Publications by authors named "Brendan J Nolan"

11 Publications

  • Page 1 of 1

Ex vivo glucocorticoid-induced secreted proteome approach for discovery of glucocorticoid-responsive proteins in human serum.

Proteomics Clin Appl 2021 Feb 28:e2000078. Epub 2021 Feb 28.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Purpose: To identify glucocorticoid-responsive proteins measurable in human serum that may have clinical utility in therapeutic drug monitoring and the diagnosis of cortisol excess or deficiency.

Experimental Design: A phased biomarker discovery strategy was conducted in two cohorts. Secretome from peripheral blood mononuclear cells (PBMC) isolated from six volunteers after ex vivo incubation ± dexamethasone (DEX) 100 ng/mL for 4 h and 24 h was used for candidate discovery and qualification using untargeted proteomics and a custom multiple reaction monitoring mass spectrometry (MRM-MS) assay, respectively. For validation, five candidates were measured by immunoassay in serum from an independent cohort (n = 20), sampled at 1200 h before and after 4 mg oral DEX.

Results: The discovery secretome proteomics data generated a shortlist of 45 candidates, with 43 measured in the final MRM-MS assay. Differential analysis revealed 16 proteins that were significant in at least one of two time points. In the validation cohort, 3/5 serum proteins were DEX-responsive, two significantly decreased: lysozyme C (p < 0.0001) and nucleophosmin-1 (p < 0.01), while high mobility group box 2 significantly increased (p < 0.01).

Conclusions And Clinical Relevance: Using an ex vivo proteomic approach in PBMC, we have identified circulating glucocorticoid-responsive proteins which may have potential as serum biomarkers of glucocorticoid activity.
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http://dx.doi.org/10.1002/prca.202000078DOI Listing
February 2021

Efficacy of Micronized Progesterone for Sleep: A Systematic Review and Meta-analysis of Randomized Controlled Trial Data.

J Clin Endocrinol Metab 2021 Mar;106(4):942-951

Department of Endocrinology (Austin Health), Heidelberg, University of Melbourne, Victoria, Australia.

Context: Preclinical data has shown progesterone metabolites improve sleep parameters through positive allosteric modulation of the γ-aminobutyric acid type A receptor. We undertook a systematic review and meta-analysis of randomized controlled trials to assess micronized progesterone treatment on sleep outcomes.

Evidence Acquisition: Using preferred reporting items for systematic review and meta-analysis guidelines, we searched MEDLINE, Embase, PsycInfo, and the Cochrane Central Register of Controlled Trials for randomized controlled trials of micronized progesterone treatment on sleep outcomes up to March 31, 2020. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42020165981. A random effects model was used for quantitative analysis.

Evidence Synthesis: Our search strategy retrieved 9 randomized controlled trials comprising 388 participants. One additional unpublished trial was found. Eight trials enrolled postmenopausal women. Compared with placebo, micronized progesterone improved various sleep parameters as measured by polysomnography, including total sleep time and sleep onset latency, though studies were inconsistent. Meta-analysis of 4 trials favored micronized progesterone for sleep onset latency (effect size, 7.10; confidence interval [CI] 1.30, 12.91) but not total sleep time (effect size, 20.72; CI -0.16, 41.59) or sleep efficiency (effect size, 1.31; CI -2.09, 4.70). Self-reported sleep outcomes improved in most trials. Concomitant estradiol administration and improvement in vasomotor symptoms limit conclusions in some studies.

Conclusions: Micronized progesterone improves various sleep outcomes in randomized controlled trials, predominantly in studies enrolling postmenopausal women. Further research could evaluate the efficacy of micronized progesterone monotherapy using polysomnography or validated questionnaires in larger cohorts.
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http://dx.doi.org/10.1210/clinem/dgaa873DOI Listing
March 2021

Estradiol Therapy in the Perioperative Period: Implications for Transgender People Undergoing Feminizing Hormone Therapy.

Yale J Biol Med 2020 09 30;93(4):539-548. Epub 2020 Sep 30.

Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia.

