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The discovery and widespread use of dopamine agonists as an effective therapy for patients with prolactinomas was a key therapeutic advance. However, despite the overall efficacy of dopamine agonists in the treatment of hyperprolactinemia, potentially committing patients to decades of therapy given medication side effects and long-term cost is an important concern. Many patients with microprolactinomas who are asymptomatic and eugonadal, have no desire for fertility, and have stable magnetic resonance imaging MRI scans can often be monitored carefully without a dopamine agonist.
However, the majority of patients with a prolactinoma, certainly those with macroadenomas, will require therapy that typically continues for many years. For this large group of patients who require treatment and respond to and tolerate a dopamine agonist, critical questions are how long should therapy be continued, and specifically what guidelines should be used to determine discontinuation of therapy?
Normal prolactin levels after discontinuation of dopamine agonist therapy have been well documented in the literature since What is the duration of normoprolactinemia after withdrawal of therapy and what are the risks of tumor enlargement?
In a subset of patients, particularly those with hyperprolactinemia and minimal MRI abnormalities, sustained normoprolactinema may reflect the natural history of the disorder, and spontaneous resolution of hyperprolactinemia may occur without dopamine agonist therapy.
Many prospective and retrospective series have been reassuring in documenting the stability of tumor size in the majority of patients with untreated microprolactinomas 1 , 2. Such patients are unlikely to have radiological evidence of tumor progression, and a spontaneous decrease in serum prolactin levels can occur, particularly in those patients who are not amenorrheic at the time of diagnosis 1.
However, early studies have shown that some patients with macroprolactinomas as well as those with microprolactinomas can maintain a normal prolactin level after discontinuation of bromocriptine therapy, suggesting, particularly with macroprolactinomas, a causal role for dopamine agonists in sustained normoprolactinemia 3 — 8.
How chronic dopamine agonist administration affects tumor mass or prolactin secretion after discontinuation is not completely clear, although such therapy can induce tumor degeneration, necrosis, and fibrosis.
In a large retrospective series of patients, Passos et al. It should be noted, however, that in this study, the majority of patients with macroprolactinomas had received prior surgical therapy. The study of Colao et al. The authors clearly indicate that these data apply to patients meeting their specific inclusion criteria and that the duration of follow-up was relatively short.
However, the finding that the majority of patients remained normoprolactinemic supported the concept that a subset of dopamine agonist-treated patients should be strongly considered for drug discontinuation. Such patients need to be carefully followed to detect recurrence of hyperprolactinemia and tumor enlargement so that treatment can be promptly resumed. The study by Kharlip et al. The risk of, predictors of, and time to recurrence in patients meeting the criteria of normoprolactinemia and tumor volume reduction after approximately 2 or more years of cabergoline treatment is reported.
The authors identified 46 patients who were treated de novo with cabergoline and who had their cabergoline dose discontinued. All patients had dopamine agonist treatment for at least 23 months, a normal prolactin level, and no evidence of critical involvement of adjacent structures or proximity of tumor to the optic chiasm, although the distance from the optic chiasm is not specified.
In addition, a decrease in macroadenoma size to less than 1 cm, or any decrease in microadenoma size, was required. Limitations of the study include the fact that not all MRI reports or images were available for review and that criteria for cabergoline discontinuation could be assessed retrospectively.
Importantly, this is a relatively high rate of recurrence, and the vast majority of recurrences occurred within 1 yr after drug discontinuation. Not unexpectedly, the size of the tumor remnant at the time of therapy was discontinued was an important predictor of recurrence, with patients who had larger tumor residuals experiencing a higher likelihood of relapse.
Of note, the rate of recurrence of hyperprolactinemia at 3 months was not significantly different between patients initially diagnosed with micro- or macroadenomas. There are several elements of this study that are helpful in informing clinicians how best to manage patients with prolactinomas.
They are 1 selection criteria for discontinuation, 2 duration of treatment and follow-up, 3 tumor size, and 4 the dopamine agonist used. Overall, the more stringent the discontinuation criteria, the more likely the patient will experience long-term remission.
A key point to remember, however, is that patients who meet these strict criteria are only a subset among all patients with prolactinomas. For example, the 46 patients reported who met criteria were obtained from an initial review of almost patients. As the authors of this report have critically emphasized, it is important not to extrapolate their findings to patients who do not meet the stated discontinuation criteria.
In addition, in this study, the median treatment time before drug withdrawal was 4. Approximately half of the patients in remission were followed for less than 15 months; clearly, the definitive results regarding long-term remission will require a much longer duration of follow-up.
The overall risk of recurrence needs to be put in the context of micro- vs. In the Colao study, almost half of all macroadenomas screened did not meet eligibility criteria for cabergoline discontinuation.
In addition, in the report by Kharlip et al. Many patients with macroprolactinomas have a significant fall in prolactin with medical treatment but do not normalize prolactin levels. In addition, many patients with large tumors have significant tumor remnant outside of the sella, in the cavernous sinus and even in relatively close proximity to the optic chiasm during chronic dopamine agonist therapy.
Finally, the current study data are restricted to the effects of cabergoline withdrawal. In addition to cabergoline, a number of dopamine agonists are clinically available, and dopamine agonists may differ in efficacy and effects of discontinuation as well as side effects.
Although bromocriptine has been prescribed for over 30 yr, the use of cabergoline increased rapidly for control of prolactin, tumor size, and clinical features such as hypogonadism 15 , Webster et al. Many subsequent studies have demonstrated the efficacy of cabergoline in patients unresponsive or poorly responsive to other dopamine agonists.
