduction: Metformin is commonly prescribed to manage polycystic ovary syndrome (PCOS), which is one of the most common endocrine disorders among women of reproductive age, and is associated with high prevalence rates of psychiatric disorders.

This study’s objective was to determine the impact of metformin on psychosocial wellbeing in terms of mental health issues which affect the QoL among Iranian women with PCOS.

Materials and Method: The present cross-sectional study was carried out on 400 patients diagnosed with PCOS and equally divided 200 respondents into with metformin group and remaining 200 respondents into without metformin group. All participants were asked to fill out the valid and reliable questionnaires of FSFI (Female Sexual Function Index), HADS (Hospital Depression and Anxiety Scale) and SF-12.

Results: There were statistically significant difference between without metformin and with metformin in terms of arousal, lubrication, pain and total FSFI score. There were statistically significant difference between the mean score of MCS, anxiety and depression in without metformin and with metformin (P<0.001).

Conclusion: Metformin may have a role in the management of psychosocial wellbeing among patient with PCOS; however, its potential effects should be further examined in randomized double-blind placebo-controlled clinical trials.

Metformin

Polycystic ovary syndrome

Anxiety

Depression

Sexual function

quality of life

Polycystic Ovarian Syndrome (PCOS) is a hetrogenous condition associated with metabolic syndrome-related or hormone-driven clininical symptoms which increases risk of developing other health complications. Often women diagnosed with PCOS are emotionally distressed causing a decrease in their quality of life (QoL)(1).

Health can be defined as a state of complete physical, mental and social well-being and not merely the absence of disease or infimity and living with clinical features of PCOS clearly has an impact on the patient overall welbeing that will certainly be negatively affected not merely by physical but also by psychology and social as well(2). These psychosocial wellbeing complications can arise due to mental health issues such as anxiety, depression, and sexual function.

several studies have investigated a link between reduced quality of life, body age concern and sexual dissatisfaction and PCO (3-6), as well as a high degree of occurance of depressive state (7), and when an adequate treatment improved all such features, quality of life and well-being improved again (8). Interestingly, such a positive effect was observed under metformin administration. Metformin is the most thoroughly investigated insulin-lowering agent used to treat PCOS. It enhances insulin sensitivity in the liver, where it inhibits hepatic glucose production and in muscle, where it improves glucose uptake and use (9).

Metformin is an established treatment of polycystic ovary syndrom (PCOS). It appears to have multiple favorable effects on menstural disorders, anovulation, hyperandrogenism, and, particularly, on metabolic and cardiovascular abnormalities in this population (10,11).

It is to be noted that in a study using metformin for PCOS, some interesting associations were observed between clinical treatment effects and psychosocial improvements, which suggest that some of the effects may be related to the clinical effects of the drug (12).

In current setting, metformin is commonly prescribed among PCOS women in accordance with evidence based assessment and its use is usually determined on a case-by-case basis in Iranian PCOS patients.

Even though there are many other factors that affect the QoL, this study focuses only on monitoring the influences of pharmaceutical care intervention, specifically metformin towards the psychosocial wellbeing in terms of mental health issues such as anxiety, depression, self-esteem and social anxiety. Overall this affects the QoL in PCOS patients.

A cross sectional survey was conducted over a period of nine months and a pilot study was conducted in advance. The study recruited 400 patients diagnosed with PCOS and equally divided 200 respondents in to with metformin group (the minimum duration of use was 6 months) and remaining 200 respondents into without metformin group, based on noting their existing pharmacotherapy for PCOS management.

Then, using the appropriate formula with α set at 0.05 and 1-β at 0.95, a sample size of 187 women was found to be required for each group. The independent variable of this study is the drug metformin. Whereas the dependent variables are the psychosocial wellbeing in terms of mental health issues of anxiety, depression, quality of life, and sexual function. This study evaluated the association of independent variable and all the dependent variables in both groups.

Upon approval of the Medical Ethics Committee of Tabiat Modares University (IR.TUMS.MEDICINE.REC.1398.834), the study was performed on 400 sexually active participants aged (18–40 years). The study group included women with PCOS referred to an infertility clinic in Arash Hospital in Tehran Province, Iran from May 2019 to February 2020.

