The importance of measuring prolactin prior to surgical management of a pituitary lesion: An illustrative case.

The characterization of sellar and suprasellar lesions is reliant on patient presentation, medical imaging, and hormone profiling. Prolactinomas are the most common type of functional pituitary adenomas, accounting for up to 57%. Importantly, prolactinomas can present without clear symptoms and with doubtful or even normal imaging. A 41-year-old male patient was referred to neurosurgery for consideration for resection of a sellar lesion, as initial CT imaging suggested a large meningioma. Subsequent MRI of the sella favored macroadenoma, meningioma, and craniopharyngioma as the top differential considerations. These conditions all indicate a diagnosis that would require surgical management. Clinical evaluation of this patient did not elicit any obvious clinical features suggestive of hyperprolactinemia. Fortunately, we obtained a full hormone panel which revealed a significantly elevated prolactin level of 17,390 µg/L. Based on this elevated prolactin level, we diagnosed a pituitary giant prolactinoma. Treatment with a dopamine agonist therapy was initiated and the response confirmed this diagnosis. This case demonstrates the importance of obtaining a prolactin level prior to surgical management of a sellar lesion. Had a prolactin level not been obtained, this patient would have undergone surgical resection based on both the imaging and clinical judgment.

Extraocular Muscle Enlargement in Acromegaly.

BACKGROUND: To determine whether acromegaly is associated with increased extraocular muscle (EOM) size at time of presentation. METHODS: Patients with a new diagnosis of acromegaly in a single tertiary care clinic with a CT scan that adequately delineated the EOMs were included. Control subjects were age- and sex-matched patients with a new diagnosis of nonfunctioning pituitary adenoma. Retrospective chart review was performed to extract baseline clinical and laboratory parameters including growth hormone, insulin-like growth factor 1, thyroid stimulating hormone, free T3, and free T4. A single neuroradiologist analyzed all CT scans and measured the maximum diameter and cross-sectional area of the superior rectus, inferior rectus, medial rectus, and lateral rectus in both eyes of all patients. RESULTS: We evaluated 17 patients with acromegaly and 18 control subjects. Mean maximum diameter of the superior, inferior, medial, and lateral recti were 4.80 mm (SD = 0.81), 4.67 mm (SD = 0.54), 4.86 mm (SD = 0.77), and 4.53 mm (SD = 0.70) respectively, in the acromegaly group. In the control group, they were 3.62 mm (SD = 0.58),3.71 mm (SD = 0.46), 3.66 mm (SD = 0.32), and 3.21 mm (SD = 0.44), respectively. The maximum diameter and cross-sectional area of all 4 EOMs measured in the acromegaly group were significantly larger ( P < 0.001) compared with the control group. CONCLUSIONS: Patients with acromegaly present with significantly enlarged EOMs compared with control subjects with nonfunctioning pituitary adenomas.

Hair cortisol analysis: An update on methodological considerations and clinical applications.

BACKGROUND: Hair cortisol analysis is increasingly being appreciated and applied in both research and medicine, aiding endocrinologists with diagnosis. CONTENT: We provide an overview of hair cortisol research in general and an update on methodological considerations including the incorporation of cortisol into hair, hair growth rates, and sampling procedures, mincing vs. grinding of samples during preparation for extraction, various extraction protocols, and quantification techniques. We compare the clinical utility and application of hair cortisol with traditional methods of measurement while acknowledging the limitations of analysis including variations in hair growth parameters. We explore the value of hair cortisol in cases of Cushing syndrome (particularly Cyclical Cushing), Adrenal insufficiency (including Addison's disease), therapy monitoring, cardiovascular disease, stress, and mental illness. SUMMARY: Hair cortisol provides a unique objective biomarker for the analysis of endogenous cortisol levels for not only clinical diagnostic purposes but also in research. The use of hair cortisol has great potential for advancing patient care.

Licorice-induced hypertension: a case of pseudohyperaldosteronism due to jelly bean ingestion.

