Anne L. S. Sullivan, MD

• Associate Professor of Family Medicine
• Roy J. and Lucille A. Carver College of Medicine
• University of Iowa
• Iowa City, Iowa

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Guidelines on male sexual dysfunction: erectile dysfunction and untimely ejaculation. Phosphodiesterase sort 5 inhibitor differentiation based on selectivity, pharmacokinetic, and efficacy profiles. Pharmacokinetics, pharmacodynamics, and efficacy of phosphodiesterase type 5 inhibitors. Avanafil for the therapy of erectile dysfunction: initial knowledge and medical key properties. Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Effect of high-fat breakfast and moderate-fat night meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. Pharmacokinetics of sildenafil after single oral doses in wholesome male subjects: absolute bioavailability, food results and dose proportionality. Systematic review of randomised managed trials of sildenafil (Viagra) within the therapy of male erectile dysfunction. Efficacy of sildenafil citrate in men with erectile dysfunction following radical prostatectomy: a systematic evaluate of scientific data. Clinical efficacy of sildenafil citrate based mostly on etiology and response to prior therapy [see comments]. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Vardenafil (Levitra) for erectile dysfunction: a scientific evaluation and meta-analysis of scientific trial stories. Safety and efficacy of vardenafil for the remedy of males with erectile dysfunction after radical retropubic prostatectomy. Vardenafil improves erectile perform in men with erectile dysfunction regardless of illness severity and disease classification. The efficacy and safety of flexible-dose vardenafil (Levitra) in a broad inhabitants of European men. Vardenafil for treatment of men with erectile dysfunction: efficacy and security in a randomized, double-blind, placebo-controlled trial. Vardenafil improved patient satisfaction with erectile hardness, orgasmic perform and sexual experience in men with erectile dysfunction following nerve sparing radical prostatectomy. Efficacy and tolerability of vardenafil in males with delicate melancholy and erectile dysfunction: the depression-related improvement with vardenafil for erectile response research. Efficacy and security of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. Efficacy, security, and treatment satisfaction of tadalafil versus placebo in patients with erectile dysfunction evaluated at tertiary-care academic centers. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized managed trial. Economic price of male erectile dysfunction using a choice analytic mannequin: for a hypothetical managed-care plan of one hundred,000 members. The prices of caring for erectile dysfunction in a managed care setting: proof from a large nationwide claims database. Vacuum constriction units in erectile dysfunction: acceptance and effectiveness in sufferers with impotence of natural or blended aetiology. Comparison of intraurethral liposomal and intracavernosal prostaglandin-E1 in the management of erectile dysfunction. Topical prostaglandin-E1 for the remedy of erectile dysfunction [see comments]. Erectile response to transurethral alprostadil, prazosin and alprostadil-prazosin combinations. Disappointing initial outcomes with transurethral alprostadil for erectile dysfunction in a urology practice setting. Intracavernosal prostaglandin E1 self vs office injection therapy in sufferers with erectile dysfunction.

