Ontogenetic Pattern of Thyroid Hormone Receptor Expression in the Human Testis

Abstract

We studied the spatiotemporal distribution of thyroid hormone nuclear receptors (TRs) alpha1 and alpha2 and beta messenger RNA (mRNA) levels in normal human testicular tissue during development and in adulthood. Nonpathological specimens from five aborted fetuses (17 and 23 weeks of gestation, three and two cases, respectively) and from four patients undergoing orchiectomy (18 months old and 38-, 42-, and 52-yr-old, respectively) were analyzed by Northern blot, semiquantitative RT-PCR amplification using DNA sequences or specifically designed primers for the TR isoforms, and in situ hybridization. By using PCR amplification, we found that TRalpha1 and TRalpha2 are both expressed at different levels in fetal and adult testis. At all ages TRalpha2 is found at higher levels. Northern analysis showed hybridization signals corresponding to the expression of TRalpha2 and TRalpha in a ratio that increased from 2.6 at 17 weeks of gestation to 12.0 in adulthood. In fact, the expression of TRalpha1 dramatically decreased throughout development, being faintly detectable in the adult testis. Expression of TRbeta was not detected at any age studied. This finding was further confirmed by PCR, which did not amplify TRbeta either in fetal or in adult testis mRNAs. In situ hybridization studies showed the absence of TRbeta and that TRalpha1 and TRalpha2 colocalized in Sertoli cells of prepubertal testis, whereas germ and interstitial cells appeared devoid of TR mRNA signals. From these results it can be concluded that the human testis exclusively expresses TRalpha, which is localized in Sertoli cells, TRbeta being always undetectable. Fetal and prepubertal ages represent the period of maximal expression of TRalpha1 and TRalpha2. The alpha2/alpha1 ratio rises dramatically after development. These results confirm a critical window for the action of thyroid hormone in human testis, in the period of maximal expression of T3 binding isoform TRalpha1, and may account for the macroorchidism without virilization occurring when hyposecretion of thyroid hormones occurs before puberty.

Clinical implications of altered thyroid status in male testicular function

“…Furthermore, changes in thyroid hormone levels during early testis development have been shown to affect testicular maturation and reproduction later in life (6). These data, in conjunction to the findings that thyroid hormone receptors are present in human and rat testes from neonatal to adult life (7,8), confirm that thyroid hormone plays a key role in testicular development. The presence of iodothyronine deiodinases, enzymes that modulate the concentration, and thus the action of thyroid hormones in different tissues, were also recently identified in the rodent testis from fetal to adult life (9)(10)(11).…”

“…Arq Bras Endocrinol Metab. 2009;53 (8):976-82 Descritores Testículo; hormônios tireoidianos; espermatogênese; reprodução; fertilidade I n mammals, altered thyroid status is known to adversely affect many organs and tissues. Nevertheless, for many years, the impact of thyroid disorders on male reproduction remained controversial.…”

Pathophysiology of Acquired Premature Ejaculation

“…As oxytocin is closely involved in the ejaculatory mechanism (108) both centrally (109) and peripherally (110), this may account for the close correlation between hyperthyroidism and PE. As an ancillary possibility, thyroid hormone receptors have been described in the animal (111) and human testis (112), and may also be present in other male genital tract structures, triggering ejaculation. Finally, although excluded in the original report (43), some cases of PE in hyperthyroidism are comorbid with ED, which may in turn exacerbate the loss of ejaculatory control (24).…”

Type 2 iodothyronine deiodinase is highly expressed in germ cells of adult rat testis

“…The ontogenic pattern of expression of the various TR subtypes in human and rat testes has been studied. TRa1 isoform was shown to be present in testis throughout development, from fetal life to adulthood, being maximally expressed in the perinatal period in both species (Buzzard et al 2000, Jannini et al 2000, Canale et al 2001. Recently, a detailed testis morphological analysis was performed on rdw mutant rats that have congenital hypothyroidism due to a missense mutation in the thyroglobulin gene (Sakai et al 2004).…”