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Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy

Isabelle Morange, Anne Barlier, Isabelle Pellegrini, Thierry Brue, Alain Enjalbert, and Philippe Jaquet

Morange I, Barlier A, Pellegrini I. Brue T, Enjalbert A, Jaquet P. Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy. Eur J Endocrinol 1996; 135:413–20. ISSN 0804–4643

Resistance to bromocriptine, defined as the absence of normalization of prolactin (PRL) levels despite a 15–30 mg daily dose of bromocriptine during at least 6 months, has been observed in 5–17% of the prolactinomas according to the literature. The recent availability of a new potent dopamine agonist, quinagolide, prompted us to analyze its long-term therapeutic effects in 28 patients with prolactinomas resistant to bromocriptine. Before bromocriptine, their PRL levels were 520 ± 185 μg/l (mean ± sem) and decreased to 291 ± 154 μg/l after a 6–21 month period of bromocriptine treatment. All the women (N = 20) remained amenorrheic and hypogonadism was not improved in men (N = 8). Subsequently, after 1 year of 150–300 μg/day quinagolide, 12/28 patients of the present series recovered normal gonadal function and their initial mean baseline PRL value (404 ± 180 μg/l) was 16 ± 2 μg/l after 1 year of treatment. A significant tumor shrinkage was observed in 5/8 macroadenomas (62%). During the 3-year follow-up period under quinagolide, a similar good control was achieved in these patients, with the exception of one man presenting with a secondary rise of PRL under quinagolide. In contrast, 15 other patients (one patient interrupted quinagolide at 6 months because of poor tolerance) were not normalized under 150–450 μg/day quinagolide. Their initial PRL levels (606 ± 298 μg/l) were reduced to 343 ± 187 μg/l (versus 463 ± 265 μg/l under bromocriptine after the same duration of treatment). Despite such a partial inhibitory effect of quinagolide, 7/12 women resumed menstrual cycles and three pregnancies occurred. In no case was any tumor shrinkage noticed during the 3–4-year follow-up. Three patients even presented, after 2 years of quinagolide treatment, with a secondary rise of PRL values associated with a further tumor growth in two patients. During the 3-year follow-up period, nine pregnancies occurred in seven women. In five women, after quinagolide withdrawal, the plasma PRL baseline values ranged from 52 to 158 μg/l and from 65 to 192 μg/l, respectively, at the first trimester and at the end of uneventful pregnancies. In contrast, in two women a rapid increase of PRL (240–400 μg/l) correlated with tumor growth during the first trimester. Such a tumor progression was blocked by quinagolide treatment but not by bromocriptine. These data, although observed in a limited series, justify the careful follow-up of pregnancies in this subclass of patients at risk. Finally, in the whole population, long-term control of hyperprolactinemia by quinagolide was obtained in 11/28 patients (39%) previously resistant to bromocriptine, and 15/20 women (75%) resumed normal gonadal function with a quinagolide daily dose of 300 μg in most of them.

I Morange, Department of Endocrinology, Hôpital de la Timone, 264 rue Saint-Pierre, 13005 Marseilles, France

Free access

Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma

Frédérique Albarel, Caroline Gaudy, Frédéric Castinetti, Tiphaine Carré, Isabelle Morange, Bernard Conte-Devolx, Jean-Jacques Grob, and Thierry Brue

Objective

Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up.

Design and patients

Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille.

Methods

Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded.

Results

Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (≥11.5%) at 9.5±5.9 weeks (mean±s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7–53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients.

Conclusion

Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.

Free access

Bilateral neck exploration in patients with primary hyperparathyroidism and discordant imaging results: a single-centre study

Melanie Philippon, Carole Guerin, David Taieb, Josiane Vaillant, Isabelle Morange, Thierry Brue, Bernard Conte-Devolx, Jean-Franois Henry, Evelyne Slotema, Frederic Sebag, and Frederic Castinetti

Introduction

Focused parathyroidectomy is the treatment of choice for patients with concordant positive imaging. Bilateral cervical exploration is performed for cases with discordant imaging, yet more than 70% of those cases are the result of a single-gland disease. As focused parathyroidectomy is generally costless and harmless, for cases with discordant imaging, we tried to determine whether preoperative characteristics can lead to a diagnosis of single-gland disease.

Methods

This study included 182 patients treated for primary hyperparathyroidism by bilateral exploration from 2009 to 2012 at La Timone Hospital, Marseille, France. We classified patients based on preoperative images and pathological results (single-gland or multiglandular disease). We then compared the demographical, laboratory and imaging results. We also asked a senior nuclear medicine practitioner who was blind to the ultrasound and pathological results to perform a second reading.

Results

Of the total number of patients, 15.4% had negative, 54.4% discordant and 30.2% concordant imaging. After reviewing the scintigraphy results, 8% of the cases with discordant imaging would have been classified as concordant with ultrasound. Subtraction scintigraphy obtained better results than dual-phase scintigraphy (concordance with ultrasound in 50 vs 31% with classical scintigraphy). For the cases of discordant imaging, no predictive factors of single-gland disease could be identified. Ultrasound and scintigraphy were similarly effective in determining the correct location of the abnormal gland.

Conclusion

Discordant results of preoperative imaging modalities do not discriminate between uniglandular and multiglandular diseases in hyperparathyroidism. Diagnostic differentiation between the different causes of hyperparathyroidism requires improvements in imaging techniques and might benefit from subtraction scintigraphy.

Free access

Diabetes in acromegaly, prevalence, risk factors, and evolution: data from the French Acromegaly Registry

Sandrine Fieffe, Isabelle Morange, Patrick Petrossians, Philippe Chanson, Vincent Rohmer, Christine Cortet, Françoise Borson-Chazot, Thierry Brue, Brigitte Delemer, and The French Acromegaly Registry

Objectives

The French Acromegaly Registry records data of acromegalic patients' since 1992 in French, Belgian (Liège), and Swiss (Lausanne) centers. We studied the prevalence of diabetes in this population looking for risk factors. Patients from one of the centers (Reims) were then analyzed more thoroughly.

Methods

This study has been conducted on all the patients recorded from 1999 until 2004 (519 patients). Evolution of cohorts' was reassessed in 2009. Of the different variables recorded in the registry: age, sex, body mass index (BMI), duration of acromegaly, GH, IGF1 and prolactin levels, pituitary tumor size, hormonal deficiencies, presence, duration and treatment of diabetes, hypertension, and rheumatological disease were analyzed.

Results

The prevalence of diabetes in the registry was 22.3%. Diabetic patients were older and had a higher BMI. Compared with the data of the French Social Security, acromegalic patients showed a more precocious apparition of diabetes and prevalence was higher in each age group.

Compared with non-diabetic acromegalic subjects, diabetic patients had a more prolonged evolution of acromegaly before diagnosis. The levels of GH and IGF1 were not significantly different between the two groups. Only hypertension was significantly more frequent in diabetic patients.

Conclusions

In our population, the prevalence of diabetes was estimated to be 22.3%. The GH and IGF1 levels did not appear as predictive factors for the presence of diabetes. On the contrary, age, BMI, and hypertension were significant risk factors as in the general population of type 2 diabetics.

Free access

Acromegaly in remission: a view from the partner

Rachel Fourneaux, Marie Vermalle, Frederique Albarel, Isabelle Morange, Thomas Graillon, Vincent Amodru, Thomas Cuny, Henry Dufour, Thierry Brue, and Frederic Castinetti

Objective

A relative can be an asset in dealing with chronic illnesses, such as acromegaly, where quality of life (QoL) is altered even after remission. However, it has been shown that quality of life of caregivers can also be impacted. Our main objective was to compare the perception of acromegaly in remission in the patient–relative dyad.

Methods

In this observational study, 27 patients in remission and relatives were first asked to complete QoL, anxiety/depression and coping strategy questionnaires. Then, the patient’s body image and self-esteem were evaluated from both the patient’s and the relative’s point of view using the same questionnaires with modified instructions.

Results

Relatives had overall an accurate estimation of patient body image using the Figure Rating Scale by Stunkard. However, there were wide variations between the patient’s and the relative’s responses regarding self-esteem and body perception. The QoL of relatives was not altered and was significantly higher in the social domain than for the patient.

Conclusions

Our results show that relatives require education concerning all the steps involved in the management of acromegaly, as they likely do not fully understand the sequelae of acromegaly.

Free access

Lack of delayed neurocognitive side effects of Gamma Knife radiosurgery in acromegaly: the Later-Ac study

Frederic Castinetti, Philippe Caron, Isabelle Raingeard, Vincent Amodru, Frederique Albarel, Isabelle Morange, Philippe Chanson, Julie Calvo, Thomas Graillon, Karine Baumstarck, Henry Dufour, Jean Regis, and Thierry Brue

Introduction

Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences.

Methods

The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up.

Results

Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P  = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK).

Conclusions

While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.