Hypertension is one of the most common problems encountered in the primary care setting. Numerous secondary causes of hypertension exist and are potentially reversible. The ability to screen for such causes and manage them effectively may spare patients from prolonged medical therapy and hypertensive complications. Licorice can cause hypertension and hypokalemia due its effects on cortisol metabolism. We report a case of jelly bean ingestion that highlights the presentation, pathophysiology and management of licorice-induced hypertension.

Hormone phase influences sympathetic responses to high levels of lower body negative pressure in young healthy women.

We tested the hypothesis that sympathetic responses to baroreceptor unloading may be affected by circulating sex hormones. During lower body negative pressure at -30, -60, and -80 mmHg, muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were recorded in women who were taking (n = 8) or not taking (n = 9) hormonal contraceptives. All women were tested twice, once during the low-hormone phase (i.e., the early follicular phase of the menstrual cycle and the placebo phase of hormonal contraceptive use), and again during the high-hormone phase (i.e., the midluteal phase of the menstrual cycle and active phase of contraceptive use). During baroreceptor unloading, the reductions in stroke volume and resultant increases in MSNA and total peripheral resistance were greater in high-hormone than low-hormone phases in both groups. When normalized to the fall in stroke volume, increases in MSNA were no longer different between hormone phases. While stroke volume and sympathetic responses were similar between women taking and not taking hormonal contraceptives, mean arterial pressure was maintained during baroreceptor unloading in women not taking hormonal contraceptives but not in women using hormonal contraceptives. These data suggest that differences in sympathetic activation between hormone phases, as elicited by lower body negative pressure, are the result of hormonally mediated changes in the hemodynamic consequences of negative pressure, rather than centrally driven alterations to sympathetic regulation.

Recombinant Human Thyroid Stimulating Hormone versus Thyroid Hormone Withdrawal for Radioactive Iodine Treatment of Differentiated Thyroid Cancer with Nodal Metastatic Disease.

Introduction. Recombinant human thyroid stimulating hormone (rhTSH) is approved for preparation of thyroid remnant ablation with radioactive iodine (RAI) in low risk patients with well differentiated thyroid cancer (DTC). We studied the safety and efficacy of rhTSH preparation for RAI treatment of thyroid cancer patients with nodal metastatic disease. Methods. A retrospective analysis was performed on 108 patients with histopathologically confirmed nodal metastatic DTC, treated with initial RAI between January 1, 2000, and December 31, 2007. Within this selected group, 31 and 42 patients were prepared for initial and all subsequent RAI treatments by either thyroid hormone withdrawal (THW) or rhTSH protocols and were followed up for at least 3 years. Results. The response to initial treatment, classified as excellent, acceptable, or incomplete, was not different between the rhTSH group (57%, 21%, and 21%, resp.) and the THW group (39%, 13%, and 48%, resp.; P = 0.052). There was no significant difference in the final clinical outcome between the groups. The rhTSH group received significantly fewer additional doses of RAI than the THW group (P = 0.03). Conclusion. In patients with nodal-positive DTC, preparation for RAI with rhTSH is a safe and efficacious alternative to THW protocol.

Risk of catecholaminergic crisis following glucocorticoid administration in patients with an adrenal mass: a literature review.

BACKGROUND: Glucocorticoids as diagnostic or therapeutic agents have been reported to carry an increased risk of catecholaminergic crisis (CC) in patients with pheochromocytoma or paraganglioma (PPGL). METHODS: We searched literature databases using the following terms: pheochromocytoma, paraganglioma, adrenal incidentaloma, steroids, glucocorticoids, dexamethasone suppression test (DST), hypertensive crisis, cosyntropin and CRH. From all published case reports (1962-2013), we reviewed medical history, presenting symptoms, dose and route of steroid administration, location and size of adrenal mass, biochemical phenotype and outcome. RESULTS: Twenty-five case reports describing a CC were identified. Three patients with an adrenal incidentaloma suffered a CC following high-dose DST, and in one case, this was fatal. In two of these patients, biochemical testing missed the diagnosis, and in the third, a DST was done despite elevated urinary metanephrines. No CC has been reported for patients undergoing a low-dose DST. Three of 16 patients who received therapeutic glucocorticoids and four of six patients following cosyntropin testing died. No specific biochemical phenotype was related to adverse events. CONCLUSIONS: Although a causal relationship cannot be established from this review, it seems prudent to exclude a PPGL in patients with a large incidentaloma or when high-dose DST is considered in a patient with an incidentaloma of any size. Our literature review does not support the need for biochemical testing for PPGL prior to a low-dose (1 mg) DST. Finally, before starting therapeutic glucocorticoids, any clinical signs or symptoms of a potential PPGL should prompt reliable biochemical testing to rule out a PPGL.

