Steroid Excess Research Articles

Carney's complex: a successful pregnancy after bilateral adrenalectomy.

Carney's complex: a successful pregnancy after bilateral adrenalectomy.

Homer 1 – a new player linking the hypothalamic-pituitary-adrenal axis activity to depression and anxiety

Homer 1 gene products are involved in the regulation of synaptic transmission and plasticity. Beside other deficits, the Homer 1 knockout (KO) mice show distinct behavioural abnormalities, such as anxiety and depression-like behaviours. In addition, we recently reported that the global deletion of the Homer 1 proteins in mice leads to a conspicuous endocrine phenotype linked to hypertrophy of the adrenal cortex, elevated basal and/or adrenocorticotropic hormone-induced corticosterone and aldosterone release in vitro and in vivo, as well as a drastic increase in the adrenocorticotropic hormone receptor mRNA in the adrenocortical cells. Interestingly, the basal secretion of adrenocorticotropic hormone was not changed in these mutants, which is in line with our recent observations, suggesting that the central limb of the hypothalamic-pituitary-adrenal axis (namely hypothalamic corticotropin-releasing hormone levels and the activation of its neurons in response to restraint stress) is not affected in the Homer 1 KO mice. On the contrary, the elevation of both plasma and intra-adrenal corticosterone and aldosterone concentrations in these mutants clearly indicates that the alteration primarily occurred in the adrenal cortex. We propose that excessive steroid release may contribute to depression- and anxiety-like behaviours and that the Homer 1 gene products may be involved in the pathogenesis of these stress-related mood disorders.

In Brief

The diagnosis of Cushing's syndrome still represents a challenge in clinical endocrinology. Because untreated Cushing's syndrome is associated with significant morbidity and mortality, and because nearly all of the physical and psychologic features are reversible with curative surgical therapy, accurate diagnosis of this endocrine disorder is essential.The source of steroid excess in Cushing's syndrome is classified as either ACTH-dependent or ACTH-independent (adrenal autonomy). The former category is the most frequent (80%) and encompasses ACTH-producing pituitary (Cushing's disease) or ectopic tumors, most commonly bronchial carcinoids. Whereas Cushing's disease is four to sixfold more prevalent in women, ectopic ACTH secretion is more common in men, largely due to the higher incidence of lung cancer in males.41 Cushing's disease accounts for 70% to 80% of ACTH-dependent disease, whereas 15% to 20% is caused by ectopic sources. Adrenal tumors autonomously producing glucocorticoids are found in 20% of patients with Cushing's syndrome, and this group comprises discrete and multiple adrenal lesions, such as adenomas, carcinomas, or micronodular and macronodular hyperplasia.54Although little is known about the pathogenesis of adrenal tumors, the origin of ACTH-producing pituitary adenomas has been investigated extensively. Although the proliferation of ACTH-secreting cells was initially hypothesized to be a possible consequence of stimulation by excess hypothalamic corticotropin-releasing hormone (CRH), the monoclonal origin of most ACTH-producing pituitary tumors strongly argues against this possibility.4 Hence, it is currently believed that the acquisition of a somatic mutation leading to a growth advantage accounts for these corticotroph adenomas, but, unlike the mutations in Gsα-proteins described in many growth hormone-producing adenomas, a specific mutation has not yet been described. Rare cases of ectopic secretion of CRH resulting in the oversecretion of pituitary ACTH have been reported.2The work-up for suspected endogenous glucocorticoid excess is divided into two consecutive steps (Table 1): (1) screening and confirmatory tests for the diagnosis of clinically relevant endogenous glucocorticoid excess, and (2) the localization (differential diagnosis) of the source of hormone excess. A variety of tests have been used for the screening, diagnosis, and localization of Cushing's syndrome, each associated with specific advantages and disadvantages.20 The currently utilized tests are summarized in Table 1.

Irreversible visual loss secondary to excessive topical steroid use in eczema

Topical steroids are invaluable in controlling numerous inflammatory skin conditions. However, they can produce significant adverse effects if used inappropriately and without supervision as illustrated in the case below. A 43-year-old male attended the ophthalmology department with a 2-week history of painless reduction in vision in his left eye. Past ophthalmic history included bilateral allergic conjunctivitis, primary open angle glaucoma (POAG) right eye, and ocular hypertension left eye, diagnosed on his first visit 18 months ago. Systemic enquiry revealed a history of asthma, hypertension, obesity, epilepsy, and atopic eczema. Current ophthalmic treatments included nedocromil sodium and latanoprost to both eyes. His only previous exposure to ophthalmic steroids was a 4-week course of dexamethasone 0.1% q.i.d. (standard practice) following uncomplicated left cataract surgery 8 months ago. Intraocular pressures (IOP) 6 weeks post-surgery were 23 and 18 mmHg right and left eye respectively. Ocular findings were as follows: Snellen acuity 6/9; hand movement with IOP of 46 and 56 mmHg in the right eye and left eye respectively (upper limit of normal IOP is 21 mmHg). Both …

