The impact of Mayer–Rokitansky–Küster–Hauser Syndrome on Psychology, Quality of Life, and Sexual Life of Patients: A Systematic Review

Background: Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare congenital syndrome characterized by uterovaginal agenesis. Most patients are diagnosed during adolescence, when body image and sexual identity are shaped. Our main objective was to investigate how MRKH syndrome affects psychology, quality of life (QoL), and the sexual life of patients compared with non-affected individuals. Methods: Original peer-reviewed research papers examining psychological outcomes, QoL, and sexual function of MRKH patients were searched in PubMed. Titles, abstracts, and full text from potentially eligible records were reviewed by two independent reviewers. Case reports and papers published not in English were excluded. Results: Our search identified 63 records, of which 20 were included: 10 examined psychological and psychosocial outcomes, 14 examined sexual function outcomes, and 6 examined QoL outcomes. Results may be affected by selection bias and confounding due to differences between MRKH patients and controls. Conclusions: MRKH could be associated with a higher prevalence of anxiety and depression symptoms and social insecurity compared with women of a similar age without the condition. MRKH could also be associated with greater pain and discomfort during sexual intercourse and limitations in arousal, lubrication, and orgasm. MRKH patients more commonly experience impairment of mental-health-related QoL, but physical-health-related QoL is not affected.


Introduction
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital disorder of the female reproductive system estimated to affect 1 in approximately 5000 females; it is characterized by the absence of the upper part of the vagina with variable uterine development [1,2]. With regard to embryology, MRKH syndrome is regarded as a result of agenesis or hypoplasia of the Müllerian duct system, or a non-fusion of the Müllerian ducts with the Wolffian ducts [3]. Instead of an anatomically and functionally typical uterus, patients with MRKH syndrome might have an obstructed uterus, one or two rudimentary uterine horns, or cavitated Müllerian remnants; a functional endometrium might be present within the aforementioned underdeveloped uterus. Ovaries are functional in the majority of MRKH patients, resulting in normal secondary sexual characteristics, although hypoplastic ovaries have been described in a portion of MRKH patients [4]. In addition to the anatomic malformations of the reproductive system, many MRKH patients have associated anomalies of the urinary tract, skeletal anomalies, and less often other anomalies involving among others the heart, the cleft palate, and hearing ability.

