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Trimethylaminuria: A Noninfectious Cause of Vaginal Odor

S.C. Mitchell, DSc, FRCPath; R.L. Smith, DSc, (Hon)MRCP; J.R. Harris, FRCP, FRCP(I)

The distinctive ÒfishyÓ vaginal odor—traditionally linked with a number of infections of the lower genital tract—is emerging as a disorder in its own right.

ABSTRACT

Two patients who were previously diagnosed with inherited (primary) fish-odor syndrome (trimethylaminuria) were examined for the presence of trimethylamine in their vaginal secretions. Their samples were compared with those obtained from a healthy control group and a cohort of patients with bacterial vaginosis (BV). As expected, those with BV secreted larger amounts of trimethylamine than the control group. However, the two patients with trimethylaminuria—although presenting with no vaginal/cervical pathology—secreted trimethylamine levels that were at least double those found in the patients with BV. This suggests that trimethylaminuria may be an underlying but unappreciated cause of vaginal malodor (especially fish-like odor) in patients found to be infection-free.

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INTRODUCTION

Vaginal malodors are usually associated with infection. An odor resembling decaying fish is almost diagnostic of BV—ie, anaerobic vaginosis, nonspecific vaginitis, Gardnerella vaginalis vaginitis, Haemophilus vaginalis vaginitis—one of the most common conditions diagnosed in women attending genitourinary clinics in England and the United States.1-5 Biochemical examination of vaginal-wash specimens obtained from patients with BV have shown increased amounts of acetate and succinate, together with occasional higher levels of other short-chained organic acids such as propionate, butyrate, isobutyrate, and isovalerate.5,6 The two alkyldiamines, putrescine and cadaverine, have also been identified, as have elevated amounts of the monoamine compounds methylamine, trimethylamine, isobutylamine, phenylethylamine, tyramine, and histamine.7-9.

Many of these compounds (which are thought to arise from bacterial metabolism) may contribute to vaginal malodor. However, it is the amine components—particularly the volatile trimethylamine—that are probably responsible for the distinctive fish-like aroma.9,10

One condition that is particularly associated with a fish-like odor is trimethylaminuria. In its primary genetic form, trimethylaminuria is caused by the failure of an isoform of the hepatic flavin-containing monooxygenase enzyme 3 (FMO3) to oxidize trimethylamine, provided via enterobacterial action on dietary precursors, into nonodorous trimethylamine N-oxide.11 The resulting excess volatile trimethylamine leaves the body via the sweat and urine, and affected women often seek treatment for distressing vaginal malodors.12-14

Until recently, trimethylaminuria was thought to be a rare condition. However, a clearer understanding of the problem (particularly at the genomic level), plus the development of relatively simple diagnostic procedures, has led to the identification of more cases.11,15,16 To determine whether women with this condition may have problems with vaginal malodor, the authors examined the trimethylamine levels in normal vaginal secretions from two trimethylaminuria patients and compared them with those found in a healthy control population and in subjects with BV.

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METHODS

Subjects

Two patients who were previously diagnosed with primary trimethylaminuria following extensive investigation—together with their parents and siblings—volunteered for the study.13,17-19 Subjects for the comparison groups were selected from women attending the Department of Genito-Urinary Medicine at Saint MaryÕs Hospital, London, England. Women were excluded from the study if they were younger than age 16 years, were menstruating or pregnant, were receiving or had received antibiotics or topical vaginal treatments within the previous month, or had a high risk of hepatitis B or human immunodeficiency virus infection. All patients gave their informed consent, and the local ethics committee approved the study.

Diagnosis

Trimethylaminuria.—The two female patients with trimethylaminuria were referred via their physicians after presenting with a history of body odor and urine smelling of rotting fish. Quantitative analysis of their urine (0 to 24 hours) for trimethylamine and its N-oxide showed that these subjects were relatively deficient in N-oxidation capacity. A subsequent oral trimethylamine load test confirmed this N-oxidation deficiency, and also indicated the heterozygous status of their parents.18,19 Examination of nucleic acid samples taken from the patients, their siblings, and their parents demonstrated the presence of a point mutation within the chromosome region encoding for FMO3, and this was associated with a dysfunctional enzyme. This particular chromosome region has subsequently been shown to be highly polymorphic.11,13,15