Menstrual cycle and sex effects on sympathetic responses to acute chemoreflex stress.

This study aimed to examine the effects of sex (males vs. females) and sex hormones (menstrual cycle phases in women) on sympathetic responsiveness to severe chemoreflex activation in young, healthy individuals. Muscle sympathetic nerve activity (MSNA) was measured at baseline and during rebreathing followed by a maximal end-inspiratory apnea. In women, baseline MSNA was greater in the midluteal (ML) than early-follicular (EF) phase of the menstrual cycle. Baseline MSNA burst incidence was greater in men than women, while burst frequency and total MSNA were similar between men and women only in the ML phase. Chemoreflex activation evoked graded increases in MSNA burst frequency, amplitude, and total activity in all participants. In women, this sympathoexcitation was greater in the EF than ML phase. The sympathoexcitatory response to chemoreflex stimulation of the EF phase in women was also greater than in men. Nonetheless, changes in total peripheral resistance were similar between sexes and menstrual cycle phases. This indicates that neurovascular transduction was attenuated during the EF phase during chemoreflex activation, thereby offsetting the exaggerated sympathoexcitation. Chemoreflex-induced increases in mean arterial pressure were similar across sexes and menstrual cycle phases. During acute chemoreflex stimulation, reduced neurovascular transduction could provide a mechanism by which apnea-associated morbidity might be attenuated in women relative to men.

The detection of cortisol in human sweat: implications for measurement of cortisol in hair.

BACKGROUND: Hair cortisol analysis has been shown to be an effective measure of chronic stress. Cortisol is assumed to incorporate into hair via serum, sebum, and sweat sources; however, the extent to which sweat contributes to hair cortisol content is unknown. METHODS: Sweat and saliva samples were collected from 17 subjects after a period of intensive exercise and analyzed by salivary enzyme-linked immunosorbent assay (ELISA). Subsequently, an in vitro test on exposure of hair to hydrocortisone was conducted. Residual hair samples were immersed in a 50-ng/mL hydrocortisone solution for periods lasting 15 minutes to 24 hours, followed by a wash or no-wash condition. Hair cortisol content was determined using our modified protocol for a salivary ELISA. RESULTS: Postexercise control sweat cortisol concentrations ranged from 8.16 to 141.7 ng/mL and correlated significantly with the log-transformed time of day. Sweat cortisol levels significantly correlated with salivary cortisol concentrations. In vitro hair exposure to a 50-ng/mL hydrocortisone solution (mimicking sweat) for 60 minutes or more resulted in significantly increased hair cortisol concentrations. Washing with isopropanol did not affect immersion-increased hair cortisol concentrations. CONCLUSIONS: Human sweat contains cortisol in concentrations comparable with salivary cortisol levels. This study suggests that perfuse sweating after intense exercise may increase cortisol concentrations detected in hair. This increase likely cannot be effectively decreased with conventional washing procedures and should be considered carefully in studies using hair cortisol as a biomarker of chronic stress.

Hormone phase dependency of neural responses to chemoreflex-driven sympathoexcitation in young women using hormonal contraceptives.