Materials and Methods
In this systematic review, we included original peer-reviewed research papers that examined psychological and/or psychosocial outcomes, quality of life, sexual function, and/or wellbeing of patients with MRKH syndrome, either before or after therapeutic interventions, compared with controls without MRKH syndrome. With regard to study design, randomized control trials (RCTs), cohort studies, case-control studies, and case series were considered as eligible in this review, as long as a direct comparison with a control group, reference sample, or the general population was performed and reported. Case reports and animal studies were excluded from this systematic review. Original research papers, which presented results on relevant outcomes for groups of patients with several diagnoses including MRKH, were included in this systematic review only if results were reported separately for the subgroup of MRKH patients. Research papers published in language other than English were not included in this systematic review.
PubMed was searched for potentially eligible research papers from inception to 8 January 2022. Our search algorithm included multiple terms that describe the MRKH syndrome as well as terms that describe the outcomes of interest for this review. A filter was applied to safely remove all animal studies, as well as studies for which the abstract was not available or there was no link for the full text. The search algorithm is presented in detail in Table 1. Asterisk (*) in PubMed is the truncation symbol and represents any group of characters, including no character; it is used in search algorithms, in order to search for all terms that begin with that basic word root.
Children 2022, 9,484 3 of 24 All records retrieved from our search were screened by two independent reviewers. Only the records that clearly did not meet our inclusion and exclusion criteria were excluded at this phase. In case of discrepancy, the record was not excluded but rather assessed in full text. Full text from potentially eligible records was retrieved and reviewed by two independent reviewers. In case of discrepancy, a third reviewer additionally assessed the study's full text for eligibility. Lastly, the reference list of all included research papers, as well as any excluded reviews, were manually searched for potentially eligible research papers that were not included in the results of our search algorithm.
Two independent reviewers tabulated the relevant data from the included research papers. Namely, we recorded the following factors: the year of publication; the county that the study took place; the recruitment strategy; the number of MRKH patients that were included in the study; details on the sample size and characteristics of the control group; the year of patients' assessment and their age at assessment; the kind of treatment that has preceded, if any; the period that passed from treatment until patient assessment; finally, the outcomes that were examined in the study, the scales used, and the findings of the study with regard to these outcomes. In cases where comparisons between MRKH patients and controls were performed in multiple time points, all results were tabulated and are discussed in this systematic review. The tabulated data by the two independent reviewers were compared for discrepancies, in which case the research paper was read by a third reviewer that independently tabulated the aforementioned relevant data and agreement was reached via discussion between all three reviewers.
To summarize and synthesize the results of the included studies, we had pre-specified three groups of relevant outcomes and further present our findings for each group separately. In particular, psychological and psychosocial outcomes comprise one group, sexual function and satisfaction comprise the second group, and quality of life comprises the last group. This systematic review includes a qualitative but not a quantitative synthesis, because of the expected heterogeneity in the scales used to assess the outcomes of interest. Sensitivity analysis was not performed. Reporting of this systematic review follows the PRISMA guidelines [7].
With regard to risk of bias assessment, non-randomized epidemiological studies are prone to several sources of bias. For the purpose of this systematic review, we pre-specified the following sources of bias as potentially relevant: confounding due to differences between the patients and control group; uncertainty about the patients' diagnosis; selection bias/missing data due to loss of follow-up data; outcomes measurement; selective reporting. Since MRKH diagnosis cannot be concealed from the study participants, bias due to the non-blinded study design was regarded as present in all of the reviewed studies. Apart from sources of bias, the following were regarded as potential sources of heterogeneity between individual studies' results: age at patient assessment; surgical or non-surgical treatment that has been applied; time interval since treatment; the country in which the study took place. Data regarding the aforementioned sources of bias and heterogeneity were recorded for all the included studies by two independent reviewers. No overall statement for risk of bias per study was provided because it is unclear whether and how the individual sources of bias should be weighted. As follows, certainty in the body of evidence for each outcome was subjectively assessed via discussion between all authors of this systematic review.

Results
In total, our search identified 63 records. Of these, 32 were excluded at the screening phase, as they clearly did not meet our inclusion and exclusion criteria based on their title and abstract. At the eligibility phase, 31 full-text articles were assessed. Of these, eight were relevant for our literature review. In addition, after screening the reference list of the included studies and those of the excluded reviews, 28 potentially relevant records were identified. Of these, 26 were assessed in full text and, finally, 12 studies were included in this systematic review. In total, 20 human studies were included in this literature review ( Figure 1). Among these 20 studies, 10 studies examined psychological and psychosocial outcomes, 14 examined sexual function and satisfaction in women with MRKH syndrome, and 6 reported on the quality of life of these patients. In 11 out of 21 studies, patients had received surgical treatment for neovagina creation; in 1 study, dilation therapy had been previously applied; in 7 studies, it was unclear which therapeutic intervention had been applied, or different therapeutic interventions had preceded the study; and in 1 study, patients were assessed prior to any treatment. Average age at outcomes assessment varied between 18 and 39.2 years and the time interval since treatment ranged from 6 months to a maximum of 20 years (Table A1).
In total, our search identified 63 records. Of these, 32 were excluded at the screening phase, as they clearly did not meet our inclusion and exclusion criteria based on their title and abstract. At the eligibility phase, 31 full-text articles were assessed. Of these, eight were relevant for our literature review. In addition, after screening the reference list of the included studies and those of the excluded reviews, 28 potentially relevant records were identified. Of these, 26 were assessed in full text and, finally, 12 studies were included in this systematic review. In total, 20 human studies were included in this literature review ( Figure 1). Among these 20 studies, 10 studies examined psychological and psychosocial outcomes, 14 examined sexual function and satisfaction in women with MRKH syndrome, and 6 reported on the quality of life of these patients. In 11 out of 21 studies, patients had received surgical treatment for neovagina creation; in 1 study, dilation therapy had been previously applied; in 7 studies, it was unclear which therapeutic intervention had been applied, or different therapeutic interventions had preceded the study; and in 1 study, patients were assessed prior to any treatment. Average age at outcomes assessment varied between 18 and 39.2 years and the time interval since treatment ranged from 6 months to a maximum of 20 years (Table A1).

