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Azoospermia in familial Mediterranean fever patients:the role of colchicine and amyloidosis
  1. ELDAD BEN-CHETRIT
  1. Department of Medicine
  2. Nephrology and Hypertension Service
  3. Department of Gynaecology
  4. Department of Pathology
  5. Hadassah University Hospital, Jerusalem, Israel
  1. Dr E Ben-Chetrit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel, POB: 12000.
  1. REBECCA BACKENROTH
  1. Department of Medicine
  2. Nephrology and Hypertension Service
  3. Department of Gynaecology
  4. Department of Pathology
  5. Hadassah University Hospital, Jerusalem, Israel
  1. Dr E Ben-Chetrit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel, POB: 12000.
  1. RONIT HAIMOV-KOCHMAN
  1. Department of Medicine
  2. Nephrology and Hypertension Service
  3. Department of Gynaecology
  4. Department of Pathology
  5. Hadassah University Hospital, Jerusalem, Israel
  1. Dr E Ben-Chetrit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel, POB: 12000.
  1. GALINA PIZOV
  1. Department of Medicine
  2. Nephrology and Hypertension Service
  3. Department of Gynaecology
  4. Department of Pathology
  5. Hadassah University Hospital, Jerusalem, Israel
  1. Dr E Ben-Chetrit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel, POB: 12000.

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Familial Mediterranean fever (FMF) is a hereditary disease characterised by recurrent episodes of fever, peritonitis, pleuritis, arthritis or erysipelas-like skin lesions. The disease affects mainly Jews, Armenians, Arabs, and Turks. Typically, the episodes last two to three days and resolve spontaneously.1 One of the main complications of FMF is the development of secondary amyloidosis (AA type). The kidneys are the main target organ involved, leading to chronic renal failure.

Colchicine has been the preferred treatment for FMF since 1972.2 It is effective in suppressing the episodes in more than 90% of the patients and prevents both the development of amyloidosis and the additional deterioration of renal functions in those with early amyloidosis.3 Colchicine exerts its main effect at the cellular level by its interaction with tubulin at the microtubules, inhibiting motility and exostosis of intracellular granules.4 Furthermore, it has also a powerful antimitotic effect by causing metaphase arrest and is capable of arresting meiosis.5 Therefore, in cases of infertility in patients treated with colchicine, it has been speculated that this medication cause azoospermia.6

In this report we describe three patients with FMF and infertility who had been taking colchicine for about one to three years before the documentation of azoospermia. All the patients had FMF for at least four years.

Two of the patients (A and B) had nephrotic syndrome at the time of diagnosis and amyloid was demonstrated by kidney and rectal biopsies. The third patient (C) had no clinical signs of amyloidosis. None of the patients experienced any scrotal attack or epididimoorchitis. All of the patients had normal serum profile of sex hormones and a normal kariotype. However, in patient A, testicular biopsy disclosed marked atrophy with Sertrolli cells only. The blood vessels were thickened and their staining by Congo red revealed abundant amyloid (fig 1). In patient B, the biopsy revealed maturation arrest of the spermatocytes with amyloidosis of the walls of the blood vessels (fig 2). In the third patient testicular biopsy showed a pure maturation arrest. Congo red staining failed to show amyloidosis.

Figure 1

(A) Testicular biopsy specimen obtained from patient A, showing atrophy and fibrosis of the tubules without Leydig cell hyperplasia. Note the thickening of the walls of the tubules and the blood vessels (arrow). (B) Illustrating birefringence of amyloid deposits in tubular and blood vessels walls after Congo red staining.

Figure 2

(A) Testicular biopsy specimen obtained from patient C, disclosed maturation arrest and thickening of the walls of the blood vessels (arrow). (B) Illustrating birefringence of amyloid deposits in tubules and blood vessels after Congo red staining.

Since the introduction of long term preventive colchicine therapy for patients with FMF, concerns have been raised about the development of adverse effects of the drug, including infertility. Initial findings suggested that male fertility was not affected by colchicine.7 A study by Bremner and Paulsen failed to show any evidence for side effects in six healthy male volunteers with normal liver and kidney function, who received commonly used doses of colchicine during four to six months.8 However, later observations disclosed that, as many as 20% of male FMF patients receiving long term colchicine therapy may develop fertility problems associated with either azoospermia or impairment of sperm penetration.9 In a recent study, Sarica et al evaluated 62 male patients with Behcet’s syndrome who were taking colchicine.10 They claimed that oligospermia (<20 × 106/ ml) was present in 23 patients (37.1%) and azoospermia in two patients. Our experience in treating more than 150 (male) FMF patients, is much more favourable. We have found only two patients with oligospermia and none of whom had amyloidosis.

Usually, FMF associated amyloidosis of the AA type involves the kidneys, liver, spleen, heart, and intestines. Involvement of the testes has been seldom reported. In an animal model, testicular amyloidosis was induced in hamsters by infecting the animals withLeishmania donovani.11 Testicular biopsies disclosed total azoospermia in the final week of the pathological process. This study and other sporadic cases12 show that amyloidosis by itself can cause oligo or azoospermia.

In FMF patients, it is tempting to ascribe the complication of azoospermia to colchicine therapy. However, testicular biopsies in two of our cases demonstrated amyloidosis of the testes. Furthermore, one of the patients had taken little colchicine before the diagnosis of infertility. Therefore, it is conceivable that the pathological process of amyloidosis may also be responsible for azoospermia in these patients.

The relatively high frequency of oligospermia and azoospermia in patients with Behcet’s disease10 compared with patients with FMF or gout is puzzling. The common presence of epididymitis or vasculitis, or both, of the testes in Behcet’s disease may have an important role in predisposing the patients to this complication while they are taking colchicine. In FMF, recurrent orchitis or epididimitis are relatively rare. However, amyloidosis of the testicular blood vessels in these patients may have a role parallel to the vasculitis in Behcet’s disease in predisposing to azoospermia while on colchicine therapy.

Based upon these findings we propose that the possibility of testicular amyloidosis should be included in the differential diagnosis of oligo or azoospermia in FMF patients.

References

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