The Impact of Obesity on the Resolution of Hypertension Following Adrenalectomy for Primary Hyperaldosteronism.

BACKGROUND: This study aims to determine the impact of patient obesity on the resolution of hypertension and pill burden post-adrenalectomy for PA. Primary hyperaldosteronism (PA) is the most common cause of secondary hypertension that may be remedied with surgery (unilateral adrenalectomy). Obesity may independently cause hypertension through several mechanisms including activation of the renin-angiotensin-aldosterone pathway. The influence of obesity on the efficacy of adrenalectomy in PA has not been established. METHODS: This is a retrospective analysis of prospectively collected data on patients undergoing adrenalectomy for PA at a single, tertiary-care surgical centre from January 2015 to December 2020. Electronic health records of patients were screened to collect relevant data. The primary outcomes of the study include post-operative blood pressure, the reduction in the number of anti-hypertensive medications and potassium supplementation burden post-adrenalectomy. RESULTS: Fifty-three patients were included in the final analysis. There was a significant reduction in the blood pressure and the number of anti-hypertensive medications in all patients after adrenalectomy (p < 0.001). Of the 34 patients (64.2%) with pre-operative hypokalaemia, all became normokalaemic and were able to stop supplementation. However obese patients required more anti-hypertensive medications to achieve an acceptable blood pressure than overweight or normal BMI patients (p < 0.01). Multivariate logistic regression analysis showed that male gender and BMI were independent predictors of resolution of hypertension (p <0.01). CONCLUSION: Unilateral adrenalectomy improves the management of hypertension and hypokalaemia when present in patients with PA. However, obesity has an independent deleterious impact on improvement in blood pressure post-adrenalectomy for PA.

Surgical findings and outcomes after unilateral adrenalectomy for primary hyperaldosteronism in cats: a multi-institutional retrospective study.

CASE SERIES SUMMARY: Twenty-nine cats from different institutions with confirmed or highly suspected primary hyperaldosteronism treated by unilateral adrenalectomy were retrospectively included in this study. The most frequent clinical signs were lethargy (n = 20; 69%) and neck ventroflexion (n = 17; 59%). Hypokalaemia was present in all cats, creatinine kinase was elevated in 15 and hyperaldosteronism was documented in 24. Hypertension was frequently encountered (n = 24; 89%). Preoperative treatment included potassium supplementation (n = 19; 66%), spironolactone (n = 16; 55%) and amlodipine (n = 11; 38%). There were 13 adrenal masses on the right side, 15 on the left and, in one cat, no side was reported. The median adrenal mass size was 2 × 1.5 cm (range 1-4.6 × 0.4-3.8); vascular invasion was present in five cats, involving the caudal vena cava in four cats and the renal vein in one. Median duration of surgery was 57 mins. One major intraoperative complication (3%) was reported and consisted of haemorrhage during the removal of a neoplastic thrombus from the caudal vena cava. In 4/29 cats (14%), minor postoperative complications occurred and were treated medically. One fatal complication (3%) was observed, likely due to disseminated intravascular coagulation. The median duration of hospitalisation was 4 days; 97% of cats survived to discharge. The potassium level normalised in 24 cats within 3 months of surgery; hypertension resolved in 21/23 cats. Follow-up was available for 25 cats with a median survival of 1082 days. Death in the long-term follow-up was mainly related to worsening of comorbidities. RELEVANCE AND NOVEL INFORMATION: Adrenalectomy appears to be a safe and effective treatment with a high rate of survival and a low rate of major complications. Long-term medical treatment was not required.

Outcomes After Surgery for Unilateral Dominant Primary Aldosteronism in Sweden.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Surgery is the mainstay of treatment for unilateral dominant PA, but reported cure rates varies. The aim of the present study was to investigate contemporary follow-up practices and cure rates after surgery for PA in Sweden. METHODS: Patients operated for PA and registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) 2009-2015 were identified. Patient data were extracted, and follow-up data (1-24 months) was recorded. Doses of antihypertensive medication and potassium supplementation were calculated using defined daily doses (DDD), and the Primary Aldosteronism Surgical Outcome (PASO) criteria were used to evaluate outcomes. RESULTS: Of 190 registered patients, 171 (47% female, mean age 53 years, median follow-up 3.7 months) were available for analysis. In 75 patients (44%), missing data precluded evaluation of biochemical cure according to the PASO criteria. Minimal invasive approach was used in 168/171 patients (98%). Complication rate (Clavien-Dindo >3a) was 3%. No mortality was registered. Pre/postoperatively 98/66% used antihypertensives (mean DDD 3.7/1.5). 89/2% had potassium supplementation (mean DDD 2.0/0) before/after surgery. Complete/partial biochemical and clinical success according to the PASO criteria were achieved in 92/7% and 34/60%, respectively. CONCLUSION: In this study, reflecting contemporary clinical practice in Sweden complete/partial biochemical and clinical success after surgery for PA was 92/7% and 34/60%. Evaluation of biochemical cure was hampered by lack of uniform reporting of relevant outcome measures. We suggest mandatory reporting of surgical outcomes using the PASO criteria for all units performing surgery for PA.

