Márk Oláh

Treatment of pituitary tumors: Dopamine agonists

The neurotransmitter/neuromodulator dopamine plays an important role in both the central nervous system and the periphery. In the hypothalamopituitary system its function is a dominant and tonic inhibitory regulation of pituitary hormone secretion including prolactin-and proopiomelanocortin-derived hormones. It is well known that dopamine agonists, such as bromocriptine, pergolide, quinagolide, cabergoline, and lisuride, can inhibit PRL secretion by binding to the D2 dopamine receptors located on normal as well as tumorous pituitary cells. Moreover, they can effectively decrease excessive PRL secretion as well as the size of the tumor in patients having prolactinoma. Furthermore, dopamine agonists can also be used in other pituitary tumors. The major requirement for its use is that the tumor cells should express D2 receptors. Therefore, in addition to prolactinomas, targets of dopamine agonist therapy are somatotroph tumors, nonfunctioning pituitary tumors, corticotroph pituitary tumors, Nelson’s syndrome, gonadotropinomas, and thyrotropin-secreting pituitary tumors. It is also an option for the treatment of pituitary disease during pregnancy. Differences between the effectiveness and the resistance of different dopaminergic agents as well as the future perspectives of them in the therapy of pituitary tumors are discussed.

A secretagogin locus of the mammalian hypothalamus controls stress hormone release

A hierarchical hormonal cascade along the hypothalamic‐pituitary‐adrenal axis orchestrates bodily responses to stress. Although corticotropin‐releasing hormone (CRH), produced by parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) and released into the portal circulation at the median eminence, is known to prime downstream hormone release, the molecular mechanism regulating phasic CRH release remains poorly understood. Here, we find a cohort of parvocellular cells interspersed with magnocellular PVN neurons expressing secretagogin. Single‐cell transcriptome analysis combined with protein interactome profiling identifies secretagogin neurons as a distinct CRH‐releasing neuron population reliant on secretagogins Ca2+ sensor properties and protein interactions with the vesicular traffic and exocytosis release machineries to liberate this key hypothalamic releasing hormone. Pharmacological tools combined with RNA interference demonstrate that secretagogins loss of function occludes adrenocorticotropic hormone release from the pituitary and lowers peripheral corticosterone levels in response to acute stress. Cumulatively, these data define a novel secretagogin neuronal locus and molecular axis underpinning stress responsiveness.

Transcriptional regulation of episodic glucocorticoid secretion

Circadian and ultradian variations of basal glucocorticoid secretion and transient elevations during stress are essential for homeostasis. Using intronic qRT-PCR to measure changes in primary transcript (hnRNA) we have shown that secretory events induced by stress or ACTH injection are followed by episodic increases in transcription of rate limiting steroidogenic proteins, such as steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage and melanocortin receptor associated protein. These transcriptional episodes imply rapid turnover of steroidogenic proteins and the need of de novo synthesis following each secretory event. In addition to episodic ACTH secretion, it is likely that intracellular feedback mechanisms at the adrenal fasciculata level contribute to the generation of episodes of transcription. The time relationship between activation and translocation of the CREB co-activator, transducer of regulated CREB activity (TORC) to the nucleus preceding transcriptional episodes suggest the involvement of TORC in the transcriptional activation of StAR and other steroidogenic proteins.

The role of endocannabinoids in the regulation of luteinizing hormone and prolactin release. Differences between the effects of AEA and 2AG.

It has been shown that the endocannabinoids inhibit luteinizing hormone (LH) and prolactin (PRL) secretion. When the effects of the two well-known endocannabinoids arachidonoylethanolamide (AEA, anandamide) and 2-arachidonoyl-glycerol (2AG) have been compared it became evident that AEA caused inhibition was higher than that one of 2AG. AEA also diminished the two investigated hormonal levels in CB1 receptor inactivated mice. AEA, being an endogenous ligand of vanilloid type 1 (TPRV1) receptor, while activating TPRV1 receptor has an effect on both LH and PRL levels decrease because these later were abolished when capsazepin, antagonist of TPRV1 receptor was previously administered to the CB1 KO animals. We postulate that the difference between the effects of AEA and 2AG on the serum levels of LH and PRL is due to the difference in receptor activation of these two compounds, namely AEA can activate both CB1 and TRPV1 receptor but 2AG acts only on CB1 receptor.

Salsolinol induces a decrease in cyclic AMP at the median eminence and an increase at the adenohypophysis in lactating rats

Investigating the cellular events in the pituitary gland, the intracellular cyclic AMP (cAMP) of the median eminence (ME), neuro-intermediate lobe (NIL) and the anterior lobe (AL) have been measured following 15-min of intravenous injection of salsolinol (SAL). Parallel to the elevation of plasma prolactin (PRL), SAL induced a significant decrease of cAMP concentration in the ME. In contrast, SAL injection resulted in a significant increase of cAMP at the level of the AL. Changes in cAMP of the NIL as well as in the plasma level of vasopressin (VP) could not be detected. The observed changes in the level of cAMP following the acute treatment of SAL in the ME and the AL seems to be related to interacting neuroendocrine signals delivered from the ME to the AL through the long portal vessels to release PRL.

