Background

Trimethylaminuria, or fish odor syndrome, includes a transient or mild malodor caused by an excessive amount of malodorous trimethylamine as a result of body secretions [1, 2]. The causal factor of excessive free trimethylamine is reduced enzyme capacity, or maybe substrate overload. The decreased enzyme capacity to form non-odorous trimethylamine N-oxide could be a result by an inherited deficiency (primary genetic trimethylaminuria) and/or by hormonal modulation or liver damage (transient trimethylaminuria) [2, 3]. For trimethylaminuria, at least 40 genetic polymorphisms of the flavin-containing monooxygenase 3 (FMO3) gene have been reported [4, 5]. For transient trimethylaminuria, a change of metabolic capacity in one individual around the time of menstruation has been reported [6]. Herein, we describe data to support the proposal that menses can be an additional factor causing transient trimethylaminuria in self-reported subjects suffering from malodor and even in healthy women harboring functionally active FMO3.

Methods

Japanese female volunteers included two subjects suffering self-reported malodor that responded to an Internet article and three healthy laboratory members as controls, ranging from 21 to 37 years of age [5, 7]. Written consent was obtained from the individuals for publication of study. FMO3 metabolic capacity (conversion of trimethylamine to trimethylamine N-oxide) was defined as the urinary ratio of trimethylamine N-oxide to total trimethylamine (% of trimethylamine N-oxide/[trimethylamine + trimethylamine N-oxide]) determined by GC [7]. The FMO3 DNA sequence of genomic DNA prepared from peripheral lymphocytes or buccal cells from the study participants was also analyzed [3, 5]. The study participants collected their urine samples using a procedure described previously [7]. The ethics committee of Showa Pharmaceutical University approved this study.

Results and discussion

As shown in Figure 1, Case (A) that was homozygous for inactive Arg500stop FMO3 [5], showed decreased metabolic capacity of FMO3 (i.e., 13 ± 10 % (mean ± SD, n = 20) of the unaffected metabolic capacity) during 120 days of observation. For Case (B) that was homozygous for common [Glu158Lys; Glu308Gly] FMO3 polymorphisms [1–3], metabolic capacity of FMO3 was almost ~90%, except for a few days surrounding menstruation. In comparison, healthy control Case (C) that harbored heterozygous polymorphisms for [Glu158Lys; Glu308Gly] FMO3 showed > 90% metabolic capacity and this was greater than the reported unaffected ratio [1, 6, 7]. However, for Case (C), on days around menstruation the FMO3 metabolic capacity was decreased to ~60–70%. Control Cases (D) and (E) that were homozygous for wild FMO3 also showed normal FMO3 metabolic capacity (i.e., ~> 90%), except for days around menstruation. Together, these results indicate that abnormal FMO3 capacity is caused by menstruation particularly in the presence, in homozygous form, of mild genetic variants such as [Glu158Lys; Glu308Gly] that cause a reduced FMO3 function. This would further suggest that sex hormones play a role in the variable regulation of FMO3. Induced FMO3 activity during pregnancy [8] has been reported, in accordance with the present results.

Figure 1
figure 1

Decreased metabolic capacity of FMO3 (△), as indicated as percent free trimethylamine (TMA, ●) to total trimethylamine (○) excreted in the urine, in relation to menstruation. Filled boxes indicate the period of menstruation. Total urinary trimethylamine and free trimethylamine concentrations were calculated as mmol trimethylamine (TMA)/mol creatinine. Cases (A) and (B) were self-reported subjects suffering from malodour genotyped for homozygotic inactive Arg500stop FMO3 and homozygotic common [Glu158Lys; Glu308Gly] FMO3, respectively. Cases (C) and (D and E) were control subjects genotyped as heterozygotic for [Glu158Lys; Glu308Gly] FMO3 and homozygotic for wild FMO3, respectively.

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Conclusion

Menses can be a factor causing transient trimethylaminuria even in healthy women harboring active enzymes. The present information could be useful in relieving the symptoms for transient and/or mild trimethylaminuria for affected females during menstruation.