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It also induces decidualization of the endo metrium, inhibits uterine contractions, will increase the vis cosity of cervical mucus, promotes lateral (alveolar) improvement of the breast glands, and increases basal physique temperature. The major C19 steroid is androstene dione, a half of which is secreted directly into plasma, with the remainder converted to estrogen by the granulosa cells. Estrogen regulates gonadotropin secretion, development of the secondary sexual characteristics of girls, uterine progress, thickening of the vaginal mucosa, thinning of the cervical mucus, linear growth of the ductal system of the breast, development spurt, epiphyseal closure, and bone mineralization. Although estrone can be secreted by the ovary, another necessary source of estrone is extraglandular conversion of androstenedione in periph eral tissues. All C18 steroids, together with estrone, estradiol, and estriol, are com monly referred to as estrogens. However, estrone and estriol are only weakly estrogenic and should be converted to estra diol to show full estrogenic action. At least seven enzymes with overlapping actions are able to changing estrone to estradiol within the ovary and extraovarian tissues. Estrone sulfate is presumed to serve as a reservoir for estrone and ultimately estradiol formation in a quantity of tissues, including these which may be targets of estrogen. A, the preovulatory follicle produces estradiol through a paracrine interplay between theca and granulosa cells. Androstenedione produced in theca-lutein cells serves as a substrate for estrone, which is further converted to estradiol in granulosa-lutein cells. The granulosalutein cell of the corpus luteum is ana tomically and functionally completely different from its counterpart within the preovulatory follicle in a quantity of ways. First, these cells are characterized by large and granular cytoplasms, are closely vascularized, and include giant portions of cho lesterol. The heterodimers of inhibin, A and B, are called inhibin A and inhibin B, respectively. All three subunits are detected in small antral fol licles by immunohistochemistry and in situ hybridiza tion. As in the case of inhibin, activins are also produced in ovarian granulosa cells and pituitary gonadotrophs. It seems that native follistatin levels in tissues modulate the consequences of activin. The sharp decline of those hormones upon regression of the corpus luteum in the course of the late luteal section abolishes this adverse feed again. If being pregnant is established by implantation of a blastocyst, the structural integrity and performance. These endocrine, paracrine, and autocrine components undoubt edly characterize only a portion of the entire picture. The causes of anovulation are numerous and could also be associated to defects in cellsurface receptors, intracellular components of sign transduction, or cellcell interactions. Although solely small quantities of estrogen are produced by a person adipocyte or pores and skin fibroblast in a steady trend, these cell varieties contribute to circulating estradiol levels due to their relative abundance. Estrone is additional converted to estrone sulfate, which serves as a reservoir for estrone in blood and other tissues. Endometrium is a multilayered mucosa specialised for implantation and support of being pregnant. A single, steady layer of epithelial cells strains the floor of the stroma and penetrates the stroma with deep invaginations virtually all the way right down to the myometrium-endometrium junction. The complete thickness of the endometrium is penetrated by the spiral arteries and their capillaries. Spiral arteries originate from the radial branches of arcuate arteries, which come up from uterine arteries. The superficial layer (functionalis) is shed during menstruation, whereas the permanent backside layer (basalis) provides rise to the regeneration of endometrium after every menstruation. The biologically lively estrogen, estradiol (E2), is produced in no less than three main sites: (1) by direct secretion from the ovary in reproductive-age ladies; (2) by conversion of circulating androstenedione (A), originating from the adrenal or ovary or both, to estrone (E1) in peripheral tissues; and (3) by conversion of A to E1 in estrogen goal tissues. In the latter two instances, estrogenically weak estrone (E1) is transformed to E2 inside the same tissue.

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Liddle syndrome can simply be distinguished from obvious mineralocorticoid excess based mostly on the nice scientific response to amiloride or triamterene combined with a sodiumrestricted food regimen, lack of efficacy of spironolactone and dexamethasone, and normal 24-hour urine cortisone/cortisol ratio. The hypertension associated with hyperparathyroidism can even occur as a complication of hypercalcemia-induced renal impairment. The treatment of hyperparathyroidism is surgical; hypertension might or might not remit after successful parathyroidectomy. Recent tendencies within the prevalence of high blood pressure and its treatment and management, 1999-2008. Trends in prevalence, consciousness, remedy, and control of hypertension in the United States, 1988-2000. Minimally invasive treatment of metastatic pheochromocytoma and paraganglioma: efficacy and security of radiofrequency ablation and cryoablation therapy. Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-metaiodobenzylguanidine remedy in a tertiary referral centre. High-dose 131Imetaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Prospective research on the prevalence of secondary hypertension among hypertensive sufferers visiting a common outpatient clinic in Japan. However, endogenous Cushing illness is uncommon, with an incidence of lower than 1 case per 1 million folks per yr. Thyroid Dysfunction Hyperthyroidism When excessive quantities of circulating thyroid hormones interact with thyroid hormone receptors on peripheral tissues, both metabolic exercise and sensitivity to circulating catecholamines improve. Thyrotoxic sufferers normally have tachycardia, high cardiac output, increased stroke quantity, decreased peripheral vascular resistance, and elevated systolic blood pressure. Treatment of thyroid hormone deficiency decreases blood pressure in most sufferers with hypertension and normalizes blood strain in a single third of them. Synthetic levothyroxine is the treatment of alternative for hypothyroidism (see Chapter 13). Pheochromocytomas in von Hippel-Lindau syndrome and a quantity of endocrine neoplasia sort 2 display distinct biochemical and medical phenotypes. Carney triad: a syndrome that includes paraganglionic, adrenocortical, and possibly different endocrine tumors. Adrenal cortical adenoma: the fourth part of the Carney triad and an association with subclinical Cushing syndrome. Reversible catecholamineinduced cardiomyopathy in a heart transplant candidate without persistent or paroxysmal hypertension. Validation of liquid chromatography-tandem mass spectrometry technique for analysis of urinary conjugated metanephrine and normetanephrine for screening of pheochromocytoma. A comparability of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. A case of bilateral fully latent adrenal tumor and concurrent nephritis with changes within the circulatory system and retinitis: Felix Fr�nkel, 1886]. Das Ganglioma embryonale sympathicum (sympathoma embryonale), eine typische b�sartige geschwuestform des sympathischen nervensystems. Diagnostic worth of elevated urinary output of noradrenaline and adrenaline in pheochromocytoma. Orthostatic hypotension as an unusual medical manifestation of pheochromocytoma: a case report. Biochemical and medical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. Malignant pheochromocytoma secreting vasoactive intestinal peptide and response to sunitinib: a case report and literature review. Parathyroid hormone-related peptide-producing non-familial pheochromocytoma in a baby. Pheochromocytoma presenting after cardiac transplantation for dilated cardiomyopathy.

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Of the remaining 127 circumstances, failure to insert the implant triggered pregnancies in eighty four girls. Other causes included incorrect timing of insertion (19 cases), expulsion of the implant out of the insertion site (3 cases), and interaction with hepatic enzyme-inducing medicines (8 cases). However, even when these methodology failures are accounted for, Nexplanon continues to have one of many highest efficacies of any methodology out there. Combined information from 11 scientific trials showed that the most common bleeding patterns with the etonogestrel implant have been amenorrhea (22%), infrequent bleeding (34%), frequent bleeding (7%), and frequent or extended bleeding, or each (18%). Of clinical relevance is that bleeding patterns experienced during the preliminary three months predicted future patterns for most ladies. Effective preinsertion counseling on the attainable changes in bleeding patterns might improve continuation rates. Several studies have observed a small (<1 kg) weight enhance in etonogestrel implant customers. In particular, girls might have considerations about implant removal, though elimination problems with single-rod units similar to Nexplanon are unusual. Side results (particularly irregular bleeding) ought to be mentioned upfront, because an sudden facet impact might cause women to request early removing of the implant. Accordingly, and as is acceptable for all sexually energetic women, implant users ought to be reminded about protected sexual practices. InsertionandRemoval Proper insertion and removing strategies are important for medical efficacy and for the prevention of issues. Proper coaching of clinicians seems to reduce the incidence of complications at insertion and removal. Complications of Nexplanon insertion are uncommon (<2%) but might embody local pain, infection, and bleeding. Prolonged use past 3 years has not been associated with any particular nonpregnancy problems. Under sterile circumstances, a 2- to 3-mm incision is made vertically over the implant. The rod is then removed utilizing the pop-out method described by Pymar and associates for Norplant System removing. The most common cause for difficulty in removing is placement of the implant too deeply. The commonest reason for this could be a lack of PatientSelection Before recommending the contraceptive implant, providers ought to review the indications and contraindications for its use. In 2006, Plan B (generic, Next Choice, Watson Pharmaceuticals) was launched as two 0. After a lot political debate in the United States, the levonorgestrel merchandise are now available in pharmacies over-the-counter for ladies aged 17 and older and by prescription for women under age 17. Waiting 12 hours to provoke remedy after unprotected intercourse increases the odds of pregnancy by nearly 50%, and its efficacy decreases linearly with time. Not all pharmacies inventory Plan B or take part on this program, but lists of collaborating pharmacies are available. Other minor antagonistic results reported by women in scientific trials included dizziness, fatigue, breast tenderness, headache, and belly pain. If the delay within the onset of menses is bigger than 1 week or if the anticipated menses is lighter than usual, a pregnancy take a look at must be carried out. Barriers to effective contraception use by adolescents embody lack of ahead planning, nonconsensual intercourse, lack of confidential care, fear of disapproval by mother and father and doctors, absence of adolescent-friendly companies, language and cultural obstacles, concern of pelvic examination, and price. The National Campaign to Prevent Teen and Unplanned Pregnancy operates an web site that gives wonderful info, determination tools, and reminders specifically designed for younger ladies. They could use these short-acting hormonal contraceptives inconsistently, which is ready to lead to very high pregnancy charges. Teenage being pregnant and parenting are precursors of poor medical, instructional, and psychosocial outcomes for mother and baby. Unscheduled bleeding may be much less acceptable to adolescents in contrast with adult women.

