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Open access

Matthias K Auer, James M Hawley, Christian Lottspeich, Martin Bidlingmaier, Andrea Sappl, Hanna F Nowotny, Lea Tschaidse, Marcus Treitl, Martin Reincke, Brian G Keevil, and Nicole Reisch

Objective

Differentiation of an adrenal from an ovarian source of hyperandrogenemia can be challenging. Recent studies have highlighted the importance of 11-oxygenated C19 steroids to the androgen pool in humans. The aim of this study was to confirm the origin of 11-oxygenated androgens in females and to explore their potential use in the diagnostics of hyperandrogenic disorders.

Methods

We measured testosterone and its precursors (dehydroepiandrosterone-sulfate and androstenedione) and 11-oxygenated androgens (11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT)) in the periphery, adrenal and ovarian veins in four different cases of hyperandrogenism in females (polycystic ovary syndrome (PCOS), primary bilateral macronodular adrenal hyperplasia, Sertoli–Leydig cell tumor and ovarian steroid cell tumor).

Results

Two patients demonstrate excessive testosterone secretion in neoplastic ovarian tumors which was not paralleled by a significant secretion of 11-oxygenated androgens as determined by adrenal and ovarian vein sampling. In androgen-secreting bilateral adrenal macronodular hyperplasia, steroid profiles were characterized by elevated 11-KT and 11-OHA4 concentrations in adrenal veins and the periphery. In the patient with PCOS, peripheral 11-KT concentrations were slightly elevated in comparison to the other patients, but the 11-KT and 11-OHA4 concentrations were comparable in ovarian veins and in the periphery.

Conclusion

This study confirms that 11-OHA4 and 11-KT are not biosynthesized by the ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Significance statement

This study confirms that 11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT) are not biosynthesized by the human ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help to identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Restricted access

Takuya Kitamura, Amy R Blinder, Kazutaka Nanba, Mika Tsuiki, Mutsuki Mishina, Hiroshi Okuno, Koki Moriyoshi, Yuto Yamazaki, Hironobu Sasano, Keisuke Yoneyama, Aaron M Udager, William E Rainey, Akihiro Yasoda, Noriko Satoh-Asahara, and Tetsuya Tagami

Although excess production of androgens and glucocorticoids has often been observed in adrenocortical carcinomas, adrenocortical adenoma with such hormonal activity is rare. Herein, we report a 41-year-old woman who presented with hyperandrogenemia and mild autonomous cortisol secretion with an undetectable level of adrenocorticotropic hormone. Imaging demonstrated a 6 cm left adrenal tumor. The histologic diagnosis of the resected adrenal tumor was adrenocortical adenoma. Pre- and post-operative serum samples were used for steroid profiling with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis of pre-operative serum revealed an abnormal buildup of steroid precursors and androgens. Importantly, circulating levels of 11-oxygenated androgens, including 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), were highly elevated. Both androgen and glucocorticoid levels significantly decreased post-operatively. Immunohistochemical analysis of steroidogenic enzymes and cofactor protein supported the tumor’s ability to directly produce 11OHT and 11KT. This study is the first to describe and characterize an adrenocortical adenoma that co-secretes glucocorticoids and 11-oxygenated androgens.

Significance statement

Due to its rarity, biochemical and histologic characteristics of androgen and glucocorticoid co-secreting adrenocortical adenomas are largely unknown. Herein, we report a case of adrenocortical adenoma that caused marked hyperandrogenemia and mild autonomous cortisol secretion. In this study, we investigated serum steroid profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and histologic characteristics of the resected tumor. LC-MS/MS revealed highly elevated levels of 11-oxygenated androgens which have not been well studied in adrenal tumors. The expression patterns of steroidogenic enzymes determined by immunohistochemistry supported the results of steroid profiling and suggested the capacity of the tumor cells to produce 11-oxygenated androgens. Measurement of 11-oxygenated steroids should facilitate a better understanding of androgen-producing adrenocortical neoplasms.