Venous thromboembolism is a documented risk of some estradiol formulations, but evidence evaluating the perioperative risk of continuation of estradiol therapy is limited. This narrative review summarizes literature related to the perioperative venous thromboembolic risk of estradiol, with a focus on feminizing genitoplasty for trans people undergoing feminizing hormone therapy. Given the dearth of evidence underlying gender-affirming hormone therapy regimens, much of the risk is based on the menopausal hormone therapy literature. However, the doses used for trans people undergoing feminizing hormone therapy can be significantly higher than those used for menopausal hormone therapy and escalating estradiol dose is associated with an increased thrombotic risk. Transdermal formulations are not associated with an increased risk in postmenopausal people. Feminizing genitoplasty is associated with a low thromboembolic risk. However, many patients are instructed to cease estradiol therapy several weeks preoperatively based on reports of increased thrombotic risk in trans people undergoing feminizing hormone therapy and hemostatic changes with the oral contraceptive pill. This can result in psychological distress and vasomotor symptoms. There is insufficient evidence to support routine discontinuation of estradiol therapy in the perioperative period. There is a need for high-quality prospective trials evaluating the perioperative risk of estradiol therapy in trans people undergoing feminizing hormone therapy to formulate evidence-based recommendations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513447PMC
September 2020

A systematic review of antiandrogens and feminization in transgender women.

Clin Endocrinol (Oxf) 2021 May 5;94(5):743-752. Epub 2020 Oct 5.

Department of Medicine, The University of Melbourne, Heidelberg, Vic., Australia.

Antiandrogens are frequently used with estradiol in transgender women seeking feminization. Antiandrogens act by various mechanisms to decrease the production or effects of testosterone, but it is unclear which antiandrogen is most effective at feminization. A systematic review was performed using PRISMA guidelines. We searched online databases (Medline, Embase and PsycINFO) and references of relevant articles for studies of antiandrogens in transgender women aged 16+ years to achieve feminization (namely changes in breast size, body composition, facial or body hair) or changes in serum total testosterone concentration when compared to placebo, estradiol alone or an alternative antiandrogen. Four studies fulfilled eligibility criteria and were included in a narrative review. The addition of cyproterone acetate, leuprolide and medroxyprogesterone acetate may be more effective than spironolactone or estradiol alone at suppressing the serum total testosterone concentration. Body composition changes appear similar in transgender women treated with estradiol and additional cyproterone acetate or leuprolide. No eligible studies adequately evaluated the effects of antiandrogens on breast development or facial and body hair reduction. It remains unclear which antiandrogen is most effective at achieving feminization. Cyproterone acetate, medroxyprogesterone acetate and leuprolide may be more effective than spironolactone at suppressing the serum total testosterone concentration. However, due to spironolactone's antagonism of the androgen receptor, it is unclear whether this results in clinically meaningful differences in feminization. Further research with clinically meaningful endpoints is needed to optimize the use of antiandrogens in transgender women.
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http://dx.doi.org/10.1111/cen.14329DOI Listing
May 2021

Relationships between body mass index with oral estradiol dose and serum estradiol concentration in transgender adults undergoing feminising hormone therapy.

Ther Adv Endocrinol Metab 2020 24;11:2042018820924543. Epub 2020 May 24.

Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia.

Aim: Feminising hormone therapy with estradiol is used to align an individual's physical characteristics with their gender identity. Given considerable variations in doses of estradiol therapy administered as gender-affirming hormone therapy (GAHT), we aimed to assess if body mass index (BMI) correlated with estradiol dose/concentration and assess the correlation between estradiol dose and estradiol concentrations.

Methods: In a retrospective cross-sectional study, we analysed transgender individuals attending a primary or secondary care clinic in Melbourne, Australia who were prescribed oral estradiol valerate for at least 6 months and had estradiol dose and concentration available. Estradiol concentration was measured by immunoassay. Outcomes were the correlation between estradiol dose and BMI, and estradiol dose and estradiol concentration.

