Impact of changes in human reproduction on the incidence of endocrine-related diseases

Figures & data

Graph 1. Age-adjusted testicular cancer incidence rates per 100,000 population England, from 1971 to 2016. Source: Cancer registration data, England.

Graph 2. Proportional differences in parity, in the Netherlands, in 1950 and 2015, data from Statistics Netherlands.

Table 1. Impact of changes in birth order distribution on testicular cancer incidence in 1950 and 2015 in the Netherlands.

Birth order	Relative risk (Prener et al. 1992)	p children born in 1950	Product 1950	p children born in 2015	Product 2015
1st	1.0 (Reference)	.272	0.272	.455	0.455
2nd	0.9	.246	0.2214	.368	0.3312
3rd	0.7	.171	0.1197	.127	0.0889
≥4	0.3	.312	0.0936	.049	0.0147
∑		1	0.7067	1	0.8898
% increase explained		(0.8898–0.7067)/0.7067 = 0.259 = 26%

Changes in birth order (or family size) between 1950 and 2015 explain a 26% increase of testicular cancer in boys born in these years.

Table 2. Impact of changes in maternal age and parity on the prevalence of hypospadias in the Netherlands in 1950 and 2016.

Parity maternal age	Relative risk (Carmichael et al.2007)	p children born in 1950	Product	p children born in 2016	Product
1+ < 30	1 (Reference)	.256	0.256	.137	0.137
1 + 30–34	2.4	.222	0.5328	.232	0.5328
1 + 35+	2.5	.251	0.6275	.177	0.4425
0^a < 30	2.8	.212	0.5936	.223	0.6244
0 30–34	5.5	.042	0.231	.160	0.88
0 35+	8.2	.017	0.1394	.069	0.5658
∑		1	2.3803	1	3.1825
% change explained		(3.1825–2.3803)/2.3803 = 0.337 = 34%

^aChildren born from nulliparous mothers.

Table 3. Impact of parity on the prevalence of childhood obesity at age 6 between children born in 1950 and 2015 in the Netherlands.

Birth order	Relative risk (Gaillard et al. 2014)	p children born in 1950	Product 1950	p children born in 2015	Product 2015
1st	1.0 (Reference)	.272	0.272	.455	0.455
2nd	0.8	.246	0.1968	.368	0.2944
3d	0.6	.171	0.1026	.127	0.0762
≥4	0.35	.312	0.1092	.049	0.01715
∑		1	0.6806	1	0.84275
% increase explained		(0.84275–0.6806)/0.6806 = 0.2382 = 24%

The change in the demographic factor Birth order between 1950 and 2015 explains an increase of 24% in childhood obesity.

Table 4. Reproductive factors reported in PubMed to be associated with any of the 18 diseases and conditions mentioned in the WHO/UNEP report on endocrine disruptors.

Disease or condition	Reproductive factor
Low semen quality	Obesity (Sharpe 2010)
Cryptorchidism	Higher risk in firstborn boys (Biggs et al. 2002)
Hypospadias	Increased risk with higher maternal age, lower risk with parity (Gaillard et al. 2014)
Preterm birth	Preterm birth rates are higher in mothers with advanced age and in primiparous mothers (Fuchs et al. 2018)
Low birth weight	Low birth weight more frequent in primiparous mothers (Suzuki et al. 2016)
Thyroid disruption	Higher rate of thyroid dysgenesis in children from mothers with advanced maternal age (Kirmizibekmez et al. 2012)
Thyroid cancer	Highest risk in firstborn children (Bevier et al. 2011)
Breast cancer	Nulliparity and older age at first pregnancy are well established risk factors (Pathak et al. 2000)
Endometrial cancer	Highest risk in firstborn girls (Bevier et al. 2011)
Ovarian cancer	Parity reduces the risk for ovarian cancer (Braem et al. 2010)
Prostate cancer	Higher risk associated with older paternal age (Zhang et al. 1999)
Testicular cancer	Highest risk in firstborn boys (Swerdlow et al. 1987)
Early onset breast development	Obesity (Kaplowitz et al. 2001)
Obesity	Elevated childhood obesity in firstborn children and from mothers with advanced maternal age (Gaillard et al. 2014)
Type II diabetes	Firstborn children have greater reduced insulin sensitivity (Ayyavoo et al. 2013).
ADHD	Higher risk with older paternal age (D’Onofrio et al. 2014), but inconsistently found
Autism	Advanced paternal age (Reichenberg et al. 2006) lowest risk in boys with birth order ≥4 (Wang et al. 2017)
Anogenital distance	No relevant human reproductive factors found in PubMed

Prener A, Hsieh CC, Engholm G, Trichopoulos D, Jensen OM. 1992. Birth order and risk of testicular cancer. Cancer Causes Control. 3:265–272.

