Thyroid hormones and adult-type Leydig cell development

Alterations in thyroid hormone levels are well known to influence key functions in growth and development. Although in many countries the diet is fortified with iodide, essential for thyroid hormone synthesis, still not all humans have access to fortified diets, leaving a substantial part of the population at risk of developing hypothyroidism. To study the effects of thyroid hormones on testicular development, and Leydig cell development in particular, we prenatally induced hyper- and hypothyroidism in rats and studied Leydig cell development from the neonate up to adulthood. Earlier studies, using 6-propyl-2-thiouracil or high doses of tri-iodothyronine, were discontinued before puberty due to side effects. We used a different approach to investigate the role of thyroid hormone on these processes; hypothyroidism was induced by feeding an iodide poor diet in combination with 0.75 w/v% sodium perchlorate added to the drinking water to inhibit the uptake of iodide by the thyroid. Hyperthyroidism was induced by supplementing the diet with low doses of thyroxine.
Differentiation of stem Leydig cells into the progenitor-type Leydig cells was delayed in both the hypo- and hyperthyroid rats. Peak levels in proliferative activity of the Leydig cells in the hypothyroid rats were reduced, and in both the hyperthyroid as well as the hypothyroid rats the Leydig cell proliferation was prolonged as compared to their euthyroid controls. In the adult hypothyroid rats the size of the Leydig cell population was decreased, while testis weight and seminiferous tubule diameter were not influenced. These results were confirmed by injection of adult hypothyroid rats with ethane dimethyl sulphonate, an alkylating agent which specifically destroys the Leydig cell population, followed by regeneration of the original Leydig cell population to its original size.
If the hypothyroid status was alleviated before 14 days postpartum the Leydig cell proliferation and development followed the pattern of the euthyroid control rats. If the hypothyroid status was alleviated at 28 days postpartum, at the time progenitor-type Leydig cells differentiate into immature-type Leydig cells, the peak levels of proliferative activity were increased as compared to the continuously hypothyroid rats. The period of proliferation, however, was prolonged, as seen in the continuously hypothyroid rats. Mating this first generation hypothyroid males with hypothyroid females resulted in the production of viable offspring, though pregnancy rate and litter size were reduced.
In conclusion, the results of the present studies suggest that euthyroid levels of thyroid hormones are essential for normal neonatal Leydig cell differentiation and proliferation. Taking into account the incidence of hypothyroidism, and the number of young people at risk of developing hypothyroidism due to insufficient iodide uptake, the clinical relevance of hypothyroidism in male gonadal development needs additional attention.