Results: Data were available for 259 individuals {median age 25.8 [interquartile range (IQR) 21.9, 33.5] years}. Median duration of estradiol therapy was 24 (15, 33) months. Median estradiol concentration was 328 (238, 434) pmol/l [89 (65, 118) pg/ml] on 6 (4, 8) mg estradiol valerate. Median BMI was 24.7 (21.8, 28.6) kg/m. There was a weak positive correlation between estradiol dose and estradiol concentration ( = 0.156,  = 0.012). There was no correlation between BMI and estradiol concentration achieved ( = -0.063,  = 0.413) or BMI and estradiol dose ( = 0.048,  = 0.536). Estradiol concentrations were within the target range recommended in consensus guidelines in 172 (66%) individuals.

Conclusion: Estradiol dose was only weakly correlated with estradiol concentration, suggesting significant interindividual variability. Prescription of estradiol dose should not be based upon an individual's BMI, which did not correlate with estradiol concentration achieved. In all, 66% of individuals achieved estradiol concentrations recommended in Australian consensus guidelines with a relatively high oral estradiol dose.
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http://dx.doi.org/10.1177/2042018820924543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249588PMC
May 2020

Prevalence of polycythaemia with different formulations of testosterone therapy in transmasculine individuals.

Intern Med J 2020 Apr 1. Epub 2020 Apr 1.

Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia.

Background: Masculinising hormone therapy with testosterone is used to align an individual's physical characteristics with their gender identity. Testosterone therapy is typically administered via intramuscular or transdermal routes and polycythaemia is the most common adverse event.

Aims: To compare the risk of polycythaemia with different formulations of testosterone therapy in transmasculine individuals.

Methods: A retrospective cross-sectional analysis was undertaken of transmasculine individuals at a primary and secondary care clinic in Melbourne, Australia. 180 individuals who were on testosterone therapy for >6 months were included. Groups included those receiving (1) intramuscular testosterone undecanoate (n = 125), (2) intramuscular testosterone enantate (n = 31), or (3) transdermal testosterone (n = 24). Outcome was prevalence of polycythaemia (defined as haematocrit >0.5).

Results: Mean age was 28.4 (8.8) years with a median duration of testosterone therapy 37.7 (24.2) months. 27% were smokers. There was no difference between groups in serum total testosterone concentration measured. Whilst there was no difference between groups in haematocrit, there was a higher proportion of patients with polycythemia in those who were on intramuscular testosterone enantate (23.3%) than on transdermal testosterone (0%), p = 0.040. There was no statistically significant difference in polycythaemia between intramuscular testosterone undecanoate (15%) and transdermal, p = 0.066 nor between intramuscular testosterone enantate and undecanoate, p = 0.275.

Conclusions: One in four individuals treated with intramuscular testosterone enantate and one in six treated with testosterone undecanoate had polycythaemia. No individual treated with transdermal testosterone had polycythaemia. This highlights the importance of regular monitoring of haematocrit in transmasculine individuals treated with testosterone and findings may inform treatment choices. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.14839DOI Listing
April 2020

Intestinal Pseudo-Obstruction and Livedo Reticularis: Rare Manifestations of Catecholamine Excess.

Am J Med 2020 09 27;133(9):e526-e527. Epub 2020 Jan 27.

Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia; Department of Medicine, The University of Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1016/j.amjmed.2019.12.030DOI Listing
September 2020

Beware Ketoacidosis with SGLT2 Inhibitors in Latent Autoimmune Diabetes of the Adult.

Am J Med 2020 08 8;133(8):e422-e424. Epub 2020 Jan 8.

Department of Endocrinology, Northern Hospital, Epping, Victoria, Australia; Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia; Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are increasingly used for the treatment of type 2 diabetes, but have been associated with ketoacidosis.

Methods/results: We report a case series of three patients with latent autoimmune diabetes of the adult who presented with ketoacidosis, including one case with normal blood glucose levels, in the context of SGLT2 inhibitor use.

Conclusions: Sodium-glucose co-transporter-2 inhibitors should be used with caution and close clinical monitoring in patients with latent autoimmune diabetes of the adult. A clinical risk score permits targeted autoantibody testing and should be undertaken prior to commencement of SGLT2 inhibitors or cessation of insulin.
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http://dx.doi.org/10.1016/j.amjmed.2019.12.006DOI Listing
August 2020

SGLT2 Inhibitors Increase the Risk of Diabetic Ketoacidosis Developing in the Community and During Hospital Admission.

