Early life events predict adult testicular function; data derived from the Western Australian (Raine)
birth cohort.
R.J. Hart
1,2,10
, D.A. Doherty
1,3
, J.A. Keelan
1,3
, R. McLachlan
4,5
, N.E. Skakkebaek
6
, R.J. Norman
7
, J.E.
Dickinson
1
, C.E. Pennell
1,3
, J.P. Newnham
1,3
, M. Hickey
8
, D.J. Handelsman
9
.
1
School of Women's and Infants' Health, University of Western Australia, Perth, WA, Australia, 6008;
2
Fertility Specialists of Western Australia, Bethesda Hospital, 25 Queenslea Drive, Claremont, WA
6010, Australia
3
Women and Infants Research Foundation, King Edward Memorial Hospital, Perth; Western
Australia, Australia.
4
Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne,
Australia.
5
Monash University, Clayton, Australia
6
University Department of Growth and Reproduction, Rigshospitalet, Department of Growth and
Reproduction, Copenhagen, Denmark.
7
Robinson Institute, University of Adelaide, Adelaide, Australia.
8
Department of Obstetrics and Gynaecology, The University of Melbourne, The Royal Women's
Hospital, Melbourne, Australia.
9
ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, Australia.
Abbreviated title: Early life influences on adult testicular function
Key words; Raine study, Testicular function, early life exposure, cord blood, growth, cigarette
smoking, in-utero, adiposity, estrogen, sperm count.
Word count; 3,112 words, 4 tables, 4 figures
Manuscript (MUST INCLUDE TITLE PAGE AND ABSTRACT) Click here to download Manuscript (MUST INCLUDE TITLE
PAGE AND ABSTRACT) Revised Manuscript.docx
10
Correspondence and reprint requests to
Prof. Roger Hart
King Edward Memorial Hospital
374 Bagot Road
Subiaco
Perth Western Australia 6008
Tel +618 93401322
Fax +61 8 93813031
E-mail roger.hart@uwa.edu.au
Study funding/competing interest(s) This study was supported by Australian NHMRC Grant Number
634457 and received support from the Raine Medical Research Foundation, The Telethon Kids
institute, The University of Western Australia, Women and Infant Research Foundation, Curtin
University and Edith Cowan University.
Authors disclosures; DAD, JAK, JED, NES, CEP, JPN, MH have nothing to declare. RJH is Medical
Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and in the
last two years has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals.
RMcL has equity interests in the Monash IVF Group. RJN has equity interests in FertilitySA, and in the
last two years has received grant support from Merck Serono and Ferring Pharmaceuticals. DJH has
received grants support from Basins and Lawley.
Grant Funding: This work was supported by NHMRC project grant (no 634557).
Abstract
Context The impact of early life events on testicular function in adulthood is not well understood.
Objective To study the early influences of fetal growth, exposures to cigarette smoke in-utero and
cord blood estrogens, and the influences of growth and adiposity in childhood through adolescence;
on testicular function in adulthood.
Design Male members of the Western Australian Pregnancy Cohort (Raine) were contacted at 20-22
years of age. Of 913 contacted 423 (56%) agreed to participate; 404 underwent a testicular
ultrasound, 365 provided a semen sample and reproductive hormones were measured (384). Fetal
growth measurements (n=137), umbilical cord estrogen concentrations (n=128), cord testosterone
(n=125), and child-adulthood growth charts (n=395) were available.
Results Median sperm output for the 18.6% of men exposed in-utero to smoking was lower than
non-exposed (82.4x10
6
vs 123.1x10
6
, p=0.029).
Sperm output in adulthood was inversely correlated with cord serum oestradiol
(p=0.019) and
estrone (p=0.018). The sperm output of men whose cord blood estradiol and estrone were <50
th
centile vs >50
th
centile was 191.1x10
6
vs 100.5x10
6
(p=0.002) and 190.0x10
6
vs 106.0x10
6
(p=0.012)
respectively.
Men with favorable fetal growth patterns in-utero were less likely to have total motile sperm counts
(TMS) within the lowest quartile (p=0.011), and men born prematurely had reduced serum
testosterone levels in adulthood, (13.4 vs 16.6nmol/L, p=0.024).
Consistent height above the 50
th
centile for age through childhood was associated with larger adult
mean testicular volume (TV) (p<0.001). Optimal BMI trajectory through childhood and adolescence
was associated with larger TV (p=0.009), and higher serum inhibin B (p=0.010) and testosterone
(p=0.003) in adulthood.
Conclusions. Exposures to maternal smoking and higher cord blood estrogens at delivery were
associated with a reduced sperm output in adulthood. Optimal adult testicular function depends on
being born at or above average weight, and maintaining optimal growth and adiposity into
adulthood.
Funding NHMRC project grant 634557.
Introduction
The influence of maternal health and early life events upon the subsequent growth and
development of a child and its lifelong predisposition to disease is well established (1). Apart from
exposure to maternal smoking leading to a reduction in semen parameters (2-5), and hormonal
markers of testicular function in adulthood (4, 5), early life influences upon testicular function in
adulthood are poorly understood. No association has been identified between birthweight or body
mass index (BMI) in childhood with semen quality in adulthood (6). Although the association of
reduced semen parameters with smoking (7) and drinking alcohol (8) in adulthood is established, the
association with obesity remains uncertain (9-12).
It is unclear whether sperm densities have been diminishing across the Western World (13-17).
Although animal studies demonstrate that exposure to exogenous estrogens (18, 19), androgen
receptor blockers (18), and sufficient doses of environmental xenoestrogens (19) can damage
testicular function. Furthermore, despite the increasing prevalence of xenoestrogens in the
environment, claims of adverse effects of global estrogen pollution on testicular function are largely
refuted by evidence that domestic animal sperm production has not changed during the last century
(20), and that men exposed prenatally to a high doses of diethylstilboestrol have normal adult
testicular function and fertility (21). Indeed the human testis appears less susceptible to exogenous
estrogens than some animal models (22), hence caution must be exercised when extrapolating data
from animal studies.
Our aim was to study the effects of early influences such as prenatal smoking, growth restraint,
prematurity, and cord blood estrogens as well as childhood and adolescent growth trajectories and
adiposity upon adult testicular function, in a birth cohort featuring reduced selection and
participation bias relative to previous studies (23).
![Table 5. Testicular volume and semen parameters and their association with steroid hormone concentrations in mixed cord blood, unless otherwise specified stratified above and below their 25th percentiles. (* Morphology above and below the 4% WHO morphology criteria, [representing the 27th centile for morphology])](/figures/table-5-testicular-volume-and-semen-parameters-and-their-39sjs0a6.webp)