INTRODUCTIONSexual dysfunctions (SD), which has traditionally included disorders of interest or desire, arousal, and inhibited orgasm, are a complex process and highly prevalent disorders for female and male in worldwide. It was suggested that the prevalence of new female sexual difficulty is 36% at 12-month follow-up.1Smith AM Lyons A Ferris JA et al.Incidence and persistence/recurrence of women's sexual difficulties: findings from the Australian Longitudinal Study of Health and Relationships. The incidence of ED, a common type of male SD, was observed in 31.7% of eligible men at a 5-year follow-up.2Martin SA Atlantis E Lange K et al.Predictors of sexual dysfunction incidence and remission in men. Epidemiologic researches have shown that endocrine disease, age, cardiovascular disease, urinary tract infections, chronic health problems, and general health play a key role in the development of female and male SD.3McCabe MP Sharlip ID Lewis R et al.Risk factors for sexual dysfunction among women and men: a consensus statement from the fourth International Consultation on Sexual Medicine 2015. However, the exact role of the endocrine disease is still not completely unclear. Recent studies have shown that hypothyroidism was associated with sexual health in both women and men.4Corona G Isidori AM Aversa A et al.Endocrinologic control of men's sexual desire and arousal/erection.,5Krysiak R Szkrobka W Okopien B. Sexual function and depressive symptoms in young women with hypothyroidism receiving levothyroxine/liothyronine combination therapy: a pilot study.Hypothyroidism can be separated into overt or subclinical based on its severity. Overt hypothyroidism is a common and multifactorial clinical disorder associated with numerous diseases and aging due to the elevated pituitary thyrotropin (TSH) concentrations and low level of free triiodothyronine (FT3) and free thyroxine/tetraiodothyronine (FT4),6Thyroid hormone therapy for hypothyroidism. while subclinical hypothyroidism is defined by low levels of TSH with normal FT4 and FT3 concentrations.7Effect of subclinical hyperthyroidism on osteoporosis: a meta-analysis of cohort studies. According to the U.S. National Health and Nutrition Examination Survey III, the prevalence of hypothyroidism was 4.6% (0.3% of overt and 4.3% of subclinical). Hypothyroidism was found to affect more women than men (ratio: 5–8: 1).8Garmendia MA Santos PS Guillen-Grima F et al.The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. A common cause of hypothyroidism is iodine deficiency. While in iodine-sufficient populations, chronic autoimmune thyroiditis (Hashimoto thyroiditis) is the most common etiological factor of hypothyroidism.9The epidemiology of thyroid disease. Undiagnosed or untreated hypothyroidism potentially has profound adverse effects that is, weight gain, fatigue, constipation, cold intolerance, and menstrual irregularities.10Song E Ahn J Oh HS et al.Sex-dependent association between weight change and thyroid dysfunction: population-level analysis using the Korean National Health and nutrition examination survey.,11Chaker L Bianco AC Jonklaas J et al.Hypothyroidism also has been associated with uterine hyperplasia and inflammation, a low fertility potential of females and reduction of steroidogenesis and spermatogenesis in males.12Aiceles V Gombar F Da FRC. Hormonal and testicular changes in rats submitted to congenital hypothyroidism in early life.,13Rodriguez-Castelan J Del MA Pina-Medina AG et al.Hypothyroidism induces uterine hyperplasia and inflammation related to sex hormone receptors expression in virgin rabbits. Besides, over the last decade, accumulating evidence has emerged showing that patients with hypothyroidism are more likely to have SD in both sexes.14Gabrielson AT Sartor RA Hellstrom W. The impact of thyroid disease on sexual dysfunction in men and women. Carani et al15Carani C Isidori AM Granata A et al.Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. reported that men with hypothyroidism are more inclined to suffer from SD than the healthy controls, such as hypoactive sexual desire (64.3% vs 17.6%), delayed ejaculation (DE) (64.3% vs 2.9%), and erectile dysfunction (ED) (64.3% vs 14.7%). Similarly, Nikoobakht et al16Nikoobakht MR Aloosh M Nikoobakht N et al.The role of hypothyroidism in male infertility and erectile dysfunction. found that the International Index of Erectile Function score in male with hypothyroidism was significantly decreased. For female subjects, Oppo et al17Oppo A Franceschi E Atzeni F et al.Effects of hyperthyroidism, hypothyroidism, and thyroid autoimmunity on female sexual function. suggested that all female sexual function index (FSFI) domains scores were significantly reduced in hypothyroidism women. Of note, with the restoration of the euthyroid state, a significant improvement in FSFI domain scores in women and erectile function in men when the restoration of the euthyroid state was achieved.17Oppo A Franceschi E Atzeni F et al.Effects of hyperthyroidism, hypothyroidism, and thyroid autoimmunity on female sexual function.,18Krassas GE Tziomalos K Papadopoulou F et al.Erectile dysfunction in patients with hyper- and hypothyroidism: how common and should we treat?.Despite the results of some studies indicating hypothyroidism may have an adverse effect on female and male sexual functioning, the association between hypothyroidism and the risk of SD remains controversial. Corona et al19Corona G Wu FC Forti G et al.Thyroid hormones and male sexual function. found that there was no association between hypothyroidism and erectile function after adjusting for potential confounders. Data from Bates et al20Bates JN Kohn TP Pastuszak AW. Effect of thyroid hormone derangements on sexual function in men and women. revealed that the impact of subclinical hypothyroidism on sexual functioning was less clear. As a result, we speculate that there may be a positive association between overt hypothyroidism and risk of SD, while no link is presented in subclinical hypothyroidism and SD. In this study, we have reviewed all of the relevant studies and subsequently conducted the quantified results via a meta-analysis so that to answer the above scientific questions.METHODSThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to conduct this systematic review and meta-analysis (Supplementary Table 1). Besides, we have registered this meta-analysis on the PROSPERO (ID: CRD42020186967, http://www.crd.york.ac.uk/PROSPERO). Data Sources and Search strategy

