J. Endocrinol. Invest. 23: 557-559, 2000 557 Sub-fertility affects 1 in 6 to 1 in 10 couples. The problem is due in 20-25% of cases to the male part- ner, in 30-40% to the female, while in about 30% of cases abnormalities are found in both partners and in 15% no specific factor is identified (1). Difficulty to procreate is in contrast with the natural genetic program of any individual, which should work towards a peak of efficiency in order to achieve the reproduction, and the transmission of inherited traits to next generations. Modern indi- viduals are made up of a range of heritable char- acteristics, each present in the past generations, in ancestors generating most of the descendants (i.e. had the greatest reproductive success). Repro- ductive failure raises an important issue: why ge- netic programs of many individuals, shaped and honed so ruthlessly over the past millennia, are un- able to translate survival and actions into repro- duction? A critical prognostic factor in infertile couples is the duration of infertility. In fact, the possibility of achieving an unassisted pregnancy is quite low in couples with a history of primary infertility of longer than 3 years. In general, the two major causes of difficulty to procreate include clinical and behav- ioral problems. Clinical infertility appears quite high, particularly in Western societies. A study in 25 coun- tries, covering more than 10,000 infertile couples, has shown that tubal blockage in females and tes- ticular malfunctioning in males are the main causes in individuals with a definite diagnosis (WHO, 1990). Most of the causes are probably secondary to past or current infections, or consequent to exposure to a wide range of modern environmental pollutants. It is possible that physiological responses that would have led to reproduction in the past envi- ronments now falter or fail, some individuals never encountering throughout their life-time the partic- ular circumstances that in previous generations would have triggered reproduction. People carrying specific alleles which react in a maladaptive way with environment will be selected against. Natural selection is therefore active in individuals whose re- productive success is below the average, just as ruthlessly as it has ever done in the evolutionary past. The logical approach to the diagnosis of male in- fertility includes a detailed history, careful clinical examination, and selected investigations to detect etiological factors which can be classified as pre- testicular, testicular, and post-testicular (2). Male re- productive genes are subjected to a rapid evolu- tion driven by sexual selection, suggesting a high- er mutation rate (3). Infertile people may now have some opportunity to take advantage of assisted conception techniques and to reproduce. The re- sult may be the persistence and expansion of lin- eages which are only adapted to reproduce in the modern environment. This suggests the importance of knowing the biological effects of alleles associ- ated with human infertility. Many genes affecting fertility have pleiotropic ef- fects. A notable example is CFTR, a glycoprotein active in exocrine glands, which causes cystic fi- brosis (CF) in the presence of gene mutations af- fecting the protein structure and its production. However, the gene encoding CFTR is also mutat- ed in about two thirds of the patients with congen- ital bilateral absence of the vas deferens (CBAVD). The reproduction of males carrying CFTR mutations by MESA/ICSI techniques could raise to 50% the risk in offspring of either a mild or a severe form of CF. For couples with a CBAVD-related infertility, CFTR mutation analysis and genetic counseling of the patient and his partner are mandatory before performing MESA/ICSI procedures. Key-words: Male infertility, genetics azoospermia, oligozoospermia. Correspondence: Prof. Bruno Dallapiccola, Dipartimento di Medicina Sperimentale, Università “La Sapienza” Roma, Istituto CSS-Mendel, Piazza Galeno 5, Roma, Italy. INTRODUCTION Male infertility, pleiotropic genes, and increased risk of diseases in future generations B. Dallapiccola* and G. Novelli** *Cattedra di Genetica Medica, Università “La Sapienza”, and Istituto CSS-Mendel; **Cattedra di Genetica Umana, Università “Tor Vergata” Roma, Italy © 2000, Editrice Kurtis