Normal Plasma ACTH Research Articles

7550 Case Report On Concurrent Metastases To The Pituitary And Adrenal From A Primary Breast Cancer

Abstract Disclosure: M.V. David-santos: None. M.C. Isidro: None. Background: Metastatic Cancer to the pituitary gland is a rare condition accounting for 0.5% of all pituitary tumors. It rarely manifests clinically and is often found incidentally. Endocrine dysfunction usually arise, with 38.4% of cases presenting with Diabetes Insipidus, while 37.7% as Panhypopituitarism. On the other hand, prevalence of adrenal metastases is at 0.5 to 3.8% with 43% occurring bilaterally. Primary adrenal insufficiency occurs at 12.4% among those with bilateral metastases. Case: A 32-year old Chinese woman was diagnosed with Stage 4 breast adenocarcinoma ER PR Her2 Neu positive with metastases to the axillary lymph nodes, bone and right adrenal in July 2021. She underwent chemotherapy with Paclitaxel and Trastuzumab then radical mastectomy of the left breast in April 2022.5 months post op, PET scan was done which showed a 11 x 18 x 21 mm pituitary mass. In light of the primary malignancy, lesion was considered a metastatic focus. At that time, patient did not exhibit any neurologic symptoms such as blurring of vision or headaches. No polyuria, polydipsia, nocturia, easy fatigability, nausea or vomiting. Physical examination findings were normal. A hormonal panel showed the following: elevated Prolactin at 150 ng/ml (NV 3-20), normal plasma ACTH IRMA 10 pg/ml (NV < 50 pg/ml), low 8AM plasma cortisol at 1.55 ug/dL (Ref 5- 25 ug/dL), TSH was low at 0.15iIU/ml (0.27-3.75) while FT4 was normal at 0.87 ng/dl (NV 0.68 - 2.56).ACTH stimulation showed low cortisol at the 30th minute and 1st hour post ACTH infusion. Serum sodium and urine Osmolality were both normal. The hyperprolactinemia was attributed to Stalk effect, while the decreased cortisol was considered as central adrenal insufficiency. She was then started on Prednisone 5mg tab daily. Repeat TSH and FT4 5 months after showed normal TSH at 1.209, low FT4 at 5.97 pmol/L (NV 9.01-19.05). She was started on Levothyroxine 50mcg daily for the central hypothyroidism.Repeat Cranial MRI 4 months post diagnosis of the pituitary mass showed increased in its size. An endoscopic transsphenoidal resection and biopsy of the pituitary mass showed metastatic carcinoma of the pituitary gland. Staining of the sellar tumor were compatible with a metastatic carcinoma of breast origin. Intensity-modulated radiation therapy (IMRT) at 400 gray was done for 5 fractions and Trastuzumab was continued. Cranial MRI done 6 months post IMRT showed decreasing size of the pituitary mass to its latest size of 6 x 9 x 13 mm as of November 2023. Latest Whole abdominal CT scan of the adrenals showed clearing of the right adrenal Nodule. Conclusion: Breast cancer may also metastasize to endocrine organs causing hormonal dysfunction. Although curative treatment is no longer the goal for Metastatic breast cancer, prolongation of the quality of life is an important aspect to consider. Hormonal work up, surveillance and hormonal replacement can help in attaining this goal. Presentation: 6/3/2024