The inclusion criteria were as follows: aged 18–40 years, married, non-pregnant, Iranian race, giving personal consent to enter the study, and PCOS diagnosed by gynecologist based on Rotterdam criteria (13, 14). Completion of primary school as the minimum level of education and no medication with hormones known to influence serum androgen levels, including anti-androgenic drugs and oral contraceptive pills during three months before the study were required. Those participants who were not eligible for the study such as patients with thyroid dysfunction, abnormal prolactin levels, congenital adrenal hyperplasia (CAH), Cushing’s syndrome (CS), androgen-secreting tumors, and diagnosed cardiovascular disease (CVD), as well as those taking oral contraceptives and anti-androgenic drugs were excluded from this study.

Questionnaires

The participants were asked to complete several self-report questionnaires, as follows: Demographic survey that included the age of the participants, their educational levels, occupational status, body mass index (BMI), infertility status, and medical history.

FSFI

Female Sexual Function Index (FSFI) questionnaire is a validated test that evaluates all phases of the female sexual cycle in the past four weeks. The questionnaire consists of 19 items divided into six subscales (domains): sexual desire, sexual arousal, lubrication, orgasm, sexual satisfaction, and dyspareunia. Each item is rated on a scale from 0 to 5 or from 1 to 5, where 0 indicates no sexual activity in the past month. Scores for each of the six domains are calculated by summing up individual domain question scores and multiplying the result by the domain factor (i.e., 0.6 for desire, 0.3 for arousal and lubrication, and 0.4 for orgasm, satisfaction, and pain). The minimum possible score to achieve is 2 and the maximum is 36. A higher score in each domain indicates a better status (15). The reliability and validity of this questionnaire have been confirmed in Iran (16).

Quality Of Life (Qol)

The Short Form Health Survey (SF-12) includes 12 questions related to eight dimensions (sexual performance, physical role, physical pain, general health, energy and vitality, social performance, emotional role, and mental health), which in divided into two subscales of physical and mental health. The greatest score obtained for each section or subscale is 100 and the least score is zero with a higher score indicating a better health status (17). The validity and reliability of this questionnaire have previously been confired in Iran (18).

Anxiety And Depression

The Hospital Anxiety and Depression Scale (HADS) is used to assess depression and anxiety. The instrument has two subscales including anxiety (HADS-A) and depression (HADS-D). It is a self-administered instrument consisting of 14 questions. The instrument has two subscales including anxiety (seven items) and depression (seven items). All items are rated from 0 to 3. Sum scores < 8 indicate normal range, scores 8–10 reflect mild alterations and scores ≥ 11 indicate clinical relevance of symptoms (19). A study on the Persian version of the HADS has shown that this scale has satisfactory reliability and validity for measuring psychological symptoms in Iranian patients (20).

Statistics

Normal and non-normal quantitative variables were reported as Mean ± Standard Deviation (SD). Qualitative variables were presented as number (percentage). Primarily, the quantitative variables were checked for normality using Kolmogorov–Smirnoff’s (KS) test. One-way ANOVA was applied for the normal variables and Kruskal-Wallis (KW) test was used for the non-normal and ordinal variables. Also, to examine the relashionship between anxiety and depression with independent variables (quantitative and qualitative variables), binary logistic regression (cut-off point 11) was used. In this study, considering the cut-off point of 11 in terms of anxiety and depression, the participants were divided into appropriate (< 11) and inappropriate groups ( > = 11), and anxiety and depression were considered as two state dependent variable. Considering this state, Binary logestic regression was used to control confounder variables and simultaneously examine the independent variablels. Also, to examine the relashionship between sexual function and independent variables (quantitative and qualitative variables), binary logistic regression (cut-off point 28) was used. In this study, considering the cut-off point of 28 in term of sexual function, the participants were divided into appropriate ( > = 28) and inappropriate groups (< 28), and sexual function was considered as two state dependent variable. Considering this state, Binary logestic regression was used to control confounder variables and simultaneously examine the independent variablels. Regression logistic coefficient was calculated. Statistical significance was set at P < 0.05. The obtained data were analyzed by the SPSS software (Statistical Package for the Social Sciences, version 22.0, SPSS Inc., Chicago, IL, USA). Confounding variables (age, BMI, education, occupation, infertility state) that may affect sexual function and QoL in wmen were selected according to previous studies (21–30).

As shown in table 1, there were statistically significant differences among the groups in characteristics of age, BMI, occupation status, educational level and infertility status (P<0.05).

