Aortic valve calcification and mild tricuspid regurgitation but no clinical heart disease after 8 years of dopamine agonist therapy for prolactinoma.

J Clin Endocrinol Metab. 2008 Sep;93(9):3348-56. Epub 2008 Jun 17.
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Aortic valve calcification and mild tricuspid regurgitation but no clinical heart disease after 8 years of dopamine agonist therapy for prolactinoma.
Kars M, Delgado V, Holman ER, Feelders RA, Smit JW, Romijn JA, Bax JJ, Pereira AM.
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. m.kars@lumc.nl

OBJECTIVE: Treatment with ergot-derived dopamine agonists, pergolide, and cabergoline has been associated with an increased frequency of valvular heart disease in Parkinson's disease. The aim of the present study was to assess the prevalence of valvular heart disease in patients treated with dopamine agonists for prolactinomas. DESIGN: This was a cross-sectional study.

PATIENTS: We performed two-dimensional and Doppler echocardiography in 78 consecutive patients with prolactinoma (mean age 47 +/- 1.4 yr, 26% male, 31% macroprolactinoma) treated with dopamine agonists for at least 1 yr (mean 8 +/- 0.6 yr) and 78 control subjects. Patients were classified according to treatment: patients treated with cabergoline (group 1: n = 47) and patients not treated with cabergoline (group 2: n = 31). RESULTS: Clinically relevant valvular heart disease was present in 12% of patients (nine of 78) vs. 17% of controls (13 of 78) (P = 0.141) and 17% (eight of 47) of patients treated with cabergoline vs. 3% (one of 31) of patients not treated with cabergoline (P = 0.062). Mild tricuspid regurgitation was present in 41% of patients vs. 26% of controls (P = 0.042), and aortic valve calcification was present in 40% of patients, compared with 18% of controls (P = 0.003). There was no relation between the cumulative dose of cabergoline and the presence of mild, moderate, or severe valve regurgitation.

CONCLUSION: Several years of dopamine agonist treatment in patients with prolactinomas is associated with increased prevalence of aortic valve calcification and mild tricuspid regurgitation but not with clinically relevant valvular heart disease. Therefore, additional studies on the adverse cardiac effects of dopaminergic drugs in prolactinoma are warranted, especially in patients with much longer use of these drugs.

1: Lancet Neurol. 2007 Sep;6(9):826-9.
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Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease.
Antonini A, Poewe W.
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. angelo3000@yahoo.com

BACKGROUND: Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment of Parkinson's disease with ergolinic dopamine agonists; however, until now, these complications have not substantially affected the routine clinical use of these drugs. The occurrence of restrictive valvular heart disease during treatment with pergolide and cabergoline caused concern about the safety of dopamine agonists in Parkinson's disease. Specifically, there is uncertainty whether fibrotic cardiac valvulopathy is due to exposure to these two ergolinic dopamine agonists or whether the abnormality is reversible. Changes in the heart valves can incur additional disability and worsen the clinical disorders of Parkinson's disease.

RECENT DEVELOPMENTS: Population studies of patients with Parkinson's disease compared with non-parkinsonian controls have reported that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets. The fibrotic changes cause thickening, retraction, and stiffening of valves, which result in incomplete leaflet coaptation and clinically significant regurgitation, and have necessitated surgical valve replacement in some patients. Pergolide and cabergoline have high affinity for the 5-HT(2B) serotonin receptors, which are expressed in heart valves and might mediate mitogenesis and, in turn, the proliferation of fibroblasts. When analysed together, current population studies of similar designs and doses report 102 patients on cabergoline, 245 patients on pergolide, 181 patients on non-ergot agonists (pramipexole and ropinirole), and 177 non-parkinsonian controls. The frequency of moderate-to-severe regurgitation in at least one heart valve was higher in patients receiving cabergoline or pergolide than in patients taking non-ergot agonists or controls, and the incidence of new-onset valvulopathy was high in patients taking the ergot-derived drugs.