Psychological and Psychosocial Outcomes
A total of 10 studies including 518 patients have examined the psychological and psychosocial impact of MRKH (Table A1). These studies were published between 1982 and 2021. The psychological and psychosocial impact of MRKH was assessed using questionnaires, including the Patient Health Questionnaire (PHQ), the Scale for the Detection of Self-Acceptance (SESA), and other internationally known, validated tools (Table A2).
In a study by Heller-Boersma et al., in which the Symptom Checklist (SCL-90-R), the Rosenberg Self-Esteem Scale (RSES), the Eating Disorder Inventory (EDI), and the Inventory of Interpersonal Problems (IIP-32) were used, it was found that MRKH patients had significantly higher scores on the first three questionnaires, indicating a higher prevalence of anxiety and depression symptomatology, eating disorders such as bulimia, and a lower selfesteem [8]. However, it should be noted that this study was embedded within a randomized control trial (RCT) that examined the effectiveness of cognitive behavioral group treatment in MRKH patients [8]. Patients that consented to participate in this study perceived a psychological intervention as potentially beneficial for them and were, therefore, more likely to experience anxiety or depression symptoms in comparison with the MRKH patients that did not consent to participate in this study. Thus, the effect of MRKH syndrome on patients' psychology might be overestimated in the study by Heller-Boersma et al. [8]. Nonetheless, in line with these findings, Chen et al. concluded that MRKH patients were more likely to suffer from depressive symptoms compared with the control group, using the Patient Health Questionnaire-9 (PHQ-9); additionally, Liao et al. demonstrated that the MRKH group had higher mean scores for anxiety, as captured in the Hospital Anxiety and Depression Scale (HADS), compared with the standardization sample [9,10]. Similarly, Fliegner et al. reported that MRKH patients had a higher score in the Social Insecurity Scale and Sexual Insecurity Scale [11]. In the study by Laggari et al., MRKH patients had a greater risk for depressive and anxiety symptoms, but the association was not significant after adjustment for socioeconomic status and chronological age, respectively [12]. On the contrary, other studies have failed to demonstrate any significant psychological or psychosocial impact of MRKH. Rall et al. concluded that there is no evidence for a somatization disorder, no association with depressive or somatic disorders, and a lack of body image disturbance in the MRKH patients group [13]. Similarly, Weijenborg et al., Gatti et al., and Rabboch et al. found no significant difference between the MRKH and the control group, using numerous questionnaires, including the Rosenberg Self-Esteem Scale (RSES) and the Beck Depression Index (BDI) ( Table A1) [14][15][16]. Interestingly, Leithner et al. found significantly fewer somatic symptoms and less psychological impairment in the MRKH group compared with the control group and no significant difference regarding body image.
It is evident that the results from studies examining the psychological and psychosocial impact of MRKH syndrome exhibit great heterogeneity [17]. Potential sources of this heterogeneity include the different age at outcomes' assessment (Table A1); for example, Rall et al. examined patients whose mean age was 19.9, whereas Weijenborg et al. examined patients whose mean age was 39.2 years [13,14]. In addition, the differences in treatment prior to the study as well as the use of different questionnaires may have contributed to the observed heterogeneity.
The results of the reviewed studies may have been influenced by systematic bias, especially due to confounding by differences between the MRKH and the control group and selection bias (Table A3). Even though, in the smaller studies, the vast majority of the invited MRKH patients were enrolled, loss of follow-up data reached 80.3% in other studies (Table A3). Nonetheless, all studies used validated tools to assess the outcomes, and there was none or little uncertainty regarding MRKH diagnosis in the majority of the reviewed studies (Table A3).
Taking all the aforementioned factors into consideration, we are moderately confident that MRKH syndrome probably affects psychologically and/or psychosocially the patients, but further research is needed in order to estimate the extent to which MRKH has a psychological and psychosocial impact on adolescents.

