Association of Graves' disease and Moyamoya syndrome in a Caucasian woman from Western Europe: vascular effects of anti-TSH receptor antibodies?

Summary: Moyamoya syndrome (MMS) refers to a rare cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches, leading to an increased risk of stroke. While prevalent in Asia, this condition is considerably less common in Western countries, including Europe. The association between MMS and Graves' disease (GD) has been well documented, primarily in Asian and American populations, notably Latin Americans. In this report, we report the first case of GD with MMS in a Caucasian woman from Western Europe. The precise mechanisms underpinning the correlation between these two conditions remain poorly elucidated but are hypothesized to involve hemodynamic alterations, the toxic effects of anti-thyroid-stimulating hormone receptor antibodies, or a shared genetic predisposition. Our clinical case underscores the significance of thyroid disease screening in suspected MMS cases, as the management of thyroid dysfunction may suffice to improve neurological symptoms. Learning points: The association between Graves' disease (GD) and Moyamoya syndrome (MMS) can manifest in a Caucasian European patient. Screening for thyroid disease is essential when MMS is suspected, as treating GD might effectively alleviate neurological symptoms. The mechanisms linking GD and MMS remain incompletely understood but may involve hemodynamic shifts, the toxic effect of anti-TSH receptor antibodies, or shared genetic factors.

Recurrence of Graves' Disease (a Th1-type Cytokine Disease) Following SARS-CoV-2 mRNA Vaccine Administration: A Simple Coincidence?

Graves' disease is the most frequent cause of hyperthyroidism in young women. This auto-immune disease is due to the production of class 1 IgG stimulating the TSH receptor. These antibodies are produced secondary to a Th1 immune response in which interferon gamma plays a key role. Vaccination is ongoing worldwide against SARS-CoV-2 and some of the vaccines include mRNA which seems to stimulate the Th1 immune response. Here, we report a case of recurrence of hyperthyroidism due to Graves' disease following mRNA vaccination and discuss the possible implicated mechanism. This observation argues for a systematic study of a population of patients with previous Graves' disease in order to assess the risk of recurrence following vaccination. LEARNING POINTS: Graves' disease is a Th1-mediated immune disease in which interferon gamma plays a key role.The recurrence of hyperthyroidism due to Grave's disease should be monitored in patients exposed to risk factors.

Clinical, Pathological, and Molecular Factors of Aggressiveness in Lactotroph Tumours.

The behaviour of lactotroph tumours varies between benign tumours, those cured by treatment, and that of aggressive tumours, and carcinomas with metastasis. Identification of clinical, pathological and molecular factors is essential for the early identification of patients that may have such aggressive tumours. Plasma prolactin levels and tumour size and invasion, per se, are not prognostic factors. However, tumours appearing at a young age (<20 years), especially in boys, and the presence of genetic predisposition have a poorer prognosis. In addition, lactotroph tumours in men differ from those in women, being larger, more often invasive, and resistant to dopamine agonists. They are also more often high-grade with a high risk of recurrence and malignancy. The expression of estrogen receptor α is lower than in women and is closely correlated to aggressiveness. Proliferation markers (Ki-67 expression: ≥3%, mitotic count n > 2) are correlated to invasion and proliferation, but, taken alone, their prognostic value is debatable. Based on a 5-tiered clinicopathological classification, and taking into account invasion and proliferation, a grade 2b (aggressive) lactotroph tumour has a 20× risk of progression compared to a grade 1a (benign) tumour. Moreover, lactotroph tumours are the second-most frequent aggressive and malignant tumour. Other factors, such as the expression of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]), the genes regulating invasion, differentiation and proliferation, adhesion molecules (E-cadherin), matrix metalloproteinase 9, and chromosome abnormalities (chromosomes 11, 19, and 1), have also been correlated with aggressiveness. Currently, clinical signs, a prognostic classification, and molecular and genetic markers may all help the clinician in the early identification of aggressive lactotroph tumours and enable stratification of their management.