WHERE NEXT?: Because of the routine prescription of pergolide and cabergoline, the switching of patients to different treatment regimens might be difficult. Moreover, whether the fibrotic changes are reversible is unknown. Finally, these adverse events do not occur in all patients, and no susceptibility factors are known. Prospective studies will assess the full effect of these abnormalities and help establish whether and when mitral valve tenting area abnormalities become clinically relevant during chronic treatment. The exact pathway leading to valvulopathy is unknown, although agonism of 5-HT(2B) receptors in the heart is implicated as a mediator in the process. Other ergolinic dopamine agonists, such as lisuride, and non-ergot dopamine agonists are devoid of 5-HT(2B) agonistic activity; therefore, their use might not induce fibrotic changes in heart valves. However, further prospective studies are needed. Such studies should also clarify the clinical relevance of mild-to-moderate echocardiographic changes and their natural history. Because of the clinical consequences of the adverse reactions, we suggest that affinity for 5-HT(2B) receptors is routinely tested in future drugs, in the laboratory or in animals, before they are given to patients.
PMID: 17706566 [PubMed - indexed for MEDLINE]



There is a 5HT2B receptor that is stimulated with dopamine agonist therapy.


Read a review on the effect of potential Cardiac Valve Effects of Dopamine Agonists:
http://pituitary.mgh.harvard.edu/docs/NCBV14I2.pdf

The Utility of Oral Glucose Tolerance Testing for Diagnosis and Assessment of Treatment Outcomes in 166 Patients with Acromegaly.

Carmichael JD, Bonert VS, Mirocha JM, Melmed S.

Department of Medicine, Division of Endocrinology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA; Biostatistics, Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Context: Growth hormone (GH) suppression after oral glucose load (OGTT) and normal age- and gender-matched IGF-I levels reflect biochemical control of acromegaly. OGTT is the gold standard for determining control of GH secretion at diagnosis and after surgical treatment, but the usefulness of performing an OGTT in patients treated with medical therapy has not been determined.

Objective: To assess relationships between basal GH levels (GH0), GH responses to OGTT (GHn), and IGF-I levels.

Design: Retrospective electronic database review

Setting: Tertiary outpatient Pituitary Center

Patients: 166 Patients with acromegaly (79F, 87M).

Four categories of testing: diagnosis (Dx), post-operative assessment without medication (POP-NM), testing during SRIF analog therapy (SA), and testing during dopamine agonist therapy (DA).

Main Outcome Measure: Basal serum GH and IGF-I levels and GH levels 2 hours after 75g OGTT.

Results: 482 simultaneous OGTT and IGF-I measurements were observed from 1985-2008. Discordant results of OGTT testing (GHn and IGF-I) were observed 33, 48, and 18% in POP-NM, SA, and DA categories, respectively. In the SA category 42% of tests were discordant with normal IGF-I and non-suppressed GHn. In contrast, 4% of tests were discordant with normal IGF-I and non-suppressed GH in those treated with DA. No significant differences in discordance were observed when GH0 was used.

Conclusions: Both basal and GH nadir levels are highly discordant with IGF-I levels during medical therapy with SRIF analogs. OGTT is not useful in assessing biochemical control in these subjects.

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I was planning on posting a review of the AACE guidelines, but that's proving to be a time-consuming effort since I'm trying to get it into a Powerpoint format. I was reading the section about diagnosis and monitoring after treatment, and started to wonder if there was any new data on the utility of the OGTT is in acromegalics after they've been diagnosed and are initiated on treatment, especially since I've never seen one done at county for diagnosis or otherwise. I came across this article in a literature search that's an e-publication from the Pituitary guru himself, Dr. Melmed. Their data shows that basal and GH nadir levels do not correlate with IGF-I levels in patients on SRIF (somatotropin release-inhibiting factor) analogs, with a discordance of 42%. The patients in their review who were post-op & not on medication also showed discordant tests in 33%. Those patients on DA (dopamine agonist) therapy had discordant tests in 18% of patients. They also mention the fact that GH nadir levels following suppression with OGTT to <0.4 mcg/L have not been associated with a decrease in morbidity and mortality, whereas suppression of basal GH levels to <2.5 mcg/L and achieving normal IGF-I levels have been shown to decrease morbidity and mortality. Makes me wonder if there's any utility in diagnosis as well since we the diagnosis is mainly clinical and IGF-I is a pretty good indicator of peripheral activity of GH. Just some food for thought...

Here's the link to the PDF:
http://jcem.endojournals.org/cgi/rapidpdf/jc.2008-1371v1