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Effects of oestradiol treatment on hot flushes in men undergoing androgen deprivation therapy for prostate cancer: a randomised placebo-controlled trial

Nicholas Russell, Rudolf Hoermann, Ada S Cheung, Jeffrey D Zajac, and Mathis Grossmann

Objective

Most men undergoing androgen deprivation therapy (ADT) for prostate cancer experience hot flushes. Current treatments have low or limited evidence of efficacy. It is likely that oestradiol depletion is the mediator of these hot flushes, and transdermal oestradiol might be an effective treatment.

Design

This is a 6-month randomised, placebo-controlled trial with the hypothesis that oestradiol would reduce hot flush frequency and intensity and improve quality of life (QoL).

Methods

Seventy-eight participants receiving ADT were randomised to 0.9 mg of 0.1% oestradiol gel per day or matched placebo. Hot flush frequency and severity were assessed by 7-day diary at baseline, month 1, month 3, and month 6. QoL was assessed by validated questionnaire.

Results

Oestradiol reduced daily hot flush frequency, with a mean adjusted difference (MAD) of –1.6 hot flushes per day (95% CI: –2.7 to –0.5; P = 0.04). The effect on weekly hot flush score was non-significant, with a MAD –19.6 (95% CI: –35.5 to –3.8; P = 0.11). On per protocol analysis, E2 significantly reduced daily hot flush frequency, with a MAD of –2.2 hot flushes per day (95% CI: –3.2 to –1.1; P = 0.001), and weekly hot flush score, with a MAD of –27.0 (–44.7 to –9.3; P = 0.02). Oestradiol had no significant effect on QoL.

Conclusion

We confirmed our hypothesis of a clinical effect of assignment to oestradiol to reduce hot flush frequency in men with castrate testosterone due to ADT. Transdermal oestradiol could be considered for men with burdensome hot flushes in whom other treatments have failed as long as the risk of breast effects and fat gain are considered.

Restricted access

Influence of cortisol cosecretion on non-ACTH-stimulated adrenal venous sampling in primary aldosteronism: a retrospective cohort study

Daniel Alexander Heinrich, Marcus Quinkler, Christian Adolf, Laura Handgriff, Lisa Müller, Holger Schneider, Lisa Sturm, Heike Künzel, Max Seidensticker, Sinan Deniz, Roland Ladurner, Felix Beuschlein, and Martin Reincke

Objective

Cortisol measurements are essential for the interpretation of adrenal venous samplings (AVS) in primary aldosteronism (PA). Cortisol cosecretion may influence AVS indices. We aimed to investigate whether cortisol cosecretion affects non-adrenocorticotrophic hormone (ACTH)-stimulated AVS results.

Design

Retrospective cohort study at a tertiary referral center.

Methods

We analyzed 278 PA patients who underwent non-ACTH-stimulated AVS and had undergone at least a 1-mg dexamethasone suppression test (DST). Subsets underwent additional late-night salivary cortisol (LSC) and/or 24-h urinary free cortisol (UFC) measurements. Patients were studied from 2013 to 2020 with follow-up data of 6 months following adrenalectomy or mineralocorticoid antagonist therapy initiation. We analyzed AVS parameters including adrenal vein aldosterone/cortisol ratios, selectivity, lateralization (LI) and contralateral suppression indices and post-operative ACTH-stimulation. We classified outcomes according to the primary aldosteronism surgical outcome (PASO) criteria.

Results

Among the patients, 18.9% had a pathological DST result (1.9–5 µg/dL: n  = 44 (15.8%); >5 µg/dL: n  = 8 (2.9%)). Comparison of AVS results stratified according to the 1-mg DST (≤1.8 vs >1.8 µg/dL: P = 0.499; ≤1.8 vs 1.8 ≤ 5 vs >5 µg/dL: P = 0.811) showed no difference. Lateralized cases with post DST serum cortisol values > 5 µg/dL had lower LI (≤1.8 µg/dL: 11.11 (5.36; 26.76) vs 1.9–5 µg/dL: 11.76 (4.9; 31.88) vs >5 µg/dL: 2.58 (1.67; 3.3); P = 0.008). PASO outcome was not different according to cortisol cosecretion.