Although the side effects of dopamine agonist therapy are well known, a more recent and as yet unresolved concern has arisen regarding the possible risk of cardiac valve abnormalities during long-term dopamine agonist therapy.
However, because a cumulative dose and duration effect was reported, concerns were raised regarding patients with prolactinomas who may be treated for decades. Although none of the published papers on prolactinoma patients to date 19 , 20 have shown an increased risk of clinically significant cardiac valve disease and although most papers have failed to show an association between dopamine agonist therapy in prolactinoma patients and echocardiographic evidence of valvular abnormalities, an increased risk of tricuspid valve regurgitation was found in one report A metaanalysis of data from six trials using cabergoline published up until October showed an increased risk of tricuspid valve regurgitation without evidence of other valve involvement It is as yet unknown whether these potential concerns have clinical significance and should produce widespread alterations in the management of patients with prolactinomas.
Toward this end, it is even more important to evaluate how long dopamine agonist therapy must be continued and to determine prospectively the effects of withdrawal of all available dopamine agonists. However, it is now clear that even in those patients who meet strict criteria, recurrence rates are relatively high, with a majority of patients projected to relapse within just 18 months.
Although recurrence of hyperprolactinemia can occur without tumor enlargement, a significant number of patients will experience hypogonadism, which may require reinitiation of therapy.
Nevertheless, if even a subset of patients can be spared the potential side effects and cost of long-term dopamine agonist administration, this will have an important impact on patient care. Individual follow-up of patients in whom dopamine agonist therapy has been discontinued, with frequent serial monitoring of symptoms, prolactin levels, and MRI scans is critical.
Longer follow-up data are key, and the endocrine community awaits these data. For article see page J Clin Endocrinol Metab 68 : — Google Scholar. Clin Endocrinol Oxf 45 : — Acta Endocrinol Copenh : — Lancet 2 : — J Clin Endocrinol Metab 60 : — Clin Endocrinol Oxf 27 : — Clin Endocrinol Oxf 34 : — J Clin Endocrinol Metab 87 : — J Endocrinol Invest 22 : — N Engl J Med : — Clin Endocrinol Oxf 67 : — Clin Endocrinol Oxf 63 : 26 — Clin Endocrinol Oxf 65 : — J Clin Endocrinol Metab 94 : — Cabergoline Comparative Study Group.
J Clin Endocrinol Metab 81 : — Endocr Pract 14 : — Eur J Endocrinol : 1 — 5. J Clin Endocrinol Metab 93 : — J Endocrinol Invest 31 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
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Oxford Academic. Select Format Select format. Permissions Icon Permissions. The natural history of untreated hyperprolactinemia: a prospective analysis. Google Scholar Crossref. Search ADS. Follow-up of patients with prolactinomas after discontinuation of long-term therapy with bromocriptine. Google Scholar PubMed. Effect of dopamine agonist withdrawal after long-term therapy in prolactinomas: studies with high-definition computerised tomography.
Poison , in biochemistry, a substance, natural or synthetic , that causes damage to living tissues and has an injurious or fatal effect on the body, whether it is ingested, inhaled, or absorbed or injected through the skin. Although poisons have been the subject of practical lore since ancient times, their systematic study is often considered to have begun during the 16th century, when the German-Swiss physician and alchemist Paracelsus first stressed the chemical nature of poisons. It was Paracelsus who introduced the concept of dose and studied the actions of poisons through experimentation. It was not until the 19th century, however, that the Spaniard Matthieu Orfila , the attending physician to Louis XVIII , correlated the chemistry of a toxin with the biological effects it produces in a poisoned individual. Both concepts continue to be fundamental to an understanding of modern toxicology. Poisoning involves four elements: the poison, the poisoned organism, the injury to the cells, and the symptoms and signs or death.
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In this review, we will present the different aspects of coumarins and derivatives, from natural origins or synthetically prepared, and their action on inflammation. Coumarins and also furo- and pyranocoumarins are found in many different plants. These compounds are very often investigated for antioxidant properties. Other biological properties are also possible and anti-inflammation activity is one of these. As coumarins are also available quite easily via synthesis, natural ones can be prepared this way but derivatives with special substituents are also feasible.
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Chemotherapy often abbreviated to chemo and sometimes CTX or CTx is a type of cancer treatment that uses one or more anti-cancer drugs chemotherapeutic agents as part of a standardized chemotherapy regimen.
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The discovery and widespread use of dopamine agonists as an effective therapy for patients with prolactinomas was a key therapeutic advance. However, despite the overall efficacy of dopamine agonists in the treatment of hyperprolactinemia, potentially committing patients to decades of therapy given medication side effects and long-term cost is an important concern. Many patients with microprolactinomas who are asymptomatic and eugonadal, have no desire for fertility, and have stable magnetic resonance imaging MRI scans can often be monitored carefully without a dopamine agonist. However, the majority of patients with a prolactinoma, certainly those with macroadenomas, will require therapy that typically continues for many years. For this large group of patients who require treatment and respond to and tolerate a dopamine agonist, critical questions are how long should therapy be continued, and specifically what guidelines should be used to determine discontinuation of therapy?
Aromaticity pdf. Aromatic Compounds Structure and nomenclature. Medicinal and aromatic plants MAPs offer opportunities for sustainable economic growth in Nepal. Predict the major product s of the following reactions and show a mechanism 3. Comparing the result of such a calculation on fifteen condensed Other articles where Benzenoid aromatic compound is discussed: hydrocarbon: Aromatic hydrocarbons: …stability and are classified as benzenoid aromatic compounds.
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