Preliminary prospective explanatory observation on the impact of 3-month steroid therapy on the objective measures of sleep-disordered breathing

Excess endogenous steroids are a risk factor for obstructive sleep apnea (OSA). The role of exogenous steroids in this setup is not known. In this study, we prospectively looked at the consequences of a 3-month steroid treatment on the objective measures of sleep-disordered breathing. Patients scheduled for long-term steroids treatment underwent two sleep studies, the first before initiation and the second after 3months of steroid therapy. Their weight and neck girth were measured. Correlations between the changes in the body weight, neck girth, and cumulative steroids dose to apnea/hypopnea index (AHI) change were examined. A group of untreated mild OSA patients (n = 23) served as control. Seventeen patients, five males and 12 females, mean age 52.4 ± 12.6years, were studied. Fifteen patients increased their mean AHI by 56% from 9.8 ± 11.8 to 15.4 ± 15.8, p = 0.004. This increment was significantly higher when compared to the control group. Body weight and neck girth changes and cumulative steroid dose were not correlated to the AHI increment (Spearman's correlation coefficient r = 0.18 and p = 0.49, r = -0.23 and p = 0.37, r = -0.17 and p = 0.51, respectively). We found that the objective measures of sleep-disordered breathing worsened after the 3-month steroid treatment. Future studies to define pertinent mechanisms and clinical relevance are warranted.

Developmental Origin of Reproductive and Metabolic Dysfunctions: Androgenic Versus Estrogenic Reprogramming

Polycystic ovary syndrome (PCOS) is one of the most common fertility disorders, affecting several million women worldwide. Women with PCOS manifest neuroendocrine, ovarian, and metabolic defects. A large number of animal models have evolved to understand the etiology of PCOS. These models provide support for the contributing role of excess steroids during development in programming the PCOS phenotype. However, considerable phenotypic variability is evident across animal models, depending on the quality of the steroid administered and the perinatal time of treatment relative to the developmental trajectory of the fetus/offspring. This review focuses on the reproductive and metabolic phenotypes of the various PCOS animal models that have evolved in the last decade to delineate the relative roles of androgens and estrogens in relation to the timing of exposure in programming the various dysfunctions that are part and parcel of the PCOS phenotype. Furthermore, the review addresses the contributory role of the postnatal metabolic environment in exaggerating the severity of the phenotype, the translational relevance of the various animal models to PCOS, and areas for future research.

AME Position Statement on adrenal incidentaloma

To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Adrenocortical carcinoma: a clinician's update

Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of β-catenin as key factors involved in the development of adrenocortical carcinoma. Most patients present with steroid hormone excess, for example Cushing syndrome or virilization, or abdominal mass effects, but a growing proportion of patients with adrenocortical carcinoma (currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeutic measures for adrenocortical carcinoma exists, but collaborative efforts, such as international conferences and networks, including the European Network for the Study of Adrenal Tumors (ENSAT), have substantially advanced the field. In patients with suspected adrenocortical carcinoma, a thorough endocrine and imaging work-up is recommended to guide the surgical approach aimed at complete resection of the tumor. To establish an adequate basis for treatment decisions, pathology reports include the Weiss score to assess malignancy, the resection status and the Ki67 index. As recurrence is frequent, close follow-up initially every 3 months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Results of a large phase III trial in advanced adrenocortical carcinoma are anticipated for 2011 and will hopefully establish a benchmark therapy. New targeted therapies, for example, IGF-1 receptor inhibitors, are under investigation and may soon improve current treatment options.