A comprehensive systematic literature search of the potential related studies was employed in MEDLINE (PubMed), EMBASE (OVID), Cochrane Library, and the PsychINFO databases from inception to May 2020. The searching was limited to the English language and human subjects. To identify the eligible studies, we used the keyword searching in the PubMed database, and the searching strategy is: (((((("Erectile Dysfunction"[Mesh]) OR sexual function) OR sexual dysfunction) OR "Sexual Dysfunctions, Psychological"[Mesh]) OR "Sexual Dysfunction, Physiological"[Mesh]) OR Impotence) AND ((((((((((("Hypothyroidism"[Mesh]) OR (Hypothyroidisms)) OR (Primary Hypothyroidism)) OR (Hypothyroidism, Primary)) OR (Primary Hypothyroidisms)) OR (Secondary Hypothyroidism)) OR (Hypothyroidism, Secondary)) OR (Secondary Hypothyroidisms)) OR (Central Hypothyroidism)) OR (Central Hypothyroidisms)) OR (Hypothyroidism, Central)). Besides, we also attempted to detect additional potential studies by manual inspection of the reference lists of the related studies.

 Assessments of Hypothyroidism and SD

Definitions of overt hypothyroidism, subclinical hypothyroidism, and SD were according to the international classification of diseases codes (ICDs). The diagnosis of overt hypothyroidism was generally followed by increasing serum concentration of TSH and reducing concentrations of FT3 and FT4, while subclinical hypothyroidism was confirmed by elevated serum TSH concentrations and normal free thyroid hormone levels. SD is diagnosed by the common use methods of the validated instruments, such as the International Index of Erectile Function-5 and International Index of Erectile Function-15 for men and FSFI for women.

 Study Selection Inclusion

Any studies reporting the prevalence of SD in patients with overt/subclinical hypothyroidism along with a normal control group were potentially considered eligible. The inclusion criteria were followed by the Patient, Intervention, Comparison, Outcome, and Study design (PICOS) evidence. The scientific question guiding for the present study was: whether patients with overt hypothyroidism or/and subclinical hypothyroidism have a significantly higher risk of SD than the healthy control group? The components for the PICOS evidence in this study was: male or female subjects with SD or sexual disorders (P); a history of overt/subclinical hypothyroidism (I); compared with the healthy normal men or women (C); the diagnosis of SD (O); any study designs were accepted (S). Furthermore, any studies reporting the relative risk (RR), hazard ratio (HR), or odds ratios (OR) with its 95% confidence intervals (CI) or providing sufficient data to calculate these effect sizes were also included. Though subclinical hypothyroidism is not considered to be “clinical hypothyroidism” condition due to those sufferers were asymptomatic or mild symptoms, we also investigated the association between subclinical hypothyroidism and SD because of its high prevalence around the world. It has clinical significance to better illuminate this issue.

 Exclusion

The exclusion criteria in the current study were: (i) those studies failed to provide the data of the normal control group; (ii) the study type was case report, review, editorial, and comment, etc.; (iii) previous publications or the duplicated data of the same clinical trials; (iv) animal experiments.