Insufficiency of the zona glomerulosa of the adrenal cortex and progressive kidney insufficiency following unilateral adrenalectomy - case report and discussion.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension and bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) seem to be the most common causes of PA. Unilateral adrenalectomy (UA) is the preferred treatment for APA, although the benefits are still difficult to assess. CASE REPORT: We present a case report of a 69-year old man with a 30 year history of hypertension and probably long-standing PA due to APA, with typical organ complications. Since repeated abdominal CT scans were equivocal, not showing radiological changes characteristic for PA, the diagnosis of APA was delayed and was only finally confirmed by adrenal venous sampling which demonstrated unilateral aldosteronism. The patient underwent UA, complicated by mineralocorticoid deficiency syndrome and increased creatinine and potassium levels. At 12 months follow-up the patient still had hyperkalemia and was fludrocortisone dependent. CONCLUSIONS: Older patients and patients with long-lasting PA who are treated with UA may demonstrate deterioration of renal function and develop transient or persistent insufficiency of the zona glomerulosa of the remaining adrenal gland necessitating fludrocortisone supplementation. Transient hyperkalemia may be observed following UA as a result of the prolonged effects of aldosterone antagonists and/or transient mineralocorticoid/glucocorticoid insufficiency. Additionally, the level of progression of chronic kidney disease after UA is difficult to predict. There likely exists a group of patients who might paradoxically have higher cardiovascular risk due to significant deterioration in kidney function not only resulting from the removal of the aldosterone induced glomerular hyperfiltration phenomenon. Identification of such a group requires further detailed investigation.

Contralateral suppression of aldosterone at adrenal venous sampling predicts hyperkalemia following adrenalectomy for primary aldosteronism.

BACKGROUND: We aimed to determine whether a greater degree of contralateral suppression of aldosterone secretion at adrenal venous sampling predicted the development of postoperative hyperkalemia after unilateral adrenalectomy for primary aldosteronism. METHODS: A retrospective analysis of patients undergoing unilateral adrenalectomy for primary aldosteronism between 2004-2015 was performed. Clinical and biochemical parameters of patients who developed hyperkalemia (≥5.2 mmol/L) after unilateral adreanlectomy were compared with those who remained normokalemic. The contralateral suppression index was defined as the aldosterone-to-cortisol ratio from the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio from the external iliac vein. RESULTS: Of 192 patients who met criteria for inclusion, 12 (6.3%) developed hyperkalemia (median serum potassium 5.5 mmol/L, range 5.2-6.2 mmol/L), with a median time to onset of 13.5 days (range 7-55 days). Five patients had transiently increased serum potassium concentrations that normalized spontaneously. Four patients received mineralocorticoid replacement therapy with fludrocortisone. On univariate analysis, hyperkalemic patients had slightly greater preoperative serum creatinine levels (1.2 vs 1.0 mg/dL, P = .01), higher postoperative creatinine (1.3 vs 1.0 mg/dL, P = .02), lesser median contralateral suppression index (0.14 vs 0.27, P = .03), and larger adenomas (1.9 vs 1.4 cm, P = .02). On multivariable logistic regression, the contralateral suppression index remained the only significant predictor of postoperative hyperkalemia (P = .04) with an optimal cut-off of <0.47. CONCLUSION: Hyperkalemia after unilateral adrenalectomy for primary aldosteronism is uncommon and usually transient, but may require mineralocorticoid supplementation. Patients with a contralateral suppression index of <0.47 require meticulous follow-up and monitoring of serum potassium concentrations after unilateral adrenalectomy.

p-Hydroxybenzyl Alcohol, an Active Phenolic Ingredient of Gastrodia elata, Reverses the Cycloheximide-Induced Memory Deficit by Activating the Adrenal Gland in Rats.