Sexual function status

The evaluation of FSFI scores and comparison of sexual dysfunction are shown in Table 2. As can be seen, there were statistically significant difference between without metformin and with metformin in terms of arousal, lubrication, pain and total FSFI score. Although the difference did not reach statistical significance in terms of desire, orgasm and satisfaction, metformin use group had the highest scores on all domains

The prevalence of sexual dysfunction in the women without metformin were significantly higher than the with metformin (P <0.001)

Quality of life status

As shown in Table 3, there was statistically significant difference between the mean score of MCS in without metformin and with metformin (P<0.001).

There was no statistically significant difference between without metformin and with metformin in PCS (P=0.085).

Anxiety and depression

It can be seen from the data in Table 3, there were statistically significant difference between the mean score of anxiety and depression in without metformin and with metformin (P<0.001).

As shown in table 4, after adjusting for age, education, occupation, BMI and infertility, logistic regression analysis showed that sexual dysfunction in metformin with group 1.7 times lower than metformin without group. In metformin group, after adjusting for confounding variables, sexual dysfunction in the arousal, satisfaction, and pain domain were significantly lower compared to without metformin group.

Also, as can be seen, in depression score, statistically significant difference between without and with metformin observed, but after controlling for depression score, age, education, occupation, BMI and infertility status, this difference was not significant. On the other hand, the odds of having anxiety score >=11, which indicates generalized anxiety disorder, was 1.43 times lower among women in the metformin group than their counterparts after controlling for anxiety score, age, education, occupation, BMI and infertility status ( OR=1.435, 95%CI, 2.591, 6.805: P<0.001 ).

PCOS is diagnosed when a group of symptoms consistently occur together as a result of hormonal imbalance such as obesity, anovulation leading to multiple cysts in the ovaries, infertility, increased peripheral estrogen that gets converted to androgen leading to hirsutism, metabolic derangements like insulin resistance, and dyslipidemia leading to coronary artery disease (31). It is one of the most common causes of female infertility (32). Studies were directing insulin resistance and hyperandrogenism as the underlying cause of PCOS- induced depression, as hyperandrogenism can lead to stigmatizing symptoms in these women and decrease their quality of life, which in turn leads to a depression mood (33).

This study conducted to evaloution the impact of prescrrbed metformin on health-related quality of Life, emotional distress and sexuality.

Anxiety, depression and quality of life (QoL):

We found statistically significant difference between without metformin and with metformin in anxiety score, even after controlling for anxiety score, age, education, occupation, BMI, and infertility

In depression score, as well as, statistically significant difference between without and with metformin observed, but after controlling for depression score, age, education, occupation, BMI and infertility status, this difference was not significant.

Numerous studies have confirmed the effectiveness of PCOS on psychological features like soaring anxiety, depression (34), and worsening of QoL (35).

It has been reported that the prominent symptoms such as obesity, infertility, acne, and hirsutism cause mental stress might be responsible for the higher prevalence of psychiatric disorders among PCOS women.(36) Also, it has been suggested that the hyperinsulinemia can be responsible for psychiatric illnesses in this group of patients because of insulin resistance and obesity (37,38).

Metformin is recommended as one of treatment option in PCOS women, especially for those who present obesity, hyperandrogenism, insulin resistance or hyperinsulinemia (39).

As per the literature, the effectiveness of metformin has emerged as a subject of great interest in the 21st century.

Several studies have investigated the antidepressant or anxiolytic effects of metformin among women with PCOS.

Habib Erensoy et al (40) examined the effects of metformin on insulin resistance and mood including in adolescent and adult women with PCOS, and found that metformin decrease IR and improve mood both in adolescent and adult women with PCOS.

In the cohort study, Fatimah AlHussain et al (41) examined the impact of prescribed metformin on the depression and anxiety and QoL of women with PCOS and observed the women on metformin had 70%lower odds of having major depression, however, no significant effect of anxiety was found.

Also, Manvikram Sing et al (42) found except for self-esteem, significant difference in anxiety, depression, social anxiety and QoL are observed in comparison without metformin group and with metformin group QoL was 5.4176 times better than without metformin group QoL.

Metformin was also found to improve the psychosocial aspects of HRQoL among women with PCOS. Hang results showed significant effects of metformin on HRQoL of PCOS patient, especially in overweight and hyperandrogenic patient (43). However we did not find a correlation between the change in HRQoL score and weight change.