 Data Extraction

Two investigators independently assessed the eligibility of the potential studies and extracted the following relevant data based on a standardized data collection form, including the first author's name, the year of publication, study regions, study design, gender, age of the patients, the number of SD in the study group and the control group, ascertainment of overt hypothyroidism and subclinical hypothyroidism, assessment of SD, type of SD.

 Quality Assessment

The cross-sectional study quality methodology checklist was conducted to rate the methodological quality of the eligible cross-sectional studies, which contained 11 items and the conformity gained with 1 star (low quality = 0–3 stars, moderate quality = 4–7 stars, high quality = 8–11 stars). The Newcastle-Ottawa Quality Assessment Scale (NOS) for the case-control studies and the cohort studies was employed to evaluate the methodological quality of these studies. This scale includes 9 domains and the conformity is assigned with 1 score, while the score of 0–3, 4–6, and 7–9 was considered to the low quality, moderate quality, and high quality, respectively. Any ambiguities were resolved by discussion or the third author.

The grading of recommendations assessment, development, and evaluation profiler (GRADE-pro, version: 3.6, McMaster University and Evidence Prime Inc.) ໿Working Group was used to calculate the absolute estimates of the risk of SD in patients with overt hypothyroidism or subclinical hypothyroidism and rank the overall quality of the evidence.

 Risk of Bias Assessment

The risk of bias for each eligible study was evaluated using the software Review Manager 5.3 (the Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen; Denmark). The results were showed as risk of bias summary and risk of bias graph.

 Meta-analyses

This meta-analysis aims to answer the overarching scientific question: is SD more prevalent in subjects with overt hypothyroidism or subclinical hypothyroidism than those without hypothyroidism (the healthy normal individuals)? The strength of the relationship between overt/subclinical hypothyroidism and SD was quantitatively pooled by calculating the overall RR with its 95% CI. The combined effects were estimated by the Z test, and the P values < 0.05 were considered to statistically significant. I2 statistic and the Cochrane Q statistic were used to evaluate the heterogeneity across the studies, while I2 > 50% indicated substantial heterogeneity, and P value of Q test < 0.10 was regarded to be significant. Considering a high likelihood of between-study variance for differences in study designed and the demographic across the included studies, a random-effect model rather than a fixed-effects model was used in this study. Sensitivity analyses were conducted to detect the potential origin of between-study heterogeneity. The publication bias test was presented by both Begg's rank-correlation test and Egger's regression asymmetry test. The above-mentioned statistical analyses were conducted with STATA version 13.0 software (Stata Corp LP, College Station, Texas).

DISCUSSIONMore and more clinical researches have confirmed that thyroid disorders are associated with a detrimental effect on the quality of life, affecting both physiological and psychological conditions. In 1995, Jannini et al28Jannini EA Ulisse S D'Armiento M Thyroid hormone and male gonadal function. published the first review that summarized all the evidence related to the topic of thyroid disease and the risk of SD. Since then, mounting studies were conducted to illuminate the impact of thyroid disease on human sexual functioning. Hyperthyroidism and hypothyroidism are common disorders causing by thyroid derangements. Clinical hypothyroidism is characterized by increased serum TSH and reduced serum FT3 and FT4, while subclinical hypothyroidism is featured by elevated serum TSH concentrations with normal FT3 and FT4. In the present study, we have managed to better explore the association between clinical/subclinical hypothyroidism and the risk of SD in both sexes which are still controversial among different studies.

Based on this meta-analysis, pooled RR from 4 included studies providing the data of overt hypothyroidism demonstrated that the prevalence of SD in both sexes was significantly higher among patients with overt hypothyroidism compared to the healthy normal subjects. Those patients with overt hypothyroidism were at 2.26-fold higher risk of SD than the general population. Results from GRADEpro indicated that the rate of events of SD on an average in overt hypothyroidism patients and the healthy individuals were 55.3–24.7%, respectively. Heterogeneity analysis revealed no substantial heterogeneity was found across these 4 studies. Further sensitivity analyses indicated that the quantification of the risk for SD in overt hypothyroidism individuals remained dramatically higher in all of the remaining studies, which suggested that the combined effects presented in this study were stable.