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These final research assist the idea that a point of physiologically decreased thyroid exercise on the tissue degree would possibly even have favorable results in the oldest-old subjects, however caution must be exercised when deciphering the predictive value of thyroid dysfunction in old topics, which can give a double-faced "Janus response" if not thought of within the appropriate context. There is, nonetheless, up to now additionally lack of proof to recommend that antithyroid treatment would possibly ameliorate dementia. [newline]Most medical studies show circadian cortisol adjustments with age (reviewed by Veldhuis and colleagues32). The question stays as to which diploma these alterations reflect or cause aging-associated adjustments in useful ability, cognition, and possibly depression. Three other hormonal systems exhibit lowered circulating hormone concentrations during regular growing older, and these adjustments have up to now been thought of primarily physiologic. Hormone alternative strategies have been developed, however many features stay controversial, and replenishing hormone blood ranges to these found in 30- to 50-year-old patients has not but uniformly proved helpful and protected. The most dramatic and rapidly occurring change in ladies round age 50 years is menopause. For a few years, the prevailing view was that menopause resulted from exhaustion of ovarian follicles. An alternative perspective is that age-related changes in the central nervous system and the hypothalamic-pituitary unit initiate the menopausal transition. The evidence that both the ovary and the mind are key pacemakers in menopause is compelling. During getting older, a gradual decline in serum complete and free testosterone ranges happens. In most women, vasomotor reactions, depressed mood, and urogenital complaints accompany this era of estrogen decline. A central pacemaker in the hypothalamus or larger mind areas (or both) is hypothesized, which along with changes in the peripheral organs (the ovaries, testicles, and adrenal cortex) regulates the growing older course of of those endocrine axes. Perimenopausal Use of Hormone Therapy Typical symptoms that end result from the sudden lower in estrogen production around menopause are menstrual cycle issues, vasomotor adjustments (hot flushes, night time sweats), and urogenital problems (atrophic vaginal irritation and dryness, dyspareunia, atrophic urethral epithelium leading to micturition disorders). Additional signs are irritability, temper swings, joint ache, and sleep disturbances. Frequency, severity, onset, and duration of symptoms vary broadly among people and among ethnic groups. It is unclear whether modifications in gonadal perform (menopause, andropause) are interrelated with the processes of adrenopause and somatopause, which occur in both women and men. However, the estrogen-progestin versus placebo trial, which involved more than sixteen,000 ladies, was discontinued early because of a rise in cardiovascular problems (coronary coronary heart disease, stroke, and venous thromboembolism) in addition to an increased incidence of breast most cancers in the therapy group. This trial was additionally stopped early as a result of a small enhance in breast cancer and coronary heart disease danger was seen, though hip fracture threat was reduced. A sequence of commentaries has addressed the variations in consequence between the observational studies and the randomized trials. In this regard much interest has focused on the "timing hypothesis," which states that estrogens are atheroprotective if utilized in an early section of atherosclerosis improvement. Comparison of the rate ratios for years 1 to 6 versus 7 to 8 confirmed a statistically significant (p < zero. Breast most cancers threat was unchanged in each the older and younger women with a previous hysterectomy handled with estrogen solely. An affiliation between endometrial most cancers and estrogen use was noticed a few years in the past. Presently suggested doses of estrogen were originally designed to stop bone loss, and progestagen regimens had been opposed to stop endometrial most cancers. Commercial preparations differ of their medical effect by design, and particular person ladies differ in their responses. The dose of estrogen essential to diminish perimenopausal symptoms, nevertheless, may be decrease in many ladies. Long-term remedy of menopausal sufferers with breast most cancers with tamoxifen additionally lowered the incidence of new (contralateral) breast cancer by 40%. In addition, the variety of cardiovascular incidents decreased by 70%, and the age-related decrease in bone mineral density was partially prevented.

