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Male subfertility has been attributed to hypothalamicpituitary disorders; developmental, structural, and acquired testicular defects; or impairment of sperm transport(1). However, in nearly half of the cases, no known causal factors or associated conditions were found (idiopathic or unexplained subfertility)(2).

The association between male gonadal dysfunction and severely reduced fetal growth has long been recognized(3, 4). We examined whether hitherto unexplained male subfertility is associated with moderately reduced fetal growth, as judged by low birth weight.

METHODS

The study aimed to include all male partners of couples (n ≅ 522) consulting because of subfertility between July 1995 and November 1996. Birth weight and gestational age, as well as present height and weight, were asked for by questionnaire. A semen sample was obtained in the hospital, 3-5 d after the last intercourse. Semen analysis was performed according to World Health Organization standards within 60 min after collection, and was considered normal if the sperm count was >20 million/mL and if > 50% of the cells were progressively motile(5); morphology was not taken into account because of low sperm density in the abnormal semen samples.

Men with abnormal semen analysis were referred to a single andrologist for medical history and clinical and laboratory examination. In addition, a standardized questionnaire was used to disclose further causes of male subfertility(6). Serum concentrations of FSH and LH were measured by immunoradiometric assay (Medgenix) and testosterone by RIA. Classification into explained or unexplained subfertility was performed by the andrologist independently of information on birth weight.

Data on birth weight and gestational age were available from a total of 214 men. The study population appeared to be representative for the clinic (seeTable 1). Birth weight was transformed into SD scores for gestational age, according to Flemish references. Of the 214 values, 206 were within 3 SD from the mean and were maintained for further analysis; there were four outliers in both the fertile and the subfertile group. The Mann-WhitneyU test was used for statistical comparisons.

Table 1 Age, adult height, BMI, birth weight, gestation length, sperm characteristics (median and range) in the study population and endocrine results in men with subfertility
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RESULTS

A total of 128 men had a normal sperm analysis and served as controls. Of the 78 men with abnormal sperm analysis (38% male factor), 60 presented for andrologic examination. Twenty-eight men (47%) were classified as having explained subfertility, which was attributed to cryptorchism (n = 10), varicocele with reflux confirmed by Doppler ultrasonography (n= 14), genetic anomaly (n = 1, Robertsonian translocation, t(13:14), trauma with hematoscrotum (n = 2), or genitourinary tract infection(n = 1). Thirty-two men (53%) were classified as having unexplained subfertility. Age, adult height, BMI, and sperm characteristics are presented in Table 1, as are the serum FSH, LH, and testosterone concentrations of men with subfertility.

Figure 1 shows birth weight SD scores of controls and of men with unexplained subfertility. Birth weight SD scores of men with normal sperm analysis were normally distributed, with a median of 0.0(P25-P75 range: -0.7 to 1.0) comparable (p = 0.48) to that of men with explained subfertility (n = 28: median 0.5 SDS; P25-P75 range: -0.6 to 0.9) and higher (p = 0.012) than that of men with unexplained subfertility (n = 32; median -0.5 SDS; P25-P75 range: -0.9 to -0.1).

Figure 1
figure 1

Birth weight SD scores of control subjects and of men with unexplained subfertility. Medians are indicated within P25-P75 ranges.

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DISCUSSION

Hitherto unexplained male subfertility appears to be associated with low birth weight. A link between male hypogonadism and low birth weight has been suggested for half a century(3). This link has been emphasized in adolescents with pronounced prenatal and postnatal growth retardation and with a characteristic physiognomy, so-called Silver-Russell syndrome(4). The present observations extend the aforementioned link to a range of birth weight that is well within normal limits. In this context, it is noteworthy that a low normal birth weight does not exclude the possibility that severe prenatal growth retardation did occur, but over a short time span, for example during a critical window of development. Alternatively, the male gonadal axis may be more sensitive than previously thought to prenatal conditions associated with growth restriction.

Several reports have suggested that sperm counts in men are declining during the past 30-50 y(7). Concomitantly the incidence of genitourinary abnormalities, such as testicular cancer, hypospadias, and cryptorchism is increasing(8–10). As these abnormalities probably arise during fetal development, an adverse effect of toxic or environmental agents (such as estrogens) on the fetal developing reproductive system is suspected(11–13).

Sperm production is limited by the number of Sertoli cells and/or the efficiency of spermatogenesis. Animal studies have shown that alteration of the number of Sertoli cells in early life determines testicular size and sperm output (not the quality but the quantity) in adulthood(14). As FSH is most important in regulating Sertoli cell multiplication, modulation of serum FSH in early fetal life may influence male gonadal function(12, 15).

The observed association supports and extends the fetal origin hypothesis. In this concept, the growth-retarded fetus adapts to undernutrition by altering some endocrine and metabolic set points(16). Low birth weight is known to be associated with increased risk for cardiovascular disease in later life(16), and recent studies have consolidated the associations of low birth weight with somatotropic and adrenocorticotropic dysfunction, as well as with decreased insulin sensitivity in childhood(17–19). The present study extends the range of diseases in adulthood that may be associated with low birth weight to include also subfertility. The pathophysiologic mechanisms governing these associations now remain to be unraveled.