Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: A nested case–referent study

Abstract

According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring. ' UICCKey words: early pregnancy; endogenous steroid hormones; testicular cancer; offspring Testicular cancer (TC) is the most frequently diagnosed cancer in male adults between ages 20 and 40 years. Age-standardized incidence rate is ranging from about 1/100,000 in Asian and African populations to approximately 9/100,000 in Denmark and Norway. 1 Overall, in most countries TC is rare, representing about 0.5-1.5% of all malignancies in the males. 2,3 Testicular tumors are a heterogeneous group of neoplasm traditionally separated by histology (seminoma and nonseminoma) and age at diagnosis (prepubertal TC, postpubertal TC and spermatocytic seminoma). Each of these tumors has its own clinical, pathologic and genetic characteristics. Prepubertal TC is rare with no apparent evidence on trends in incidence rates over time, 4 whereas, the incidence of postpubertal TC has more than doubled over the last 40 years. 2,5 Histology and the early age-specific incidence peak of TC suggest that its risk factors operate early in life, possibly already in utero. Most probably, exposures acting during fetal life disturb normal development of the primordial germ cells or gonocytes, generating carcinoma in situ (CIS) lesions, which eventually will progress into clinically detectable cancer of the young adults. 6,7 According to the leading hypothesis on TC etiology exposure to a specific pattern of steroid hormones in utero is the major determinant of TC risk. In particular, high levels of estrogens and low levels of and...

Association of testicular germ cell tumor with polymorphisms in estrogen receptor and steroid metabolism genes

“…This hypothesis also includes a possible role for endogenous and exogenous hormones or hormone-like substances (endocrine disruptors) mainly acting as estrogens or anti-androgens. Although direct evidence in humans is lacking, numerous animal models support this notion (Sharpe 2003, Sharpe & Skakkebaek 2008, and associations of TGCT with maternal estrogen and androgen levels in early pregnancy have been reported (Holl et al 2009).…”

“…Probably, a combination of high gonadotropin levels coupled with unbalanced androgen/estrogen levels and/or activity is the key event for TGCT development and progression (Garolla et al 2005, Rajpert-De Meyts 2006. Supporting this hypothesis, recently an association of TC with maternal estrogen and androgen levels in early pregnancy has been reported (Holl et al 2009). In addition, exposure to endocrine-disrupting chemicals acting as either weak estrogen agonist or androgen antagonist via binding to the estrogen and androgen receptors has been suggested to be associated with the risk of TGCT and other reproductive disorders (Wohlfahrt-Veje et al 2009).…”

Histological Assessment of Gonads in DSD: Relevance for Clinical Management

“…These factors suggest that initial steps in TGCC development take place during embryogenesis. Increased exposure to estrogens or anti-androgens is the proposed common denominator, but studies show inconsistent results, and a final conclusion cannot be made yet [McGlynn et al, 2005;Holl et al, 2009;Kortenkamp et al, 2014]. Together, these genetic and environmental risk factors are translated into a number of clinical characteristics such as family occurrence, infertility, cryptorchidism, urological anomalies, and DSD with a lifetime risk of 25% (in the presence of GBY [gonadoblastoma region on the Y chromosome], see below) [Rijlaarsdam and Looijenga, 2014].…”

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer

“…The actions of luteinizing hormone (LH) are critical for postnatal Leydig cell differentiation (Saez, 1994), and it is known that Leydig cell function is indeed impaired in testes with CIS (Petersen et al, 1999). In the fetal human testis, ERβ is expressed in peritubular myoid cells, fetal Leydig cells and gonocytes (O'Donnell et al, 2001;Saunders et al, 1998) and a high intrauterine oestrogen level has been suggested as a risk factor for testicular cancer in humans (Holl et al, 2009;Rajpert-De Meyts and Skakkebaek, 1993;Sharpe and Skakkebaek, 1993;Storgaard et al, 2006) as well as in rodents (Newbold et al, 1987). Oestrogens are able to stimulate proliferation of rat neonatal gonocytes in vitro (Li et al, 1997), induce spermatogenesis in hypogonadal mice (Ebling et al, 2000), and prevent apoptosis of human adult post-meiotic germ cells (Pentikainen et al, 2000).…”

“…Supporting this hypothesis, an association of TGCC with maternal oestrogen and androgen levels in early pregnancy has been reported recently (Holl et al, 2009). Although the mechanisms are unknown, it has been suggested that an early arrest of gonocyte differentiation, followed by increased proliferation could result in impaired cell division and accumulation of genomic aberrations (Rajpert-De Meyts, 2006), leading to the formation of transformed pre-carcinoma in situ (CIS) cells, also known as intratubular germ-cell neoplasia unclassified Skakkebaek et al, 1982).…”