Novel Androstenetriol Interacts with the Mitochondrial Translocator Protein and Controls Steroidogenesis

Steroid hormones are metabolically derived from multiple enzymatic transformations of cholesterol. The controlling step in steroid hormone biogenesis is the delivery of cholesterol from intracellular stores to the cytochrome P450 enzyme CYP11A1 in the mitochondrial matrix. The 18-kDa translocator protein (TSPO) plays an integral part in this mitochondrial cholesterol transport. Consistent with its role in intracellular cholesterol movement, TSPO possesses a cholesterol recognition/interaction amino acid consensus (CRAC) motif that has been demonstrated to bind cholesterol. To further investigate the TSPO CRAC motif, we performed molecular modeling studies and identified a novel ligand, 3,17,19-androsten-5-triol (19-Atriol) that inhibits cholesterol binding at the CRAC motif. 19-Atriol could bind a synthetic CRAC peptide and rapidly inhibited hormonally induced steroidogenesis in MA-10 mouse Leydig tumor cells and constitutive steroidogenesis in R2C rat Leydig tumor cells at low micromolar concentrations. Inhibition at these concentrations was not due to toxicity or inhibition of the CYP11A1 enzyme and was reversed upon removal of the compound. In addition, 19-Atriol was an even more potent inhibitor of PK 11195-stimulated steroidogenesis, with activity in the high nanomolar range. This was accomplished without affecting PK 11195 binding or basal steroidogenesis. Finally, 19-Atriol inhibited mitochondrial import and processing of the steroidogenic acute regulatory protein without any effect on TSPO protein levels. In conclusion, we have identified a novel androstenetriol that can interact with the CRAC domain of TSPO, can control hormonal and constitutive steroidogenesis, and may prove to be a useful tool in the therapeutic control of diseases of excessive steroid formation.

Progress in pharmaceutical treatment for adrenocotical carcinoma

Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis.Patients usually present with signs of steroid hormone excess (e.g.Cushing's syndrome, Conn's syndrome, virilization) or an abdominal mass.In functional cases, Cushing's syndrome is the most frequent presentation.Mitotane is still the most important single drug for ACC treatment, and it plays a role in adjuvant therapy postoperatively as well as in advanced disease.In advanced ACC, a combination of mitotane with etoposide, doxorubicin, cisplatin or streptozotocin with mitotane may be used.Targeted therapies, such as insulin-like growth factor Ⅰ (IGF- Ⅰ)receptor inhibitor and multiple kinase inhibitors like sunitinib and sorafenib hold great promises. Key words: Adrenocortical carcinoma; Mitotane; Cytotoxic chemotherapy; Targeted therapy

The complexity of laboratory testing and diagnosis of steroid excess syndromes associated with herbal remedy use1

The complexity of laboratory testing and diagnosis of steroid excess syndromes associated with herbal remedy use1

Renal Sinus Lipomatosis in Transplanted Kidneys: An Unusual Clinical Case

Renal sinus lipomatosis (RSL) represents an abnormal proliferation of the adipose tissue surrounding the renal pelvis of uncertain origin, associated with aging, obesity, steroid excess, infections, and calculosis. It represents a rare complication in transplanted kidneys, and, despite the accurate and prolonged radiological followup of transplanted organs, only a few cases of RSL have been described in graft recipients, with no remarkable effects on renal function. The diagnosis relies on ultrasonography (US), magnetic resonance imaging (MRI), computed tomography (CT), and, finally, percutaneous biopsy. We describe the case of an extensive RSL in a 38-year-old renal transplant recipient, diagnosed by ultrasonography and computed tomography. The patient underwent a radiologic study because of an acute, asymptomatic renal impairment, that led to the diagnosis of a RSL of unusual dimensions, associated with a discrete hydronephrosis. Paradoxically, after a short course of steroids, the recovery of renal function and the partial resolution of calyceal dilatation were observed. The rarity of this affection, the need of a differential diagnosis with fat-containing tumors, and the possibility of parenchymal inflammation associated with RSL, potentially responsive to steroids, are also discussed.

A Case Report of Bilateral Adrenocortical Carcinoma Complicated by Adrenal Insufficiency

Adrenocortical carcinoma is often functional and presents with signs and symptoms of adrenal steroid hormone excess. Adrenal insufficiency secondary to bilateral adrenocortical carcinoma is a particularly rare complication. We recently encountered a case of bilateral adrenocortical carcinoma complicated by adrenal insufficiency. A 52-year-old male was transferred to this hospital com plaining of general weakness and weight loss. A bilateral adrenal mass was detected on abdomen CT. Plasma cortisol and aldosterone failed to rise during the rapid ACTH stimulation test. The CT-guided adrenal biopsy revealed findings consistent with adreno cortical carcinoma. Left hemiparesis was developed and brain metastasis was detected via brain MRI. Despite the application of gamma knife surgery and chemotherapy, the disease progressed and the patient died. (Endocrinol Metab 26:243-247, 2011)

