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Warrick J Inder

While the ACTH1–24 test has some well-documented shortcomings, it is the most widely used test to diagnose primary and secondary adrenal insufficiency. However, this synthetic ACTH preparation is not readily available in some countries. Research from India has demonstrated that using a long-acting porcine sequence ACTH has similar diagnostic performance to ACTH1–24 at around 25% of the cost. This may allow access to a robust test for adrenal insufficiency to developing countries and potentially allow thousands of patients to be identified and appropriately treated.

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Christina Jang, Varuni R Obeyesekere, Frank P Alford, and Warrick J Inder

Objective

Cortisol has been traditionally implicated in the causation of peri-operative skeletal muscle (SkM) insulin resistance, but cortisol levels return to normal within 72 h of surgery. Tissue cortisol bioactivity may be prolonged by local upregulation of the enzyme 11βHSD1. We aimed to investigate the changes of SkM 11βHSD1 enzyme activity and mRNA expression, relative to plasma cortisol, insulin and glucose levels following elective abdominal surgery.

Patients and design

Eight non-diabetic subjects (two male, six female) underwent serial plasma hormone sampling and muscle biopsy of vastus lateralis at baseline and on day 5 following elective laparoscopic cholecystectomy.

Methods

SkM 11βHSD1 and H6PDH mRNA levels were measured by quantitative RT-PCR and enzyme activity by % conversion of 3H cortisone to cortisol. Plasma glucose, insulin, free fatty acids (FFA), tumour necrosis factor-α and cortisol by standardised assays.

Results

Compared with baseline, SkM 11βHSD1 activity was significantly increased on day 5 after surgery (14.7±2.1 vs 20.4±3.2%, P=0.005). Neither 11βHSD1 nor H6PDH mRNA levels were altered after surgery. Plasma cortisol (P=0.027), FFA (P=0.01) and glucose (P=0.004) rose rapidly following surgery and had returned to baseline values by 24 h post-surgery. There was no significant change in plasma insulin.

Conclusions

This is the first study to demonstrate an upregulation of SkM 11βHSD1 activity in response to a physiological stressor. Sustained activation of this enzyme may increase tissue cortisol bioactivity.

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Andrea Lamprecht, Jane Sorbello, Christina Jang, David J Torpy, and Warrick J Inder

Objective

To evaluate pituitary function, sexual function and quality of life (QoL) in patients on oral or transdermal opioids.

Design and methods

Cross-sectional study comparing pituitary function, QoL and sexual function in people on long-term opioid therapy (n = 40) vs an age- and sex-matched control group (n = 25). Baseline pituitary function was assessed on blood samples collected prior to 0900 h. Further testing with corticotropin (250 µg IV) and metyrapone (30 mg/kg) stimulation tests was undertaken on participants with serum cortisol <250 nmol/L. Validated questionnaires completed to assess QoL, fatigue and sexual function.

Results

Secondary adrenal insufficiency (SAI) was identified on the basis of a failed stimulation test in 22.5% of opioid users vs no controls (P = 0.01). Opioid users with SAI had a higher median morphine-equivalent daily dose (MEDD), P = 0.037 – 50% with MEDD >200 mg and 0% with MEDD <60 mg had SAI. Among male participants, testosterone was inversely associated with BMI (P = 0.001) but not opioid use. A non-significant trend to low testosterone <8 nmol/L in male opioid users (11/24 opioid users vs 2/14 control, P = 0.08) suggests a small subgroup with opioid-induced androgen deficiency. Opioid users had greater fatigue, reduced quality of life in all subsections of the SF-36 and impaired sexual function in both males and females (all scores P < 0.001 compared to controls).

Conclusion

Long-term opioid therapy was associated with dose-related SAI in over 20% of chronic pain patients and is associated with poor quality of life, fatigue and sexual dysfunction. Obesity confounds the interpretation of opioid-induced male androgen deficiency.

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Johanna L Barclay, Carolyn J Petersons, Sahar Keshvari, Jane Sorbello, Brenda L Mangelsdorf, Campbell H Thompson, Johannes B Prins, Morton G Burt, Jonathan P Whitehead, and Warrick J Inder

Objective

Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects.

Design and methods

Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency.

Results

In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P<0.0001) and plasma TSP1 concentrations (P<0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535–756) ng/ml, than in healthy volunteers, 272 (237–336) ng/ml (P<0.0001). Plasma TSP1 >400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86–199) to 256 (133–516) ng/ml, (P<0.01) in patients with secondary adrenal insufficiency.

Conclusions

TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

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David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn Ga Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Wittert

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Methods: Men (n=303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo(P)-controlled randomized clinical trial of TU treatment were recruited for a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after last injection) and 6, 12, 18, 24, 40 and 52 weeks later.

Results: In the nested cohort of TU-treated men, serum T was initially higher but declined to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 showed no difference between T and P treated men. Initially fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since last injection.

Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

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Nèle F Lenders, Adam C Wilkinson, Stephen J Wong, Tint T Shein, Richard J Harvey, Warrick J Inder, Peter E Earls, and Ann I McCormack

Objective

The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours.

Methods

This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent’s Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the 'histological cohort'. Patients with at least 12 months of post-surgical follow-up were included in the subgroup 'clinical cohort'. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying 'higher-risk' histological subtypes was assessed.

Results

There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher-risk histological subtype tumours. These were associated with tumour invasiveness (P = 0.050), early recurrence (12–24 months, P = 0.013), shorter median time to recurrence (49 (IQR: 22.5–73.0) vs 15 (IQR: 12.0–25.0) months, P = 0.005) and reduced recurrence-free survival (P = 0.031).

Conclusions

Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.

Restricted access

David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn G A Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Wittert

Context

The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective

The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Materials and Methods

Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later.

Results

In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since the last injection.

Conclusions

After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.