Infertility occurs in 10-15% of couples with male factor infertility representing ~50% of cases [1]. The incidence of genetic causes related to male infertility seems to be increasing [2]. In addition to genes on the Y chromosome, genes on autosomal chromosomes also appear to be implicated in spermatogenesis [3].
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by iron overload leading to hepatic cirrhosis, diabetes mellitus, hypogonadism, arthropathy and cardiomyopathy, if untreated [4]. Patients absorb only a few milligrams of iron in excess of physiological needs per day, so that clinical manifestations often occur between 40-60 years of age, when 20-40 g of excess iron have accumulated. Symptoms occur more frequently in males than in females due to the protective effects of physiological blood loss during menstruation [5].
The hemochromatosis (HFE) gene is located at 6p21.3, some 4.5 Mb telomeric to HLA-A, and encodes a protein highly similar to HLA class I molecules [6]. Two missense mutations were initially identified: a C->T substitution that changes the 282 cysteine to tyrosine (C282Y) and a C->G transition that changes the 63 histi­dine to aspartic acid (H63D). The C282 homozygosity occurs in 80-100% of HH patients of North European descent [6-8], but lower frequencies are associated with clinical disease in Mediterranean and Southern European populations [9,10]. The frequency of the C282Y hetero­zygosity in Caucasian subjects of European ancestry is ~10-15% [11], while the H63D heterozygosity is present in 15-40% of Caucasians. Some compound heterozygotes (C282Y/H63D) develop clinical symptoms of HH. The H63D is not as penetrant as the C282Y mutation, although rare cases of HH with an H63D homozygosity have been reported [12]. A third mutation, an A->T transition, that replaces 65 serine with cysteine (S65C) is present in ~1.5% of the European population, and may cause a mild form of HH in combination with C282Y [13]. Other rare mutations have been reported in individual families [14,15].
Loss of libido and testicular atrophy are common in HH patients, with loss of potency occurring in up to 35% of men and amenorrhea in 15% of women. Hypogonadism may be due to hypothalamic, pituitary or gonadal dysfunction [16]. Since the frequency of the two most common HFE mutations among infertile males has not been reported, we determined the frequency of HFE mutations between infertile/subfertile males and fertile males to assess a possible association of HFE mutations with male infertility.