Testicular function and fertility in men with homozygous alpha-1 antitrypsin deficiency

Fertility and testicular function were studied in eight men with severe homozygous (Pi ZZ variant genotype) alpha-1 antitrypsin (AAT) deficiency. Age- and marital duration standardized fertility, clinical androgenic features, mean testicular volume, plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and semen analysis were all normal apart from a reduction in semen volume. Mean plasma total and free testosterone were elevated and the percentage free testosterone reduced compared with age-matched, healthy fertile controls indicative of increased sex-hormone binding globulin (SHBG) levels representing an early marker for subclinical hepatic dysfunction associated with AAT-deficiency. In view of the preservation of normal fertility and testicular function despite chronic respiratory disease and premature death with deleterious AAT gene variants, it is proposed that the high prevalence of genetic polymorphism in the AAT protein may be maintained by the chronological asynchrony of the periods of maximal male reproductive activity (40 years) and the late onset (greater than 40 years) of symptoms in severe AAT deficiency rather than by any balance between reduced reproductive fitness of homozygotes and heterozygote advantage.