 PubMed Web of Science ®Google Scholar

Gaillard R, Rurangirwa AA, Williams MA, Hofman A, Mackenbach JP, Franco OH, Steegers EA, Jaddoe VW. 2014. Maternal parity, fetal and childhood growth, and cardiometabolic risk factors. Hypertension. 64:266–274.

 PubMed Web of Science ®Google Scholar

Sharpe RM. 2010. Environmental/lifestyle effects on spermatogenesis. Philos Trans R Soc Lond B Biol Sci. 365:1697–1712.

 PubMed Web of Science ®Google Scholar

Biggs ML, Baer A, Critchlow CW. 2002. Maternal, delivery, and perinatal characteristics associated with cryptorchidism: a population-based case-control study among births in Washington State. Epidemiology. 13:197–204.

 PubMed Web of Science ®Google Scholar

Fuchs F, Monet B, Ducruet T, Chaillet N, Audibert F. 2018. Effect of maternal age on the risk of preterm birth: A large cohort study. PLoS One. 13:e0191002.

 PubMed Web of Science ®Google Scholar

Suzuki K, Nomura K, Takenoshita S, Ando K, Kido M. 2016. Combination of parity and pre-pregnancy BMI and low birth weight infants among Japanese women of reproductive age. Ind Health. 54:515–520.

 PubMed Web of Science ®Google Scholar

Kirmizibekmez H, Guven A, Yildiz M, Cebeci AN, Dursun F. 2012. Developmental defects of the thyroid gland: relationship with advanced maternal age. J Clin Res Pediatr Endocrinol. 4:72–75.

 PubMed Web of Science ®Google Scholar

Bevier M, Weires M, Thomsen H, Sundquist J, Hemminki K. 2011. Influence of family size and birth order on risk of cancer: a population-based study. BMC Cancer. 11:163.

 PubMed Web of Science ®Google Scholar

Pathak DR, Osuch JR, He J. 2000. Breast carcinoma etiology: current knowledge and new insights into the effects of reproductive and hormonal risk factors in black and white populations. Cancer. 88:1230–1238.

 PubMed Web of Science ®Google Scholar

Braem MG, Onland-Moret NC, van den Brandt PA, Goldbohm RA, Peeters PH, Kruitwagen RF, Schouten LJ. 2010. Reproductive and hormonal factors in association with ovarian cancer in the Netherlands cohort study. Am J Epidemiol. 172:1181–1189.

 PubMed Web of Science ®Google Scholar

Zhang Y, Kreger BE, Dorgan JF, Cupples LA, Myers RH, Splansky GL, Schatzkin A, Ellison RC. 1999. Parental age at child’s birth and son’s risk of prostate cancer. The Framingham Study. Am J Epidemiol. 150:1208–1212.

 PubMed Web of Science ®Google Scholar

Swerdlow AJ, Huttly SR, Smith PG. 1987. Prenatal and familial associations of testicular cancer. Br J Cancer. 55:571–577.

 PubMed Web of Science ®Google Scholar

Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME. 2001. Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics. 108:347–353.

 PubMed Web of Science ®Google Scholar

Ayyavoo A, Savage T, Derraik JG, Hofman PL, Cutfield WS. 2013. First-born children have reduced insulin sensitivity and higher daytime blood pressure compared to later-born children. J Clin Endocrinol Metab. 98:1248–1253.

 PubMed Web of Science ®Google Scholar

D’Onofrio BM, Rickert ME, Frans E, Kuja-Halkola R, Almqvist C, Sjolander A, Larsson H, Lichtenstein P. 2014. Paternal age at childbearing and offspring psychiatric and academic morbidity. JAMA Psychiatry. 71:432–438.

 PubMed Web of Science ®Google Scholar

Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, et al. 2006. Advancing paternal age and autism. Arch Gen Psychiatry. 63:1026–1032.

 PubMed Web of Science ®Google Scholar

Wang C, Geng H, Liu W, Zhang G. 2017. Prenatal, perinatal, and postnatal factors associated with autism: a meta-analysis. Medicine (Baltimore). 96:e6696.

 PubMed Web of Science ®Google Scholar