Hormone fluctuations in women may influence muscle sympathetic nerve activity (MSNA) in a manner dependent on the severity of the sympathoexcitatory stimulus. This study examined MSNA patterns at rest and during chemoreflex stimulation in low- (LH) vs. high-hormone (HH) phases of contraceptive use in healthy young women (n = 7). We tested the hypothesis that MSNA would be greater in the HH phase at baseline and in response to chemoreflex stimulation. MSNA recordings were obtained through microneurography in LH and HH at baseline, during rebreathing causing progressive hypoxia and hypercapnia, and during a hypercapnic-hypoxic end-inspiratory apnea. Baseline MSNA burst incidence (P = 0.03) and burst frequency (P = 0.02) were greater in the HH phase, while MSNA burst amplitude distributions and hemodynamic measures were similar between phases. Rebreathing elicited increases in all MSNA characteristics from baseline (P < 0.05), but was not associated with hormone phase-dependent changes to MSNA patterns. Apnea data were considered in two halves, both of which caused large increases in all MSNA variables from baseline in each hormone phase (P < 0.01). Increases in burst incidence and frequency were greater in LH during the first half of the apnea (P = 0.03 and P = 0.02, respectively), while increases in burst amplitude and total MSNA were greater in LH during the second half of the apnea (P < 0.05). These results indicate that change in hormone phase brought on through use of hormonal contraceptives influences MSNA patterns such that baseline MSNA is greater in the HH phase, but responses to severe chemoreflex stimulation are greater in the LH phase.

Ciprofloxacin and rifampin have opposite effects on levothyroxine absorption.

BACKGROUND: Levothyroxine (L-T4) absorption varies between individuals, and can be affected by various concomitantly administered drugs. Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose. METHODS: The effects of two antibiotics on T4 absorption were prospectively assessed in a double-blind, randomized, crossover fashion. Eight healthy volunteers received 1000 µg L-T4 combined with placebo, ciprofloxacin 750 mg, or rifampin 600 mg as single doses. We measured total plasma thyroxine (T4) concentrations over a 6-hour period after dosing using liquid chromatography-tandem mass spectrometry. For each study arm, areas under the T4 plasma concentration-time curve (T4 AUCs) were compared. RESULTS: Coadministration of ciprofloxacin significantly decreased the T4 AUC by 39% (p = 0.035), while, surprisingly, rifampin significantly increased T4 AUC by 25% (p = 0.003). CONCLUSION: Intestinal absorption of L-T4 is differentially affected by acute coadministration of ciprofloxacin or rifampin. Mechanistic studies focused on intestinal and possibly hepatic thyroid hormone transporters are required to explain the observed drug interactions with L-T4.

Effect of short-term proton pump inhibitor treatment and its discontinuation on chromogranin A in healthy subjects.

CONTEXT: Chromogranin A (CgA) is used as a generic tumor marker for neuroendocrine tumors. Proton pump inhibitors (PPI) are known to increase CgA, but it is not clear to what extent, and there is little information on how long PPI need to be discontinued before the effect of PPI has disappeared. Furthermore, is it not known whether this PPI effect is dependent on the CgA assay used. OBJECTIVE: The aim of the study was to determine the effect of 7-d treatment with a PPI and its discontinuation on CgA in serum and plasma comparing four CgA assays. DESIGN AND PARTICIPANTS: Seventeen healthy subjects took lansoprazole 30 mg at bedtime for 7 d, and blood samples for CgA were obtained at baseline, d 7 of PPI use, and 1, 2, 4, and 7 d after discontinuation of the PPI. In all samples, CgA was measured using the following assays: Alpco (serum and plasma), Cis-Bio (serum and plasma), DAKO, and Cis-Bio radioisotope assay. RESULTS: When using the same assay, CgA was higher in plasma than in serum. Treatment with a PPI for 1 wk resulted in a significant (about 2.5-fold) increase in CgA with significant interindividual variation. After discontinuation of PPI, serum CgA gradually declined, with a half-life of 4-5 d. CONCLUSION: Short-term PPI use results in a significant increase of CgA in serum and plasma, an effect that is largely independent of the assay used. PPI need to be discontinued for 2 wk to fully eliminate their effect on CgA. This effect of PPI needs to be considered when interpreting results of CgA measurements.

The effects of opioids and opioid analogs on animal and human endocrine systems.