Conclusions

Marked cortisol cosecretion has the potential to influence non-ACTH-stimulated AVS results. While this could result in falsely classified lateralized cases as bilateral, further analysis of substitutes for cortisol are required to unmask effects on clinical outcome.

Open access

Long-acting PEGylated growth hormone in children with idiopathic short stature

Xiaoping Luo, Sha Zhao, Yu Yang, Guanping Dong, Linqi Chen, Pin Li, Feihong Luo, Chunxiu Gong, Zhuangjian Xu, Xu Xu, Haihong Gong, Hongwei Du, Ling Hou, Yan Zhong, Qiao Shi, Xuefeng Chen, Xiuli Chen, Liya Xu, Ruoqian Cheng, Chang Su, Yaping Ma, Lulian Xu, Lina Zhang, and Honghua Lu

Objective

To evaluate the safety and efficacy of weekly PEGylated-recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS) in China.

Design and methods

This was a multicenter, phase II study in which all subjects were randomized 1:1:1 to weekly s.c. injections of PEG-rhGH 0.1 (low-dose (LD) group) or 0.2 mg/kg/week (high-dose (HD) group) or control for 52 weeks. The primary end point was change (Δ) in height s.d. score (HT-SDS) from baseline to week 52. Secondary end points were height velocity (HV), bone maturity, insulin-like growth factor-1 (IGF-1) SDS, and IGF-1/insulin-like growth factor-binding protein-3 (IGFBP-3) molar ratio.

Results

A total of 360 children with ISS were recruited in the study (n  = 120 in each group). At week 52, ΔHT-SDS was 0.56 ± 0.26, 0.98 ± 0.35, and 0.20 ± 0.26 in the LD, HD, and control groups, respectively (within-group P < 0.0001; intergroup P < 0.0001). Statistically significant values of ΔHV, IGF-1, IGF-1/IGFBP-3 ratio, and IGF-1 SDS at week 52 from baseline were observed in both treatment groups (P < 0.0001). There were clear dose-dependent responses for all auxological variables. PEG-rhGH was well tolerated throughout the treatment period with treatment-emergent adverse events (TEAEs) reported in 86.5%, 84.6%, and 91.3% of children in the HD, LD, and control groups, respectively. The incidence of TEAEs was similar in all treatment groups despite the difference in doses. A total of 27 (8.7%) children experienced drug-related TEAEs.

Conclusion

Fifty-two-week treatment with PEG-rhGH 0.1 or 0.2 mg/kg/week achieved significant improvement in HT-SDS and other growth-related variables, including HV, IGF-1 SDS, and IGF-1/IGFBP-3 ratio, in a dose-dependent manner. Both doses were well tolerated with similar safety profiles.

Free access

Pituitary apoplexy and SARS-CoV-2 infection: we need to look beyond the acute phase

Abdallah Al-Salameh, Joe Balmain, and Rachel Desailloud

Free access

Pituitary apoplexy in SARS-CoV-2 infected is not necessarily related to the virus

Josef Finsterer

Open access

Polycystic ovary syndrome and leukocyte telomere length: cross-sectional and longitudinal changes

Johanna Pölönen, Pekka Pinola, Justiina Ronkainen, Alex I Blakemore, Jessica L Buxton, Juha S Tapanainen, Stephen Franks, Terhi T Piltonen, Sylvain Sebert, and Laure Morin-Papunen

Objective

Telomeres are DNA–protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population.

Design

This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL.

Methods

The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age.

Results

Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P < 0.001), but not in women with PCOS (P = 0.96).

Conclusions

This finding may suggest a difference in the LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.

Restricted access

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study

Mirela Diana Ilie, Chiara Villa, Thomas Cuny, Christine Cortet, Guillaume Assie, Bertrand Baussart, Mathilde Cancel, Philippe Chanson, Bénédicte Decoudier, Elise Deluche, Anna Luisa Di Stefano, Delphine Drui, Stephan Gaillard, Bernard Goichot, Olivier Huillard, Anthony Joncour, Delphine Larrieu-Ciron, Rossella Libe, Guillaume Nars, Alexandre Vasiljevic, and Gérald Raverot

Objective

After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs.