J Clin Endocrinol Metab 2019 08;104(8):3077-3087

Department of Endocrinology and Diabetes, Alfred Health, Melbourne, Victoria, Australia.

Context: Diabetic ketoacidosis (DKA) has been associated with the use of sodium glucose cotransporter 2 inhibitors (SGLT2is).

Objective: To determine the incidence, characteristics, and outcomes of DKA in SGLT2i users vs nonusers with type 2 diabetes.

Design: Retrospective, multicenter, controlled cohort study.

Setting: All public hospitals in Melbourne and Geelong (combined population of 5 million), Australia, from 1 September 2015 to 31 October 2017.

Patients: Consecutive cases of DKA that developed in the community, or during the course of hospital admission, in patients with type 2 diabetes.

Main Outcome Measures: In SGLT2i users vs nonusers: (i) OR of DKA developing during hospital admission, and (ii) incidence of DKA.

Results: There were 162 cases of DKA (37 SGLT2i users and 125 non-SGLT2i users) with a physician-adjudicated diagnosis of type 2 diabetes. Of these, DKA developed during the course of inpatient admission in 14 (38%) SGLT2i users vs 2 (2%) non-SGLT2i users (OR, 37.4; 95% CI, 8.0 to 175.9; P < 0.0001). The incidence of DKA was 1.02 per 1000 (95% CI, 0.74 to 1.41 per 1000) in SGLT2i users vs 0.69 per 1000 (95% CI, 0.58 to 0.82 per 1000) in non-SGLT2i users (OR, 1.48; 95% CI, 1.02 to 2.15; P = 0.037). Fifteen SGLT2i users (41%) had peak blood glucose <250 mg/dL (14 mmol/L) compared with one (0.8%) non-SGLT2i user (P < 0.001).

Conclusions: SGLT2i users were more likely to develop DKA as an inpatient compared with non-SGLT2i users. SGLT2i use was associated with a small but significant increased risk of DKA.
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http://dx.doi.org/10.1210/jc.2019-00139DOI Listing
August 2019

Characterization of the serum and salivary cortisol response to the intravenous 250 µg ACTH stimulation test.

Endocrine 2018 03 3;59(3):520-528. Epub 2018 Jan 3.

Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.

Purpose: The ACTH stimulation test is commonly used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Given variations in CBG concentration and binding affinity, serum total cortisol may misclassify some patients. Salivary cortisol correlates well with serum free cortisol but is easier to measure and widely available in commercial laboratories. The aim of this study was to investigate the utility of measuring salivary cortisol during the ACTH stimulation test.

Design And Methods: Case-control study in a clinical research facility. Eighty-seven patients with suspected cortisol deficiency, twenty-four healthy controls, and ten healthy women on the oral contraceptive (OC) underwent an intravenous 250 µg ACTH stimulation test. Concordance of ACTH stimulated serum and salivary cortisol was evaluated.

Results: There was a significant difference in serum cortisol between the healthy volunteers and the women on the OC (P < 0.001) but no difference in salivary cortisol. The lower limit of the reference interval for salivary cortisol at 60 min was 26 nmol/L. 27/89 (30%) of tests with suspected HPA axis disorder failed the 60 min serum cortisol cut-off of 500 nmol/L. Of these, 24/27 (89%) had a salivary cortisol of <26 nmol/L. In contrast, 12/19 (63%) tests and 5/43 (12%) tests where the 60 min serum cortisol was 500-599 and ≥600 nmol/L, respectively had a salivary cortisol of <26 nmol/L.

Conclusions: Salivary cortisol provides additional diagnostic value during the 250 µg ACTH stimulation test in patients with proven or suspected alterations in CBG and potentially those with a borderline 60 min serum cortisol 500-599 nmol/L.
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http://dx.doi.org/10.1007/s12020-017-1505-0DOI Listing
March 2018

Testosterone treatment in older men: glass half empty or half full?

Asian J Androl 2017 Sep-Oct;19(5):512-514

Department of Endocrinology, Austin Health, Heidelberg, Victoria 3084, Australia.

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http://dx.doi.org/10.4103/aja.aja_14_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566841PMC
September 2018