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Approximately 5% of androstenedione is transformed to testosterone in extra ovarian tissues, finally producing androgen extra. SertoliLeydig cell tumors, which account for fewer than 1% of all solid ovarian tumors, are most likely to happen during the second to fourth decades of life, whereas hilus cell tumors occur more incessantly in postmenopausal women. In girls with both sort of tumor, the serum testosterone level is markedly elevated. Granulosatheca tumors primarily produce estradiol however may occasionally produce testosterone. Rapidly progressing signs of androgen extra suggest the presence of an androgenproducing tumor except proved in any other case. This fast development is typical of both ovarian and adrenal androgenproducing tumors. Progression is normally related to defeminizing signs, corresponding to lack of feminine physique contour, increased muscle mass, and decreased breast measurement. As the tumor continues to develop, increasingly more testosterone is produced, leading to quickly worsening hirsutism and progressive virilization. Elevated serum testosterone levels are characteristically related to ovarian tumors. This change may be medi ated by production and secretion of testosterone immediately by the tumor or by secretion of enormous portions of andro stenedione that are transformed to testosterone in extrago nadal tissues. In deciphering testosterone levels, the clinician ought to be conversant in the normal ranges of the scientific labora tory used. A worth of three times the uppernormal range (or >2 ng/mL) suggests a neoplasm, particularly if the clini cal history supports this prognosis. Lower serum testoster one ranges occasionally could additionally be related to virilizing ovarian tumors. If an androgensecreting tumor is sus pected, measurement of androstenedione is clinically useful. A severely elevated degree of androstenedione is according to an ovarian or adrenal tumor. When an elevated level of testosterone is related to suggestive medical historical past, meticulously performed transvaginal extremely sonography is essentially the most delicate technique to detect an ovarian tumor. In distinction to testosteronesecreting tumors of the ovary, testosteronesecreting tumors of the adrenal are rare. The cells of some testosteroneproducing adrenal tumors might resemble ovarian hilus cells, which are analogous to Leydig cells. Levels of quite lots of adrenal steroids, including cortico steroids, may be elevated in various mixtures within the presence of an adrenal tumor. Virilizing ovarian tumors are encountered far more incessantly than those of adrenal origin. If the presentation is suitable with an androgen secreting tumor and the ovaries are normal by transvaginal ultrasonography, the adrenals must be evaluated next by imaging. These numbers are supplied only as pointers, not as guidelines, and there are exceptions. First, as a outcome of tumors secrete androgens episodically, multiple measurement could also be required to detect a signifi cantly elevated degree. Even gentle elevations in a postmeno pausal girl are highly suspicious for an androgen secreting tumor. The clinician ought to question whether an ovarian or adrenal tumor detected by imaging is the precise supply of androgen excess earlier than resorting to its surgical resection. The analysis and prevalence of nonclassic adrenal hyperplasia proceed to be debated, although the dysfunction clearly exists. Other phrases which were used to describe this syndrome embrace lateonset, adultonset, attenuated, incomplete, and cryptic adrenal hyperplasia. This form of adrenal hyperplasia is caused by a partial deficiency in 21hydroxylase activity. The prevalence of this disorder varies in accordance with ethnic background, and the prevalence reported by different investigators has varied broadly. The characteristic presentation consists of anovulatory uterine bleeding and progressive hirsutism of pubertal onset.