Restricted access

Maria Riedmeier, Boris Decarolis, Imme Haubitz, Joachim Reibetanz, Armin Wiegering, Christoph Härtel, Paul-Gerhardt Schlegel, Martin Fassnacht, and Verena Wiegering

Objective

Pediatric adrenocortical carcinoma (pACC) is rare and prognostic stratification remains challenging. We summarized the clinical prognostic factors of pACC and determined the prognostic value of the pediatric scoring system (pS-GRAS) in adaption to the recommendation (S-GRAS) of the European Network for the Study of Adrenal Tumors for the classification of adult ACC.

Design

Analysis of pACC patients of 33 available retrospective studies in the literature.

Methods

We searched the PubMed and Embase databases for manuscripts regarding pACC. The pS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2–3 = 1; 4 = 2 points), grade (Ki67 index/rate of mitosis 0–9%/low = 0; 10–19%/intermediate = 1; ≥20%/high = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3 points), age (<4 years = 0; ≥4 years = 1 point), hormone-related symptoms (androgen production = 0; glucocorticoid/mixed/no hormone production = 1 point) generating 10 scores and 4 groups (1: 0–2, 2: 3–4, 3: 5, 4: 6–9). The primary endpoint was overall survival (OS).

Results

We included 733 patients. The median age was 2.5 years and >85% of pACC showed hormone activity (mixed 50%, androgen 29%, glucocorticoid 21%). Androgen production was associated with a superior OS. Increasing age correlated with higher rates of inactive or only glucocorticoid-producing tumors, advanced tumor stage, and case fatality. Especially infants < 4 years showed more often low-risk constellations with an increased OS for all tumor stages. The pS-GRAS score correlated with clinical outcome; median OS was 133 months (95% CI: 36–283) in group 1 (n = 49), 110 months (95% CI: 2.9–314) in group 2 (n = 57), 49 months (95% CI: 5.8–278) in group 3 (n = 18), and 16 months (95% CI: 2.4–267) in group 4; (n = 11) P < 0.05).

Conclusion

The pS-GRAS score seems to have a high predictive value in the pACC patients, may serve as a helpful tool for risk stratification in future studies, and should be evaluated prospectively in an international context.

Free access

Sheng-Yin Chen, Jui-Yi Chen, Wei-Chieh Huang, Troy Hai Kiat Puar, Peng Chin Kek, Jeff S Chueh, Yen-Hung Lin, Vin-Cent Wu, and TAIPAI Study Group

Background

In patients with primary aldosteronism (PA), long-term cardiovascular and mortality outcomes after adrenalectomy vs mineralocorticoid receptor antagonist (MRA) have not been compared yet. We aim to compare the clinical outcomes of these patients after treatment.

Design and Methods

A systematic review and meta-analysis was conducted by searching PubMed, Cochrane library, and Embase from no start date restriction to 18 December 2021. Our composite primary outcomes were long-term all-cause mortality and/or major adverse cardiovascular events (MACE), including coronary artery disease (CAD), stroke, arrhythmia, and congestive heart failure. We adopted the random-effects model and performed subgroup analyses, meta-regression, and trial sequential analysis (TSA).

Results

A total of 9 studies with 8473 adult patients with PA (≥18 years) were enrolled. A lower incidence of composite primary outcomes was observed in the adrenalectomy group (odds ratio (OR): 0.46 (95% CI: 0.38–0.56), P < 0.001). We found a lower incidence of all-cause mortality (OR: 0.33 (95% CI: 0.15–0.73), P = 0.006) and MACE (OR: 0.55, (95% CI: 0.40–0.74), P = 0.0001) in the adrenalectomy group. The incidence of CAD (OR: 0.33 (95% CI: 0.15–0.75), P = 0.008), arrhythmias (OR: 0.46 (95% CI: 0.27–0.81), P = 0.007), and congestive heart failure (OR: 0.52 (95% CI: 0.33–0.81), P = 0.004) was also lower in adrenalectomy group. The metaregression showed patient’s age may attenuate the benefits of adrenalectomy on composite primary outcomes (coefficient: 1.084 (95% CI: 1.005–1.169), P = 0.036). TSA demonstrated that the accrued sample size and effect size were sufficiently large to draw a solid conclusion, and the advantage of adrenalectomy over MRA was constant with the chronological sequence.

