Endocrinopathy in POEMS Syndrome: The Mayo Clinic Experience

ORIGINAL ARTICLE ENDOCRINOPATHY IN POEMS SYNDROME

Endocrinopathy in POEMS Syndrome: The Mayo Clinic Experience GUNJAN Y. GANDHI, MD, MSC; RITA BASU, MD; ANGELA DISPENZIERI, MD; ANANDA BASU, MD; VICTOR M. MONTORI, MD, MSC; AND MICHAEL D. BRENNAN, MD

OBJECTIVE: To determine the prevalence and characteristics of endocrinopathies at diagnosis of POEMS (p olyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. PATIENTS AND METHODS: From January 1, 1960, through June 30, 2006, we identified 170 patients with POEMS syndrome in the Mayo Clinic dysproteinemia database. We abstracted information about endocrine abnormalities from their medical records. RESULTS: Of the 170 patients with POEMS syndrome during the entire study period, the 64 patients seen after 2000 had more complete endocrine evaluations; of these 64 patients, 54 (84%) had a recognized endocrinopathy (38 men; median age, 50 years; interquartile range, 43-59 years). Hypogonadism was the most common endocrine abnormality; 26 (79%) of 33 men had subnormal total testosterone levels, and 10 men had gynecomastia. Among the 35 patients with measured prolactin levels, 7 men and 3 women had elevated levels. Hypothyroidism was noted in 17 men and 11 women. Abnormalities in glucose metabolism were present in 24 (48%) of 50 patients; 16 patients had impaired fasting glucose levels, and 8 were diagnosed as having diabetes. Adrenal insufficiency (defined by an abnormal response of cortisol to stimulation with standard high-dose [250 µg] synthetic adrenocorticotropic hormone) was noted in 6 of 9 patients tested. Fourteen (27%) of 51 patients tested had hypocalcemia. Twentynine (54%) of 54 patients had evidence of multiple endocrinopathies in the 4 major endocrine axes (gonadal, thyroid, glucose, and adrenal). CONCLUSION: The high prevalence of endocrinopathy in our study, to our knowledge the largest published series of POEMS cases, calls for a thorough endocrine investigation in patients presenting with this syndrome.

Mayo Clin Proc. 2007;82(7):836-842 ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; PTH = parathyroid hormone; VEGF = vascular endothelial growth factor

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n 1980, Bardwick et al1 coined the acronym POEMS to represent a rare multisystem syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Two major criteria and at least 1 minor criterion should be satisfied to differentiate this syndrome from neuropathy associated with monoclonal gammopathy of undetermined significance, myeloma, primary systemic amyloidosis, and Waldenström disease. The major criteria include polyneuropathy and a clonal plasma proliferative disorder (almost always λ). The minor criteria include osteosclerotic bone lesions; Castleman disease; papilledema; organomegaly, including lymphadenopathy; 836

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edema, pleural effusion, or ascites; endocrinopathy; and skin changes.2 Individual patients may have some or all of the features at the time of diagnosis or during follow-up. Syndrome synonyms include osteosclerotic myeloma, Crow-Fukase syndrome, Takatsuki syndrome, or plasma cell dyscrasia, endocrinopathy, and polyneuropathy.3,4 Although a detailed understanding of the pathogenesis is lacking, increased levels of cytokines, particularly vascular endothelial growth factor (VEGF), are a common finding and may play an important role in the disorder.5-7 Vascular endothelial growth factor is a growth factor for endothelial cells that induces an increase in vascular permeability, is important in angiogenesis, and often decreases with successful therapy.8-11 Peripheral neuropathy is the dominant and frequently the presenting symptom. Because the characteristics of the neuropathy are similar to those of chronic inflammatory demyelinating polyneuropathy, patients are frequently misdiagnosed as having chronic inflammatory demyelinating polyneuropathy or monoclonal gammopathy of undetermined significance–associated peripheral neuropathy. Not until additional features of the POEMS syndrome are recognized is the correct diagnosis made and effective therapies initiated. Endocrinopathy is a central feature of POEMS syndrome. Several hormonal disorders have been described, including hypogonadism, diabetes mellitus, hypothyroidism, hyperprolactinemia, adrenal insufficiency, gynecomastia in men, breast engorgement in women, hyperestrogenemia, and hypoparathyroidism.1-3,12-14 The cause of endocrinopathies is unknown. Circulating antibodies directed against hormones or specific hormone receptors have not been found.1 At autopsy, endocrine glands appear From the Division of Endocrinology, Diabetes, Metabolism, and Nutrition (G.Y.G., R.B., A.B., V.M.M., M.D.B.), Knowledge and Encounter Research Unit (G.Y.G., V.M.M.), and Division of Hematology (A.D.), Mayo Clinic, Rochester, Minn. Data were presented in part at the Endocrine Society’s 86th Annual Meeting; New Orleans, La; June 16-10, 2004; and at the Endocrine Society’s 89th Annual Meeting; Toronto, Ontario; June 2-5, 2007. Individual reprints of this article are not available. Address correspondence to Gunjan Y. Gandhi, MD, MSc, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (email: [email protected]). © 2007 Mayo Foundation for Medical Education and Research

