Low birth weight for gestational age and subsequent male gonadal function

doi:10.1067/mpd.2002.126300

The Journal of Pediatrics

Volume 141, Issue 3, September 2002, Pages 376-380

https://doi.org/10.1067/mpd.2002.126300 Get rights and content

Abstract

Objective: To verify whether a reduced birth weight for gestational age was associated with a testicular dysfunction in postpubertal boys. Study design: Boys born small for gestational age (SGA) (n = 25) were compared to 24 born with an appropriate weight. All subjects were postpubertal (mean age 17.5 ± 1.3 and 17.6 ± 2.0 years, respectively). The following clinical and endocrinologic variables were evaluated: final height, target height, body mass index, testicular volume, follicle-stimulating hormone, luteinizing hormone, testosterone, and inhibin B. Results: The SGA group had reduced testicular size (16.3 ± 2.7 mL vs 22.8 ± 3.2 mL; P <.0001) with a lower testosterone level (3.76 ± 1.35 ng/mL vs 4.77 ± 1.55 ng/mL; P <.05) and a higher LH value (4.41 ± 1.61 IU/L vs 3.44 ± 1.29 IU/L; P <.05). Among the SGA group, 54% had a mean testicular volume >2 SD below the control mean (ie, <16 mL) and in these subjects, the inhibin B level was low (143 ± 46 pg/mL vs 229 ± 76 pg/mL; P <.0001). SGA patients with smaller testes had lower final height relative to target height(P <.05 vs patients with larger testes) and for the SGA group, inhibin B correlated with testicular size (P <.0001). Positive correlations also were found between the reduction of final height relative to target height and testicular volume (P <.005) and inhibin B values (P <.05). Conclusions: SGA subjects have pituitary-gonadal axis function that tends toward hypogonadism. There is a disruption of the exocrine function in subjects with smaller testicular size who failed to show a complete height catch-up growth. This study supports a link between low birth weight and lower fertility in adult males. (J Pediatr 2002;141:376-80)

Section snippets

Subjects

Boys (n = 25) born small for gestational age (SGA) (birth weight <10th percentile for gestational age)¹² were examined at a mean age of 17.5 ± 1.3 years (range, 15.2-20.8). Mean birth weight was 1689 ± 368 g (range, 800-2050) and mean gestational age was 36 ± 2 weeks (range, 28-40). Subjects with chromosomal, intrauterine infection or syndromal causes for intrauterine growth retardation were excluded. Five of these subjects had been corrected for unilateral (4 cases) or bilateral (1 case)

Results

The study consisted of 49 young men; 25 were SGA and 24 had an appropriate neonatal weight (Table).Although FH SD score was similar in the two groups, TH was significantly lower in the control group because these subjects were followed for constitutional short stature that is often familial. SGA patients did not reach their potential adult stature because they had a decrease of FH compared with TH that was significantly higher than in control subjects.

Mean testicular volume was reduced in SGA

Discussion

The definition of SGA as a birth weight <10th percentile for gestational age is commonly used,14, 15, 16 and SGA children may be at increased risk for some adult diseases.1, 2, 3, 4, 5, 6, 7, 8, 9 A link between male hypogonadism and low birth weight was suggested.17, 18 Francois et al¹¹ correlated unexplained subfertility in men with a reduced birth weight SD score compared with normal controls. Recent clinical investigations have demonstrated the role of inhibin B in the regulation of

Acknowledgements

We thank Stefano Gualandi, PhD, for technical assistance.

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Cited by (94)