Conclusions

In conclusion, adrenalectomy could be preferred over MRA for patients with PA in reducing the risk of all-cause mortality and/or MACE and should be considered as the treatment of choice. That patients with PA could get less benefit from adrenalectomy as they age warrants further investigation.

Restricted access

Alessandro Prete, Carla Gambale, Virginia Cappagli, Valeria Bottici, Piercarlo Rossi, Marco Caciagli, Piermarco Papini, Donatella Taddei, Simona Ortori, Luciano Gabbrielli, Alessandro Celi, Gabriele Materazzi, Rossella Elisei, and Antonio Matrone

Objective

Selpercatinib is a highly selective RET-inhibitor drug, approved for the treatment of RET-altered lung and thyroid cancers. So far, RET-altered medullary thyroid cancer (MTC) patients treated with selpercatinib showed a remarkable objective response rate and safety profile. However, new treatment emerging adverse events (TEAEs) have been recently reported. The aim of this study was to evaluate the prevalence, features, and clinical management of effusions that are one of these TEAEs.

Design

Around 10 of 11 patients with advanced MTC enrolled in the LIBRETTO-201 clinical trial at Endocrinology Unit of the Pisa University Hospital were evaluated for the presence and management of effusions.

Methods

We retrospectively evaluated MTC patients treated with selpercatinib. The presence of pleural, pericardial, abdominal, and/or pelvic effusions was evaluated by reviewing the computerized tomography scan performed during the study protocol and up to 24 months of observation.

Results

All but one MTC patient experienced previous multikinase inhibitors treatment. Three patients already had effusions before starting selpercatinib treatment. New effusions appeared in eight of ten (80%) patients during the treatment. A chylous nature was documented in patients who underwent fluid aspiration. Whenever a dose reduction was performed, a significant positive effect was observed.

Conclusions

Chylous effusions are a new TEAE of selpercatinib treatment. They can appear or worsen at any time during the treatment. For cases with asymptomatic and mild effusions, active surveillance may be appropriate and safe. In symptomatic and/or moderate/severe cases, aspiration of the fluid and a dose reduction can improve this AE, strongly supporting a cause-effect correlation with selpercatinib.

Significance statement

Effusions, particularly of chylous nature, represent emergent and quite frequent adverse events in the management of patients affected by advanced MTC on treatment with the highly selective inhibitor selpercatinib. In this study, we evaluated, in a series of MTC patients treated with selpercatinib, the prevalence of pleural, pericardial, abdominal, and/or pelvic effusions. Insights into the diagnosis and treatment of the effusions are provided as well as suggestions for clinical management.

Free access

Karl-Heinz Storbeck

Restricted access

Tessel M Boertien, Eus J W Van Someren, Adriaan D Coumou, Annemieke K van den Broek, Jet H Klunder, Wing-Yi Wong, Adrienne E van der Hoeven, Madeleine L Drent, Johannes A Romijn, Eric Fliers, and Peter H Bisschop

Objective

Pituitary tumours that compress the optic chiasm are associated with long-term alterations in sleep–wake rhythm. This may result from damage to intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting from the retina to the hypothalamic suprachiasmatic nucleus via the optic chiasm to ensure photoentrainment (i.e. synchronisation to the 24-h solar cycle through light). To test this hypothesis, we compared the post-illumination pupil response (PIPR), a direct indicator of ipRGC function, between hypopituitarism patients with and without a history of optic chiasm compression.

Design

Observational study, comparing two predefined groups.

Methods

We studied 49 patients with adequately substituted hypopituitarism: 25 patients with previous optic chiasm compression causing visual disturbances (CC+ group) and 24 patients without (CC– group). The PIPR was assessed by chromatic pupillometry and expressed as the relative change between baseline and post-blue-light stimulus pupil diameter. Objective and subjective sleep parameters were obtained using polysomnography, actigraphy, and questionnaires.

Results

Post-blue-light stimulus pupillary constriction was less sustained in CC+ patients compared with CC– patients, resulting in a significantly smaller extended PIPR (mean difference: 8.1%, 95% CI: 2.2–13.9%, P = 0.008, Cohen’s d = 0.78). Sleep–wake timing was consistently later in CC+ patients, without differences in sleep duration, efficiency, or other rest–activity rhythm features. Subjective sleep did not differ between groups.

