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DOPAMINE, NOREPINEPHRINE, AND epinephrine belong to a class of neurotransmitters known as catecholamines, which are structurally defined by a catechol ring and an amine side chain. Catecholamines and indolamines (i.e., serotonin) are referred to as monoamines. Monoamines are small, water-soluble molecules that are the decarboxylated derivatives of amino acids. Production from their respective amino acids is catalyzed by several enzymes that act in sequence, the first of which serves as the rate-limiting step. Monoamines are stored at high concentrations in secretory granules. These granules provide protection against degradation by metabolic enzymes and enable a regulated release via exocytosis. Like other neurotransmitters, monoamines act very rapidly and their action can be terminated by both metabolic conversion to inactive compounds as well as by reuptake into the producing cell.
Dopamine is synthesized primarily in the central nervous system (CNS), but limited production also occurs in the adrenal medulla. Dopamine is also detectable in a few non-neuronal tissues, e.g., the pancreas and the anterior pituitary. Dysfunction of dopaminergic systems is associated with a number of diseases. For example, deficiency of dopamine in midbrain nigrostriatal neurons has long been recognized in the pathogenesis of Parkinson’s disease, while overactivity of the limbic and cortical dopaminergic neurons has been implicated in schizophrenia and psychoses. These dopaminergic neurons are also affected by neurotoxins, psychostimulants, and drugs of abuse. In the neuroendocrine axis, dysfunction of hypothalamic dopamine or its pituitary receptors leads to hyperprolactinemia and reproductive disturbances. It is not surprising, therefore, that this relatively simple molecule has been at the center of interest of basic scientists and clinicians alike for many years.
Within the brain, catecholamines function as classical neurotransmitters, i.e., they communicate between neurons and act within the anatomically confined space of the synapse. However, by virtue of their presence in the circulation and action on distant target organs, catecholamines from the adrenal medulla were among the first compounds classified as hormones in the early 1900s. Not until the 1970s, however, did the role of dopamine as an inhibitor of the pituitary lactotrophs become recognized. Since then, dopamine has been clearly established as the primary regulator of PRL gene expression and release. On the other hand, among the many factors capable of stimulating PRL, none has emerged as a leading candidate for a PRL releasing factor (PRF). Therefore, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators.
In 1985, we published a review in this journal entitled “Dopamine: A Prolactin Inhibiting Hormone” (1). The present update covers pertinent information that has been gathered since the publication of this report. During the last 15 yr, this field has witnessed unparalleled progress, including the cloning of dopamine and PRL receptors (PRL-Rs), the characterization of the dopamine transporter, the recognition of the role that estrogen and its receptors play in PRL homeostasis, and the generation of transgenic animals deficient in all these genes. In terms of therapeutic applications, dopaminergic agonists have become the mainstay treatment for suppressing PRL in hyperprolactinemic patients and for shrinking prolactinomas.
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Estrogens are responsible for the higher basal serum PRL levels, the enhanced responsiveness to PRL secretagogues, and the higher incidence of prolactinomas in women than men. In contrast to rats, estrogens have little effect on acute PRL release in humans. Circulating PRL levels do not increase during the preovulatory LH surge and are basically unchanged throughout the menstrual cycle (377). Also, oral contraceptives do not appreciably increase serum PRL levels and do not contribute to prolactinoma development or growth. There are only a few studies on the in vitro effects of estrogens on human lactotrophs. Cultured lactotrophs from midterm fetal pituitaries do not respond to E2 (358), although they already express both ERα and ERβ at this time (378). However, E2 increases PRL release from acutely dispersed adult human pituitary cells, but does not reverse the dopamine-mediated inhibition (378A ). This indicates that estrogen is a more effective stimulator of lactotrophs when the dopaminergic inhibition is absent or reduced. Studies with monkeys also suggest that there is no simple causal relationship between estrogen and PRL release (360). - See more at:
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The treatment of prolactinomas includes surgical resection, radiation, and therapy with dopamine agonists. Several large studies reveal that transsphenoidal surgery for tumor removal can result in normal plasma PRL levels in 60–70% of patients with microprolactinomas and in 25–30% of those with macroprolactinomas (for review, see Refs. 406 and 407). The mortality rate is less than 1%, and major complications of surgery include CSF rhinorrhea and transient diabetes insipidus. The larger the tumor, the lower the curative success rate and the higher the recurrence rate. Pituitary irradiation in the treatment of prolactinomas is less common, and data of its success are more limited. Since the early 1970s, surgery with or without radiotherapy has been progressively replaced by dopamine agonist therapy and is now generally reserved for patients who do not respond to dopamine, are intolerant of dopamine agonists, or do not wish to undergo years of medical therapy.