As well as, It has been determined in this study, in the SF-12 questionnaire, in MCS domain, statistically significant difference between without and with metformin observed, which corresponded to the study of Han et al. Hahn et al (12) have found metformin improve the psychosocial aspects of HRQoL after six month of treatment. He reported metformin treatment, HRQoL, particularly the psychosocial aspects (indicated by significant increase in SF-36 scales Vitality, Social Function, Emotional Role Function, Mental Health, Psychological Sum scale improved. These improvements in HRQL were significantly correlated with a reduction in body weight and significantly more pronounced in patients with normalized menstrual cycles. Additionally, recent studies have also supported these outcomes by indicating the consistent efficacy of this drug treatment (8, 44).

However, not all of the results of these studies are in agreement. Moll E et al (45), reported the HRQoL scores of patients with PCOS receiving clomiphene plus metformin were significantly lower than the scores for those receiving plus a placebo; this difference was attributable primarily to the higher incidence of gastrointestinal side effects among the patients on metformin. As well as Kashani et al (46), in a randomized controlled trial, assessed the efficacy of two insulin sensitizers (metformin and pioglitazone) in depressed obese patients with PCOS, reported that piglitazone resulted in a significantly better improvement in depression after six weeks of follow-up than metformin.

The possible meaning of the positive correlation between metformin use and HRQoL might be linked to the effect of metformin on improve insulin-sensitizing activity, insulin resistance, which is common among PCOS women and lowering the insulin level is associated with a reduction in free testosterone and androstandione. As well as metformin reduces hepatic production of glucose thereby decreasing the release of free fatty acids.

Sexual dysfunction

Sexual functioning and response in women is a complicated psychobiosocial phenomenon and is affected by multiple factors. In PCOS women, the factors affecting sexual functioning include, infertility, deranged hormone levels especially androgens, obesity, and associated problems like metabolic syndrome, body image issues, and low self-esteem (47). Sexual dysfunction (SD) is one of the common and curable problems that contribute to emotional stresses and marital problems (48).

In evaluation of FSFI scores and comparison of sexual dysfunction we observed, there were statistically significant difference between without metformin and with metformin in terms of arousal, lubrication, pain and total FSFI score. Although the difference did not reach statistical significance in terms of desire, satisfaction and orgasm, metformin use group had higher scores than without metformin group. Sexual function is a debated issue in PCOS patients. On the one hand the presence of hirsutism and other signs of hypreandrogenemia and infertility are a potential source of distress and low self-esteem. Similar to other studies (12, 49), metformin treatment has beneficial effects on sexual function in our study population. The possible reason for this could be related to the effect of metformin on body weight (50), menstrual cycle and androgen levels (51, 52). We however did not find a correlation between the change in FSFI score and weight change, change in androgen levels or change in length of menstrual cycle. The results for domains desire, satisfaction and orgasm however are not statistical significant probably because of the small number of patients.

The present findings revealed that metformin has a positive impact in enhancing mental health issues of psychosocial wellbeing hence positively affecting the QoL of Iranian women.

Of the strengths of the present study, this study is one of the first attempts to thoroughly perceive the impact of metformin treatment on psychosocial wellbeing in terms of mental health issues which affects the QoL among Iranian women. Moreover, it provided an important opportunity to advance the understanding of the requirement of specific mental health screening for these women. As well as, the effects of metformin on multiple variable- anxiety, depression, HQRoL, and sexual function- were analyzed. However, this study had some limitations. First, it was conducted in a tertiary center. Secondly, Information on the dosage of the drug was taken from the participants. Since this information was self-reported and we could not validate whether the patients were prescribed the same dosage, we removed the dosage variable from the analysis. Thirdly, our results were based on patients reporting of HRQoL outcomes, and thus, self- reporting bias could not be avoided. Finally, this study did not include objective measures (e.g., pregnancy rate) as indicators for metformin treatment. So, improvement in subjective outcomes (e.g. HRQoL) may not be explained as the result of changes in objective measures of clinical outcomes.

We suggest multi-center investigations with more in-depth and longitudinal research on the long-term effects of the drug and compliance among women with PCOS.

Despite the deficiency of this study, the collected data suggest that metformin treatment improves the mental well-being of patients with PCOS. The current findings support the notion that all patients with PCOS should undergo psychological screening and receive appropriate interventions whenever required. Finally, future studies should verify the findings of this study using more robust study designs, such as randomized double-blind placebo-controlled clinical trials.