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ENDOCRINOPATHY IN POEMS SYNDROME

structurally normal and without defining characteristics.15 Therefore, it seems likely that the endocrine abnormalities reflect a functional rather than structural disturbance of gland function. Most of the information regarding endocrinopathies in POEMS syndrome is from isolated case reports or small case series that have not systematically studied the various endocrine manifestations in this disorder. To take advantage of our institution’s experience with a large series of patients, we sought to determine the prevalence and characteristics of endocrinopathies at diagnosis of POEMS syndrome to further our understanding of this enigmatic disorder.

TABLE 1. Criteria for Diagnosis of POEMS Syndrome2* Criteria type Major Minor

Known associations

PATIENTS AND METHODS All patients with POEMS syndrome who met minimal criteria for inclusion in the study were identified through the Mayo Clinic dysproteinemia database.2 From January 1, 1960, through June 30, 2006, 170 patients (115 previously described2,16) met both major criteria and 1 minor criterion for the diagnosis of POEMS syndrome (Table 1). Because of the high prevalence of diabetes mellitus and thyroid abnormalities, these diagnoses alone were not sufficient to meet the minor criterion. Using a standardized data extraction form, we abstracted information from the medical records of these patients regarding their endocrine abnormalities at the time of diagnosis of POEMS syndrome. Diabetes mellitus and hypothyroidism were not attributed to POEMS syndrome unless these reportedly occurred months to years after the onset of at least another feature of POEMS syndrome. As we conducted our investigation, we noticed a difference in the extent of endocrine evaluation over time. Patients seen before 2000 had few endocrine tests, particularly when they had no endocrine-related symptoms. Conversely, patients seen in 2000 or later had a more complete endocrine evaluation. Thus, we decided to focus our results on the subset of patients seen in 2000 or later. The Mayo Foundation Institutional Review Board approved the study in accordance with Minnesota state law that regulates research from medical records. RESULTS Of the 170 patients with POEMS syndrome, 106 were treated before 2000, and 64 were treated in 2000 or later (Table 2). A total of 118 patients (69%; 95% confidence interval, 62%-76%) had a recognized endocrinopathy (89 men; median age, 54 years, interquartile range, 47-63 years). Fifty-four (84%) of the 64 patients treated in 2000 or later (95% confidence interval, 73%-92%) had a recogMayo Clin Proc.

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Possible associations

Description Polyneuropathy Monoclonal plasma proliferative disorder Sclerotic bone lesions† Castleman disease† Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy Edema (pleural effusion or ascites) Endocrinopathy (adrenal, thyroid,‡ pituitary, gonadal, parathyroid, pancreatic‡) Skin changes (hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails) Papilledema Clubbing Weight loss Thrombocytosis Polycythemia Hyperhidrosis Pulmonary hypertension Restrictive lung disease Thrombotic diatheses Arthralgias Cardiomyopathy (systolic dysfunction) Fever Low vitamin B12 values Diarrhea

*Two major criteria and at least 1 minor criterion are required for diagnosis. POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. †Osteosclerotic disease or Castleman disease is usually present. ‡Because of the high prevalence of diabetes mellitus and thyroid abnormalities, these diagnoses alone are not sufficient to meet this minor criterion. From Blood,2 with permission.

nized endocrinopathy (median age, 50 years; interquartile range, 43-59 years; 38 men). GONADAL AXIS Hypogonadism was the most common endocrine abnormality. Thirty-three (87%) of 38 men had testosterone levels measured; 26 (79%) had levels below the lower limit of the normal range for total testosterone. Twenty-five (96%) of these 26 patients had estimation of free testosterone levels performed as well, which showed low levels in all cases. Twenty-three (61%) of 38 men reported erectile dysfunction. In 23 men with available data, 7 (30%) had evidence of primary hypogonadism, whereas 16 (70%) had secondary hypogonadism. Ten men (43%) had gynecomastia, of whom only 1 had elevated estrogen levels (of the 4 men in whom estrogen levels were measured). PROLACTIN AXIS Among the 35 patients with measured prolactin levels, 10 (29%; 7 men and 3 women) had levels higher than the upper limit of the normal range. In most cases, prolactin concentrations were noted to be mildly elevated. Two women had irregular menses, 1 of whom also had galactorrhea.

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TABLE 2. Endocrine Abnormalities in the Recent Cohort (2000-2006)*† No. (%) of patients (N=64)

Characteristic Patients with endocrinopathy M/F Median age (y) (IQR) Race White Hispanic African American Mean body mass index (SD) Erectile dysfunction Hypogonadism (men) Gynecomastia (men) Hyperprolactinemia Hypothyroidism Glucose intolerance Adrenal insufficiency Hypocalcemia Evidence of multiple endocrine abnormalities

54 (84) 38/16 50 (43-59) 48 5 1 25 (4) 23/38 (61) 26/33 (79) 10/38 (26) 10/35 (29) 28/48 (58) 24/50 (48) 6/9 (67) 14/51 (27) 29/54 (54)

*Data are number (percentage) of patients unless otherwise indicated. IQR = interquartile range. †Reference ranges for plasma, serum, or blood concentrations are as follows: thyrotropin, 0.3 to 5.0 mIU/L; free thyroxine, 0.8 to 1.8 ng/dL; fasting glucose, 70 to 100 mg/dL; calcium, 8.9 to 10.1 mg/dL; phosphorus, 2.5 to 4.5 mg/dL; morning cortisol, 7 to 25 µg/dL; adrenocorticotropic hormone, 10 to 60 pg/mL; total testosterone, 240 to 950 ng/dL; free testosterone, 9 to 30 ng/dL; and prolactin, 4 to 23 ng/mL for males and 4 to 30 ng/mL for females.

THYROID AXIS Elevated thyrotropin concentrations were noted in 28 (58%) of 48 patients (17 men and 11 women). Half of these patients (14/28) had mild increases in thyrotropin levels (>5 but 95% of cases) is suggestive of a key role in the pathogenesis, histopathologic review of affected organs and nerves does not support that it is a form of deposition disorder.3,17 Antibodies to human herpesvirus were reported in 78% of patients who have POEMS syndrome with Castleman disease and 22% of those with POEMS syndrome without Castleman disease.18 No circulating antibodies against hormones or hormone receptors seem to be present.1,12 No characteristic findings are seen in endocrine organ studies at autopsy.15 Considerable interest has been demonstrated in the role of cytokines (chiefly interleukin 1β, interleukin 6, and tumor necrosis factor α) as mediators of POEMS syndrome.5,19 The site of activation of the cytokine network is not yet known, but macrophages, not T cells, are assumed to be activated. Compared with patients with multiple myeloma, patients with POEMS syndrome had higher serum levels of proinflammatory cytokines (interleukin 1β, tumor necrosis factor α, and interleukin 6) and lower levels of an antagonistic cytokine (transforming growth factor β1), suggesting a loss of balance between proinflammatory and anti-inflammatory cytokines.5 Vascular endothelial growth factor is the leading candidate as a pathogenic factor in POEMS syndrome and often decreases with successful treatment.8-10 Also, VEGF plays a critical role in angiogenesis.11 One might hypothesize that overexpression of VEGF in POEMS syndrome might affect several of the endocrine axes because of a disruption of the local balance of angiogenic factors that appears to be important in the regulation of hormone secretion in many endocrine glands. Because dopamine agonists disrupt VEGF signaling, these Mayo Clin Proc.

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agents might have a role in the treatment of the endocrine manifestations of POEMS syndrome.11 Interestingly, prolactin levels were elevated in several of our patients. Thus, VEGF could potentially account for organomegaly, skin lesions, edema, and possibly polyneuropathy and endocrinopathies in POEMS syndrome. Many of the endocrine abnormalities seen in patients with POEMS syndrome could be due to chronic illness or illnesses commonly observed in this age population. Unfortunately, no studies have assessed endocrinopathies in patients with POEMS syndrome compared with an ageand sex-matched population or patients with chronic disease. Although previous studies have compared cytokines5 and VEGF8 levels in patients with POEMS syndrome to other causes of polyneuropathy (multiple myeloma, chronic inflammatory demyelinating polyneuropathy), they did not specifically report on endocrine laboratory or clinical abnormalities. As indicated in Table 4, the prevalence of hypogonadism, diabetes, and hypothyroidism is significantly greater in patients with POEMS syndrome compared with population-based longitudinal cohorts.20-22 HYPOGONADISM We confirmed the high prevalence of hypogonadism in patients with POEMS syndrome.2,3,12 Hypogonadism was secondary (hypogonadotropic hypogonadism) in most cases. In comparison, Soubrier et al12 reported an equal incidence of primary (hypergonadotropic hypogonadism) (5/9) and secondary (4/9) hypogonadism in these patients. In our series, a significant proportion of men who did not report erectile dysfunction had low testosterone levels. We also noted gynecomastia in men and irregular menses in women, which others have described.1,3,12

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TABLE 4. Prevalence of Common Endocrine Disorders in the General Population Compared With POEMS Syndrome20-22* Prevalence (%) General population Endocrine disorder Hypogonadism Diabetes (diagnosed) Impaired fasting glucose Hypothyroidism (clinical plus subclinical)

Overall

Men

Women

Patients with POEMS syndrome

6.6 (40-59 y) 29.9

12 (50-59 y) 7.5 (40-59 y) 37.2

5.7 (40-59 y) 22.9

79 16 32

4.6

58

*POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.