Based on the subgroup analysis, we should also note that women with overt hypothyroidism rather than men with overt hypothyroidism were correlated with a significant higher risk of SD. There are two explanations for this phenomenon. First, only 2 studies were included when separately analyzed with male subjects21Veronelli A Masu A Ranieri R et al.Prevalence of erectile dysfunction in thyroid disorders: comparison with control subjects and with obese and diabetic patients.,24Krysiak R Szkrobka W Okopien B. The effect of L-thyroxine treatment on sexual function and depressive symptoms in men with autoimmune hypothyroidism. or female subjects,22Atis G Dalkilinc A Altuntas Y et al.Sexual dysfunction in women with clinical hypothyroidism and subclinical hypothyroidism.,23Pasquali D Maiorino MI Renzullo A et al.Female sexual dysfunction in women with thyroid disorders. each of the included study might dominate the overall RR after pooling. We could not judge which independent analysis was more reliable due to the limited eligible studies. Second, the sample size among these studies was variable. For example, in the 2 eligible studies21Veronelli A Masu A Ranieri R et al.Prevalence of erectile dysfunction in thyroid disorders: comparison with control subjects and with obese and diabetic patients.,24Krysiak R Szkrobka W Okopien B. The effect of L-thyroxine treatment on sexual function and depressive symptoms in men with autoimmune hypothyroidism. reporting male participants, the sample size ranged from 24 (Krysiak et al’s study24Krysiak R Szkrobka W Okopien B. The effect of L-thyroxine treatment on sexual function and depressive symptoms in men with autoimmune hypothyroidism.) to 164 (Veronelli et al’s study21Veronelli A Masu A Ranieri R et al.Prevalence of erectile dysfunction in thyroid disorders: comparison with control subjects and with obese and diabetic patients.), which was considered to be the potential source of the heterogeneity. Therefore, our findings should be interpreted with caution because of the limited eligible studies and the various sample size across any studies.

Different from the case of overt hypothyroidism, synthetic RR from 5 eligible studies reporting subclinical hypothyroidism did not support such a positive association between subclinical hypothyroidism and SD regardless of gender (RR = 1.3, 95% CI: 0.85–1.99, P = 0.229). The rate of events of SD in patients with subclinical hypothyroidism and the general population was 43.9–47.0%, respectively. In the subgroup analysis, no significant association between subclinical hypothyroidism and SD was detected in those included studies reporting either males or females (male: RR = 5.0, 95% CI: 0.68–36.66, P = 0.113; female: RR = 1.2, 95% CI: 0.79–1.81, P = 0.387). Substantial heterogeneity (I2 = 71%) was identified across these 5 relevant studies. Different ages of the participants, sample size, study design, geographical area, duration of subclinical hypothyroidism, and varied characteristics of the subjects could all be partly responsible for the substantial heterogeneity in those studies investigating subclinical hypothyroidism. Sensitivity analyses on the subclinical hypothyroidism further confirmed there was no positive relationship between subclinical hypothyroidism and SD (P > 0.05 for all). Such analyses yielded negligible changes in the results of RR and the GRADE-profiler indicated a moderate quality of evidence, thereby emphasizing the robustness of our study.

