[Meningioma under progestin treatment : what attitude to adopt ?] / Méningiome sous traitement progestatif : quelle attitude adopter ?

The risks of meningioma associated with the use of cyproterone acetate at high doses (25 to 100 mg/day) have been known since 2007. Recently, two additional molecules have been incriminated: nomegestrol acetate and chlormadinone acetate. The higher the cumulative dose and the longer the treatment duration, the bigger the risk of meningioma (12-fold after 5 years of treatment for nomegestrol acetate, and 7-fold after 3.5 years of treatment for chlormadinone acetate). Nevertheless, these medications have many indications that demonstrate their importance in the daily practice of the general practitioner, of the gynecologist and of the reproductive endocrinologist. Therefore, caution is required when introducing a powerful progestin that is incriminated in the long term at high doses. If the benefit/risk balance favours the initiation of progestin therapy, it is recommended to use the minimal effective dose and to limit the duration of use. Clinical and brain imaging monitoring should also be performed. Finally, if a meningioma develops on progestin, it is recommended that any medication containing a progesterone agonist be suspended.

Les risques de méningiome liés à la consommation de l'acétate de cyprotérone à de fortes doses (25 à 100 mg/jour) sont connus depuis 2007. Récemment, deux molécules supplémentaires ont été incriminées : l'acétate de nomégestrol et l'acétate de chlormadinone. Le risque de développer un méningiome est d'autant plus important que la dose cumulée est grande et que la prescription se prolonge dans le temps (risque multiplié par 12 à partir de 5 ans de traitement pour l'acétate de nomégestrol, et multiplié par 7 à partir de 3,5 ans de traitement par acétate de chlormadinone). Néanmoins, ces médications possèdent de nombreuses indications témoignant de leur importance dans la pratique quotidienne du médecin généraliste, du gynécologue et de l'endocrinologue de la reproduction. Dès lors, la vigilance est de mise lors de l'introduction d'un progestatif puissant incriminé à long terme et à haute dose. Si la balance bénéfices/risques plaide en faveur de l'instauration d'un traitement par progestatif, il est recommandé d'utiliser la dose minimale efficace et d'en limiter la durée d'utilisation. Une surveillance clinique et par imagerie cérébrale systématique est vivement recommandée. Enfin, en cas de détection d'un méningiome, il est recommandé de suspendre toute médication contenant un agoniste de la progestérone.

The Role of MCM9 in the Etiology of Sertoli Cell-Only Syndrome and Premature Ovarian Insufficiency.

Infertility in couples is a common problem, with both female and male factors contributing to similar extents. Severe, congenital disorders affecting fertility are, however, rare. While folliculogenesis and spermatogenesis are generally orchestrated via different mechanisms, some genetic anomalies can impair both female and male gametogenesis. Minichromosome maintenance complex component 9 (MCM9) is involved in DNA repair and mutations of the MCM9 gene have been previously reported in females with premature ovarian insufficiency (POI). MCM9 is also an emerging cancer risk gene. We performed next-generation and Sanger sequencing of fertility and related genes and hormonal and imaging studies in a kindred whose members had POI and disordered spermatogenesis. We identified a homozygous pathogenic MCM9 variant, c.394C>T (p.Arg132*) in three sisters affected by POI due to ovarian dysgenesis and their brother who had normal pubertal development but suffered from non-obstructive azoospermia. Testicular biopsy revealed Sertoli cell-only testicular histopathology. No evidence of early onset cancer was found in the homozygotic family members, but they were all young (<30 years) at the time of the study. In the male patient the homozygous MCM9 variant led to normal pubertal development and hormonal levels but caused a Sertoli-cell-only syndrome with non-obstructive azoospermia. In the homozygous females studied, the clinical, hormonal, and gonadal phenotypes revealed ovarian dysgenesis consistent with previous reports. Active screening for potential colorectal and other cancer risks in the homozygotic MCM9 subjects has been instigated.

Demonstration of the inferior intercavernous sinus is closely linked to the extent of pneumatization of the sphenoid sinus: useful information for the pituitary surgeon.

PURPOSE: To study the utility of T2-weighted MRI sequences in the identification of the inferior intercavernous sinus (IICS), a potential source of bleeding during transsphenoidal surgery of pituitary adenomas. METHODS: Pituitary sagittal T1W and coronal T2W MRI sequences were analyzed in 237 consecutive patients, after the exclusion of postoperative MRIs and those revealing an empty sella or a pituitary macroadenoma. Sphenoid sinus pneumatization was defined as incomplete (group 1) if it did not reach the nadir of the sella turcica, as complete (group 2) if it extended beyond the nadir of the sella or asymmetric (group 3), when only one side of the sinus was completely pneumatized. RESULTS: In Group 2 (70% of the patients), the IICS was rarely visualized on coronal T2W MRI (6/167 patients-3.6%), whereas in Group 1 it was identified in nearly all patients (55/57 patients - 96.5%, p < 0.001). In Group 3, the IICS was only visible above the non-pneumatized part of the sphenoid sinus. CONCLUSIONS: The IICS can be identified on coronal T2W images in patients with an incompletely pneumatized sphenoid sinus, but very rarely in patients with a totally pneumatized sinus. This information can help to increase awareness among pituitary surgeons of the need to potentially manage IICS bleeding during transsphenoidal surgery in patients with an incompletely pneumatized sphenoid sinus.