Bromocriptine was the first dopamine agonist to be widely used in the treatment of hyperprolactinemia (see Table 1). This ergot alkaloid has been introduced into medical practice after extensive characterization of its binding to dopamine receptors, inhibition of PRL secretion in vitro and in vivo, and suppression of tumor size in animal studies (for review, see Ref. 427). Treatment of hyperprolactinemic women with bromocriptine results in normoprolactinemia and return to ovulatory menses in 70–90% of patients (428). A similar success rate in correcting serum PRL levels and sexual dysfunction has been reported for male patients treated with bromocriptine (422). The effectiveness of bromocriptine in reducing tumor size varies among patients and length of treatment and does not always correlate well with circulating PRL levels. The 5–15% of tumors that do not respond to bromocriptine appear to be due to low expression of D[SUB]2[/SUB]R and possibly result from a decrease in the relative proportion of the short receptor isoform (429).
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Although dopamine is a small and relatively simple molecule, it fulfills many diverse functions. Within the brain, it acts as a classical neurotransmitter that exerts its actions within seconds. Yet, its attenuation or overactivity can lead to some of the most protractive neurological and psychological disorders. Within the pituitary, dopamine suppresses the high intrinsic secretory activity of lactotrophs. As this requires a continuous input of dopamine, the hypothalamic dopaminergic neurons differ from their striatal counterparts by being constitutively active. Acting via type 2 receptors that are functionally linked to membrane channels, dopamine rapidly inhibits PRL release from storage vesicles by controlling calcium fluxes. In addition, the G protein-linked receptor activates several interacting signaling pathways, resulting in the inhibition of PRL gene expression and the suppression of lactotroph proliferation. Although the mechanism of cell growth suppression by dopamine is not completely understood, this property has been exploited in the treatment of patients with prolactinomas and the restoration of their reproductive or neurological functions. In fact, the transfer of dopaminergic agonists/antagonists from the research bench to clinical practice and the generation of more effective and selective dopaminergic drugs is one of the most rewarding outcomes of basic research in this field.
Dopamine is synthesized primarily in the central nervous system (CNS), but limited production also occurs in the adrenal medulla. Dopamine is also detectable in a few non-neuronal tissues, e.g., the pancreas and the anterior pituitary. Dysfunction of dopaminergic systems is associated with a number of diseases. For example, deficiency of dopamine in midbrain nigrostriatal neurons has long been recognized in the pathogenesis of Parkinson’s disease, while overactivity of the limbic and cortical dopaminergic neurons has been implicated in schizophrenia and psychoses. These dopaminergic neurons are also affected by neurotoxins, psychostimulants, and drugs of abuse. In the neuroendocrine axis, dysfunction of hypothalamic dopamine or its pituitary receptors leads to hyperprolactinemia and reproductive disturbances. It is not surprising, therefore, that this relatively simple molecule has been at the center of interest of basic scientists and clinicians alike for many years.
Within the brain, catecholamines function as classical neurotransmitters, i.e., they communicate between neurons and act within the anatomically confined space of the synapse. However, by virtue of their presence in the circulation and action on distant target organs, catecholamines from the adrenal medulla were among the first compounds classified as hormones in the early 1900s. Not until the 1970s, however, did the role of dopamine as an inhibitor of the pituitary lactotrophs become recognized. Since then, dopamine has been clearly established as the primary regulator of PRL gene expression and release. On the other hand, among the many factors capable of stimulating PRL, none has emerged as a leading candidate for a PRL releasing factor (PRF). Therefore, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators.