Though overt hypothyroidism is significantly associated with SD in both men and women, the exact mechanism of clinical hypothyroidism on SD is not completely clarified. Some recent studies have shown that several associated factors have been implicated. Hypothyroidism-induced decreased thyroid hormone levels were significantly correlated with female SD. Data from Oppo et al17Oppo A Franceschi E Atzeni F et al.Effects of hyperthyroidism, hypothyroidism, and thyroid autoimmunity on female sexual function. indicated that all FSFI domains, in women with overt hypothyroidism, were closely correlated with serum FT4 and inversely with serum TSH. In the same study, corresponding therapy could normalize sexual desire, satisfaction, and pain in hypothyroid women. Similarly, Carani et al15Carani C Isidori AM Granata A et al.Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. also demonstrated that half of DE patients with overt hypothyroidism were resolved after thyroid hormone normalization. Hence, hypothyroidism should be excluded in each patient presenting with DE, and if present a corresponding hormonotherapy might improve hypothyroidism-induced SD.Clinical hypothyroidism may cause SD by regulating the hypothalamus–pituitary–thyroid axis. This axis lies in parallel to the hypothalamus–pituitary–gonadal axis. As aforementioned, overt hypothyroidism is characterized by increased TSH and thyrotropin-releasing hormone, which increases the production of prolactin (PRL). Consequent hyperprolactinemia can lead to reduced testosterone by suppressing the mammary expression of GnRH,29Rieanrakwong D Laoharatchatathanin T Terashima R et al.Prolactin suppression of gonadotropin-releasing hormone initiation of mammary gland involution in female rats. having an indirect effect on ED and the enhancement of dopamine metabolism in specific brain areas having a direct effect on male and female SD.30Drago F Pellegrini-Quarantotti B Scapagnini U et al.Short-term endogenous hyperprolactinaemia and sexual behavior of male rats.,31Maggi M Buvat J Corona G et al.Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). Corona et al32Corona G Mannucci E Fisher AD et al.Effect of hyperprolactinemia in male patients consulting for sexual dysfunction. reported that a severely reduced libido was significantly associated with the higher PRL level. Similarly, the study conducted by Krysiak et al24Krysiak R Szkrobka W Okopien B. The effect of L-thyroxine treatment on sexual function and depressive symptoms in men with autoimmune hypothyroidism. also showed that patients with overt hypothyroidism have higher prolactin levels than that of healthy controls, and prolactin levels have a negative association with erection and sexual satiety in men. However, the relationship between hypothyroidism and ED remains controversial. A large study involving 2,146 sample size demonstrated no effect of hyperprolactinemia on ED.32Corona G Mannucci E Fisher AD et al.Effect of hyperprolactinemia in male patients consulting for sexual dysfunction.Tian et al.33Tian L Zhang L Liu J et al.Effects of TSH on the function of human umbilical vein endothelial cells. demonstrated the expression level of nitric oxide of endothelial was inhibited by elevated TSH. Yildirim et al34Yildirim MK Bagcivan I Sarac B et al.Effect of hypothyroidism on the purinergic responses of corpus cavernosal smooth muscle in rabbits. found that penile smooth muscle in hypothyroid rabbits was less relaxing than control groups.Also, hypothyroidism-induced atherosclerosis and its complications are important causes for female and male SD. Krysiak et al5Krysiak R Szkrobka W Okopien B. Sexual function and depressive symptoms in young women with hypothyroidism receiving levothyroxine/liothyronine combination therapy: a pilot study. reported that hypothyroidism might decrease blood inflow and contributed to the development of female SD by inducing local atherosclerosis. Recent studies also have described a significant association between atherosclerosis and ED.35Bernal E Torres M Alcaraz A et al.Association between erectile dysfunction and carotid subclinical atherosclerosis in HIV-infected patients.,36Randrup E Baum N Feibus A. Erectile dysfunction and cardiovascular disease. A large study conducted by Park et al37Park HJ Kim J Han EJ et al.Association of low baseline free thyroxin levels with progression of coronary artery calcification over 4 years in euthyroid subjects: the Kangbuk Samsung Health Study. found that a lowed FT4 level was significantly associated with a high risk of atherosclerosis in men and women. Another study involving 5,608 subjects showed that antithyroid antibodies are closely associated with chronic inflammation, which causes endothelial dysfunction and atherosclerosis.38Liu J Duan Y Fu J Wang G. Association between thyroid hormones, thyroid antibodies, and cardiometabolic factors in non-obese individuals with normal thyroid function. Veronelli et al39Veronelli A Mauri C Zecchini B et al.Sexual dysfunction is frequent in premenopausal women with diabetes, obesity, and hypothyroidism, and correlates with markers of increased cardiovascular risk. A preliminary report. suggested that the presence of antithyroid antibodies was negatively correlated with the FSFI score. Consequently, hypothyroidism might decrease vaginal, clitoral, and penile engorgement by inducing local atherosclerosis and led to the development of female and male SD.Moreover, overt hypothyroidism was also associated with depression, irritability, and anxiety, which all undoubtedly contributed to SD in both men and women.14Gabrielson AT Sartor RA Hellstrom W. The impact of thyroid disease on sexual dysfunction in men and women.,26Krysiak R Drosdzol-Cop A Skrzypulec-Plinta V et al.Sexual function and depressive symptoms in young women with thyroid autoimmunity and subclinical hypothyroidism.,40Siegmann EM Muller H Luecke C et al.Association of depression and anxiety disorders with autoimmune thyroiditis: a systematic review and meta-analysis.,41Balercia G Boscaro M Lombardo F et al.Sexual symptoms in endocrine diseases: psychosomatic perspectives. Romero et al42Romero-Gomez B Guerrero-Alonso P Carmona-Torres JM et al.Mood disorders in levothyroxine-treated hypothyroid women. reported that the prevalence of anxiety in hypothyroid patients was 63–65%, and a higher incidence of thyroid dysfunction has been found in patients with depressive disorders. Krysiak et al24Krysiak R Szkrobka W Okopien B. The effect of L-thyroxine treatment on sexual function and depressive sy