Design and methods

This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally.

Results

Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center.

Conclusions

Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas.

Significance statement

This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Restricted access

Spatiotemporal variation of childhood hyperthyroidism: a 10-year nationwide study

Joëlle Le Moal, Julie Chesneau, Sarah Goria, Priscilla Boizeau, Jérémie Haigneré, Florentia Kaguelidou, and Juliane Léger

Objective

Childhood hyperthyroidism is mostly caused by Graves’ disease, a rare autoimmune disease in children. Epidemiological data are scarce and the variability of within-region incidence is unknown. We aimed to provide the first description of temporal trends in pediatric hyperthyroidism in France and to explore spatial trends, with a view to identifying possible environmental triggers.

Design and methods

We performed an observational population-based study on data collected from the National Health Data System, covering the 2008–2017 period and the whole of France. We identified patients with an indicator reflecting incident cases of treated hyperthyroidism, in children aged 6 months–17.9 years, localized at the scale of the département (equivalent to a county) of residence. We performed descriptive analyses of incidence rate by sex, age, and year, and used a spatiotemporal model for estimation at département level.

Results

We identified 4734 incident cases: 3787 girls (80%) and 947 boys (20%). The crude incidence rate was 3.35 (95% CI: 3.26; 3.45) per 100 000 person-years over the study period. We estimated the increase in incidence between 2008 and 2017 at 30.1% (19.0%; 42.3%). Annual incidence rate increased linearly over the 10-year period in both girls and boys, rising similarly in all age groups and in all départements. The spatial model highlighted marked heterogeneity in the risk of childhood hyperthyroidism across France.

Conclusion

The trend toward increasing incidence observed may reflect changes in genetic and environmental interactions, and the marked spatial heterogeneity may reflect localized ethnic or environmental factors worthy of further investigation.

Free access

Subclinical thyroid dysfunction and incident diabetes: a systematic review and an individual participant data analysis of prospective cohort studies

Heba Alwan, Fanny Villoz, Martin Feller, Robin P F Dullaart, Stephan J L Bakker, Robin P Peeters, Maryam Kavousi, Douglas C Bauer, Anne R Cappola, Bu B Yeap, John P Walsh, Suzanne J Brown, Graziano Ceresini, Luigi Ferrucci, Jacobijn Gussekloo, Stella Trompet, Massimo Iacoviello, Jae Hoon Moon, Salman Razvi, Isabela M Bensenor, Fereidoun Azizi, Atieh Amouzegar, Sergio Valdés, Natalia Colomo, Nick J Wareham, J Wouter Jukema, Rudi G J Westendorp, Ki Woong Kim, Nicolas Rodondi, Cinzia Del Giovane, and

Objective

Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes.

Methods

We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up.

Results

Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88–1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82–1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87–1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88–1.29). The results were robust in all sub-group and sensitivity analyses.

Conclusions

This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes.

Significance statement

Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.

Open access

Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool

Marianna Minnetti, Valeria Hasenmajer, Emilia Sbardella, Francesco Angelini, Chiara Simeoli, Nicola Di Paola, Alessia Cozzolino, Claudia Pivonello, Dario De Alcubierre, Sabrina Chiloiro, Roberto Baldelli, Laura De Marinis, Rosario Pivonello, Riccardo Pofi, and Andrea M Isidori

Objective

Registry data show that Cushing’s syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool.

Methods

We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test–retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections.

Results

In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3–9.9)), mycoses (4.4 (2.1–8.8)), and flu (2.9 (1.4–5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7–8.0)) and flu (3.2 (1.5–6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6–3.9)), mycoses (2.3 (1.4–3.8)), and gastrointestinal infections (2.2 (1.5–3.3)), independently of any glucocorticoid replacement dose.

Conclusions

The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.