In 1985, we published a review in this journal entitled “Dopamine: A Prolactin Inhibiting Hormone” (1). The present update covers pertinent information that has been gathered since the publication of this report. During the last 15 yr, this field has witnessed unparalleled progress, including the cloning of dopamine and PRL receptors (PRL-Rs), the characterization of the dopamine transporter, the recognition of the role that estrogen and its receptors play in PRL homeostasis, and the generation of transgenic animals deficient in all these genes. In terms of therapeutic applications, dopaminergic agonists have become the mainstay treatment for suppressing PRL in hyperprolactinemic patients and for shrinking prolactinomas.
- - - Updated - - -
Estrogens are responsible for the higher basal serum PRL levels, the enhanced responsiveness to PRL secretagogues, and the higher incidence of prolactinomas in women than men. In contrast to rats, estrogens have little effect on acute PRL release in humans. Circulating PRL levels do not increase during the preovulatory LH surge and are basically unchanged throughout the menstrual cycle (377). Also, oral contraceptives do not appreciably increase serum PRL levels and do not contribute to prolactinoma development or growth. There are only a few studies on the in vitro effects of estrogens on human lactotrophs. Cultured lactotrophs from midterm fetal pituitaries do not respond to E2 (358), although they already express both ERα and ERβ at this time (378). However, E2 increases PRL release from acutely dispersed adult human pituitary cells, but does not reverse the dopamine-mediated inhibition (378A ). This indicates that estrogen is a more effective stimulator of lactotrophs when the dopaminergic inhibition is absent or reduced. Studies with monkeys also suggest that there is no simple causal relationship between estrogen and PRL release (360). - See more at:
- - - Updated - - -
The treatment of prolactinomas includes surgical resection, radiation, and therapy with dopamine agonists. Several large studies reveal that transsphenoidal surgery for tumor removal can result in normal plasma PRL levels in 60–70% of patients with microprolactinomas and in 25–30% of those with macroprolactinomas (for review, see Refs. 406 and 407). The mortality rate is less than 1%, and major complications of surgery include CSF rhinorrhea and transient diabetes insipidus. The larger the tumor, the lower the curative success rate and the higher the recurrence rate. Pituitary irradiation in the treatment of prolactinomas is less common, and data of its success are more limited. Since the early 1970s, surgery with or without radiotherapy has been progressively replaced by dopamine agonist therapy and is now generally reserved for patients who do not respond to dopamine, are intolerant of dopamine agonists, or do not wish to undergo years of medical therapy.
Bromocriptine was the first dopamine agonist to be widely used in the treatment of hyperprolactinemia (see Table 1). This ergot alkaloid has been introduced into medical practice after extensive characterization of its binding to dopamine receptors, inhibition of PRL secretion in vitro and in vivo, and suppression of tumor size in animal studies (for review, see Ref. 427). Treatment of hyperprolactinemic women with bromocriptine results in normoprolactinemia and return to ovulatory menses in 70–90% of patients (428). A similar success rate in correcting serum PRL levels and sexual dysfunction has been reported for male patients treated with bromocriptine (422). The effectiveness of bromocriptine in reducing tumor size varies among patients and length of treatment and does not always correlate well with circulating PRL levels. The 5–15% of tumors that do not respond to bromocriptine appear to be due to low expression of D[SUB]2[/SUB]R and possibly result from a decrease in the relative proportion of the short receptor isoform (429).
- - - Updated - - -
Although dopamine is a small and relatively simple molecule, it fulfills many diverse functions. Within the brain, it acts as a classical neurotransmitter that exerts its actions within seconds. Yet, its attenuation or overactivity can lead to some of the most protractive neurological and psychological disorders. Within the pituitary, dopamine suppresses the high intrinsic secretory activity of lactotrophs. As this requires a continuous input of dopamine, the hypothalamic dopaminergic neurons differ from their striatal counterparts by being constitutively active. Acting via type 2 receptors that are functionally linked to membrane channels, dopamine rapidly inhibits PRL release from storage vesicles by controlling calcium fluxes. In addition, the G protein-linked receptor activates several interacting signaling pathways, resulting in the inhibition of PRL gene expression and the suppression of lactotroph proliferation. Although the mechanism of cell growth suppression by dopamine is not completely understood, this property has been exploited in the treatment of patients with prolactinomas and the restoration of their reproductive or neurological functions. In fact, the transfer of dopaminergic agonists/antagonists from the research bench to clinical practice and the generation of more effective and selective dopaminergic drugs is one of the most rewarding outcomes of basic research in this field.
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