Approach to the Patient with Adrenocortical Carcinoma

Adrenocortical cancer (ACC) is a rare and often aggressive malignancy that requires multidisciplinary expertise for optimal management. It can present with symptoms of rapidly appearing excess steroid secretion or an abdominal mass, or it can be discovered incidentally. Thorough imaging and endocrine evaluations can identify the majority of ACCs amongst adrenal tumors; however, some smaller ACCs are better identified using fluorodeoxyglucose-positron emission tomography/computed tomography scan. Complete resection by an expert surgeon is the only potentially curative treatment for ACC, and tumor spillage should be avoided. Histopathology is important for diagnosis, but immunohistochemistry markers and gene profiling of the resected tumor may become superior to current staging systems to stratify prognosis. Despite complete resection in stage I-III tumors, approximately 40% of patients develop metastasis within 2 yr. Some retrospective studies indicate that adjuvant mitotane therapy prolongs disease-free survival, leading several centers to recommend its administration; prospective studies are under way to provide future evidence-based recommendations. For locally invading ACC, extensive en bloc resection is attempted, followed by adjuvant mitotane and, in selected cases, adjuvant radiotherapy. When ACC is not surgically resectable, mitotane therapy is adjusted to reach serum levels of 14-20 μg/ml. Careful replacement of glucocorticoid and mineralocorticoid deficiency after surgery or mitotane therapy is important; steroid excess from remaining tumor burden should also be controlled to avoid its morbidities. For metastatic disease, combination chemotherapy should be administered, if possible, in the context of multicenter collaborative research protocols. New insights in the molecular pathogenesis of ACC should allow the development of improved targeted therapies.

Bilateral synchronous rupture of the quadriceps tendon

Bilateral simultaneous rupture of the quadriceps tendon is a rare entity. They are often associated with degenerative changes of the tendons and predisposing conditions such as diabetes or excessive steroid use. They most commonly tend to occur in patients of 40 years of age or older. We describe a case of a 67-year-old man with simultaneous rupture of both quadriceps tendons. The diagnosis can be difficult and often delayed or missed in the initial examination. We report bilateral quadriceps tendon rupture in a previously healthy patient with good post-operative functional outcome.

Dexamethasone administration inhibits skeletal muscle expression of the androgen receptor and IGF‐1 – implications for steroid‐induced myopathy

Glucocorticoids are a well-recognized cause of muscle weakness. The early effects of glucocorticoids on skeletal muscle (SkM) androgen and IGF-1 pathways have not been previously investigated in human subjects. To determine if administration of the potent glucocorticoid dexamethasone down-regulates SkM androgen receptor and the IGF-1 signalling pathway. Twenty-four subjects (12 men and 12 women), including 12 with type 2 diabetes and 12 nondiabetics were enrolled. Venous blood sampling and biopsy of vastus lateralis were performed before and after administration of oral dexamethasone 4 mg/day for 4 days. Changes in plasma testosterone and IGF-1, SkM androgen receptor mRNA, SkM IGF-1mRNA and SkM IGF-1 receptor mRNA by quantitative RT-PCR after dexamethasone. Relative expression of SkM androgen receptor was similar in male (1.63 +/- 0.37) vs. female (1.57 +/- 0.30) subjects, despite the significant difference in plasma testosterone levels. Plasma IGF-1 and SkM expression of IGF-1 and IGF-1 receptor were also similar between males and females. Following dexamethasone, there was a significant down-regulation of SkM androgen receptor (1.60 +/- 0.23 vs. 1.11 +/- 0.16, P < 0.05) and IGF-1 (1.72 +/- 0.29 vs. 1.06 +/- 0.14, P < 0.05) mRNA, but no change in expression of the IGF-1 receptor. Plasma testosterone fell significantly in both sexes (male: 15.0 +/- 1.3 vs. 11.3 +/- 1.2 nmol/l, P < 0.01, female: 1.8 +/- 0.5 vs. 0.5 +/- 0.1 nmol/l, P < 0.05). Exogenous steroid excess results in relative androgen deficiency at two levels, reduced circulating testosterone and SkM androgen receptor mRNA, along with reduced SkM IGF-1 mRNA. These defects may contribute to the development of steroid-induced myopathy.

Spinal epidural lipomatosis: An unusual cause of relapsing and remitting paraparesis

Epidural lipomatosis is a rare entity to cause spinal cord compression and neurological deficits. This is usually associated with excess of steroids in the body either because of endogenous source as in Cushings disease or exogenous intake as in some diseases like systemic lupus erythematosus, in some endocrinopathies or in morbid obesity. But in some cases no cause has been found. Such idiopathic cases of spinal epidural lipomatosis have also been reported. Here, we report a case of idiopathic spinal epidural lipomatosis with relapsing and remitting paraparesis which is quite unusual. Treatment depends upon neurological status of the patient. We operated the patient as he had significant neurological compromise and he improved significantly.