Pituitary MRI Features in Acromegaly Resulting From Ectopic GHRH Secretion From a Neuroendocrine Tumor: Analysis of 30 Cases.

CONTEXT: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. OBJECTIVE: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. DESIGN: Multicenter, international, retrospective. SETTING: Tertiary referral pituitary centers. PATIENTS: Thirty ectopic acromegaly patients having GHRH hypersecretion. INTERVENTION: None. MAIN OUTCOME MEASURE: MRI characteristics of pituitary gland, particularly T2-weighted signal. RESULTS: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. CONCLUSIONS: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Pituitary MRI in Cushing's disease - an update.

Pituitary MRI is essential in the diagnosis of ACTH-dependent Cushing's syndrome, but its results are inconsistent. The demonstration of a sellar image compatible with the diagnosis of corticotropinoma varies from 40% to 90%, depending on the centre where the imaging is performed. In fact, the expertise of the neuroradiologist, use of a Tesla 3.0 MRI and choice of sequences are fundamental. The T2 and 3D gradient echo sequences after gadolinium injection are the most informative and today allow the detection of macro- and microadenomas in almost all cases. The diagnosis of numerous picoadenomas (<3-4 mm) is more challenging. The 2D and 3D spin echo or delayed T1 SE or FLAIR sequences after gadolinium can be used as a complement or to confirm a suspicious image. Characterization of corticotropinomas remains problematic. However, the correct assessment of so-called incidentalomas by recognizing artifacts, anatomical variants and frequent Rathke's cleft cysts eliminates around 90% of the incidentalomas that mimic pituitary adenomas, as repetitively reported in the literature. For the time being, there is reason to believe that hybrid imaging combining PET and MRI such as 11C-methionine PET coregistered with volumetric MRI will solve the diagnosis of corticotropinomas in the near future.

Restoration of Fertility in Patients with Spontaneous Premature Ovarian Insufficiency: New Techniques under the Microscope.

Premature ovarian insufficiency (POI), a condition affecting up to 1% of women by the age of 40 years, is characterized by an extremely low chance of spontaneous pregnancy. Currently, fertility restoration options are virtually nonexistent for this population. To become pregnant, the only solution is egg donation. Interestingly, animal studies have provided encouraging results in terms of fertility restoration, and consequently, research has begun into the most promising approaches for women suffering from POI. The PubMed database was searched for studies in which techniques aiming at restoring fertility in women with spontaneous POI were tested. Although robust studies are lacking, the literature suggests a positive effect of certain techniques on fertility restoration in women with POI. The most promising approaches seem to be intraovarian injection of autologous platelet-rich plasma or of mesenchymal stem cells. In addition to these, in vitro and mechanical activation of dormant follicles and etiology-driven therapies have also been studied with mixed results. No safety concerns were raised in these studies. The absence of robust studies does not allow us to draw meaningful conclusions on the efficacy or superiority of any single technique at this stage, and so research in this area should continue using robust study designs, i.e., multicenter randomized controlled trials including sufficient subjects to achieve statistical power.

Thyroid cancer in the Democratic Republic of the Congo: Frequency and risk factors.

BACKGROUND: The prevalence of thyroid cancer is increasing steadily in most countries, partly due to better, earlier diagnosis. However, there is little data for developing countries, where the technical platform is often very limited, especially in Africa. OBJECTIVES: To assess the frequency of thyroid cancer in the Democratic Republic of the Congo (DRC) and to analyze the epidemiological, clinical, and ultrasound risk factors. MATERIAL AND METHODS: This is a multicenter cross-sectional study of 594 patients operated on for a thyroid mass from 2005 to 2019, in 35 centers in the DRC and for whom histopathological analyses were performed. RESULTS: The frequency of thyroid cancers in our cohort was 20%, mostly in patients over the age of 40 (62% of patients). These cancers were mainly diagnosed at the clinical stage, due to the presence of palpable masses. Papillary cancer was the most common (67.2% of patients), followed by follicular cancer (28% of cases). We found a high prevalence of anaplastic cancer (7.6%). These frequencies are probably the consequence of the fact that histopathological analyses are not systematically performed in the DRC, but mostly on tissues that the thyroid surgeons suspect to be malignant. Age ≥60 years, the presence of adenopathies upon palpation or on ultrasound, the solid nature and hypoechogenicity of nodules, the presence of macronodules and calcifications were the factors independently associated with the diagnosis of cancer in the study population. CONCLUSIONS: In this first study performed in the DRC, we have found that thyroid cancer is common. It is mainly detected at clinical stages, with patients over the age of 40 years and women being the most affected. The histopathology distribution differs from that in developed countries, with a lower prevalence of papillary cancer and a higher prevalence of the anaplastic type. In developing countries, it appears necessary to introduce the use of more precise diagnostic tools for thyroid cancer and also, to reinforce the improvement of known, controllable risk factors such as iodine deficiency.

Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development.

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically female patient with pubertal delay had a 46,XY karyotype and was diagnosed with 46,XY disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower-molecular-weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46,XY DSD illustrates how different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.

Adipsic diabetes insipidus revealing a bifocal intracranial germinoma.

Adipsic diabetes insipidus is a rare complication of intracranial tumors in which impaired antidiuretic hormone secretion is associated with the loss of thirst sensation. Here, we present the case of a patient with bifocal intracranial germinoma, diagnosed due to symptoms mainly caused by adipsic diabetes insipidus. This is, to our knowledge, the first case of adipsic diabetes insipidus revealing an intracranial germinoma reported in the literature. We describe the diagnostic procedures and the three-year follow-up of this patient. Management of intracranial germ-cell tumors is made complex by the wide range of histological features. Although germinomas have a generally better prognosis than most nongerminomatous tumors, they can have severe or even life-threatening presentations. Adipsic diabetes insipidus is one such severe presentation and its rarity can make it difficult to recognize and manage. Awareness of this potential entity is therefore important for clinical practice.

AIP mutations and gigantism.

AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities.

X-LAG: How did they grow so tall?

X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101 gene. XLAG has a remarkably distinct phenotype with disease onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history.

T2-weighted MRI signal intensity as a predictor of hormonal and tumoral responses to somatostatin receptor ligands in acromegaly: a perspective.

T2-weighted MRI signal intensity of GH-secreting pituitary adenomas is gaining recognition as a marker of disease characteristics and may be a predictor of response to treatment of acromegaly. Adenomas that are T2-hypointense are more common, are smaller and are less likely to invade the cavernous sinus compared to the T2-iso and hyperintense tumors. T2-hypointense tumors are also accompanied by higher IGF1 values at baseline. When presurgical somatostatin receptor ligand (SRL) therapy is administered, T2-hypointense adenomas have better hormonal responses and have greater tumor shrinkage. Adjuvant SRL therapy of patients with T2-hypointense tumors that are uncured by surgery is also associated with a better hormonal response. We review the studies that have dealt with the T2-weighted signal intensity of GH-secreting pituitary tumors and elaborate on the details and nuances of this promising avenue of research.

A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation.

Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P < 0.001). Tumor shrinkage on SSA was also significantly greater in the T2-hypo-intense group (38%) compared with the T2-iso- and hyper-intense groups (8% and 3%, respectively; P < 0.0001). The response to SSA correlated with the calculated T2 intensity: the lower the T2-weighted intensity, the greater the decrease in random GH (P < 0.0001, r = 0.22), IGF-1 (P < 0.0001, r = 0.14) and adenoma volume (P < 0.0001, r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

MANAGEMENT OF ENDOCRINE DISEASE: Pituitary 'incidentaloma': neuroradiological assessment and differential diagnosis.

Pituitary incidentalomas are a by-product of modern imaging technology. The term 'incidentaloma' is neither a distinct diagnosis nor a pathological entity. Rather, it is a collective designation for different entities that are discovered fortuitously, requiring a working diagnosis based on the input of the radiologist, endocrinologist and often a neurosurgeon. In addition to pathological conditions affecting the pituitary gland, a thorough knowledge of the radiological characteristics of normal variants and technical artifacts is required to arrive at an accurate differential diagnosis. After careful radiological and hormonal evaluation, the vast majority of pituitary incidentalomas turn out to be non-functioning pituitary microadenomas and Rathke's cleft cysts (RCCs). Based on the low growth potential of non-functioning pituitary microadenomas and RCCs, periodic MRI surveillance is currently considered the optimal management strategy. Stricter follow-up is required for macroadenomas, as increases in size occur more frequently.

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

Breast cancer in a male-to-female transsexual patient with a BRCA2 mutation.

Breast cancer is rare in male patients. Certain predisposing factors, be they genetic (e.g., BRCA2 gene mutations) or hormonal (imbalance between estrogen and androgen levels), have been implicated in male breast cancer pathophysiology. Male-to-female (MtF) transsexualism is a condition that generally involves cross-sex hormone therapy. Anti-androgens and estrogens are used to mimic the female hormonal environment and induce the cross-sex secondary characteristics. In certain situations, the change in the hormonal milieu can be disadvantageous and favor the development of hormone-dependent pathologies, such as cancer. We report a case of a MtF transgender patient who developed breast cancer after 7 years of cross-sex hormonal therapy. The patient was found to be BRCA2 positive, and suffered recurrent disease. The patient was unaware of being a member of an established BRCA2 mutation-positive kindred. This represents the first case of a BRCA2 mutation predisposing to breast cancer in a MtF transgender patient.

Parathyroid carcinoma: Challenges in diagnosis and treatment.

Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer continues to cause challenges for diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid disease and parathyroid carcinoma. An abnormal ratio (>1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing receptor, have a sustained effect in lowering serum calcium levels. Bone anti-resorptive therapy, like intravenous bisphosphonates (pamidronate and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed.