With fewer than 200 reported cases, Cushing’s syndrome (CS) in pregnancy remains a diagnostic and therapeutic challenge. In normal pregnancies, misleading signs may be observed such as striae or hypokalemia, while plasma cortisol and urinary free cortisol may rise up to 2- to 3-fold. While the dexamethasone suppression test is difficult to use, reference values for salivary cortisol appear valid. Apart from gestational hypertension, differential diagnosis includes pheochromocytoma and primary aldosteronism. The predominant cause is adrenal adenoma (sometimes without decreased ACTH), rather than Cushing’s disease. There are considerable imaging pitfalls in Cushing’s disease. Aberrant receptors may, in rare cases, lead to increased cortisol production during pregnancy in response to HCG, LHRH, glucagon, vasopressin or after a meal. Adrenocortical carcinoma (ACC) is rare and has poor prognosis. Active CS during pregnancy is associated with a high rate of maternal complications: hypertension or preeclampsia, diabetes, fractures; more rarely, cardiac failure, psychiatric disorders, infection and maternal death. Increased fetal morbidity includes prematurity, intrauterine growth retardation and less prevalently stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism. Therapy is also challenging. Milder cases can be managed conservatively by controlling comorbidities. Pituitary or adrenal surgery should ideally be performed during the second trimester and patients should then be treated for adrenal insufficiency. Experience with anticortisolic drugs is limited. Metyrapone was found to allow control of hypercortisolism, with a risk of worsening hypertension. Cabergoline may be an alternative option. The use of other drugs is not advised because of potential teratogenicity and/or lack of information. Non-hormonal (mechanical) contraception is recommended until sustained biological remission is obtained.
Thierry Brue, Vincent Amodru, and Frederic Castinetti
Frederic Castinetti, Thierry Brue, and Oskar Ragnarsson
Treatment of Cushing’s disease (CD) is one of the most challenging tasks in endocrinology. The first-line treatment, transsphenoidal pituitary surgery, is associated with a high failure rate and a high prevalence of recurrence. Re-operation is associated with an even higher rate of a failure and recurrence. There are three main second-line treatments for CD – pituitary radiation therapy (RT), bilateral adrenalectomy and chronic cortisol-lowering medical treatment. All these treatments have their limitations. While bilateral adrenalectomy provides permanent cure of the hypercortisolism in all patients, the unavoidable chronic adrenal insufficiency and the risk of development of Nelson syndrome are of concern. Chronic cortisol-lowering medical treatment is not efficient in all patients and side effects are often a limiting factor. RT is efficient for approximately two-thirds of all patients with CD. However, the high prevalence of pituitary insufficiency is of concern as well as potential optic nerve damage, development of cerebrovascular disease and secondary brain tumours. Thus, when it comes to decide appropriate treatment for patients with CD, who have either failed to achieve remission with pituitary surgery, or patients with recurrence, the pros and cons of all second-line treatment options must be considered.
Thierry Brue and Sally A Camper
Recent studies have shown a novel mechanism of combined pituitary hormone deficiency associated with mutations in POU1F1, altering the balance of alternative-splicing, which results in over-expression of the beta isoform of POU1F1. These studies underscore the need for biologists, in the context of routine molecular diagnosis of this condition, to investigate alternative splicing in POU1F1 as well as in other genes.
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
Frédérique Albarel, Frédéric Castinetti, and Thierry Brue
In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.
Cynthia Ramiandrasoa, Frédéric Castinetti, Isabelle Raingeard, Patrick Fenichel, Olivier Chabre, Thierry Brue, and Blandine Courbière
Little is known about Sheehan's syndrome (SS), even though it is believed that its incidence is low. The aims of this study were to determine the clinical features and diagnostic delay of SS and to ascertain whether early signs could have allowed earlier diagnosis.
Subjects and methods
All patients with SS diagnosed in reference units in the southeast of France between 1980 and 2011 were recruited for this study. Data on obstetrical history, clinical symptoms suggestive of hypopituitarism, early signs, hormone analysis, and magnetic resonance imaging were collected.
Of the 40 women found to have SS, 39 were studied. Mean delay in the diagnosis of SS was 9±9.7 years. We found that four of the 35 assessable patients were diagnosed with agalactia, 16 of the 29 assessable ones with amenorrhea, 19 of the 39 with hypothyroidism, eight with acute adrenal insufficiency, and 15 with asthenia. Among the patients for whom there was a diagnostic delay of more than 1 year (n=28), seven had headaches during the postpartum period, all assessable patients had agalactia, six of the 22 assessable ones had amenorrhea, seven of 28 had hypothyroidism, and 12 of 28 had asthenia.
Most signs of SS are aspecific and classical signs such as agalactia and amenorrhea are often difficult to detect, which can explain the long diagnostic delay. We suggest that all women failing to lactate after postpartum hemorrhage (PPH) should be evaluated by measuring prolactin levels and women with signs such as amenorrhea and asthenia, even several years after PPH, should undergo a blood test including assessment of thyroxine, TSH, 0800 h ACTH–cortisol, and IGF1 levels.
Frédérique Albarel, Caroline Gaudy, Frédéric Castinetti, Tiphaine Carré, Isabelle Morange, Bernard Conte-Devolx, Jean-Jacques Grob, and Thierry Brue
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.
Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded.
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.
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.
Frederic Castinetti, Rachel Reynaud, Alexandru Saveanu, Nicolas Jullien, Marie Helene Quentien, Claire Rochette, Anne Barlier, Alain Enjalbert, and Thierry Brue
Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.
Thierry Brue, Frederic Castinetti, Frida Lundgren, Maria Koltowska-Häggström, Patrick Petrossians, and on behalf of all ACROSTUDY investigators
Pegvisomant (Somavert, Pfizer Inc.) is the first and only available GH receptor antagonist. ACROSTUDY is an international surveillance study that offers inclusion in a web-based registry to all patients with acromegaly treated with pegvisomant; it aims at monitoring long-term safety and efficacy of this compound.
Patients and methods
This report summarizes the main baseline characteristics of this particular population of patients. In February 2009, over 300 centres in 10 countries had contributed 792 patients. A gradual increase in cumulative patient recruitment was observed since the launching of ACROSTUDY in 2004: from 116 patients in 2005, it steeply increased to 792 at the latest data freeze in February 2009. At the time of enrolment, 91.8% of patients were already treated with pegvisomant but baseline was considered at the time of pegvisomant start. IGF1 concentrations were measured at local laboratories.
Of all patients, 80% were reported to have had surgery and 33% to have received radiation therapy. Of the 792 patients, 14% had received no prior medical treatment before pegvisomant start, 65.9% had received somatostatin analogues and 18.6% dopamine agonists. Interestingly, 66.7% had received only pegvisomant at study start, while it was taken in association with dopamine agonists in 5.7%, with somatostatin analogues in 23.4% and with both types of agents in 3.8%. Mean IGF1 at baseline was 522 ng/ml.
Analysis of the baseline features of these patients treated with pegvisomant and reported in the ACROSTUDY database underscores the severity of the disease in this subset of the population of patients with acromegaly previously unresponsive to several medical, surgical or radiation treatment approaches.
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
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.
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.
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.
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.