Role of Hormones, Genes, and Environment in Human Cryptorchidism

Abstract

Cryptorchidism is the most frequent congenital birth defect in male children (2-4% in full-term male births), and it has the potential to impact the health of the human male. In fact, although it is often considered a mild malformation, it represents the best-characterized risk factor for reduced fertility and testicular cancer. Furthermore, some reports have highlighted a significant increase in the prevalence of cryptorchidism over the last few decades. Etiology of cryptorchidism remains for the most part unknown, and cryptorchidism itself might be considered a complex disease. Major regulators of testicular descent from intraabdominal location into the bottom of the scrotum are the Leydig-cell-derived hormones testosterone and insulin-like factor 3. Research on possible genetic causes of cryptorchidism has increased recently. Abundant animal evidence supports a genetic cause, whereas the genetic contribution to human cryptorchidism is being elucidated only recently. Mutations in the gene for insulin-like factor 3 and its receptor and in the androgen receptor gene have been recognized as causes of cryptorchidism in some cases, but some chromosomal alterations, above all the Klinefelter syndrome, are also frequently involved. Environmental factors acting as endocrine disruptors of testicular descent might also contribute to the etiology of cryptorchidism and its increased incidence in recent years. Furthermore, polymorphisms in different genes have recently been investigated as contributing risk factors for cryptorchidism, alone or by influencing susceptibility to endocrine disruptors. Obviously, the interaction of environmental and genetic factors is fundamental, and many aspects have been clarified only recently.

Factors controlling testis descent

“…All these androgen effects are mediated by the ligand binding to the intracellular nuclear androgen receptor (AR) and activating androgen-responsive genes (17). The Leydig cell also produces insulin-like 3 (INSL3) that is at least part controlled by human chorionic gonadotrophin (hCG) and luteinising hormone (LH) (18). This peptide, by binding to its receptor leucine-rich repeat-containing G proteincoupled receptor 8 (LGR8), is also a factor in the control of testis descent.…”

“…Also, AMH receptor-deficient mice have normal testis descent (30). Disruption of some Hox genes in the mouse lead to cryptorchidism but this is probably not relevant to human studies of cryptorchidism (18).…”

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

“…The majority of the previous studies have been performed to exploit polymorphisms in sex hormone and endocrine-related genes, such as insulin-like factor 3 (INSL3), INSL3 receptor (LGR8 or GREAT), androgen receptor, estrogen receptors 1 and 2 (ESR1 and ESR2), steroid-5a-reductase, mastermind-like domain containing 1 (Cxorf6), activating transcription factor 3, fibroblast growth factor 8 and FGF receptor 2. [6][7][8][9][10][11][12] However, few of these studies have focused on polymorphisms in genes involved in drug metabolism that might influence individual susceptibility to exogenous agents such as EEDs. It is well known that both the metabolism of EEDs and male sexual differentiation are mediated by a series of transcription factors and cytochrome P450 (CYP) enzymes.…”

Development of the Gubernaculum During Testicular Descent in the Rat

“…It is generally agreed that testicular descent in mammals occurs in two distinct steps with different anatomy and hormonal regulation (Hutson, 1985;Amann and Veeramachaneni, 2007;Foresta et al, 2008;Hughes and Acerini, 2008;Feng et al, 2009). In the first, or transabdominal phase, the genitoinguinal ligament, also known as the ''gubernaculum,'' undergoes enlargement or the ''swelling reaction.''…”