Conclusion

Previous optic chiasm compression due to a pituitary tumour in patients with hypopituitarism is associated with an attenuated PIPR and delayed sleep timing. Together, these data suggest that ipRGC function and consequently photoentrainment of the central biological clock is impaired in patients with a history of optic chiasm compression.

Restricted access

Laura Bessiène, Sandrine Moutel, Marine Lataud, Anne Jouinot, Fidéline Bonnet-Serrano, Jean Guibourdenche, Chiara Villa, Bertrand Baussart, Stephan Gaillard, Maxime Barat, Anthony Dohan, Xavier Bertagna, Bertrand Dousset, Jérôme Bertherat, and Guillaume Assié

Objectives

After bilateral adrenalectomy in Cushing’s disease, corticotroph tumor progression occurs in one-third to half of patients. However, progression speed is variable, ranging from slow to rapid. The aim was to explore corticotroph progression speed, its consequences and its risk factors.

Design

A retrospective single-center observational study.

Methods

In total,103 patients with Cushing’s disease who underwent bilateral adrenalectomy between 1990 and 2020 were included. Clinical, biological, histological and MRI features were collected. Median duration of follow-up after bilateral adrenalectomy was 9.31 years.

Results

In total,44 patients progressed (43%). Corticotroph tumor progression speed ranged from 1 to 40.7 mm per year. Progression speed was not different before and after bilateral adrenalectomy (P  = 0.29). In univariate analyses, predictive factors for rapid corticotroph tumor progression included the severity of Cushing’s disease before adrenalectomy as the cause of adrenalectomy, high ACTH in the year following adrenalectomy and high Ki67 immunopositivity in the tumor. During follow-up, early morning ACTH absolute variation was associated with corticotroph tumor progression speed (P-value = 0.001). ACTH measurement after dynamic testing did not improve this association.

Conclusion

After adrenalectomy, corticotroph progression speed is highly variable and manageable with MRI and ACTH surveillance. Progression speed does not seem related to bilateral adrenalectomy but rather to intrinsic properties of highly proliferative and secreting tumors.

Open access

Susan L Samson, Lisa B Nachtigall, Maria Fleseriu, Mojca Jensterle, Patrick J Manning, Atanaska Elenkova, Mark E Molitch, William H Ludlam, Gary Patou, Asi Haviv, Nienke R Biermasz, Andrea Giustina, Christian J Strasburger, Laurence Kennedy, and Shlomo Melmed

Objective

The objective of this study is to report results from the open-label extension (OLE) of the OPTIMAL trial of oral octreotide capsules (OOC) in adults with acromegaly, evaluating the long-term durability of therapeutic response.

Design

The study design is an OLE of a double-blind placebo-controlled (DPC) trial.

Methods

Patients completing the 36-week DPC period on the study drug (OOC or placebo) or meeting predefined withdrawal criteria were eligible for OLE enrollment at 60 mg/day OOC dose, with the option to titrate to 40 or 80 mg/day. The OLE is ongoing; week 48 results are reported.

Results

Forty patients were enrolled in the OLE, 20 each having received OOC or placebo, with 14 and 5 patients completing the DPC period as responders, respectively. Ninety percent of patients completing the DPC period on OOC and 70% of those completing on placebo completed 48 weeks of the OLE. Maintenance of response in the OLE (i.e. insulin-like growth factor I (IGF1) ≤ 1.0 × upper limit of normal (ULN)) was achieved by 92.6% of patients who responded to OOC during the DPC period. Mean IGF1 levels were maintained between the end of the DPC period (0.91 × ULN; 95% CI: 0.784, 1.045) and week 48 of the OLE (0.90 × ULN; 95% CI: 0.750, 1.044) for those completing the DPC period on OOC. OOC safety was consistent with previous findings, with no increased adverse events (AEs) associated with the higher dose and improved gastrointestinal tolerability observed over time.

Conclusions

Patients with acromegaly maintained long-term biochemical response while receiving OOC, with no new AEs observed with prolonged OOC exposure.