EXTREMELY HIGH DIRECT PLASMA RENIN IN A YOUNG WOMAN WITH NEGATIVE IMAGING FOR RENOVASCULAR HYPERTENSION

Objective: Direct plasma renin (DPR) has a much broader distribution than plasma renin activity (PRA). The finding in one patient of extremely high DPR values without apparent cause led us to the diagnosis and successful treatment of renovascular hypertension which had been initially ruled out by magnetic resonance angiography. Design and method: Review of the patient’s clinical records and the relevant literature. Results: A 39-year-old woman, long-term user of oral contraceptives was referred to our Hypertension Clinic. For the last two years she had presented severe hypertension, with BP often > 200/120 mmHg, poorly responding to antihypertensive drugs including ACEI or ARB plus calcium antagonists, diuretics, spironolactone, doxazosin and bisoprolol. She reported frequent holocranial non-pulsatile headaches without pallor, tachycardia, nausea or other vegetative symptoms. Laboratory testing was normal except for albuminuria (378 mg/g Cr) with normal plasma creatinine,eGFR, potassium, TSH and ACTH. Blood pressure remained high after contraceptive withdrawal. Physical examination showed only grade I overweight. ABPM showed diurnal 198/96 mmHg and nocturnal 186/89 mmHg, non-dipper without marked highs or lows. Echocardiography showed moderate LVH but ruled out heart failure. All drugs except diltiazem and doxazosin were withdrawn for a month, plasma metanephrines and cortisol suppression were normal, and plasma aldosterone was in the upper normal range (29.6 ng/dL) while DPR was extremely high (2196 mU/L, normal upper limit 39 mU/L). Renovascular hypertension (or reninoma) was suspected, but magnetic resonance renal angiography was informed as normal. However, the left kidney was significantly smaller and hypoperfused. A standard renal angiogram showed fibromuscular dysplasia with severe left stenosis. Angioplasty was performed, and after 3 months the patient’s blood pressure is well controlled with 120 mg slow-release diltiazem daily, and her plasma angiotensin and renin are normal. Conclusions: DPR can be raised by low-salt diet, hypovolemia, drugs such as diuretics, ACEIs and ARBs, hyperthyroidism, pheochromocytoma/paraganglioma and edematous states (heart or liver failure, nephrotic syndrome). However these conditions are unlikely to cause extremely high renin. Renovascular hypertension or reninoma should be suspected, even when the initial imaging seems negative. Fibromuscular dysplasia is likelier than atherosclerotic stenosis or reninoma in contraceptive users.

Deksametazon Süpresyon Testlerinin Hiperkortizolizm Ayırıcı Tanısında Kullanımı

Dexamethasone suppression tests (DST) are practical, cheap and safe tests which are used to evaluate endogenous hypercortisolism. They are based on the principle that glucocorticoids exogenously given at supraphysiological doses suppress the production of CRH, ACTH and cortisol by binding to central glucocorticoid receptors. Lack of suppression of cortisol production suggest endogenous hypercortisolism. Additionally, DST may be used in the diagnosis of glucocorticoid remediable hyperaldosteronism. Due to strong glucocorticoid activity, lack of mineralocorticoid activity and lack of cross-reaction with the measurement of cortisol, dexamethasone is the preferred drug for the tests. As a screening tool in endogenous hypercortisolism, overnight 1 mg DST is used. If screening test is negative, hypercortisolism is excluded; but if the test is positive, 2-day 2 mg DST should be performed to confirm the diagnosis of Cushing’s syndrome. If endogenous hypercortisolism is confirmed, plasma ACTH should be measured. Undetectable plasma ACTH level suggest ACTH-independent Cushing’s syndrome, but inappropriately normal or high plasma ACTH level suggest ACTH-dependent Cushing’s syndrome. High dose DST (overnight 8 mg or 2-day 8 mg) should be performed to discriminate pituitary or extra-pituitary cause in the patients with ACTH-dependent Cushing’s syndrome. In the presence of pituitary Cushing’s disease, because of relatively preserved negative feedback mechanism, high dose dexamethasone may suppress ACTH. In ectopic ACTH secretion, due to lack of a normal negative feedback mechanism, ACTH cannot be suppressed by high dose dexamethasone. Extraordinarily, ectopic ACTH production in some neuroendocrine tumors may be suppressed by high dose dexamethasone, but no suppression may be observed in some patients with pituitary Cushing’s disease. When applying DST, serum and plasma samples should be collected in appropriate route, and they should be transferred by true collection tubes and in right storage conditions.

Enjeksiyon stresi ve düşük doz ACTH uyarısında kortizol yanıtlarının karşılaştırılması

Objective: We performed a placebo-controlled, single-blind, pilot study to compare the efficacy and safety of low dose cosyntropin stimulation test with injection stress in the diagnosis of secondary adrenocortical insufficiency. Material and Methods: Twenty-five patients (22 F, 3 M) with a low or normal plasma ACTH level, morning plasma cortisol level

Is routine endocrine evaluation necessary after paediatric traumatic brain injury?

Traumatic brain injury (TBI) is a common event in childhood. It is a recognised cause of hypopituitarism both in adult and paediatric patients. Routine endocrine evaluation has been proposed for adult TBI-survivors; nevertheless, incongruous data have been reported in children. The goal of this study was to describe the prevalence of pituitary dysfunction after TBI in a cohort of children. This is a cross-sectional study comprising retrospective medical record review and prospective testing. Children with brain injury discharged from the Paediatric Intensive Care Unit from year 2004 to 2009 were recruited. Height and weight were recorded, systemic examination was performed and baseline pituitary function tests were undertaken. Provocative tests were performed only if abnormal basal levels were detected. Thirty-six patients were collected; the mean age at assessment was 7.2years and the mean interval since injury 3.3years. All patients had skull fracture or intracranial haemorrhage; 36.6% of them had moderate to severe TBI. No abnormalities were found on examination. Low serum IGF 1 levels were detected in four patients and two patients had low serum cortisol levels with inappropriately normal plasma ACTH concentrations. No evidence of pituitary dysfunction was observed in these patients after clinical follow-up, repeated baseline hormone levels or dynamic function tests. No endocrine sequelae have been detected in this population. The routine endocrine evaluation in children with mild to moderate TBI might not be justified, according to our findings.

Cortisol Binding Globulin: More Than Just a Carrier?

In the current issue of the JCEM, Torpy et al. (1) describe the case of a 9-yr-old boy from Chile with recurring, severe headaches and postexertion fatigue. The boy's complaints did not prevent him from participating in regular school activities, which is a hint for a seasoned pediatrician to look for true pathology (sick kids often want to attend school, whereas children with psychosomatic complaints display school avoidance) (2). The boy's mother and his two older sisters were healthy, whereas the father had a history of migraine headaches. Parental concerns about his growth and stature triggered a referral to a pediatric endocrinologist (V. Mericq; Ref. 1), who assured the patient and his family that he would achieve normal adult height based on her general assessment and, more specifically, based on his delayed bone age in combination with his father's history of constitutional delay of growth and development. However, the previous diagnosis of migraines (a head magnetic resonance imaging had been normal) and the complaint of fatigue raised the physician's suspicion to go beyond a basic work-up; a low plasma morning cortisol and inappropriately normal plasma ACTH levels were followed up with an ACTH stimulation test, which showed an insufficient plasma cortisol response. Thus, the overall picture was consistent with secondary adrenal insufficiency. Lack of clinical response to steroid replacement and continued parental worries led to another consultation and consideration of an exceedingly rare condition. The latter brought Mericq and Torpy (now on opposite sides of the world) together again, both having received further training at the National Institutes of Health Clinical Research Center in Bethesda, Maryland, where rare conditions are common and common conditions are rare. In collaboration with their colleagues, they identified a single base mutation in the gene encoding corticosteroid binding globulin (CBG). This mutation in exon 2, which they named “Santiago,” caused a frameshift and premature stop codon at amino acid 26. As expected, CBG plasma levels were approximately 50% of normal. The father and both daughters were heterozygous for the same mutation; however, this boy's other allele was affected, too. He and his asymptomatic mother shared an amino acid substitution (Ala246Ser) reported to be possibly associated with chronic fatigue and somewhat elevated CBG levels (3).

Primary Empty Sella with Partial Hypopituitarism and Autoimmune Thyroiditis

Laboratory Work-up : LH and FSH were low with estradio l at pre-puber ta l leve l , suggest ing hypogonadotropic hypogonadism. Prolactin was slightly elevated. Twenty four-hour urinary free cortisol and 8AM serum cortisol were low with low normal plasma ACTH, indicating secondary adrenal insufficiency. TSH was elevated with depressed FT4 and elevated antithyroglobulin, suggesting autoimmune thyroiditis. The following tests were normal: growth hormone, FBS and 2-hour OGTT. Patient had delayed bone age by the Greulich-Pyle method. Bone densitometry revealed osteoporosis. Patient had 46XX karyotype. Pelvic ultrasound revealed infantile uterus. Sellar MRI showed empty sella.