Sexual Function Outcomes
Fourteen studies evaluated the impact of MRKH syndrome on the sexual function and satisfaction of patients, using a variety of questionnaires and validated tools (Tables A1 and A2). The studies were published between 1982 and 2021 and included a total of 625 patients. Twelve out of fourteen studies used the Female Sexual Function Index (FSFI). The FSFI evaluates 5 domains: arousal, satisfaction, desire, pain, and lubrication [18]. Other questionnaires that were used include the following: the Female Genital Self-Image Scale (FGSIS), used by Weijenborg et al. and Pastor et al.; the Sexual Arousability Inventory (SAI), used by Raboch et al.; and a structured clinical interview, "Psychosexual biography", used by Beisert et al. [14,16,19,20].
Four studies, those by Raboch, Liu, Zhu, and Cheikhelard, which recruited patients that had been surgically treated almost exclusively, showed no difference in sexual function between the MRKH and the control groups [16,[21][22][23]. Interestingly, in the study by Leithner et al., the MRKH group had marginally higher FSFI scores postoperatively [17]. On the contrary, in three studies (Rall et al., Fliegner et al., Liao et al.), MRKH patients had lower mean total FSFI scores and lower scores in all of the subscales compared with the reference sample, indicating reduced sexual function and stronger limitations within the domains of desire, arousal, lubrication, orgasm, and pain [10,11,13]. In two of these studies (Rall et al. and Fliegner et al.), the majority of patients had been previously operated upon, whereas in the study of Liao et al., previous treatment of the participants was unclear [10,11,13]. An important finding of Rall was that the FSFI total scores in MRKH patients remained lower even after postoperative improvement [13]. In addition, two studies by Nadarajah and Fedele, respectively, associated MRKH with an inability to maintain lubrication and to experience orgasm, as well as with stronger pain during sexual intercourse [24,25]. The other domains of FSFI showed no significant difference [24,25]. Notably, Fedele et al. recruited MRKH patients postoperatively, whereas Nadarajah et al. recruited patients after treatment with dilators [24,25]. Csermely et al. reported that the MRKH group postoperatively showed significantly less lubrication and had significantly more discomfort (pain) during sexual intercourse, but had no other significant difference compared to the control group [26]. In line with the aforementioned findings, Weijenborg and Pastor studied MRKH patients postoperatively and associated MRKH syndrome with higher incidence of Female Sexual Dysfunction (FSD), the presence of some or higher levels of pain during intercourse, and significantly lower self-esteem, as the assessment of genital perception, using the Female Genital Self-Image Scale (FGSIS), showed a significantly lower score [14,19]. Lastly, Beisert et al. noted that the frequency of vaginal and oral intercourse as well as the frequency of orgasms during vaginal intercourse was significantly lower in the MRKH group [20]. It is worth mentioning that, in the same study, women with MRKH were found to engage in vaginal and oral intercourse later compared with the controls. All other aspects of the clinical interview showed no significant difference between the two groups [20].
With regard to sexual functioning outcomes among women with MRKH, some heterogeneity is observed, since four out of fourteen studies showed no significant difference between the two groups. An important source of this heterogeneity is the difference in type of treatment and age at which the MRKH patients had been treated (Table A1) [21,24,25]. It is evident that this difference in treatment and age at treatment could affect the sexual functioning outcome and the way that the MRKH population perceives and experiences sexual intercourse. An additional source of heterogeneity among the reviewed studies is the use of different questionnaires to assess the targeted outcomes.
Regarding bias assessment, all the reviewed studies used validated questionnaires to examine sexual function outcomes (Table A3). Concerning selection bias, 0-75.5% of the invited MRKH patients did not finally participate (Table A3). Furthermore, in 5 out of 14 studies, the diagnostic algorithm for MRKH syndrome was not explicitly stated (Table A3). Last but not least, confounding factors-attributable to sociodemographic differences between the MRKH and control group-likely affected the results of the reviewed studies, even though 9 out of 14 studies enrolled age-matched controls (Table A3).
We are, therefore, moderately confident that reviewed evidence supports an association between MRKH syndrome and poorer sexual function outcomes, even though this was not the case in all the conducted studies.
Four out of six studies reported significant impairment of mental-health-related quality of life, and generally indicated poorer mental health of MRKH patients compared with the control groups [10,13,17,23]. The last two studies, by Kaloo and Kimberley, demonstrated no association between MRKH and deterioration of the quality of life [27,28]. Kaloo et al., however, reported that the sexual activity of MRKH women was significantly lower than the average in the normal female Finnish population [28]. It is worth mentioning that, in the studies by Liao, Leithner, Cheikhelard, and Rall, the physical health of MRKH patients did not differ from controls [10,13,17,23].
Regarding the physical health component of the quality of life of MRKH patients, the studies report no heterogeneity, since none of the studies found any significant association between MRKH syndrome and a poorer physical health. There is, however, some heterogeneity regarding the mental health component of quality of life and general wellbeing. Differences in power among the studies may explain to an extent this heterogeneity (Table A1). For example, Kimberley studied only 28 MRKH patients and found no association, whereas Cheikhelard studied 131 and reported poorer mental-health-related quality of life; notably, the same questionnaire was used in both studies [23,27]. Furthermore, the use of different tools and questionnaires could have also affected heterogeneity, since the Sintonen 15D questionnaire was used only by Kallo et al., who reported no impact of MRK syndrome on quality of life [28].
With regard to risk of bias assessment, issues arise again due to significant differences between the MRKH and the control group; notably, in three out of six studies, general population samples served as control groups (Table A3). In addition, 16.7-67% of eligible MRKH patients were not included in the reviewed studies, indicating that selection bias may have influenced the results (Table A3).
Therefore, we are moderately confident that the reviewed evidence supports that MRKH is associated with a poorer mental-health-related quality of life, but physical-healthrelated quality of life is not affected by the syndrome.