Effects of assisted reproductive techniques on offspring gonadal function: a systematic review and meta-analysis
2023, F and S Reviews
To evaluate whether the use of assisted reproductive techniques (ARTs) affected the gonadal function of the offspring. Numerous concerns have emerged over the years about the use of ARTs and their effects on the health of the offspring.
Data were extracted through extensive searches in the PubMed and Scopus databases from their establishment until August 2022. Meta-analysis was performed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. All eligible studies were selected according to the Population, Exposure, Comparison/Comparator, Outcomes, Study design model. All studies that analyzed pubertal development and testicular and ovarian function of offspring conceived using ARTs were included. The quality of the studies was assessed using the Cambridge Quality Checklists. For the different outcomes, the standardized mean difference (SMD), the mean difference, and the odds ratio were evaluated. Cochran-Q and I² statistics were used to evaluate statistical heterogeneity. Differences in pubertal development, hormone levels, and sperm function in ART-conceived subjects compared with spontaneously conceived (SC) control subjects.
Children conceived using ART do not appear to have impaired pubertal development or achievement of pubertal milestones. From an endocrine point of view, ART-conceived males showed lower sex hormone-binding globulin levels than the control group (SMD = −0.25 [−0.44, −0.05]; I² = 29%) and a tendency to lower testosterone levels (SMD = −0.16 [−0.32, 0.01]; I² = 0). Lower levels of inhibin B, on the other hand, were present only in intracytoplasmic sperm injection-born males compared with the control group (SMD = −0.24 [−0.44, −0.04]; I² = 0). In females, higher luteinizing hormone levels were found in the ART group than in the control group (SMD = 0.33 [0.06, 0.59]; I² = 17%). In contrast, lower levels of 17ß-estradiol were observed only in the intracytoplasmic sperm injection group compared with girls with SC (SMD = −0.39 [−0.74, −0.03]; I² = 0). However, no definitive conclusions can be drawn considering the heterogeneity of hormonal assessments in females. Finally, young adults born from ART had a reduced sperm concentration (SMD = −0.34 [−0.57, −0.11]; I² = 0), total sperm count (SMD = −0.28 [−0.51, −0.05]; I² = 0), and normal sperm morphology (SMD = −0.35 [−0.58, −0.13]; I² = 0) compared with those SC.
A slight alteration in the function of the male germinal epithelium appears to be associated with the use of ART, as shown by the reduced levels of inhibin B and the altered sperm parameters.
Birth characteristics in men with infertility
2020, Reproductive BioMedicine Online
Citation Excerpt :
On the other hand, a registry study from 2001 (Ozturk et al., 2001) found no association between LBW and male infertility (diagnosed using World Health Organization criteria [WHO] from 1999, when the cut-off levels for a normal semen sample were higher). If the fetus is exposed to an unfavourable environment, the risk of altered development of genital organs increases, which might affect reproductive function (Francois et al., 1997; Cicognani et al., 2002; Main et al., 2006; Faure et al., 2015). The aim of the present study was to describe the birth characteristics of male partners in couples with infertility.
Are low birth weight, prematurity, being born small for gestational age, or both, associated with a higher risk of male factor infertility in adulthood?
Retrospective study of a clinical sample of 892 men, diagnosed with an infertility factor (male, female, combined or unexplained) together with their female partner at a University Hospital clinic in Sweden between 2005 and 2010. Data on birth weight and gestational age at birth were retrieved from the Swedish Medical Birth Register. The distribution of non-optimal birth characteristics in relation to infertility factor was described. A control group was created consisting of two men for each index man, born in Sweden in the same year as each index men, as well as a reference group consisting of all men born in Sweden the same years.
The likelihood of having been born small for gestational age was almost fivefold higher in men with male factor infertility than in men with unexplained infertility (OR 4.84, 95% CI 1.32 to 17.80). Men with male factor infertility were more often born with non-optimal birth characteristics than the control group (14.8% versus 8.5%; P = 0.010) and the reference group (14.8% versus 11.4%; P < 0.001). Men with azoospermia were more often born with non-optimal birth characteristics, compared with men without azoospermia (21.3% versus 12.1%; P = 0.038).
The results suggest an association between intrauterine growth restriction and male factor infertility in adulthood.
Androgen receptor expression in preputial dartos tissue correlates with physiological androgen exposure in congenital malformations of the penis and in controls
2020, Journal of Pediatric Urology
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Whether other local mechanisms (e.g., local immunological or vascular factors) show a similar age-related pattern is unclear and warrants further studies. Cryptorchidism and low birth weight occur with increased frequency in boys with hypospadias and may be associated with decreased testicular function later in life [27,28]. However, no difference in AR expression, based on immunohistochemical AR staining, was found in cases with cryptorchidism, nor in those born preterm or SGA in comparison with controls.
The androgen receptor (AR) plays an important role in the development of male genitalia, and impaired androgen signalling has been hypothesised to underlie congenital penile malformations (CPM) such as hypospadias. Previous studies exploring the role of AR expression in the development of CPM have yielded conflicting results.
To assess AR expression in human foreskin of boys/men born with hypospadias, buried penis versus controls.
Foreskin samples of 428 boys and men undergoing primary penile surgery (198 controls, 197 hypospadias, and 33 buried penis) were collected between October 2013 and July 2018. AR staining was performed in all samples and semi-quantitatively scored by two researchers independently, using a modified quick score (mQuicks) that assesses the proportion and intensity of AR staining in smooth muscle fibres.
