Molecular Endocrinology and Signal Transduction

The normal function of the testis, dependent on pituitary gonadotropins, involves the production of sperm in the seminiferous tubules and the synthesis of androgens, mainly testosterone, in the interstitial cells of Leydig (LC). Testosterone production is essential for normal sexual function, maintenance of secondary sexual characteristics, normal spermatogenesis, and maintenance of hematopoiesis and muscle and bone mass.
In recent years it has been accepted that, although pituitary luteinizing hormone (LH) is the main regulator of testicular steroidogenesis, factors produced by the various cell populations of the testis (Sertoli cells, peritubular cells, macrophages and mast cells) modulate the actions of the hormone, acting autocrine and/or paracrine. These factors would also be capable of modulating LH in its role as regulator of the differentiation and proliferation of immature LC.
Our working group has shown that the nitric oxide synthase/nitric oxide (NOS/NO) and heme oxygenase/carbon monoxide (HO/CO) and histamine (HA) systems modulate the effects of the aforementioned anterior pituitary hormone.
In the testicle, the factors described can act through different (or similar) transduction mechanisms to activate or inhibit steroid synthesis, at the level of the steroidogenic pathway and/or in the expression of the StAR protein, which regulates the transport of cholesterol to the mitochondria. In addition to the known involvement of cAMP in LH signal transduction, other second messengers may be involved in the final biological response.

Undoubtedly, the existence of local cellular interactions capable of modulating the actions of pituitary hormones provides an efficient mechanism for regulating testicular function, avoiding the generation of all-or-nothing responses and allowing the gland to respond finely and adjusted to the different stimuli, be they physiological or pathological. Thus, the general objective of this part of the project is the study of the regulation of steroidogenesis in the testicle, by locally produced factors: HA, NO and CO, the interrelationship between them and the molecular mechanisms involved. Likewise, the possible participation of these factors as modulators of the proliferation and differentiation of steroidogenic cells will be evaluated.

The results obtained will allow a better understanding of the processes related to human fertility.

Recently, in the laboratory we have incorporated a second line of research, based on the study of Leydig cell tumors. Leydig cell tumors (LCT) are the most common non-germ cell tumors of the testis. They present two incidence peaks, 20% in children and 80% in adults. There are no specific symptoms associated with TCL. They often produce androgens, but they can also secrete estradiol, causing excessive growth of breast tissue (gynecomastia). Patients with TCL usually also present with erectile dysfunction, decreased libido, oligozoospermia, feminine distribution of pubic hair and/or testicular atrophy. In children, precocious puberty may occur.
LCTs are normally benign, but 10% have a malignant evolution, and can spread to the lymph nodes of the abdomen, liver, lung, bone and brain. The average survival of patients with metastatic Leydig cell tumors is two years, since they do not respond well to chemotherapy or radiotherapy. Most of them are young men of reproductive age. New therapeutic alternatives are therefore necessary to improve the survival of these patients, as well as to preserve their fertility. In this sense, in recent years, studies have been carried out to identify potential target molecules for therapies aimed at blocking fundamental mechanisms for the growth of LCTs and/or their malignancy.
Histamine (HA) is a biogenic amine that, since it was first described in 1907 until today, has acquired an enormous biological role. Numerous publications have documented the existence of a functional histaminergic system in the testes of various species, capable of contributing to the regulation of steroidogenesis in Leydig cells. In turn, recent results from our laboratory indicate that the expression and activity levels of HDC, the only HA-producing enzyme in mammals, are significantly higher in tumor Leydig cells than in normal Leydig cells, and that HA is capable of to stimulate cell proliferation only in tumor Leydig cells. Thus, based on the above considerations, the general objective of this line of work is to study the possible participation of HA in the biology of LCTs, investigating both the mechanisms associated with the stimulation of cell proliferation and its ability to regulate tumor neoangiogenesis.

Cushing’s Syndrome (CS) is defined as the chronic excess of glucocorticoids in the blood. It is one of the most prevalent endocrine diseases in dogs. According to ACTH levels, it can be classified as ACTH-dependent or ACTH-independent, as in human medicine. CS is characterized by disturbances in the metabolism of carbohydrates and lipids, among which the tendency to fasting hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis and, in the most severe cases, Diabetes Mellitus. These disturbances originate because cortisol antagonizes many insulin functions, inducing a state of insulin resistance. Thus, chronic hypercortisolism stimulates hepatic gluconeogenesis, interferes with GLUT-4 recruitment, inhibits insulin secretion, and can even induce pancreatic β-cell apoptosis.

The general objective of this line of work is to implement adjuvant treatments to control the metabolic alterations of dogs with Cushing’s Syndrome (CS), such as the tendency to hyperglycemia and dyslipidemia, so that associated comorbidities can be reduced (Diabetes Mellitus, arterial hypertension, nephropathy), which are the causes that precipitate the death of the animal.