The efficiency of progesterone vaginal gel versus intramuscular progesterone for luteal phase supplementation in gonadotropin-releasing hormone antagonist cycles: a prospective clinical trial

We compared the efficiency of progesterone vaginal gel (PVG) with intramuscular progesterone (IMP) supplementation for luteal phase support after in vitro fertilization and embryo transfer in gonadotropin-releasing hormone (GnRH) antagonist cycles. The treatment outcomes were similar for PVG and IMP for luteal support in GnRH-antagonist protocols. With its ease of use, high tolerability by patients, and fewer side effects, PVG can be a successful alternative to IMP.

A Case of Intratracheal Schwannoma Presenting to the Emergency Department With a Diagnosis of Asthmatic Attack: A Clue to Suspect the Cause of Upper Airway Obstruction to Be Other Than Asthma

We have read with interest the article by Erol et al. reporting a case of tracheal schwannoma presenting as acute asthmatic attack ( 1 Erol M.M. Uzun H. Tekinbas C. Gunduz A. Turedi S. Kosucu P. A case of intratracheal schwannoma presenting at the emergency department with a diagnosis of asthmatic attack. J Emerg Med. 2008 April 23; ([Epub ahead of print]) PubMed Google Scholar ). Schwannoma is a rare cause of upper airway obstruction, often misdiagnosed as asthma, that does not respond to therapy and often presents late in its course, with iatrogenic manifestation of excessive steroid use, such as Cushing's syndrome. Schwannoma rarely presents as acute asthma. Recognition of the cause of the upper airway obstruction is essential to preclude affected patients being prescribed lengthy courses of systemic corticosteroids ( 2 Kenyon N.J. Jarjour N.N. Severe asthma. Clin Rev Allergy Immunol. 2003; 25: 131-149 Crossref PubMed Scopus (9) Google Scholar , 3 Tilles S.A. Differential diagnosis of adult asthma. Med Clin North Am. 2006; 90: 61-76 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 4 Higgins J.C. The ‘crashing asthmatic'. Am Fam Physician. 2003; 67: 997-1004 PubMed Google Scholar , 5 Balkissoon R. Occupational upper airway disease. Clin Chest Med. 2002; 23: 717-725 Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar ). Therefore, relevant points regarding this case are presented to provide clues for when to search for alternate causes of obstruction other than asthma (i.e., asthma imitators). ResponseJournal of Emergency MedicineVol. 38Issue 2PreviewWe would like to thank Dr. Almarri for his interest in and valuable contributions to our case report. We are setting out our views below to clarify the points raised by Dr. Almarri. Full-Text PDF

Blunted Sleep-Related Luteinizing Hormone Rise in Healthy Premenarcheal Pubertal Girls with Elevated Body Mass Index

Our objective was to determine whether excessive adiposity is associated with alteration of the normal hormonal changes of early pubertal girls. Healthy 6.4- to 9.5-yr-old, prepubertal (PRE, n = 20) and 9.4- to 13.0-yr-old pubertal premenarcheal volunteers (PUB, n = 20) were divided into excessive-weight (EW) or normal-weight (NW) groups according to the 85th percentile body mass index. INTERVENTIONS AND SETTING: Overnight blood sampling; GnRH agonist (GnRHag), low-dose ACTH, oral glucose tolerance tests, and pelvic ultrasonograms were performed in our Clinical Research Center. EW girls were similar in age and baseline and ACTH- and GnRHag-stimulated androgen levels to stage-matched NW girls. However, the sleep-related LH rise was blunted in EW-PUB girls compared with NW-PUB girls. The sleep-related rise of mean LH in EW-PUB [0.68 +/- 0.35 (sem) U/liter] was insignificant, less than that of NW-PUB (2.1 +/- 0.45, P < 0.05) and not significantly different from that of PRE girls (0.08+/-0.03). EW-PUB had slower LH pulse frequency and a lower rise in LH pulse amplitude during sleep than NW-PUB girls (both P < 0.05). Overnight FSH patterns paralleled LH patterns, whereas estradiol levels were similar in stage-matched NW and EW groups, differing between stages as expected. Early morning and peak LH, FSH, and estradiol responses to GnRHag were similar in EW-PUB and NW-PUB and significantly greater than those of PRE girls. Healthy EW-PUB girls have significantly blunted sleep-related LH production. These data suggest that excess adiposity, in the absence of sex steroid excess, may subtly suppress hypothalamic-pituitary-gonadal function in premenarcheal pubertal girls.