The interobserver variability of the mQuicks had a high level of agreement for the total score, as well as for the subscores. Two phases of high AR expression were observed in all groups, the first following the postnatal gonadotropin surge (i.e., mini-puberty) and the second in (pre-) puberty. No differences in AR expression were found in hypospadias or buried penis cases as compared to controls matched for age at time of surgery.
This study describes the physiological evolution in AR expression in the human foreskin of boys with CPM and explains the cause of the previously reported, conflicting results. Despite the very large cohort, the limitations of this study are the low number of cases younger than six months at the time of surgery and the lack of Tanner stages to correlate with the mQuicks in adolescents.
The mQuicks is a straightforward and informative tool to semi-quantitatively assess AR expression in the dartos tissue. In this study, AR expression in human foreskin shows a bimodal distribution in boys with CMP and controls, following physiological androgen exposure. No statistically significant difference in AR expression could be found between both groups. Whether other local mechanisms are affected by these physiological changes is currently unclear. However, strict age-matching should be considered when exploring the mechanisms underlying disturbed penile and urethral development in CMP.
Review: Understanding the role of androgens and placental AR variants: Insight into steroid-dependent fetal-placental growth and development
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It is unclear how androgens affect intrauterine growth outcomes. Human population studies have demonstrated small for gestational age (SGA) male neonates have significantly reduced levels of testosterone when compared to appropriate for gestational age (AGA) neonates [32]. Similarly, Carlsen et al. [33] demonstrated negative associations between testosterone levels at 17 and 33 weeks’ gestation and birthweight (g) in female neonates.
The role of steroids throughout pregnancy and their effect on placental physiology is well established, especially for estrogens, progestogens, and glucocorticoids; however, the role of androgens – particularly within the context of placental physiology – remains largely unexplored. Androgens are often defined as the male sex-steroids and are fundamental for the defeminisation and masculinisation of male fetuses. Therefore, the placenta may adapt to these steroids in a sex-specific manner, with males being more receptive to changes in these steroids concentrations, when compared with females; however, their involvement in female intrauterine development has been investigated in several studies and may suggest females have a level of responsiveness to these steroids. While the former may be true, studies have reported sex-specific differences in the expression and activity of factors involved in androgen biosynthesis and bioavailability, with males consistently demonstrating greater degrees of altered protein and gene expression when compared with females. Understanding the placental androgen axis is essential as many pregnancy comorbidities are associated with elevated concentrations of androgens and perturbed intrauterine development or growth. Indeed, it appears that specific pathophysiologies of pregnancy can modulate the activity of key factors involved in the placental androgen axis and this may contribute to the etiology of sex-specific developmental outcomes from certain pregnancy complications. This review will provide insight into what is currently known regarding androgen signalling and the human placenta, and how this complex system may regulate sex-specific growth and developmental outcomes in normal and adverse pregnancies.
IUGR: Genetic influences, metabolic problems, environmental associations/triggers, current and future management
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The children with intrauterine growth restriction (IUGR) especially if they make a catch-up growth in early life have a higher risk for long term problems including short stature and also developing metabolic syndrome, Type 2 diabetes, insulin resistance and cardiovascular diseases. The studies also support that these children may have abnormalities in pubertal timing, adrenarche and reproductive function. The aim of this review was to summarize the published reports mainly on puberty and reproductive functions in children born IUGR at older ages in association with metabolic problems that they encounter. Possible mechanisms explaining these outcomes are discussed. Lastly strategies that may be taken for the prevention of IUGR related morbidities at later life are shortly presented.
Intrauterine Growth Restriction: Postnatal Monitoring and Outcomes
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Insulin resistance, dyslipidemia, and hyperandrogenism can lead to PCOS in adolescence. Boys who were born SGA may have smaller testicular volume and lower serum inhibin B and testosterone concentrations.109 Growth-restricted boys could have abnormal sperm counts as a result of lower birth weight.

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^☆: This paper was partially presented as a poster at the LWPES and ESPE 6th Joint Meeting, July 6-10, 2001, Montréal, Québec, Canada.

^☆☆: Reprint requests: Prof Alessandro Cicognani, MD, Clinica Pediatrica, Università degli Studi di Bologna, Via Massarenti 11, 40138 Bologna, Italy.

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Original ArticlesLow birth weight for gestational age and subsequent male gonadal function☆,☆☆

Abstract

Section snippets

Subjects

Results

Discussion

Acknowledgements

Lancet

Lancet

Lancet

Early Hum Dev

J Pediatr

J Pediatr

Fertil Steril

Blood pressure in a national birth cohort at the age of 36 related to social and familial factors, smoking and body mass

BMJ

Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15,000 Swedish men and women born 1915-29

BMJ

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (syndrome X): relation to reduced fetal growth

Diabetologia

Adrenarche and fetal growth

Pediatr Res

Insulin resistance in short children with intrauterine growth retardation

J Clin Endocrinol Metab

Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth

J Clin Endocrinol Metab

Low birth weight and subsequent male subfertility

Pediatr Res

Original Articles
Low birth weight for gestational age and subsequent male gonadal function☆,☆☆