Sex-Related Differences in Lactotroph Tumor Aggressiveness Are Associated With a Specific Gene-Expression Signature and Genome Instability.

Sex-related differences have been reported in various cancers, in particular men with lactotroph tumors have a worse prognosis than women. While the underlying mechanism of this sexual dimorphism remains unclear, it has been suggested that a lower estrogen receptor alpha expression may drive the sex differences observed in aggressive and malignant lactotroph tumors that are resistant to dopamine agonists. Based on this observation, we aimed to explore the molecular importance of the estrogen pathway through a detailed analysis of the transcriptomic profile of lactotroph tumors from 20 men and 10 women. We undertook gene expression analysis of the selected lactotroph tumors following their pathological grading using the five-tiered classification. Chromosomic alterations were further determined in 13 tumors. Functional analysis showed that there were differences between tumors from men and women in gene signatures associated with cell morphology, cell growth, cell proliferation, development, and cell movement. Hundred-forty genes showed an increased or decreased expression with a minimum 2-fold change. A large subset of those genes belonged to the estrogen receptor signaling pathway, therefore confirming the potent role of this pathway in lactotroph tumor sex-associated aggressiveness. Genes belonging to the X chromosome, such as CTAG2, FGF13, and VEGF-D, were identified as appealing candidates with a sex-linked dysregulation in lactotroph tumors. Through our comparative genomic hybridization analyses (CGH), chromosomic gain, in particular chromosome 19p, was found only in tumors from men, while deletion of chromosome 11 was sex-independent, as it was found in most (5/6) of the aggressive and malignant tumors. Comparison of transcriptomic and CGH analysis revealed four genes (CRB3, FAM138F, MATK, and STAP2) located on gained regions of chromosome 19 and upregulated in lactotroph tumors from men. MATK and STAP2 are both implicated in cell growth and are reported to be associated with the estrogen signaling pathway. Our work confirms the proposed involvement of the estrogen signaling pathway in favoring the increased aggressiveness of lactotroph tumors in men. More importantly, we highlight a number of ER-related candidate genes and further identify a series of target molecules with sex-specific expression that could contribute to the aggressive behavior of lactotroph tumors in men.

Partial denial of pregnancy at 32 weeks in a diabetic and suicidal patient: A case report. What Are the Treatment Recommendations?

BACKGROUND: Denial of pregnancy is an issue that is often discovered a posteriori with sometimes dramatic complications. Denial of pregnancy is considered partial when the woman becomes aware of the pregnancy after the fifth month before delivery. The populations studied were heterogeneous, which made it impossible to establish a standard algorithm of the treatment and support of a discovery of partial denial of pregnancy. SUBJECTS AND METHODS: Based on a literature review and a discussion of partial denial of pregnancy case and the consequential treatment with a five-year follow-up, the global management recommendations need consideration in the case of partial denial of pregnancy. RESULTS: The reported case confirmed the significance of the trauma caused by the discovery of pregnancy in a patient in denial, but also showed that this trauma can extend to caregivers concerned by the treatment. CONCLUSION: Continuous training of all caregivers for denial of pregnancy is essential even if the issue may be considered infrequent. Contraception, prevention of sexually transmitted diseases and the importance of gynecological follow-up must be systematically addressed in a medical consultation. A standard algorithm for the treatment of partial denial is difficult to establish, but the rapid mobilization of a multidisciplinary team or hospitalization is recommended for the announcement of the diagnosis as well as personalized support during ultrasounds. The establishment of a relationship of trust remains the major issue.

Resistance to levothyroxine in a bariatric surgery patient: an indication for liquid formulation?

We report the case of a 49-year-old female patient with hypothyroidism who underwent bariatric surgery and developed severe hypothyroidism despite high doses of oral levothyroxine (L-T4) tablets. Initially, a high-dose L-T4 tablets absorption test was performed to exclude pseudo-malabsorption. In view of a modest increase in serum T4 levels, L-T4 liquid formulation absorption test was performed, and showed faster and more efficient absorption of thyroid hormones. We discuss the issue of distinguishing malabsorption from pseudo-malabsorption, review the literature concerning the benefits of liquid L-T4 in cases of impaired absorption such as bariatric surgery and consider the socio-economic implications of different liquid formulations.

Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth.

CONTEXT: A sex difference in the progression of prolactin (PRL) tumors has been disputed for years. OBJECTIVE: To compare tumor characteristics and postoperative clinical course between men and women, and correlate data with estrogen receptor alpha (ERα (ESR1)) expression status. DESIGN, PATIENTS, AND METHODS: Eighty-nine patients (59 women and 30 men) operated on for a prolactinoma and followed for at least 5 years were selected. Tumors were classified into five grades according to their size, invasion, and proliferation characteristics. The ERα expression was detected by immunohistochemistry and a score (0-12) calculated as the product of the percentage of positive nuclei and the staining intensity. RESULTS: We found a significant preponderance of high-grade tumors among men and a lower surgical cure rate in men (23%) than in women (71%). Patients resistant to medical treatment were mainly men (7/8), six of whom showed tumor progression despite postoperative medical treatment, which led to multiple therapies and eventually death in three. The median score for ERα expression was 1 in men (range, 0-8) and 8 in women (range, 0-12) (P<0.0001). The expression of ERα was inversely correlated with tumor size (r=-0.59; P<0.0001) and proliferative activity. All dopamine agonist-resistant tumors and all grade 2b (invasive and proliferative) tumors (from ten men and four women) were characterized by low ERα expression. CONCLUSIONS: PRL tumors in men are characterized by lower ERα expression, which is related to higher tumor grades, resistance to treatment, and an overall worse prognosis.

Therapy of endocrine disease: the challenges in managing giant prolactinomas.

Giant prolactinomas are rare tumours, representing only 2-3% of all prolactin (PRL)-secreting tumours and raising special diagnostic and therapeutic challenges. Based on several considerations developed in this review, their definition should be restricted to pituitary adenomas with a diameter of 40  mm or more, significant extrasellar extension, very high PRL concentrations (usually above 1000  µg/l) and no concomitant GH or ACTH secretion. Giant prolactinomas are much more frequent in young to middle-aged men than in women, with a male to female ratio of about 9:1. Endocrine symptoms are often present but overlooked for a long period of time, and diagnosis is eventually made when neurologic complications arise from massive extension into the surrounding structures, leading to cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos. PRL concentrations are usually in the range of 1000-100,000  µg/l, but may be underestimated by the so-called 'high-dose hook effect'. As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction in tumour size in three-fourths of the patients and PRL normalization in 60-70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment) or to patients with insufficient tumoural response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours, which are not controlled despite combined medical and surgical treatments. Because of these various challenges, we advocate a multidisciplinary management of these giant tumours in expert centres.

Giant prolactinomas in women.

OBJECTIVE: To characterise distinctive clinical features of giant prolactinomas in women. DESIGN: A multicentre, retrospective case series and literature review. METHODS: We collected data from 15 female patients with a pituitary tumour larger than 4 cm and prolactin levels above 1000 µg/l and identified 19 similar cases from the literature; a gender-based comparison of the frequency and age distribution was obtained from a literature review. RESULTS: The initial PubMed search using the term 'giant prolactinomas' identified 125 patients (13 women) responding to the inclusion criteria. The female:male ratio was 1:9. Another six female patients were found by extending the literature search, while our own series added 15 patients. The median age at diagnosis was 44 years in women compared with 35 years in men (P<0.05). All cases diagnosed before the age of 15 years were boys. In women (n=34), we observed a minor peak incidence during the third decade of life and a major peak during the fifth decade. Amenorrhoea was a constant feature with seven cases of primary amenorrhoea. In eight women with onset of secondary amenorrhoea before the age of 40 years, the diagnosis was made 2-31 years later (median 9 years) and in all but one because of tumour pressure symptoms. The prolactin levels were above 10,000 µg/l in 15/34 and misdiagnosis due to 'hook effect' occurred in two of them. Eighteen patients were treated with cabergoline; standard doses (<2.0 mg/week) were able to normalise prolactin in only 4/18 patients, and 7/18 patients were resistant to weekly doses ranging from 3.0 to 7.0 mg. CONCLUSION: Giant prolactinomas are rare in women, often resistant to dopamine agonists and seem to be distributed in two age groups, with a larger late-onset peak.