Early deprivation leads to altered behavioural, autonomic and endocrine responses to environmental challenge in adult Fischer rats

Depression is diagnosed on the basis of abnormal positive affects (anhedonia) and negative affects (low mood, helplessness, coping deficit, fatigue), and associated physiological abnormalities include hyperactivity of the HPA endocrine system and autonomic nervous system. Adverse early life environments, including parent-offspring emotional and physical neglect, are associated with traits of altered physiological and neurobiological function and long-term predisposition to depression. Animal studies based on early life adversity can potentially yield environmental models of the developmental behavioural neurobiology of depression. In Wistar rats, we demonstrated that isolation of pups from dam and littermates at room temperature for 4 h per day on P1-14 (early deprivation, ED) led to adulthood anhedonia-like traits of reduced motivation to obtain gustatory reward and reduced social motivation, relative to subjects left undisturbed during infancy (non-handling, NH). We hypothesized that the depression-like effects of ED would be even more pronounced and multiple in the stress hyper-responsive Fischer rat strain. The effects of ED were studied relative to NH and 15 min of daily isolation (early handling, EH). Relative to NH and EH, which exhibited remarkably similar phenotypes, ED led, principally in males, to chronic traits of: reduced motivation for and consumption of gustatory reward; increased activity in the pre-test and test phases of the forced swim test; reduced coping behaviour in an aversive environment; attenuated plasma corticosterone stress response to a normal plasma ACTH stress response; increased hypertensive response to a novel environment; and increased prefrontal cortical serotonin. High sensitivity to an aversive early environment in male Fischer rats therefore constitutes an important model for the study of affective development and its neurobiology.

Possible Relationship between Elevated Plasma ACTH and Tall Stature in Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency (FGD) is characterized clinically by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but not with mineralcorticoid deficiency. Excessive growth was described previously in some patients with FGD, many of whom were shown to have mutations in the ACTH receptor gene. The mechanisms responsible for their excessive growth are unknown. We analyzed the ACTH receptor gene in three patients with FGD and discussed the causes of excessive growth in FGD. No mutations were detected in the coding and promoter regions of the ACTH receptor gene of one female patient who had tall stature (+ 2.41S.D.) and advanced bone age (10 years 9 months) when she was 4 years 9 months old. Her plasma ACTH level had been elevated until then (124-2,684 pg/ml). Moreover, plasma estradiol was elevated for her age (21.3 pg/ml), and it decreased in response to the dexamethasone suppression test (from 25.4 to 6.9 pg/ml). Elevated plasma estradiol was apparently related to the increase in plasma ACTH and played a major role in excessive growth in this patient. On the other hand, the genetic analysis showed that the other two patients who were siblings were homozygous for the R137W mutation. Clinically, they responded well to hydrocortisone replacement therapy with almost normal plasma ACTH levels. Although all patients with the R137W mutation reported previously were tall, our patients were of normal height. We speculate that the major causes of excessive growth in FGD are not only from ACTH receptor mutation, but also from the action of elevated plasma ACTH.

A Case of ACTH-Producing Pheochromocytoma Associated with Pregnancy

Ectopic ACTH syndrome is rarely caused by pheochromocytoma. We report a case of a 28-year-old woman with Cushing's syndrome due to ACTH-producing adrenal pheochromocytoma. She had delivered preterm baby at 32nd week of gestation with 'severe preeclampsia'. After delivery, persistent hypertension accompanied by severe headache led her to being misdiagnosed as Cushing's syndrome due to right adrenal adenoma (normal plasma ACTH level) and cerebral vasculitis of unknown etiology. She was referred to our hospital for surgical treatment. Repeated biochemical studies suggested coexistence of ectopic ACTH syndrome and pheochromocytoma. To reverse her clinical deterioration, right total and left subtotal adrenalectomy was performed with presumptive diagnosis of 1) right adrenal pheochromocytoma causing ectopic ACTH syndrome or 2) coexistence of ACTH-dependent Cushing's syndrome and right adrenal pheochromocytoma. Pathologic examination of right adrenal mass revealed pheochromocytoma which showed strong immunostaining for ACTH. Plasma ACTH and urinary cortisol excretion normalized after surgery, but she succumbed to multiple cerebral infarcts and disseminated intravascular coagulation. Pregnancy and inappropriately low plasma ACTH at initial evaluation might have hampered early diagnosis. To our knowledge, this is the first description of a case with ectopic ACTH syndrome due to pheochromocytoma associated with pregnancy.