FSFI: Female Sexual Function Index

HADS: Hospital Anxiety and Depression Scale

PCOS: Polycystic Ovary Syndrome

SF-12: Short Form Health Survey

BMI: Body Mass Index

QoL: Quality of Life

FSD: Female Sexual Dysfunction

IR: Insulin Resistance

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Tarbiat Modares University of Medical Sciences (IR.TUMS.MEDICINE.REC.1398.834). All procedures were in accordance with the ethical standards of the Regional Research Committee and with the Declaration of Helsinki 1964 and its later amendments. After explaining the study's purposes, the informed consent was collected from all participants and they were informed that their participation was voluntary, confidential, and anonymous. Furthermore, they were apprised of their right to withdraw from the research at any time.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no conflict of interest.

Funding

None

Authors' contributions

Sh.JS and F.B contributed to the conception and design of the study; Sh.JS and F.B did the literature search; M.N, A.M, and F.B performed the statistical analysis; Sh.JS, F.B, A.M, A.M and M.N wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Acknowledgments

This study was carried out with the kind collaboration of the participants. It is a part of research work done in Tarbiat Modares University, Tehran, Iran. There were no conflicts of interest.

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Table 1: Comparison demographic characteristics between without metformin, with metformin

Variable	Without Metformin n =200	With Metformine n=200	P-value
Age (year)*	30.61+5.40	34.00+4.215	<.0.001
BMI (Kg/m²⁾)*	26.36+4.00	27.01+3.15	0.021
Occupation status**			0.004
Housewife	180 (90%)	151 (75.5%)
Employed	20 (10%)	49 (24.5%)
Educational level**			0.015
Primary	49 (24.5%)	15(7.5%)
Secondary	74 (37%)	81 (40.5%)
Higher	77 (38.5)	104 (52%)
Infertility Status**			<0.001
Yes	164(82%)	174(87)
No	36(18%)	26(13)

HA: Hyperandrogenism, OD: Ovulatory Dysfunction, PCOM: Polycystic Ovarian Morphology BMI: Body Mass Index. WHR: Waist Hip Circumference Ratio, PCOS: Polycystic Ovary Syndrome

* Values are given as mean ± SD using Kruskal-Wallis test.

** Values are given as number (%) by using Chi-square test.

Table 2: Comparison of FSFI scores and dysfunction between without metformin and with metformin

Variable	Without Metformin n =200	With Metformin n =200	P-value
Desire	3.69+.841	3.74+.766	0 .828
Arousal	3.94+.97	4.56+.866	<0.001
Lubrication	4.69+.956	4.92+.908	0.012
Orgasm	4.50+1.005	4.70+.937	0.065
Satisfaction	4.78+1.041	4.84+.934	0 .883
Pain	3.12+1.099	4.75+1.151	<0.001
Total FSFI	24.75+3.827	27.52+3.442	<0.001
Dysfunction			<0.001
Yes	157(78.5)	117(58.5)
No	43(21.5)	83(41.5)

Table 3: Sum scores and total scores for domain subgroups of QoL and HADS, between without metformin, and with metformin

Variable	Without Metformin n =200	With Metformin n=200	P-value
Anxiety	10.68±3.91	8.36±3.84	<0.001
Depression	6.76±3.720	5.09± 3.79	<0.001
MCS	40.98±9.79	48.67±9.00	<0.001
PCS	44.25±7.42	45.34 ±7.67	0.085

Table 4: Logistic regression analyses for association between treatment with metformin and scores on Hospital Anxiety and Depression Scales (HADS) and scores of FSFI

Variable	P-value	Odds-Ratio	95%Confidence Interval
Variable	P-value	Odds-Ratio	Lower	Upper
Anxiety	<0.001	1.435	2.591	6.805
Depression	0.091	0.563	0.914	3.373
Desire	0.954	0.015	0.596	1.628
Arousal	0.004	0.714	1.263	3.298
Orgasm	0.093	0.442	0.930	2.605
Lubrication	0.530	0.184	0.677	2.137
Satisfaction	0.014	0.755	1.163	3.895
Pain	<0.001	2.568	7.691	22.102
Total. Score	<0.001	1.693	3.202	9.228

Adjusted to age, education, occupation, BMI, infertility

No competing interests reported.

Evaluation the Impact of Prescribed Metformin on Health-related quality of Life: A Cross- sectional Study

Status:

Version 1

Abstract

Introduction

Materials And Methods

Questionnaires

FSFI

Quality Of Life (Qol)

Anxiety And Depression

Statistics

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1