Bacterial Vaginosis.—Secretions were collected from the lateral vaginal fornix with a cotton-wool-tipped swab to measure pH using indicator paper. A positive amine-test result was recorded when a ÒfishyÓ odor was released following addition of vaginal secretions to a small volume of 20% aqueous potassium hydroxide. Specimens were taken from the urethra and endocervix with plastic culture loops (10 mcL) for preparation of gram-stained smears and saline wet mounts that were examined by oil-immersion and phase-contrast microscopy. Additional aliquots of these secretions were transported to the microbiology laboratory for subsequent culture for Neisseria gonorrhoeae and yeasts, specifically Candida albicans. Chlamydial infection was sought by a positive reaction with an enzyme-linked immunosorbent assay (ELISA) for Chlamydia trachomatis antigen. Cultures for herpes simplex virus and serologic tests for syphilis were performed when clinically indicated. Bacterial vaginosis was diagnosed in women meeting three of four criteria—ie, a thin, homogenous vaginal discharge; vaginal pH > 4.5; a positive amine-test result; and the presence of Òclue cellsÓ (squamous vaginal epithelia covered with bacteria) on saline wet mount.

Trimethylamine Analysis

Secretions were collected from the lateral vaginal fornix using a cotton-wool-tipped wooden swab that was then placed in an airtight, screw-capped vial containing hydrochloric acid (0.5 mL). The vials were immediately frozen at -20¡C and transported to the laboratory for subsequent analysis by head-space gas chromatography.20 All analyses were undertaken in duplicate, with high-amine samples diluted as appropriate.20

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RESULTS

As the amount of vaginal secretion initially collected onto the swab and the amount of secretion subsequently extracted from the swab into the hydrochloric acid solution undoubtedly varied from patient to patient, quantitative analyses of these samples were not attempted. However, the integrated peak areas provided an accurate measure of trimethylamine presented to the analysis procedure, and thus served as a semiquantitative guide (rank) for the relative amount of amine initially present in the vaginal secretions (Table).

For the control (N = 39) and BV (N = 38) groups, no significant statistical differences were found between the age of the patients and the presence of trimethylamine in their vaginal secretions (product moment correlation coefficient, StudentÕs t-test between subgroups). Also, no statistically significant differences were observed when groups of smokers (control N = 10, BV N = 24) versus nonsmokers, or oral contraceptive users (control N = 9, BV N = 12) versus nonusers were compared (x-squared test). There were more patients in the BV group with higher trimethylamine levels (20 to 39 mcg) than would be expected when compared with healthy controls (P < .01, x-squared test). The two patients with trimethylaminuria, who were both nonsmokers and free from any vaginal/cervical pathology, had trimethylamine levels that were very high (> 80 mcg)—ie, at least 100% greater than the patients with BV and 300% greater than controls (Table).

Table not available online

Table. Trimethylamine Levels in Subjects’ Vaginal Secretions

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DISCUSSION

The observation that the group of patients diagnosed with BV had higher levels of trimethylamine in their vaginal secretions than would have been expected when compared with healthy subjects supports the view that trimethylamine is a major contributor to the malodor associated with this condition.9 This is not surprising, as a ÒfishyÓ odor (especially in an alkaline environment) is almost diagnostic of BV. That trimethylamine is generated by the vaginal microbial flora is implied in the successful treatment of BV with metronidazole and the subsequent loss of malodor. Indeed, studies have shown the disappearance of short-chained organic acids following such treatment, suggesting alterations in the vaginal microbial ecosystem.5 It is also possible that oral metronidazole may decrease the enterobacterial liberation of trimethylamine from dietary precursors, thereby reducing gastrointestinal absorption and the subsequent amount of amine available for secretion into the vagina. This hypothesis appears to be contradicted by previous observations, where no significant association was evident between the urinary trimethylamine concentration and that in the vaginal discharge,9 although another published study intimates in its favor.21

Nevertheless, in the present investigation, the two patients with trimethylaminuria exhibited levels of trimethylamine far greater than those seen in the patients with BV—who also typically complain of a fishy vaginal odor. The absence of vaginal/cervical pathology in patients with trimethylaminuria precludes bacterial infection as a cause, and implies that excessive amounts of trimethylamine must be reaching the vaginal secretions from other sources. A single large dose or a weekÕs course of oral metronidazole (or tinidazole), a standard treatment for BV, may well be initially effective for treating trimethylaminuria, decreasing the ability of the gastrointestinal microbes to liberate trimethylamine from dietary precursors and hence reducing trimethylamine uptake and circulatory levels.16 However, with the cessation of medication and the reestablishment of the gastrointestinal microorganisms, the vaginal malodor will reappear.