The present study investigated the ameliorating effects of p-hydroxybenzyl alcohol (HBA), an active phenolic ingredient of Gastrodia elata, on cycloheximide (CXM)-induced impairment of passive avoidance response and clarified the role of adrenal glands on the effect of HBA in rats. An adrenalectomy (ADX) caused the memory deficit from 1 to 3 days after surgery. Administration of corticosterone (CORT) plus glucose completely recovered the memory deficit caused by ADX, and this effect was better than that of glucose or CORT alone. HBA ameliorated the memory deficit induced by CXM in sham and ADX rats, but ADX partially blocked it. Furthermore, plasma glucose, epinephrine and adrenal steroid levels of ADX rats significantly decreased. Sham rats who received HBA had an increase in plasma glucose and adrenal steroid levels. Therefore, we suggest that the reversal of CXM-induced memory deficit by HBA was partially dependent on adrenal glands through the increase of the levels of plasma adrenal steroids.

The orexigenic effect of orexin-A revisited: dependence of an intact growth hormone axis.

Fifteen years ago orexins were identified as central regulators of energy homeostasis. Since then, that concept has evolved considerably and orexins are currently considered, besides orexigenic neuropeptides, key modulators of sleep-wake cycle and neuroendocrine function. Little is known, however, about the effect of the neuroendocrine milieu on orexins' effects on energy balance. We therefore investigated whether hypothalamic-pituitary axes have a role in the central orexigenic action of orexin A (OX-A) by centrally injecting hypophysectomized, adrenalectomized, gonadectomized (male and female), hypothyroid, and GH-deficient dwarf rats with OX-A. Our data showed that the orexigenic effect of OX-A is fully maintained in adrenalectomized and gonadectomized (females and males) rats, slightly reduced in hypothyroid rats, and totally abolished in hypophysectomized and dwarf rats when compared with their respective vehicle-treated controls. Of note, loss of the OX-A effect on feeding was associated with a blunted OX-A-induced increase in the expression of either neuropeptide Y or its putative regulator, the transcription factor cAMP response-element binding protein, as well as its phosphorylated form, in the arcuate nucleus of the hypothalamus of hypophysectomized and dwarf rats. Overall, this evidence suggests that the orexigenic action of OX-A depends on an intact GH axis and that this neuroendocrine feedback loop may be of interest in the understanding of orexins action on energy balance and GH deficiency.

Influence of the HPA axis on the inflammatory response in cutaneous wounds with the use of 670-nm laser photobiomodulation.

This study evaluated the influence of hypothalamic-pituitary-adrenal (HPA) axis in cutaneous wounds subjected to laser biomodulation. A total of 48 rats were divided into two groups: Group I (GI) with 24 adrenalectomized animals and Group II (GII) with 24 non-adrenalectomized animals. Each group was divided into two subgroups: the irradiated subgroup which laser was applied to four points at the edges of the wound (670 nm laser, 9 mW) and control subgroup. Rats in each subgroup were sacrificed at 24 or 72 h. Adrenal glands were only removed from GI rats. Three days after adrenalectomy, a cutaneous wound was made. An immunohistochemical analysis was performed using anti-CD45 and anti-CD8 antibodies. Flow cytometry was used to count T lymphocytes and their subpopulations in blood. Decreases in the number of CD45-positive inflammatory cells and in the total numbers of CD8- and CD45-positive cells were observed in histological sections of adrenalectomized animals subjected to laser biomodulation at 24h. Similar results were observed for distribution of total lymphocytes in blood (p<0.05). The action of 670 nm laser does not depend exclusively on HPA axis. It is believed that corticosteroid-promoting enzymes liberated in non-adrenal tissues may influence immune response under the influence of this type of phototherapy.

Lowering corticosterone levels reinstates hippocampal brain-derived neurotropic factor and Trkb expression without influencing deficits in hypothalamic brain-derived neurotropic factor expression in leptin receptor-deficient mice.

