A Novel Antigonadotropic Role of Thyroid Stimulating Hormone on Leydig Cell-Derived Mouse Leydig Tumor Cells-1 Line

Abstract

Subclinical hypothyroid men characterized by a rise in only thyroid stimulating hormone (TSH) levels, and normal thyroid hormone levels showed a fall in their serum progesterone and testosterone levels. This suggested a role of TSH in regulating Leydig cell steroidogenesis. Therefore, we investigated the direct role of TSH on steroid production and secretion using a mouse Leydig tumor cell line-1 (MLTC-1). MLTC-1 cells were treated with different doses of TSH isolated from porcine pituitary as well as recombinant TSH. Steroid secretion was measured by radioimmunoassay (RIA). The mRNA levels of steroidogenic enzymes were quantitated by real-time polymerase chain reaction (RT-PCR), whereas the corresponding protein levels were determined by western blot. In MLTC-1 cells, pituitary TSH as well as recombinant TSH inhibited progesterone and testosterone secretion in a dose-dependent manner. The inhibitory action of TSH on steroid secretion was unique and not mimicked by other anterior pituitary hormones including follicle stimulating hormone and adrenocorticotropic hormone. Recombinant TSH showed no effect on steroidogenic acute regulatory protein and CYP11A1, the enzymes catalyzing the nonsteroidogenic and steroidogenic rate-limiting steps of steroid synthesis, respectively. Recombinant TSH was shown to inhibit steroidogenesis in MLTC-1 cells by inhibiting the 3-β hydroxy steroid dehydrogenase mRNA and protein levels, the enzyme that catalyzes the conversion of pregnenolone to progesterone. This inhibitory effect of TSH is probably direct as both mRNA and protein of the TSH receptor were shown to be present in the MLTC-1 cells.

The Thyroid Hormone Axis and Female Reproduction

“…TSH is a glycoprotein that shares its alpha subunit with LH and FSH and has been implicated in precocious puberty (Van Wyk-Grumbach syndrome) through its actions on the FSH receptors [ 43 ]. TSH receptors have also been observed in both human follicular and Leydig cells [ 44 , 45 ]. Furthermore, TSH causes proliferation of the endometrial tissue in women with endometriosis [ 46 ].…”

The Mysterious Universe of the TSH Receptor

“…In the ovary, the TSH-R has been found in granulosa cells ( 30 ) where its expression is increased by gonadotropins and decreased by estrogen ( 23 ). In murine models, the presence of TSH-R has been demonstrated in the testis and TSH has been shown to inhibit steroidogenesis ( 31 ). A role of TSH/TSH-R in the seasonal effects on gonadal growth in some animals has also been suggested ( 23 ).…”

“…TSH acting on the testis may contribute to compromised secretion of androgens in hypothyroidism ( 31 ).…”

“…• Compromised androgen secretion in hypothyroidism. (23,30,31) Immune system (mRNA and proteindemonstrated in some cells)…”