Dose-response relationship between plasma ACTH and serum cortisol in the insulin-hypoglycaemia test in 25 healthy subjects and 109 patients with pituitary disease.

The insulin hypoglycaemia test (IHT) is believed to be the most reliable test for evaluating the entire hypothalamo-pituitary-adrenal (HPA) axis. The lower limit for the normal peak serum cortisol response has been reported to be between 500 and 580 nmol/l. Reference levels for a normal plasma ACTH response have not been reported recently. We performed the IHT in 25 healthy subjects and in 109 patients with proven or suspected pituitary disorders with serial measurements of serum or plasma cortisol and of plasma ACTH, in order to establish reference levels and to study the dose-response relationship between ACTH and cortisol in this test. In most patients, other pituitary hormonal axes were evaluated in addition. With the cortisol kit from Diagnostic Products Corporation (DPC), serum cortisol was about 13% lower than plasma (EDTA) levels with an excellent correlation between serum and plasma (r = 0.976; P<0.001). In the normals, the lower limit of the cortisol response (mean cortisol peak level minus 2 SD.) was 570 nmol/l for plasma and 500 nmol/l (calculated) for serum, while the lower limit of the ACTH response was 17.6 pmol/l (80 ng/l). In normals, the cortisol response was independent of the magnitude of the ACTH response. Seventeen out of 30 patients with ACTH responses to levels < 8.8 pmol/l (< 40 ng/l) had subnormal cortisol responses. However, 38 of the patients with pituitary disease had normal cortisol responses in spite of subnormal ACTH responses (group 2), while 47 patients had completely normal IHT results (group 1). Patients in group 2 had more often additional pituitary hormone deficiencies than those of group 1. The dose-response relationship between ACTH and cortisol in the patients resembled a dose-response curve that had been set up previously in normal subjects who received incremental doses of subcutaneous human ACTH (1-39). The normal increment of plasma ACTH in the IHT is greater than necessary for stimulating serum cortisol to levels > 500 nmol/l. Patients with a subnormal ACTH but normal cortisol response in the IHT have a decreased ACTH secretory reserve. It is unlikely that they are at increased risk of developing an adrenal crisis perioperatively or in other stressful situations unless pituitary function deteriorates. The ACTH-cortisol relationship in the IHT performed in patients with pituitary disease shows no sharp dividing line between normality and disease, and whether a patient needs permanent glucocorticoid substitution is a discretionary decision.

SUBCLINICAL CUSHING'S SYNDROME

Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (< 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome.

Psychological and endocrine correlates of chronic pelvic pain associated with adhesions

Chronic pelvic pain (CPP) is a frequent and often unexplained gynecological complaint. We attempted to evaluate stress history, psychological features and hypothalamic-pituitary-adrenal (HPA) axis Junction in a group of patients suffering from CPP associated with pelvic adhesions. We recruited 10 patients with CPP and adhesions and 14 painfree, infertile control patients who underwent gynecological examination and diagnostic laparoscopy in a general hospital Psychological assessment included structured interviews on sexual and physical abuse experiences and major life events as well as questionnaires on pain characteristics and depression, lb evaluate HPA axis Junction, we measured plasma adrenocorticotropin (ACTH) and salivary cortisol responses to the administration of 100 μg human corticotropin-releasing factor (CRF). Results revealed high, but not statistically increased, prevalence rates of sexual and physical abuse for patients with CPP and adhesions as compared to controls. Patients with CPP and adhesions reported a significantly higher total number of major life events. Mean depression scores were normal in both groups. Patients with CPP and adhesions demonstrated normal plasma ACTH, but decreased salivary cortisol levels in the CRF stimulation test. These preliminary findings suggest that stress and neuroendocrine changes may also contribute to the pathophysiology of CPP with an identified organic correlate.