BACKGROUND/AIMS: Changes in the glucocorticoid milieu contribute to alterations in neurotropic factor expression across multiple brain regions. Insulin-resistant diabetes is often accompanied by dysregulation of adrenal steroid production in humans and animal models. Leptin receptor-deficient mice (db/db) show reduced expression of brain-derived neurotropic factor (BDNF) in the hippocampus and increases in circulating corticosterone levels, but the extent to which elevated corticosterone levels mediate deficits in BDNF expression has not been determined. METHODS: Using in situ hybridization, we measured the expression of BDNF, its receptor TrkB, and neurotropin-3 (NT-3) in the hippocampus and hypothalamus of db/db mice and wild-type controls following adrenalectomy and low-dose corticosterone replacement (ADX+CORT) or sham operation. RESULTS: Lowering corticosterone levels restored BDNF and TrkB expression in the hippocampus of db/db mice. However, deficits in hypothalamic BDNF expression were not reversed following ADX+CORT. There was no effect of genotype or adrenalectomy on NT-3 expression in any brain region examined. CONCLUSION: Leptin receptor-deficient mice exhibit reduced BDNF expression in the hippocampus and hypothalamus. In the db/db mouse hippocampus, suppression of BDNF occurs in a glucocorticoid-dependent fashion, while hypothalamic BDNF expression is reduced via glucocorticoid-independent mechanisms. Region-specific signals therefore play a role in the interaction between corticosteroids and neurotropic factor expression.

Adrenalectomy enhances endotoxemia-induced hypophagia: higher activation of corticotrophin-releasing-factor and proopiomelanocortin hypothalamic neurons.

Inflammatory and infectious processes evoke neuroendocrine and behavioral changes known as acute-phase response that includes activation of the hypothalamo-pituitary-adrenal (HPA) axis and reduction of food intake. Besides its action as the most important ACTH secretagogue, corticotrophin-releasing factor (CRF), synthesized in the paraventricular nucleus (PVN), is also involved in the control of food intake. Alpha-melanocyte stimulating hormone (alpha-MSH) in the arcuate nucleus also plays a role in the energy homeostasis, possessing anorexigenic effects. To investigate the participation of neuropeptides involved in the regulation of food intake during endotoxemia, we administrated lipopolysaccharide (LPS) in sham-operated and adrenalectomized (ADX) male Wistar rats to evaluate food intake, hormone responses and Fos-CRF and Fos-alpha-MSH immunoreactivity in the PVN and arcuate nucleus, as well as CRF and POMC mRNA expression in these hypothalamic nuclei. In sham-operated rats, treatment with LPS (100 microg/kg) showed lower food intake, higher plasma ACTH and corticosterone levels, as well as an increase in Fos-CRF double labeled neurons and CRF mRNA expression in the PVN, with no changes in Fos-alpha-MSH immunoreactivity and POMC mRNA expression in the arcuate nucleus, compared to saline treated rats. After LPS treatment, ADX rats showed further increase in plasma ACTH levels, marked decrease of food intake, higher Fos-CRF immunoreactive neurons in the PVN and CRF mRNA expression, as well as an increase in Fos-alpha-MSH immunoreactivity and POMC mRNA expression in the arcuate nucleus, compared to sham-operated rats treated with LPS. In conclusion, the present data indicate that the marked hypophagia during endotoxemia following ADX is associated with an increased activation of CRF and POMC neurons in the hypothalamus and an increased mRNA expression of these neuropeptides.

Role of maternal adrenal glands on the developing serotoninergic and aminoacidergic systems of the postnatal rat brain.

Serotonin, gamma-aminobutyric acid and glutamate, which are regulated by glucocorticoids in the central nervous system, are involved in neuroendocrine functions and the development of the brain. The present study investigates the effect of maternal adrenalectomy on the developing serotoninergic, GABAergic and glutamatergic systems. Neurotransmitter levels were measured in four brain areas of both male and female offspring on postnatal days 1, 8, 12 and 22. At postnatal day 1 and 8, the pups of adrenalectomized dams showed higher concentrations of serotonin than controls in all the brain areas studied. Serotonin levels decreased significantly in males at postnatal day 22 in the hippocampus and cortex. During the first 2 weeks of postnatal life, the lack of maternal corticosterone produced an increase in glutamate and a reduction in gamma-aminobutyric acid concentrations, mainly in males. Further, on postnatal day 1, increased serotonin and glutamate levels and lower levels of gamma-aminobutyric were observed in the hypothalamus of male pups born to adrenalectomized dams. The absence of maternal corticosterone affects the pattern of development of the serotoninergic system, especially in the hippocampus and cortex, and particularly in males. A delay in the maturation of the aminoacidergic systems, mainly of the GABAergic system and in males, was also seen. A sexually dimorphic response to the removal of maternal glucocorticoids was seen in terms of neurotransmitter levels, mainly in the hippocampus and hypothalamus.