Discussion
In this systematic review of the literature, the psychology, quality of life, and sexual life of patients with MRKH syndrome was studied in comparison to non-affected individuals. Overall, we concluded that MRKH could be associated with a higher prevalence of anxiety and depression symptoms, as well as with social insecurity, in comparison with women of similar age without the condition. Regarding the sexuality of MRKH patients, most studies agreed that MRKH is associated with greater pain and discomfort during sexual intercourse as well as with strong limitations in arousal, lubrication, and orgasm. Moreover, MRKH women with a neovagina experience sexuality-related distress, suffer from sexual dysfunction more often, and report lower sexual esteem and genital self-image compared with controls, reflecting that MRKH women might feel insecure about themselves. Lastly, MRKH patients more commonly experience significant impairment of the mental-health-related quality of life, but physical-health-related quality of life does not seem to be influenced by MRKH.
The impact of MRKH syndrome on psychology, sexual life, and quality of life of patients has been long suspected. The American College of Obstetricians and Gynecologists (ACOG) recommends that all patients with MRKH should be offered psychological counseling and be encouraged to connect with support groups in order to deal with this great emotional burden, and underlines that the psychological impact of the diagnosis should not be underestimated [29]. With regard to psychological counseling, cognitive-behavioral group treatment has been shown to significantly reduce psychological symptoms, as captured in the Symptom Checklist-90 (SCL-90) [30]. Women with the syndrome have agenesis of the uterus and the upper third of their vagina; thus, the main focus of clinical management has traditionally been to increase the vaginal length, either by surgical or by nonsurgical techniques [4]. The aforementioned anatomical abnormalities associated with MRKH can lead to difficulties during sexual intercourse and infertility, causing confusion of identity and negative self-beliefs. The majority of cases are diagnosed during adolescence, when body image and sexual identity are shaped. Permanent loss of bodily integrity, even fertility, and the need for the artificial creation of a neovagina can have an impact on identity and self-evaluation in this sensitive age. Taking into account the emotional distress associated with infertility alone, we can expect that the diagnosis of MRKH-as well as the distress caused by a potential surgical therapy-may compromise emotional wellbeing, relationship outcomes, and sexual function [9]. While living with this condition, depression, anxiety, and even suicidal thoughts can appear [31,32]. The results of this systematic review also support the hypothesis that deep dyspareunia may be associated with the creation of the artificial neovagina.
However, as interesting as the findings of this systematic review may be, several aspects of MRKH impact on psychology, sexual life, and quality of life remain understudied. Most importantly, there is a marked lack of evidence for the period of adolescence, when the diagnosis is usually made. The average age at which assessment was made was less than 22 years old only in four out of the twenty reviewed studies. Furthermore, the vast majority of studies did not include pretreatment data, which is usually the case for adolescent patients, but rather evaluated the patients and assessed the targeted outcomes only after treatment for MRKH syndrome. In addition, many geographical regions and cultures are under-represented in the reviewed studies; in particular, fifteen studies were conducted in Europe, three studies in China, and two in Australia, while patients from Bangladesh were recruited in just one study. Therefore, the majority of patients included in the reviewed studies shared a similar cultural background and similar sexual experiences and perceptions regarding sexual satisfaction and outcomes. It is, therefore, unclear how MRKH syndrome affects psychology, sexual life, and quality of life of patients of non-Western and non-Chinese origin. Furthermore, the extent to which infertility mediates the effect of MRKH syndrome on patients' psychology has been markedly understudied. Infertility is regarded as one of the most difficult aspects of MRKH syndrome for patients to accept, but uterine transplantation emerges as a therapeutic solution for infertility. Finally, all of the reviewed studies have used psychometric instruments of symptomatic evaluation to assess psychological outcomes, rather than diagnostic instruments. Therefore, MRKH syndrome could be associated with anxiety and depression symptoms, but it remains unknown whether clinical depression and anxiety disorders are more frequent among MRKH patients in comparison with the general population.
To our knowledge, this is the first study that has systematically reviewed quality of life, psychological, and psychosocial outcomes, as well as sexual function outcomes, in MRKH patients in comparison with healthy controls. These outcomes are known to be complex, heterogeneous, and multifactorial in origin. The adaption of a broad search and reference screening strategy is a strength of this literature review, even though the search algorithm in PubMed has not been optimized based on the literature found via the references screening. Other limitations of this systematic review are that the protocol was not registered a priori, and databases other than PubMed, as well as the grey literature, were not searched. In addition, a language criterion was applied, resulting in the exclusion of one potentially relevant paper. Finally, the retrieval of identified research records was incomplete, as three potentially relevant records (all identified from reference screening) were not accessible in full text.