Neurotoxic Lesions Induced by Monosodium Glutamate Result in Increased Adenopituitary Proopiomelanocortin Gene Expression and Decreased Corticosterone Clearance in Rats

Hypothalamic-pituitary-adrenocortical function in rats with brain lesions induced by neonatal monosodium glutamate (MSG) treatment (4 mg/g, 5 administrations, i.p.) was evaluated in the present study. Using in situ hybridization we found increased proopiomelanocortin (POMC) mRNA levels in the adenopituitary and normal corticotropin-releasing hormone mRNA levels in the hypothalamic paraventricular nucleus in MSG-treated rats. The total content of pituitary adrenocorticotropin (ACTH) was not changed, while pituitary ACTH concentration was higher in MSG-treated compared to control rats. The number of ACTH-immunostained cells per a constant area of adenohypophysial section, as measured by immunohistochemistry, was unchanged indicating that no significant condensation of corticotropes occurred. Basal plasma ACTH concentrations were not different, whereas morning corticosterone levels were elevated in rats with MSG treatment. While ACTH response to stress stimuli was similar in both groups of rats, corticosterone response to exogenous ACTH (500 ng/kg, i.v., Synacthen), short-lasting handling and immobilization was of the same magnitude but prolonged in MSG-treated rats. Based on the decline of [³H]corticosterone in plasma, a decreased corticosterone clearance rate was found in MSG-treated rats. These findings suggest that MSG treatment results in increased POMC gene expression per corticotrope of the atrophic pituitary resulting in maintenance of normal pituitary ACTH stores and plasma ACTH levels. Elevated basal levels of corticosterone in plasma as well as prolonged corticosterone responses to stimulations in rats treated with MSG seem to be due to a decreased clearance rate of corticosterone.

A case of cyclical Cushing's disease associated with corticosteroidbinding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease

We experienced an extremely unusual combination of Cushing's disease and corticosteroid-binding globulin (CBG) deficiency that has been reported in only one similar case to date. A 53-year-old woman presented at a medical clinic with clinical Cushing's disease. However, her plasma levels of adrenocorticotropin (ACTH) and cortisol were in the normal range. Six months later, during a second visit, a high urinary excretion of 17-hydroxycorticosteroids was found, but plasma ACTH and cortisol levels were normal again. Further investigation revealed a decreased CBG concentration. Free plasma cortisol levels were clearly elevated. Furthermore, the Cushing's disease of our patient was complicated by periodic secretion of ACTH and cortisol, with high or normal outputs of corticosteroids occurring alternately every 1-3 days, which explained the occasionally normal plasma ACTH and cortisol levels. A combination of a decreased serum CBG concentration and periodic secretion of ACTH can be an important pitfall in the diagnosis of Cushing's disease.

Elevated plasma adrenocorticotropin concentration as evidence of limited adrenocortical reserve in patients with adrenomyeloneuropathy.

Adrenal insufficiency occurs in approximately two thirds of patients with adrenomyeloneuropathy. Its development may precede or follow the onset of neurological disease. To define the sensitivity of various tests of adrenal cortical function, we reviewed adrenocortical function tests in 28 patients with adrenomyeloneuropathy who had normal ACTH stimulation tests at the time of enrollment into an ongoing dietary study. Endocrine studies performed at 6-month intervals included a conventional ACTH stimulation test, plasma ACTH and cortisol concentrations, and 24-h urinary cortisol and aldosterone excretion rates. Eleven patients (39%) developed an elevated plasma ACTH concentration after a median follow-up of 3 yr. Their 24-h urinary cortisol and plasma basal and ACTH-stimulated cortisol concentrations were all normal. The mean basal cortisol level tended to be lower in patients who had increased plasma ACTH levels than in patients who maintained a normal plasma ACTH concentration during the study period (408 +/- 22 vs. 491 +/- 33 nmol/L; P = 0.05). Patients who had an increased plasma ACTH concentration and symptoms consistent with adrenal insufficiency had a lower mean 24-h urinary free cortisol level than those with normal plasma ACTH (196 +/- 22 vs. 281 +/- 30 nmol/day; P < 0.05). Plasma ACTH concentrations were persistently elevated in six patients in whom subsequent values were available. One individual later developed a subnormal ACTH-stimulated cortisol concentration consistent with overt adrenal insufficiency. Our results suggest that conventional provocative and integrative tests of adrenocortical function may not be sufficient to identify patients with adrenomyeloneuropathy who have compensated adrenal hypofunction. An elevated plasma ACTH concentration may represent an early marker for adrenocortical dysfunction and incipient adrenal insufficiency in AMN patients.