Dopamine-Regulated Adrenocorticotropic Hormone Secretion in Lactating Rats: Functional Plasticity of Melanotropes

Pro-opiomelanocortin (POMC) is processed to adrenocorticotropic hormone (ACTH) and β-lipotropin in corticotropes of the anterior lobe, and to α-melanocyte-stimulating hormone (α-MSH) and β-endorphin in melanotropes of the intermediate lobe (IL) of the pituitary gland. While ACTH secretion is predominantly under the stimulatory influence of the hypothalamic factors, hormone secretion of the IL is tonically inhibited by neuroendocrine dopamine (NEDA) neurons. Lobe-specific POMC processing is not absolute. For example, D2 type DA receptor (D2R)-deficient mice have elevated plasma ACTH levels, although it is known that corticotropes do not express D2R(s). Moreover, observations that suckling does not influence α-MSH release, while it induces an increase in plasma ACTH is unexplained. The aim of the present study was to investigate the involvement of the NEDA system in the regulation of ACTH secretion and the participation of the IL in ACTH production in lactating rats. Untreated and estradiol (E2)-substituted ovariectomized (OVX) females were also studied. The concentration of ACTH in the IL was higher in lactating rats than in OVX rats, while the opposite change in α-MSH level of the IL was observed. DA levels in the IL and the neural lobe were lower in lactating rats than in OVX rats. Suckling-induced ACTH response was eliminated by pretreatment with the DA receptor agonist, bromocriptine (BRC). Inhibition of DA biosynthesis by α-methyl-p-tyrosine (αMpT) and blockade of D2R by domperidone (DOM) elevated plasma ACTH levels, but did not influence plasma α-MSH levels in lactating rats. The same drugs had opposite effects in OVX and OVX + E2 animals. In lactating mothers, BRC was able to block ACTH responses induced by both αMpT and DOM. Surgical denervation of the IL elevated basal plasma levels of ACTH. Taken together, these data indicate that melanotropes synthesize ACTH during lactation and its release from these cells is regulated by NEDA neurons.

The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release

This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1‐knockout (KO) and/or wild‐type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1‐KO or CB1 antagonist‐treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1‐KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1‐KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin‐cannabinoid–CB1–AMPK pathway.—Kola, B., Wittman, G., Bodnár, I., Amin, F., Lim, C. T., Oláh, M., Christ‐Crain, M., Lolli, F., van Thuijl, H., Leontiou, C. A., Füzesi, T., Dalino, P., Isidori, A. M., Harvey‐White, J., Kunos, G., Nagy, G. M., Grossman, A. B., Fekete, C., Korbonits, M., The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release. FASEB J. 27, 5112–5121 (2013). www.fasebj.org

Dephosphorylation/inactivation of tyrosine hydroxylase at the median eminence of the hypothalamus is required for suckling-induced prolactin and adrenocorticotrop hormone responses.

We have recently found that dopamine (DA) released from terminals of the hypothalamic neuroendocrine dopamine (NEDA) neurons plays a role not only in prolactin (PRL), but also in adrenocorticotrop hormone (ACTH) secretion, without having any influence on alpha-melanocyte-stimulating hormone (alpha-MSH) release in lactating dams. The aim of our present studies was to further investigate this DAerg regulation of ACTH using consecutively applied physiological stimulation (suckling) and pharmacological inhibition of the rate-limiting enzyme of DA synthesis (tyrosine hydroxylase, TH) by alpha-methyl-p-tyrosine (alpha-MpT) that acutely affect secretion of these pituitary hormones during lactation. Following 4h separation period, two experimental groups were formed. In the first group, lactating rats were assembled with their litters for 60 min prior to alpha-MpT. In the second group, the alpha-MpT was injected first and 60 min later suckling stimulus was applied. Plasma samples were taken in every 15 min during the 90 min experimental period. Concentrations of plasma PRL, ACTH and alpha-MSH were measured by specific RIAs. Both stimuli applied in the first sequence, significantly elevated plasma PRL and ACTH levels in separated lactating dams, without having any effect on alpha-MSH secretion. Suckling applied in the first sequence was able to block the alpha-MpT-induced elevation of ACTH secretion, while PRL response was also significantly attenuated. alpha-MpT pretreatment prevented both PRL and ACTH responses to suckling stimulus. Investigating the dephosphorylation/inactivation of TH in the arcuate nucleus-ME (TIDA) regions, no pTH-immunoreactive perikarya or terminals can be found in continuously suckled dams. In contrast, after 4h separation of the mothers from their litters, pTH-immunoreactivity can be clearly visualized in the external zone of ME. In alpha-MpT pretreated mothers following 4h separation no pTH positive terminals are visible. No changes in the TH immunostaining can be observed in any of these experimental groups. In conclusion, dephosphorylation/inactivation of TH (the rate-limiting enzyme of the DA biosynthesis) in NEDA neurons is required for suckling-induced PRL and ACTH responses.

The Regulation of Pituitary Prolactin Secretion: Hypothalamic, Intrapituitary and Intracellular Factors and Signaling Mechanisms

© 2013 Nagy et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Regulation of Pituitary Prolactin Secretion: Hypothalamic, Intrapituitary and Intracellular Factors and Signaling Mechanisms

The Role of Prolactin in the Regulation of Male Copulatory Behavior

In developed countries, the elderly population increases at an accelerated rate due to a decrease in the birth rate and the prolongation of life through medical development. Moreover, increases in the elderly population allow the prediction of an increase in hyperprolactinemia caused by aging. It is well known that hyperprolactinemia decreases libido and causes oligozoospermia [1]. On the other hand, hyperprolactinemia is caused by or associated with, a variety of pathogenic stages: pituitary adenoma, hypothalamic disorders, hypogonadism and hypothyroidism, and is detected in patients with infertility [2, 3], impotence and hypogonadism [4]. PRL is a polypeptide hormone that is synthesized and secreted from mammotropes in the anterior lobe of the pituitary gland [5]. Many studies have documented a critical role of PRL in the maintenance of lactation in women and female animals [6, 7] as well as in immunregulation in both, males and females [8], however, its role in sexual behavior is not entirely clear [9-16].