Advances in the identification of novel targets for prolactinoma treatments resistant to current therapies

In the year 2010, a study of the Division of Endocrinology of the “Hospital de Clinicas José de San Martin” showed that 79 per cent of the patients diagnosed with lesions on the hypothalamic- hypophyseal area of the brain had tumours at the base of the brain, and of those, 19 per cent were prolactinomas, a type of benign tumour of the pituitary gland that is responsible for several hormone secretions.

However, when treatment time comes, 15 per cent of the patients with prolactinoma did not manage to normalize prolactin levels or reduce the tumoral level with conventional therapies so they had to undergo a surgery accompanied by radiotherapy, in some cases.

A group of scientists of the Laboratory of Hormonal Physiopathology of the Institute of Biology and Experimental Medicine (IBYME, CONICET), led by Graciela Díaz-Torga, managed to describe the system that regulates prolactin secretions and the cell proliferation in men and women, what could result in the finding of potential target of cells of alternative therapies against these resistant prolactinomas. This will avoid the surgery, what would lead to a reduction of risks for patients and the costs for health systems.

“The prolactinomas are characterized by an increase in the number and size of the cells that secrete prolactin, the lactotrophs,that increment significantly their role. Furthermore, the dopamine released by the hypothalamus inhibits the lactotrophs proliferation and the prolactin secretion. That is why the drugs traditionally used for the treatment of these tumours are known as dopamine antagonists”, Diaz-Torga, independent researcher of CONICET and director of the IBYME Laboratory, explains.

Since the dopamine inhibits prolactin secretion (PRL) and cell proliferation, in general, with the dopaminergic drugs’ treatment, the tumour can be reduced and the blood hormone levels are normalized. However, between a 15 to 20 per cent of the prolactinomas do not respond to these drugs.

“The absence of alternative therapies for these tumours resistant to dopaminergic drugs shows the need to deepen our knowledge of mechanisms underlying the formation of tumor in search of new therapeutic targets”, Díaz –Torga comments.

Maria Victoria Recouvreux, fellow under the direction of Díaz-Torga, explains that in normal conditions, the prolactin regulates its own secretion, “stimulating the dopamine release in the hypothalamus treatment, what inhibits the PRL secretion in lactotrophs”. At the same time, the prolactine functions as a growth factor and fosters cell proliferation.

According to the researchers, these mechanisms of self regulation stop working because of the prolactinomas because the dopaminergic neurons become refractory to high levels of PRL.

To face this challenge, Díaz and her group of researchers of IBYME studied the pituitary TGF-β1 system, an inhibitory mechanism of the proliferation and secretion of prolactin.

In 2011, they described the regulation through dopamine and estrogens and they found that a low percentage of the total of TGF- β1 in the pituitary gland was found in active status. Then, in 2012, they demonstrated that by incrementing the local activity of the TGF-β1, it is possible to reduce the size of a prolactinoma and normalize prolactin values in serum. These advances were published in two articles of the magazine Endocrinology.

“In our research work, we found that the recovery of the activity of TGF- β1 system in animal models of resistant prolactinomas inhibits the PRL secretion and decreases tumor growth. Therefore we postulate the TGF-β1 system as a potential target for alternative therapies for dopamine agonist-resistant prolactinomas”, the fellow comments.

Recently, Recouvreux published other findings of her doctoral thesis in the same magazine. There, they described how the regulation through the estrogen system is linked to the differential effect of these tumours in women and men of reproductive age.

Díaz-Torga states that the prolactinomas have greater impact on women than in men. In the second and the third decade of life the relationship is from 10 to 1. But after the age of 50, when the estrogen levels in women fall, the impact/incidence of prolactinomas equalizes between the sexes.

“We study if differences in the TGF-β1 pituitary activity could explain the sexual difference in the prolactinomas’ impact. Besides, we described the sexual differences in the TGF-β1 system: it is stronger in the pituitary of male than in the female’s and it is also less sensitive to the loss of dopamine control that takes place in resistant prolactinomas”, the CONICET researcher explains.

“We managed to demonstrate that lower level of circulating estrogens in male rats favour the presence of a stronger TGF-β1 system in the pituitary of that sex. This could explain the protection against the development of the prolactinomas in males, even in the case of the loss of dopamine control”, Recouvreux concludes.