Pediatric Research - Fulltext: Volume 42(6) December 1997 p 899-901 Low Birth Weight and Subsequent Male Subfertility





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Pediatric Research:Volume 42(6)December 1997pp 899-901

Low Birth Weight and Subsequent Male Subfertility [Rapid Publication]

Department of Paediatrics [I.F., F.d.Z.] and Fertility Center [C.S., T.D'H., D.V.], University of Leuven, Belgium Received for rapid publication May 27, 1997: accepted August 20, 1997 Correspondence and reprint requests: F. de Zegher, M.D., Ph.D., Department of Paediatrics, University Hospital, Gasthuisberg, 3000 Leuven, Belgium.

Male subfertility often remains unexplained. Severe intrauterine growth retardation has previously been linked to hypergonadotropic hypogonadism. We examined whether reduced fetal growth, as judged by low birth weight, is associated with unexplained male subfertility later in life. Birth weight and gestational age were obtained by questionnaire from male partners of couples consulting for subfertility, and were transformed into birth weight SD scores. Men with normal semen analysis (n = 128) had a median birth weight SD score of 0.0 (P25-P75 range: -0.7 to 1.0), comparable to that of men with explained subfertility (n = 28), and higher (p= 0.012) than that of men with unexplained subfertility (n = 32; median -0.5 SD score; P25-P75 range: -0.9 to -0.1). These results extend the link between reduced fetal growth and male subfertility to a range of birth weight that is well within normality. The pathophysiologic mechanism governing this association now remains to be unraveled.

Article Outline ● ABSTRACT ● METHODS ● RESULTS ● DISCUSSION ● REFERENCES Figures/Tables ● Table 1 ● Figure 1

Abbreviation: BMI, body mass index 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.

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!1675702673!181195628!8091!-1 (1 of 4) [2008-03-25 21:28:21]

Pediatric Research - Fulltext: Volume 42(6) December 1997 p 899-901 Low Birth Weight and Subsequent Male Subfertility.

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

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

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. Acknowledgment. The authors gratefully acknowledge the assistance of Karin Vanweser in the preparation of the manuscript.!1675702673!181195628!8091!-1 (2 of 4) [2008-03-25 21:28:21]

Pediatric Research - Fulltext: Volume 42(6) December 1997 p 899-901 Low Birth Weight and Subsequent Male Subfertility.

1. Griffin JE, Wilson JD 1992 Disorders of the testes and the male reproductive tract. In: Wilson JD, Foster DW (eds) Williams Textbook of Endocrinology. WB Saunders, Philadelphia, pp 828-830 [Context Link] 2. Baker HG, Burger HG, de Kretser DM 1986 Relative incidence of etiological disorders in male infertility. In: Santen RJ, Swerdloff RS (eds) Male Reproductive Dysfunction: Diagnosis and Management of Hypogonadism, Infertility and Impotence. Marcel Dekker, New York, pp 341-372 [Context Link] 3. Silver HK 1953 Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropin. Pediatrics 12:368 [Medline Link] [Context Link] 4. Angehrn V, Zachmann M, Prader A 1979 Silver-Russell syndrome. Observations in 20 patients. Helv Paediatr Acta 34:297-308 [Context Link] 5. WHO 1992 Collection and examination of human semen. In: World Health Organization Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Cambridge University Press, Cambridge, pp 3-27 [Context Link] 6. Rowe PJ, Comhaire FH, Hargreave TB, Mellows HJ 1993 Male partner. In: World Health Organization Manual for the Standardized Investigation and Diagnosis of the Infertile Couple. Cambridge University Press, Cambridge, pp 6-39 [Context Link] 7. Carlsen E, Giwercman A, Keiding N, Skakkebaek N 1992 Evidence for decreasing quality of semen during past 50 years. BMJ 305:609-613 [Context Link] 8. Akre O, Ekbom A, Hsieh CC, Trichopoulos D, Adami HO 1996 Testicular nonseminoma and seminoma in relation to perinatal characteristics. JNCI 88:883-889 [Context Link] 9. Sweet RA, Schrott HG, Kurland R, Culp OS 1974 Study of the incidence of hypospadias in Rochester, Minnesota, 1940-1970, and a case-control comparison of possible etiologic factors. Mayo Clin Proc 49:52-58 [Context Link] 10. Berkowitz GS, Lapinski RH, Godbold JH, Dolgin SE, Holzman IR 1995 Maternal and neonatal risk factors for cryptorchidism. Epidemiology 6:127-131 [CrossRef] [Context Link] 11. Sharpe RM, Skakkebaek NE 1993 Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 341:1392-1395 [Medline Link] [CrossRef] [Context Link] 12. Sharpe RM 1993 Declining sperm counts in men-is there and endocrine cause? J Endocrinol 136:657-660 [Context Link] 13. Kold Jensen T, Toppari J, Keiding N, Skakkebaek NE 1995 Do environmental estrogens contribute to the decline in male reproductive health? Clin Chem 41:1896-1901 [Context Link] 14. Orth JM. Gunsalus GL, Lamperti AA 1988 Evidence from Sertoli cell-depleted rats indicates that spermatid number in adult depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 122:787-794 [Context Link] 15. Cortes D. Muller J, Skakkebaek NE 1987 Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Int J Androl 10:589-596 [Context Link] 16. Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS 1993 Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938-941 [Medline Link] [CrossRef] [Context Link] 17. de Zegher F, Francois I, van Helvoirt M, Van den Berghe G. 1997 Small as fetus and short as child: from endogenous to exogenous growth hormone. J Clin Endocrinol Metab 82:2021-2026 [CrossRef] [Context Link] 18. Francois I, de Zegher F 1997 Adrenarche and fetal growth. Pediatr Res 41:440-442 [Fulltext Link] [CrossRef] [Context Link] 19. Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA, Gluckman PD 1997 Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 82:402-406 [CrossRef] [Context Link]

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Pediatric Research - Fulltext: Volume 42(6) December 1997 p 899-901 Low Birth Weight and Subsequent Male Subfertility.

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