madman
Super Moderator
Abstract
Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients. Prolactin normalization is achieved in 80-90% of prolactinomas treated with cabergoline. Patients resistant to the standard dose can escalate the dose of cabergoline up to the maximum tolerated dose. The expression of dopamine (D2) receptors and dopamine affinity is decreased in aggressive and resistant prolactinomas. Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent. TMZ is effective in 40-50% of treatedlactotroph tumors showing at least a partial response. However, patients tend to escape from the effect of TMZ after a limited time of response. Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitors. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.
Introduction
Prolactinomas are benign anterior pituitary adenomas composed of lactotroph cells that produce and secrete excess prolactin (PRL). These adenomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Prolactinomas are more common in females but are also diagnosed in males. Based on their size at presentation, these tumors are divided into microprolactinomas (<10 mm) frequent in women, and macroprolactinomas (>10 mm), more frequent in men (1).
Prolactin production and release from pituitary lactotroph cells is tonically suppressed by dopamine secreted from specific neurons in the arcuate nucleus of the hypothalamus. After crossing, dopamine reaches the anterior pituitary through the hypothalamus-pituitary portal venous system, where it binds to D2 dopamine receptors (D2R)which are expressed by both, normal and tumoral lactotrophs. D2R are seven transmembrane domain G-protein-coupled receptors (2), and when activated by dopamine they suppress PRL synthesis and release and decrease cell proliferation.
Patients diagnosed with prolactinomas often present with symptoms related to hyperprolactinemia, including galactorrhea, ovarian dysfunction, amenorrhea and infertility in women, and hypogonadism in men. In addition, symptoms related to the mass effect on surrounding tissues are frequent in patients with invasive macroadenomas, especially in men, and result in headaches, chiasmal compression, ophthalmoplegia, and, occasionally, hypopituitarism (1).
*Dopamine Agonists
Medical treatment with dopamine agonists(DAs) is considered the primary and “gold standard” therapy for most patients with prolactinoma, whether female or male, microadenomas macroadenomas, and intrasellar or aggressive tumors. Bromocriptine, an ergot derivative with an agonist binding to the D2R, originally marketed as Parlodel, was the first DA to demonstrate efficacy already 50 years ago. Bromocriptine has a short half-life and is administered 2-3 times a day at a daily dose of 2.5-15mg. Bromocriptine normalized PRL in 80-90% of microprolactinomas and 70% of macroprolactinomas, with tumor shrinkage and normal gonadal function in most patients (1). Over the past 25 years, cabergoline, originally marketed as Dostinex, has become the most widely used DA worldwide. Cabergoline is a long-acting D2 receptor agonist, an ergot derivative, given to patients with prolactinoma once or twice weekly. Cabergoline is also used to treat patients with Parkinson’s disease. Most prolactinoma patients achieve hormonal remission, symptom control, and adenoma shrinkage with a weekly dose of 0.5-2mg (3). Cabergoline is considered the preferred DA for prolactinomas due to its increased efficacy, safety profile, and convenient administration schedule. Prolactin normalization is achieved in 80-90% of prolactinomas with cabergoline (4-5). With increasing adenoma size, the remission rate decreases to 70-80% in macroprolactinomas. Moreover, the shrinkage effect of macroprolactinomas is remarkable (6-7) and visual impairment improves in 70—90% of patients carrying macroadenomas with chiasmal damage. Characteristically, visual field improvement can be observed within a few days of treatment initiation.
*Resistant Prolactinomas
*Molecular Pathophysiology
*Treatment of Dopamine-resistant Prolactinomas—the Multimodal Approach
*Temozolomide
*Other Experimental Therapies
Summary
Most DA-resistant lactotroph tumors will respond to a combined treatment approach that includes high-dose cabergoline, pituitary surgery, and sellar radiosurgery for adenoma remnants if identified. The use of TMZ for resistant prolactinomas is limited and is considered the last option for aggressive or metastatic tumors. Experience with new experimental therapies is limited, but some patients with refractory prolactinomas may benefit from the use of pasireotide, or certain types of inhibitors whether the immune checkpoint, the tyrosine-kinase, or the aromatase ones.
Prolactinomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Medical treatment with dopamine agonists (DA), mainly cabergoline, is considered the primary therapy for these patients. Prolactin normalization is achieved in 80-90% of prolactinomas treated with cabergoline. Patients resistant to the standard dose can escalate the dose of cabergoline up to the maximum tolerated dose. The expression of dopamine (D2) receptors and dopamine affinity is decreased in aggressive and resistant prolactinomas. Patients with aggressive and DA-resistant adenomas or with rare PRL-secreting carcinomas can be treated off-label with temozolomide (TMZ), a DNA alkylating agent. TMZ is effective in 40-50% of treatedlactotroph tumors showing at least a partial response. However, patients tend to escape from the effect of TMZ after a limited time of response. Other therapeutic options include aromatase inhibitors, the somatostatin receptor ligand pasireotide, peptide receptor radionuclide therapy (PRRT), immune-checkpoint inhibitors, tyrosine-kinase inhibitors, or everolimus, the mammalian target of rapamycin inhibitors. These experimental treatments were effective in some patients carrying refractory prolactinomas showing usually partial tumor control. However, the number of treated patients with any of these new therapeutic options is very limited and treatment results are inconsistent, thus additional experience with more patients is required.
Introduction
Prolactinomas are benign anterior pituitary adenomas composed of lactotroph cells that produce and secrete excess prolactin (PRL). These adenomas are the most common functional pituitary tumors, accounting for 40% of all pituitary adenomas. Prolactinomas are more common in females but are also diagnosed in males. Based on their size at presentation, these tumors are divided into microprolactinomas (<10 mm) frequent in women, and macroprolactinomas (>10 mm), more frequent in men (1).
Prolactin production and release from pituitary lactotroph cells is tonically suppressed by dopamine secreted from specific neurons in the arcuate nucleus of the hypothalamus. After crossing, dopamine reaches the anterior pituitary through the hypothalamus-pituitary portal venous system, where it binds to D2 dopamine receptors (D2R)which are expressed by both, normal and tumoral lactotrophs. D2R are seven transmembrane domain G-protein-coupled receptors (2), and when activated by dopamine they suppress PRL synthesis and release and decrease cell proliferation.
Patients diagnosed with prolactinomas often present with symptoms related to hyperprolactinemia, including galactorrhea, ovarian dysfunction, amenorrhea and infertility in women, and hypogonadism in men. In addition, symptoms related to the mass effect on surrounding tissues are frequent in patients with invasive macroadenomas, especially in men, and result in headaches, chiasmal compression, ophthalmoplegia, and, occasionally, hypopituitarism (1).
*Dopamine Agonists
Medical treatment with dopamine agonists(DAs) is considered the primary and “gold standard” therapy for most patients with prolactinoma, whether female or male, microadenomas macroadenomas, and intrasellar or aggressive tumors. Bromocriptine, an ergot derivative with an agonist binding to the D2R, originally marketed as Parlodel, was the first DA to demonstrate efficacy already 50 years ago. Bromocriptine has a short half-life and is administered 2-3 times a day at a daily dose of 2.5-15mg. Bromocriptine normalized PRL in 80-90% of microprolactinomas and 70% of macroprolactinomas, with tumor shrinkage and normal gonadal function in most patients (1). Over the past 25 years, cabergoline, originally marketed as Dostinex, has become the most widely used DA worldwide. Cabergoline is a long-acting D2 receptor agonist, an ergot derivative, given to patients with prolactinoma once or twice weekly. Cabergoline is also used to treat patients with Parkinson’s disease. Most prolactinoma patients achieve hormonal remission, symptom control, and adenoma shrinkage with a weekly dose of 0.5-2mg (3). Cabergoline is considered the preferred DA for prolactinomas due to its increased efficacy, safety profile, and convenient administration schedule. Prolactin normalization is achieved in 80-90% of prolactinomas with cabergoline (4-5). With increasing adenoma size, the remission rate decreases to 70-80% in macroprolactinomas. Moreover, the shrinkage effect of macroprolactinomas is remarkable (6-7) and visual impairment improves in 70—90% of patients carrying macroadenomas with chiasmal damage. Characteristically, visual field improvement can be observed within a few days of treatment initiation.
*Resistant Prolactinomas
*Molecular Pathophysiology
*Treatment of Dopamine-resistant Prolactinomas—the Multimodal Approach
*Temozolomide
*Other Experimental Therapies
Summary
Most DA-resistant lactotroph tumors will respond to a combined treatment approach that includes high-dose cabergoline, pituitary surgery, and sellar radiosurgery for adenoma remnants if identified. The use of TMZ for resistant prolactinomas is limited and is considered the last option for aggressive or metastatic tumors. Experience with new experimental therapies is limited, but some patients with refractory prolactinomas may benefit from the use of pasireotide, or certain types of inhibitors whether the immune checkpoint, the tyrosine-kinase, or the aromatase ones.
