This is the first study to report an unexpectedly low rate of clinical signs of androgen excess in a sample of 69 women with MRKH syndrome, as many as 60.8% of which had biochemical hyperandrogenemia. Androgen excess is one of the most common endocrinopathies, affecting approximately 7% of reproductive-aged women, the majority with a diagnosis of polycystic ovary syndrome (PCOS) and both clinical and biochemical evidence of hyperandrogenism. Clinically, hyperandrogenism manifests primarily as acne, androgenetic hair loss, and hirsutism. However, an element of observer bias in the evaluation of signs of hirsutism and clinical hyperandrogenism has been discussed in this context [29–32].
Interestingly, acne as a clinical sign of androgen excess was reported only by 12 (28.6%) of the 42 hyperandrogenemic women amongst the 69 respondents in our study. No other signs of hyperandrogenism were observed. The incidence of PCOS in our patients was not higher than described in the general population . While nearly all cases of WNT4 mutations reported in the literature to date had clinical and biochemical signs of androgen excess as pathognomonic signs [8–12], these signs were not seen in our cohort. There was also no correlation between MRKH syndrome with associated malformations and hyperandrogenemia or acne. Recent data suggest that WNT4 mutations cause specific regulation of androgen synthesis enzymes. Thus, according to one study, the absence of a WNT4 mutation in four adolescent girls with MRKH syndrome and clinical and biochemical hyperandrogenism strongly suggests the potential involvement of other constituents of the Wnt4/β-catenin signaling pathway . We therefore conclude that a WNT4 mutation is unlikely to be the cause of MRKH syndrome in the majority of our hyperandrogenemic patients.
According to many epidemiological studies evaluating current skin status in adolescents, acne prevalence ranges between 80% more than 90% [14, 15, 33]. Two studies reported mean prevalence in adults as 31.9% and 54% [17, 34]. Considering that our survey included MRKH women aged 16 to 44, acne prevalence would have been expected to be much higher than the 24.6% observed in this study. Despite the high percentage of hyperandrogenemia the chi-square test showed that at 24.6%, the prevalence of acne in the adolescent and adult women with MRKH participating in our study was significantly lower than in comparable cohorts of women and girls without MRKH [14–16].
Thus about 50% of our respondents affected by acne had physiological acne, whereas other studies have reported higher percentages of physiological acne [16, 35]. On the other hand, compared to the French study by Poli et al. , we found that the severity score including counted skin lesions was an average 1.6 points and 1.3 points higher in our patients with clinical and physiological acne, respectively.
Medical treatment of acne was infrequent and non-specific in our sample of MRKH women. Only 4% of all women took oral contraceptives, which are associated with a significantly lower prevalence of acne. Oral contraceptives may modify the androgenic effect and thus influence both the prevalence and severity of acne [36, 37]. Whereas 55% of adolescents aged 14–19 years  and one third of all fertile women in Germany use oral contraceptives, the percentage of MRKH patients taking oral contraceptives is very low, this being due to infertility. In view of this, one would have expected acne to be even more prevalent among the adolescents with MRKH as oral contraceptives are effective in treating acne and can be considered a preventive treatment. Paradoxically, the highest percentage of acne treatment in our study was found in the respondents without acne. One possible explanation for this finding could be that these women had had acne at some time and had been treated successfully.
Analysis of the questionnaire results did not reveal any correlation between risk and stress factors, e.g. nicotine use, quality of sleep, make-up use, and the prevalence or severity of acne. The effect of nicotine consumption on acne has been addressed in various studies. Some found a positive correlation between the daily number of cigarettes smoked and acne, while in others there was no correlation [39, 40]. According to the Federal Statistical Office of Germany, the percentage of smokers among 15 to 45–year-old females was 15–30.4% in 2009 . Although our sample of MRKH included 35% smokers, acne prevalence was far below average.
The menstrual period, presumed to be one of the most important aggravating factors in acne [42, 43], is naturally missing in MRKH. However, women with MRKH syndrome have functional ovaries and therefore experience exactly the same cyclic hormone changes as women without the syndrome but have a low prevalence of acne. While the acne questionnaire used in our study did not specifically ask about cyclically recurring symptoms, this question was generally addressed at the routine follow-up visits after neovagina surgery.
With respect to the correlation between quality of life factors and acne severity, the DLQI indicated only a slight decrease in quality of life. No respondent reported severe changes in quality of life. Several studies have reported a similar degree of “emotional impairment” as reported by patients with chronic disabling asthma, epilepsy, diabetes, arthritis , or psoriasis . In our study, quality of life was only mildly to moderately affected by acne, the highest observed score being 9 out of 30. This relatively low score may be considered plausible, however, in view of the great impact on quality of life associated with the absence of the uterus and vagina and the infertility this entails.
A limitation of the present study is the low rate of returned questionnaires. This was likely due in part to the fact that the MRKH syndrome is a rare condition, but may partly also be explained by the observation that women with MRKH tend to avoid constant confrontation with their condition once they have undergone surgical treatment.
As pointed out in the 2012 European evidence-based (S3) guidelines for the treatment of acne, there are inherent difficulties in objectively measuring acne. No international consensus has been reached on a uniform classification system for acne. However, this diversity and the frequent lack of validation limits the direct comparability of different trials [19, 46, 47]. Counting acne lesions – particularly currently inflamed lesions, as in our study – is a widespread and reliable method of classifying acne [48, 49].
Further common grading systems, such as the Global Acne Grading System (GAGS) , the Leeds acne grading system , and the German guidelines  assess current skin status but do not consider a patient’s medical history and lifestyle. Therefore our acne definition also refers exclusively to current skin status. The study definitions for assessing the presence or absence of acne were confirmed by high concordance (72%) between self-assessment (“Do you have acne?”) and the acne index of current skin status. In contrast, there was only a 45% agreement between self-assessment and a definition based on the anamnestic criterion from the French study by Poli et al.  as to the number of pustules or papulonodules patients had had on their face during the last three months. The latter study, according to which the prevalence of acne in French women was 41%, cannot be directly compared with our study because of the acne definition used in that study. We used the same clinical criteria but focused on currently active lesions whereas the French study additionally covered the acne history of the preceding three months. However, their question as to the number of facial pustules or papulonodules occurring during the preceding three months may have been ambiguous since “during” can be interpreted cumulatively as meaning “in total”, or, in terms of prevalence, as “once or at the same time” within the past 3 months. Adding the same anamnestic aspects to the current acne definition used in our study revealed a large discrepancy between the current skin status and that of the preceding three months. With 36 out of 55 (65%) women in the acne group reporting no current acne lesions, this would have resulted in a cumulative overestimation of previous skin lesions.