Opioid abuse has increased in the last decade, primarily as a result of increased access to prescription opioids. Physicians are also increasingly administering opioid analgesics for noncancer chronic pain. Thus, knowledge of the long-term consequences of opioid use/abuse has important implications for fully evaluating the clinical usefulness of opioid medications. Many studies have examined the effect of opioids on the endocrine system; however, a systematic review of the endocrine actions of opioids in both humans and animals has, to our knowledge, not been published since 1984. Thus, we reviewed the literature on the effect of opioids on the endocrine system. We included both acute and chronic effects of opioids, with the majority of the studies done on the acute effects although chronic effects are more physiologically relevant. In humans and laboratory animals, opioids generally increase GH and prolactin and decrease LH, testosterone, estradiol, and oxytocin. In humans, opioids increase TSH, whereas in rodents, TSH is decreased. In both rodents and humans, the reports of effects of opioids on arginine vasopressin and ACTH are conflicting. Opioids act preferentially at different receptor sites leading to stimulatory or inhibitory effects on hormone release. Increasing opioid abuse primarily leads to hypogonadism but may also affect the secretion of other pituitary hormones. The potential consequences of hypogonadism include decreased libido and erectile dysfunction in men, oligomenorrhea or amenorrhea in women, and bone loss or infertility in both sexes. Opioids may increase or decrease food intake, depending on the type of opioid and the duration of action. Additionally, opioids may act through the sympathetic nervous system to cause hyperglycemia and impaired insulin secretion. In this review, recent information regarding endocrine disorders among opioid abusers is presented.

Testosterone concentrations in hair of hypogonadal men with and without testosterone replacement therapy.

BACKGROUND: The measurement of testosterone (T) is essential for the diagnosis of male hypogonadism and for monitoring treatment. Samples need to be obtained at specific times in relation to the diurnal rhythm and therapeutic T injections. In this study, we explored the measurement of T in hair as an alternative method to assess gonadal status and long-term T exposure in men. SUBJECTS AND METHODS: Thirty-six male subjects comprising 17 healthy volunteers, 10 untreated hypogonadal men, and nine hypogonadal men receiving T injections were studied. T was measured in serum and in hair. T in hair was measured using a commercially available salivary T enzyme immunoassay kit adapted for this use. RESULTS: The T concentration in the hair of hypogonadal men receiving T injections was significantly higher than that in untreated hypogonadal volunteers, but not eugonadal men. Median T concentrations were 3.66 (range, 0.82-15.00), 0.94 (range, 0.33-3.68), and 1.85 (range, 0.58-3.06) pg/g hair, respectively. CONCLUSIONS: T in hair reflects gonadal status in men and may be useful for monitoring T therapy over several weeks to months in hypogonadal men.

Bromide as marker for drug adherence in hypertensive patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Insufficient drug adherence is an important reason for inadequate blood pressure control. Currently, methods that measure drug adherence objectively are lacking. Objective methods are needed to help improve blood pressure control and outcome in hypertensive patients. WHAT THIS STUDY ADDS: Potassium bromide added to antihypertensive drugs can be used to monitor drug adherence in individual patients. However, although this method is objective, it is rather time-, cost- and work-consuming. AIMS Adherence to antihypertensive medication is essential for adequate long-term control of blood pressure (BP). This study investigated different methods of measuring adherence in hypertensive patients. METHODS: Patients were included if BP was insufficiently controlled on monotherapy. After a placebo period patients were treated with trandolapril 2 mg/verapamil SR 180 mg (TV). BP was determined using a mercury sphygmomanometer and ambulatory BP monitoring. Adherence was measured by capsule counting, electronic registration of pill-box openings and by measuring serum bromide concentrations. Potassium bromide was added to each TV capsule. RESULTS: Thirty patients participated in the study. Treatment with TV significantly lowered office BP and ambulatory BP. Results for electronic monitoring and adherence based on bromide measurements were comparable. Adherence was slightly higher when assessed by capsule counting. CONCLUSIONS: Measuring serum bromide concentrations may be suitable for assessment of adherence to drug therapy giving comparable results to electronic monitoring. Using capsule counting, electronic monitoring and measurement of bromide concentrations, nonadherent patients were identified.

Measurement of cortisol in human hair as a biomarker of systemic exposure.