Characterization of resistance to the prolactin-lowering effects of cabergoline in macroprolactinomas: a study in 122 patients.

CONTEXT: Macroprolactinomas poorly responsive to dopamine-agonists are often more aggressive and are usually termed 'resistant' but this clinical concept has always been defined empirically. OBJECTIVE: To define resistance to cabergoline (CAB) on the basis of a dose-response relationship established in a large series of macroprolactinoma patients and to assess the influence of gender and tumor invasiveness on the response to treatment. DESIGN: Retrospective study. METHODS: One hundred and twenty-two patients (72 women and 50 men) primarily treated with CAB for at least 1 year were included. Main outcome measures were serum prolactin (PRL) and tumor size. RESULTS: Normalization of PRL was obtained in 115 out of the 122 patients (94%). The majority of patients (96/115, 83%) were controlled with a CAB dose < or =1.5 mg/week. Most of the other patients (19/26) had only a partial resistance, responding to a further increase of the CAB dose. Beyond the dose of 3.5 mg/week, there was no clear advantage in further increasing the dose instead of continuing the treatment at the same dose. Most tumors (98/119 assessable cases, 82%) showed a significant shrinkage during CAB treatment. It was more likely to occur in cases of PRL normalization. Both cavernous sinus invasion and male gender were significantly and independently associated with partial or complete resistance to treatment. CONCLUSIONS: Most macroprolactinomas primarily treated with CAB are adequately controlled with doses < or =1.5 mg/week. About 20% of patients, mainly men and/or those with invasive tumors will require a higher dose of CAB. We suggest defining such patients as resistant to CAB.

Influence of parasellar extension of macroprolactinomas defined by magnetic resonance imaging on their responsiveness to dopamine agonist therapy.

OBJECTIVE AND DESIGN: The resistance of macroprolactinomas to dopamine agonist (DA) therapy, whether defined as an absence of PRL normalization or the lack of significant tumour shrinkage after prolonged treatment at high doses, is usually regarded as unpredictable. The aim of this retrospective study, conducted in a teaching hospital, was to determine whether cavernous sinus (CS) invasion assessed by magnetic resonance imaging (MRI) is associated with a higher rate of resistance to DA therapy. METHODS: Forty-nine patients with a macroprolactinoma were included in this study and classified into four groups according to the percentage of encasement of the intracavernous internal carotid artery (ICA) by the tumour. All patients received DA as the primary treatment, mainly cabergoline (CAB). PRL normalization and tumour shrinkage during treatment were evaluated as a function of CS invasion. RESULTS: Tumours encasing more than three-quarters of the intracavernous ICA (group 4) were less responsive to DA therapy, exhibiting a lower rate of early (< or = 3 months) PRL normalization (8%vs. 69% in the others groups; P < 0.01) under a higher dose of CAB (median: 3.5 mg vs. 1.0 mg per week; P < 0.01). CS invasion was a strongly significant and independent predictor of hormonal resistance to CAB (P < 0.01). This hormonal resistance occurred in eight patients (16%), all but one belonging to group 4. Significant tumour shrinkage was observed in 31 out of 45 assessable cases (69%) and was more likely to occur in the case of PRL normalization (P < 0.01). CONCLUSIONS: Parasellar extension of macroprolactinomas, assessed on the basis of strict MRI criteria, may predict a negative response to DA. The responsiveness of noninvasive macroprolactinomas (over 90%) is similar to that reported in microprolactinomas, whereas invasive tumours are resistant to treatment in more than 50% of cases.