[Behavioral effects of L-tryptophan and p-chlorophenylalanine after adrenalectomy or dexamethasone administration in rats]. / Povedencheskie éffekty L-triptofana i p-khlorfenilalanina posle adrenaléktomii ili vvedeniia deksametazona u krys.

Effects of acute administration of L-tryptophan (L-TRP. 250.0 mg/kg, i.p.) on active avoidance conditioning and "open-field" behavior were studied in male rats after adrenalectomy of dexamethasone administration. L-TRP inhibited the acquisition and reproduction of active avoidance reaction in adrenalectomized and dexamethasone-treated rats. Moreover, L-TRP decreased horizontal locomotor activity and grooming behavior in the "open field" on adrenalectomized rats. On the contrary, p-CPA restored the active avoidance conditioning in adrenalectomized rats and rats with excess of glucocorticoids. Also, p-CPA increased the total locomotor activity and grooming behavior in the "open field" in adrenalectomized rats, but decreased horizontal locomotor activity and enhanced emotional reaction in dexamethasone-treated rats in the "open field".

The daily pattern of Fos synthesis by hypothalamic pro-opiomelanocortin neurons is unaffected by adrenalectomy in the rat.

At the onset of dark, a large population of rat mediobasal hypothalamic (MBH) pro-opiomelanocortin (POMC) neurons starts spontaneously expressing Fos-immunoreactivity (Fos-IR). Here we studied the effect of adrenalectomy upon this expression since circulating corticosteroids, which increase in the rat with the onset of behavioural wakening, are thought to modulate the basal expression of MBH POMC mRNA. Hence, groups of intact, adrenalectomised and sham-operated rats were sacrificed at times when Fos synthesis by POMC neurons is known to show either nadir (at light-offset) or peak (6 h after light-offset) values. Brains were processed for Fos- and/or POMC immunohistochemistry. This allowed us to show that, in all experimental groups, Fos-IR is hardly expressed in MBH POMC neurons at the onset of dark, whereas it is strongly induced 6 h later. We concluded that such an induction is not triggered through the known evening rise of plasma corticosteroid levels.

Combined effects of adrenalectomy and noise exposure on compound action potentials, endocochlear potentials and endolymphatic potassium concentrations.

The effects of removal of endogenous corticosteroids via bilateral adrenalectomy in combination with noise exposure (30 min at 100 dB) were determined by recording compound action potential (CAP) and endocochlear potentials (EP), and by measuring potassium concentrations (K+e) within the endolymph. Thirty-eight Long-Evans rats were divided into groups according to experimental treatments: adrenalectomy (ADX) or non-ADX and noise exposure or non-noise exposure. CAP thresholds, EP and K+e values were subjected to repeated-measures analysis of variance with group and time as factors classifying the measurements. Noise exposure resulted in significant elevations of CAP thresholds in both the ADX and non-ADX animals, but had no effect on either EP or endolymphatic K+e. Recovery was noted during all post-exposure measurement periods and was significantly faster for ADX animals. EP and K+e did not change during or after noise exposure. ADX animals showed a non-significant reduction of EP and a statistically significant increase of K+e during all measurement periods as compared to non-ADX animals.

Case report: silent thyroiditis after adrenalectomy in a patient with Cushing's syndrome.

A case of silent thyroiditis after unilateral adrenalectomy for treatment of Cushing's syndrome is reported. The left adrenocortical adenoma was resected. Glucocorticoid was replaced after the operation and was gradually tapered. Thyrotoxic symptoms with painless goiter occurred 9 months after the adrenalectomy when a replacement dose of prednisolone was tapered to 5 mg/d. Plasma-free thyroid hormones increased and thyrotropin was suppressed. Thyroidal uptake of radioactive iodine was extremely low. Both titers of antimicrosomal and antithyroglobulin antibodies stayed at high levels throughout the observation period from the preoperative stage. Normalization of thyroid functions was obtained 3 months after the onset of thyrotoxicosis with beta-adrenergic blocker alone. It was speculated that exposure to a large amount of endogenous and supplementary exogenous glucocorticoid protected the patient's immune system from autoimmune attack of thyroid antigens and that tapering of the supplementary glucocorticoid caused exacerbation of immune responses, resulting in overt thyroid dysfunction even 9 months after adrenalectomy.