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CONCLUSION

The possibility of trimethylaminuria as an underlying, but unappreciated, cause in patients who present with fish-like vaginal malodor should be considered —especially when no infectious cause can be identified. Although the two patients reported here displayed the primary genetic form of trimethylaminuria, thereby inheriting a relatively inefficient flavin monooxygenase system, 11 the consequences may be partially offset by decreasing the substrate load that the enzyme has to process. Modification of the diet to decrease trimethylamine intake has led to a reduction in odor problems, and appears to be an appropriate step in the management of this condition. 22-24

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ACKNOWLEDGEMENT

The authors would like to thank Dr R. Ayesh and staff in the Genito-Urinary Clinic of Saint MaryÕs Hospital, London, England, for assistance in the collection of clinical samples.

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S.C. Mitchell, Dsc, FRCPath, is a reader in drug metabolism, Faculty of Medicine, Division of Biomedical Sciences. R.L. Smith, DSc, (Hon)MRCP, is emeritus professor of pharmacology, Faculty of Life Sciences, Division of Biomedical Sciences. Both are at the Imperial College, Sir Alexander Fleming Building, South Kensington, London, England. J.R. Harris, FRCP, FRCP(I), is consultant physician in genitourinary/HIV medicine, Saint Mary's Hospital, Faculty of Medicine, Imperial College, Paddington, London, England.

References

1. Eschenbach DA, Hillier S, Critchlow C, Stevens C, DeRouen T, Holmes KK. Diagnosis and clinical manifestations of bacterial vaginosis. Am J Obstet Gynecol. 1988;158(4):819-828.
2. Hillier S, Holmes KK. Bacterial vaginosis. In: Holmes KK, Mardh PA, Sparling PF et al, eds. Sexually Transmitted Diseases. 2nd ed. New York, NY: McGraw-Hill; 1990:547-559.
3. Martius J, Krohn MA, Hillier SL, Stamm WE, Holmes KK, Eschenbach DA. Relationships of vaginal Lactobacillus species, cervical Chlamydia trachomatis and bacterial vaginosis to preterm birth. Obstet Gynecol. 1988;71(1):89-95.
4. Winceslaus SJ, Calver G. Recurrent bacterial vaginosisÑan old approach to a new problem. Int J STD AIDS. 1996;7(4):284-287.
5. Spiegel CA, Amsel R, Eschenbach D, Schoenknecht F, Holmes KK. Anaerobic bacteria in nonspecific vaginitis. N Engl J Med. 1980;303(11):601-607.
6. Hill LV. Anaerobes and Gardnerella vaginalis in non-specific vaginitis. Genitourin Med. 1985;61(2):114-119.
7. Chen KC, Forsyth PS, Buchanan TM, Holmes KK. Amine content of vaginal fluid from untreated and treated patients with nonspecific vaginitis. J Clin Invest. 1979;63(5):828-835.
8. Chen KC, Amsel R, Eschenbach DA, Holmes KK. Biochemical diagnosis of vaginitis: determination of diamines in vaginal fluid. J Infect Dis. 1982;145(3): 337-345.
9. Brand JM, Galask RP. Trimethylamine: the substance mainly responsible for the fishy odor often associated with bacterial vaginosis. Obstet Gynecol. 1986;68(5): 682-685.
10. Clay JC. The odour of non-specific vaginitis: a review. Eur J Clin Microbiol. 1982;1(5):317-319.
11. Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos. 2001;29(4 pt 2):517-521.
12. Ayesh R, Mitchell SC, Zhang A, Smith RL. The fish odour syndrome: biochemical, familial, and clinical aspects. BMJ. 1993;307(6905):655-657.
13. Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17(4):491-494.
14. Mitchell SC. The fish-odor syndrome. Perspect Biol Med. 1996;39(4):514-526.
15. Cashman JR, Camp K, Fakharzadeh SS, et al. Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr Drug Metab. 2003;4(2):151-170.

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