PURPOSE: Current methods for measuring long-term endogenous production of cortisol can be challenging due to the need to take multiple urine, saliva or serum samples. Hair grows approximately 1 centimeter per month, and hair analysis accurately reflects exposure to drug abuse and environmental toxins. Here we describe a new assay for measurement of cortisol in hair, and determined a reference range for non-obese subjects. METHODS: For measurement of cortisol in hair we modified an immunoassay originally developed for measuring cortisol in saliva. We compared hair samples obtained from various parts of the head, and assessed the effect of hair dying. We analyzed hair samples from non-obese subjects, in whom we also obtained urine, saliva and blood samples for cortisol measurements. RESULTS: The mean extraction recovery for hair cortisol standards of 100 ng/ml, 50 ng/ml and 2 ng/ml (n=6) was 87.9%, 88.9% and 87.4%, respectively. Hair cortisol levels were not affected by hair color or by dying hair samples after they were obtained. Cortisol levels were decreased in hair that was artificially colored before taking the sample. The coefficient of variation was high for cortisol levels in hair from different sections of the head (30.5 %), but was smaller when comparing between hair samples obtained from the vertex posterior (15.6%). The reference range for cortisol in hair was 17.7-153.2 pg/mg of hair (median 46.1 pg/mg). Hair cortisol levels correlated significantly with cortisol in 24-hour urine (r=0.33; P=0.041). CONCLUSION: The correlation of hair cortisol with 24-hour urine cortisol supports its relevance as biomarker for long-term exposure.

Bromide as a marker to measure adherence to drug therapy.

OBJECTIVE: Several methods have been described to measure adherence to prescribed drug therapy. However, most of these have been shown to be inaccurate. Bromide is an anion that is readily absorbed in the gut and has an elimination half-life of about 12 days. In the present study, we investigated the pharmacokinetic properties of bromide with the objective to use it as a measure of drug adherence. METHODS: Three groups of each 8 healthy volunteers took 15, 24 or 30 mg potassium bromide, respectively, daily for 20 weeks. Serum concentrations of bromide were measured every two weeks. RESULTS: There was a linear relationship between the daily dosage taken and the mean increase of bromide concentration. In every group considerable inter-individual variability was seen. Correction for body weight resulted in an improved correlation between daily bromide dose and increase in concentration (r=0.78, p<0.01). CONCLUSIONS: Unfortunately, the inter-individual variability in clearance of bromide was considerable. This limits the use of bromide to primarily measuring adherence in individual patients during long term follow-up. Bromide appears to be a potentially useful marker to be added to drugs for assessment of individual adherence to long term drug therapy. This needs to be investigated in various patients, particularly for patients with relatively asymptomatic diseases (e.g. hypertension).

Cortisol, 11beta-hydroxysteroid dehydrogenases, and hypertension.

Hypersecretion of cortisol is associated with hypertension. In addition, an abnormal cortisol metabolism may play a role in the pathogenesis of hypertension. The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes catalyze interconversion of cortisol and cortisone and play an important role in the regulation of the effects of cortisol. Activity of 11beta-HSD type 2, converting active cortisol in inactive cortisone, is crucial in preventing access of cortisol to the renal mineralocorticoid receptors (MRs). Decreased activity of this isozyme in the kidney, either congenitally in Apparent Mineralocorticoid Excess syndrome or acquired following licorice consumption, allows cortisol access to the MRs, resulting in hypokalemic hypertension. In normotensive subjects, an association has been demonstrated between blood pressure increase on a high-salt diet and a mild decrease of renal 11beta-HSD2 activity. In ectopic adrenocorticotropic hormone (ACTH), plasma cortisol levels are very high, resulting in mineralocorticoid hypertension caused by saturation of the available renal 11beta-HSD2 capacity. Activity of the 11beta-HSDs has also been demonstrated in many extrarenal sites. Several studies have demonstrated extrarenal effects of cortisol on blood pressure, as well as a possible role for altered extrarenal 11beta-HSD activities in the pathogenesis of hypertension. More studies are needed to clarify the role of 11beta-HSDs in the pathogenesis of hypertension.