The hypothalamic-pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone.

Plasma ACTH and cortisol concentrations are frequently elevated in patients in intensive care units (ICU). To examine the functional integrity of the hypothalamic-pituitary-adrenal axis during critical illness, we evaluated prospectively 53 ICU patients in a general medical ICU. Thirty-one patients and 7 normal controls underwent an overnight dexamethasone suppression test (3 mg dexamethasone, orally, at 2300 h). Plasma ACTH and serum cortisol were measured at 0900 h. In a separate experiment, 22 patients and 7 control subjects underwent a CRH stimulation test [100 micrograms human (h) CRH, iv]. ACTH and cortisol concentrations were determined from -15 to 120 min. Compared to normal controls, plasma ACTH and serum cortisol concentrations were not fully suppressible by dexamethasone [mean +/- SEM: plasma ACTH, 21 +/- 4 vs. 3 +/- 0.5 pg/mL (4.7 +/- 0.9 vs. 0.7 +/- 0.1 pmol/L); serum cortisol, 13.9 +/- 1.9 vs. 1.5 +/- 0.3 micrograms/dL (390 +/- 50 vs. 40 +/- 10 nmol/L); P = 0.0001], demonstrating an altered glucocorticoid feedback in the ICU patients. Patients undergoing hCRH stimulation had clearly elevated mean baseline plasma ACTH and serum cortisol concentrations [ACTH, 78 +/- 20 pg/mL vs. 15 +/- 3 in controls (17.2 +/- 4.4 vs. 3.4 +/- 0.7 pmol/L; P = 0.007); cortisol, 36.8 +/- 3.4 micrograms/dL vs. 9.6 +/- 1.2 (1020 +/- 80 vs. 260 +/- 30 nmol/L; P = 0.0001)]. Despite elevated baseline glucocorticoid concentrations, stimulation with hCRH resulted in significantly higher peak plasma ACTH concentrations 15 min after hCRH than in controls [134 +/- 31 vs. 48 +/- 9 pg/mL (29.5 +/- 6.8 vs. 10.6 +/- 2.0 pmol/L); P < 0.05]. Serum cortisol concentrations in ICU patients were significantly elevated throughout the test period (P = 0.0001) and rose to a peak of 43.9 +/- 3.5 micrograms/dL compared to 18.2 +/- 2.0 micrograms/dL in controls (1210 +/- 70 vs. 500 +/- 60 nmol/L). We conclude that ICU patients have a markedly altered responsiveness of their pituitary corticotroph to suppression with dexamethasone and stimulation with hCRH. These findings may be explained by altered pituitary glucocorticoid feedback and/or hypersecretion of peptides with CRH-like activity (vasopressin and cytokines) during critical illness.

Abnormal Pituitary-Adrenal Responses to Corticotropin-Releasing Hormone in Patients with Seasonal Affective Disorder: Clinical and Pathophysiological Implications

CRH has been shown to produce increased locomotion, arousal, and anorexia in experimental animals. A deficiency of CRH in patients with seasonal affective disorder could contribute to the characteristic lethargy, hypersomnia, and hyperphagia characteristic of this illness. To test this hypothesis, we studied basal plasma ACTH and cortisol levels and their responses to ovine CRH in controls and depressed patients with seasonal affective disorder before and after light treatment. Untreated seasonal affective disorder patients showed normal basal plasma cortisol and ACTH levels, but their responses to CRH tended to be delayed and were significantly reduced. When patients were studied after 9 days of light treatment, a significant increase in plasma ACTH and cortisol responses to CRH was observed. Our findings in untreated patients with seasonal affective disorder are similar to those in patients with Cushing's disease 2 weeks after transsphenoidal hypophysectomy, who uniformly show sustained suppression of their CRH neuron because of long-standing hypercortisolism. This findings suggest that the CRH neuron of patients with seasonal affective disorder is hypofunctional. We postulate that the clinical symptomatology in patients with seasonal affective disorder could reflect deficient activity of this important arousal-producing system.

Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism

In the present work the possible use of loperamide, an opiate agonist, in the dynamic evaluation of patients with suspected hypercortisolism was investigated. The effects of loperamide on plasma ACTH and cortisol levels were evaluated in normal subjects and in 58 patients with suspected Cushing's syndrome. The results were compared to those obtained after the overnight dexamethasone suppression test. In normal subjects plasma ACTH and cortisol levels were significantly (p less than 0.005) suppressed by both loperamide (16 mg po) and dexamethasone (1 mg po). In 17 patients, in whom the diagnosis of Cushing's syndrome was confirmed by subsequent investigations, neither loperamide or dexamethasone inhibited cortisol (from a baseline of 606 +/- 55 nmol/L) to a nadir of 502 +/- 43 nmol/L and 539 +/- 50 nmol/L, respectively) and ACTH concentration (from a basal level of 70.1 +/- 11.8 pg/ml to a nadir of 46.0 +/- 8.6 pg/ml and 54.3 +/- 7.5 pg/ml, respectively). In 34 patients, in whom the suspect of hypercortisolism was ruled out, either loperamide or dexamethasone suppressed the pituitary-adrenal axis: cortisol and ACTH levels significantly fell from 417 +/- 24 nmol/L and 28.3 +/- 3.5 pg/ml to 60 +/- 6 nmol/L and 14.4 +/- 1.4 pg/ml after loperamide and to 26 +/- 4 nmol and 16.4 +/- 1.7 pg/ml after dexamethasone. In 7 patients discordant responses were observed. In 3 patients treated with antiepileptic drugs ACTH and cortisol levels were inhibited by loperamide, but not by dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-releasing hormone stimulation test before and after transsphenoidal selective microadenomectomy in 30 patients with Cushing's disease.

Thirty patients with ACTH-dependent Cushing's disease were tested with CRH before and 7-10 days and 3-6 months after selective transsphenoidal adenomectomy. In 28 of 30 patients an adenoma was found, and in 22 (79%) clinical and endocrinological remission occurred. Preoperatively, the majority of the patients had basal and CRH-stimulated plasma ACTH levels that were markedly increased compared to those in normal subjects. On the basis of the CRH stimulation test and low dose (2 mg) dexamethasone suppression test results 7-10 days after surgery, these 30 patients were divided into 4 groups. Groups I, II, and III were patients in remission, as defined by undetectable, subnormal, or normal basal plasma ACTH and cortisol levels in addition to sufficient suppression of cortisol (less than 2 micrograms/dL) during the low dose (2 mg) dexamethasone suppression test. Patients in group IV were not in remission. In group I (n = 6), CRH failed to raise undetectable basal ACTH levels in the early postoperative period; however, 3-6 months later plasma ACTH did increase in response to CRH. In group II (n = 11), undetectable or low basal ACTH levels increased after CRH, and the increase was similar to that in normal individuals. In group III (n = 5), basal ACTH levels were normal, and the response to CRH was exaggerated, but all patients responded normally to the dexamethasone suppression test. The CRH-induced ACTH increase in group III was significantly greater (P less than 0.003) than that in normal subjects, but was similar to that in patients not in remission in group IV (n = 6). Three to 6 months later, the ACTH response to CRH in group III was normal. In summary, the CRH test 7-10 days after surgery in patients with Cushing's disease indicated remission when there was no CRH-induced ACTH response or the response was normal (groups I and II). The test failed to predict remission in patients with an exaggerated CRH-induced ACTH response (groups III and IV). However, with regard to group II, the CRH-induced ACTH increase 1 week after selective adenomectomy indirectly supports the concept of CRH deficiency during hypercorticism and thus, in these patients as well as in group I, a pituitary origin of the disease.