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Genetic counseling consultation must be thought of earlier than genetic testing is carried out. Genotype-phenotype correlations may be used to divide sufferers into two groups: type 1 and type 2. CarneyTriadorSyndrome the Carney triad (gastrointestinal stromal tumor, pulmonary chondroma, and catecholamine-secreting paraganglioma; less frequent neoplasms include esophageal leiomyoma and adrenal adenoma) is one other syndrome related to catecholamine-secreting tumors. Additional features of the Carney triad include esophageal leiomyomas and adrenocortical adenomas. The adrenocortical adenomas may be nonfunctioning or might secrete cortisol autonomously. Cluster 2 tumors are often adrenal pheochromocytomas with an adrenergic biochemical phenotype. Cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype (see Table 16-4). An asymptomatic individual at risk for illness on the basis of household history of pheochromocytoma/ paraganglioma should have genetic testing provided that an affected member of the family has a known mutation. Genetic testing can be complicated, and testing of one family member has implications for related people. Genetic counseling is beneficial to help households perceive the implications of genetic take a look at results, to coordinate testing of at-risk people, and to assist households work by way of the psychosocial issues which will come up before, throughout, or after the testing process. The clinician may obtain a list of clinically accredited molecular genetic diagnostic laboratories. Prospective studies to guide the clinician within the frequency, age to begin, and type of testing are missing. Because paragangliomas may be nonfunctioning or may be detected earlier than catecholamine-secretory autonomy is evident, periodic imaging research are advised. In addition, as new tumor associations are identified, extra surveillance testing will be indicated. Diagnostic Investigation DifferentialDiagnosis Numerous problems may cause indicators and signs that will immediate the clinician to check for pheochromocytoma (see Table 16-3). In addition, levels of fractionated catecholamines and metanephrines may be elevated in a number of clinical eventualities, including withdrawal from drugs or medication. At Mayo Clinic, the most dependable case-detection technique is measurement of fractionated metanephrines and catecholamines in a 24-hour urine assortment (sensitivity, 98%; specificity, 98%). The index of suspicion for pheochromocytoma ought to be excessive within the following eventualities: resistant hypertension; spells with related pallor; a household historical past of pheochromocytoma; a genetic syndrome that predisposes to pheochromocytoma. The diagnostic cutoffs for many 24-hour urinary fractionated metanephrine assays are primarily based on normal ranges derived from normotensive volunteer reference teams, and this may end up in extreme false-positive take a look at outcomes. Tricyclic antidepressants are the drugs that interfere most incessantly with the interpretation of 24-hour urinary catecholamines and metabolites. To effectively display screen for catecholaminesecreting tumors, remedy with tricyclic antidepressants and other psychoactive brokers listed in Table 16-5 should be tapered and discontinued no less than 2 weeks earlier than any hormonal assessments. Furthermore, catecholamine secretion could additionally be appropriately elevated in situations of physical stress or illness. Therefore, the medical circumstances beneath which catecholamines and metanephrines are measured should be assessed in every case. The excessive false-positive rate for plasma fractionated catecholamines and fractionated metanephrines triggered the development of a confirmatory check, the clonidine suppression check. Because of advances in the methodology for measuring catecholamines and metanephrines, phentolamine, glucagon, histamine, metoclopramide, and tyramine checks are rarely needed. From 1975 to 1994 at Mayo Clinic, we carried out histamine and glucagon stimulation testing in 542 patients in whom pheochromocytoma was extremely suspected regardless of normal 24-hour urinary excretion of complete metanephrines or catecholamines; not one affected person had a positive stimulation check in this setting. Measurements of urinary catecholamines and metabolites could also be invalid if the patient has superior renal insufficiency. The findings of 1 examine instructed that plasma concentrations of fractionated metanephrines are elevated roughly twofold in sufferers with renal failure and may be useful in the biochemical evaluation of patients with marked renal insufficiency or renal failure. As with other similar problems, factitious pheochromocytoma could be very difficult to confirm. The patient may "spike" the 24-hour urine container, or the catecholamines may be administered systemically. The most common places of catecholamine-secreting paragangliomas include superior abdominal para-aortic region, 46%; inferior stomach para-aortic area, 29%; urinary bladder, 10%; mediastinum, 10%; head and neck, 3%; and pelvis, 2%.

References

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