Conclusions
In conclusion, the results of this systematic review emphasize the need for psychological support and counseling regarding sexual life among MRKH patients. Gynecologists, pediatricians, and other specialists who treat MRKH syndrome are encouraged to take into consideration the challenges of living with MRKH syndrome and to investigate the multiple clinical needs of this population more thoroughly. Depressive symptoms and mood disorder screening in this vulnerable group is of the utmost importance.
Author Contributions: E.T. and A.E. were the two independent reviewers and contributed to writing; M.-K.L. was the third reviewer; P.C., M.E. and E.K. contributed to editing; P.C. contributed to reviewing the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.
Institutional Review Board Statement: Ethical review and approval were waived for this study due to study design (Systematic Review).

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.

Conflicts of Interest:
The authors declare no conflict of interest.   The FSDS-R score was significantly higher in operated women compared with the control group (14.5 ± 6.5 vs. 6.5 ± 4.6). Sexual function as indicated by FSFI total score was similar between groups, which did not significantly differ statistically (29.9 ± 2.7 vs. 30.0 ± 2.1). However, the groups differed in four (desire, lubrication, orgasm, and comfort) of the six FSFI domains, with women with a neovagina reporting significantly more frequent orgasms and higher sexual desire but less lubrication and more discomfort (pain) during intercourse. (2) Genital self-image -> Female Genital Self-Image Scale (FGSIS):

Appendix A
FGSIS assessment of genital perception showed a significantly lower score in women with a neovagina (22.  In none of the four scales ("Attractiveness/Self-Confidence"; "Accentuation of Physical Appearance"; "Insecurity/Concern", "Physical/Sexual discomfort") a significant difference was observed.
No significant difference was found between the patients and the controls in the domains regarding desire, arousal, and satisfaction.
-   Age-matched healthy women without the condition were enrolled. However, all participants had to be at least 18-years old and had to live in a steady heterosexual relationship, whereas the same inclusion criterion is not explicitely reported for the control group.
Little uncertainty present (All women with MRKH syndrome who were known by the Dutch peer support group "The foundation of MRK women")