Although estrogen was not routinely checked in our patients, other investigators have proposed hyperestrogenemia as a unifying hypothesis for endocrinopathy.23 In those patients, an accelerated conversion of androgens into estrogens was found. Increased estrogen could potentially also cause hyperprolactinemia either directly or by modifying the estrogen-testosterone ratio.24 The cause of hyperprolactinemia remains unclear. An increased intracranial pressure in patients with POEMS syndrome may result in disturbed hypothalamic function, loss of inhibitory dopaminergic pathways, and hyperprolacteinemia.1 Although hyperprolactinemia may cause hypogonadism, normalization of prolactin with bromocriptine had no effect on androgen and gonadotropin levels.1 Treatment of hypothyroidism when present did not resolve the hyperprolactinemia. Also, 2 eugonadal men with POEMS syndrome were noted to have primary follicle-stimulating hormone (FSH) hypersecretion, suggesting that primary FSH hypersecretion in the absence of primary testicular failure should be added to the list of endocrinopathies of POEMS syndrome.25 An isolated elevation of FSH levels with normal levels of FSH and testosterone can also occur in Sertoli cell–only syndrome, which has a wide variety of causes, including antineoplastic therapy with radiation and chemotherapy. It is not routine practice at our institution to obtain fertility data, perform sperm analyses, or consider cryopreservation of sperm before chemotherapy or radiotherapy in these patients. GLUCOSE ABNORMALITIES An abnormality in glucose metabolism was a common endocrine manifestation in our series, a finding that is consistent with previously reported large series.2,3,12 Most patients have impaired fasting glucose levels and need lifestyle interventions. Patients with diabetes tend to have modest insulin requirements.1 Antibodies to pancreatic islet cells were not demonstrated in 2 patients with POEMS syndrome.1 Potential confounders to the high incidence of glucose abnormalities to remember are the increased fre840

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quency of impaired fasting glucose levels and diabetes mellitus in the general population, the number of patients with POEMS syndrome taking corticosteroids at diagnosis, and stress hyperglycemia from severe illness. We established a clear temporal relationship between glucose intolerance and POEMS syndrome and ruled out corticosteroid use at the time of testing in our series of patients. HYPOTHYROIDISM After carefully establishing that at least 1 of the features of POEMS syndrome preceded hypothyroidism months to years after the onset of hypothyroidism, we noted that a significant proportion of patients had hypothyroidism. Most patients had mild primary hypothyroidism, which is consistent with other reports.1,2,12,13,26,27 Interestingly, Soubrier et al described secondary (central) hypothyroidism in 2 of 10 patients with hypothyroidism in their series of 25 patients. Although the cause remains elusive, specific antibody-binding activity directed against pituitary tissue was demonstrated in a patient with POEMS syndrome and hypothyroidism.28 However, the thyrotropin levels were high. Thyroid microsomal antibodies or thyroglobulin antibodies have not been found.1 ADRENAL INSUFFICIENCY Adrenal insufficiency has been described infrequently in patients with POEMS syndrome.2,14,26 We noted an abnormal ACTH stimulation test result in most of those tested. However, data are insufficient to comment on whether this was primary or secondary adrenal insufficiency. Previous case reports describing adrenal insufficiency in this disorder have noted it to be a primary adrenal disorder,14,26 but none measured adrenal autoantibodies. Bardwick et al1 did not detect circulating inhibitors of ACTH in the serum of the 2 patients described. The isolated elevation in ACTH levels with a normal cortisol level (seen in 7 of 13 patients) could indicate “compensated” cortisol levels; the fact that we saw this in more than half the patients tested (7/13) indicates that this is unlikely to be attributable to assay or biological variability.

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CALCIUM ABNORMALITIES Although experts have not associated calcium abnormalities to POEMS syndrome, we noted that approximately one third of patients in our series had low calcium levels. Although parathyroid function was not routinely measured in these patients, no evidence was available of primary hypoparathyroidism in those cases in which PTH levels were measured. To our knowledge, there has been only 1 report of established primary hypoparathyroidism (low calcium, high phosphate, and undetectable PTH levels) in association with vitamin D deficiency.13 Another case report described a patient with hypocalcemia, hyperphosphatemia, low-normal vitamin D levels, and an inappropriately normal PTH level, suggestive of an abnormal parathyroid response.26 Routine measurement of calcium and phosphate levels and, if abnormal, measurement of PTH, creatinine, and vitamin D levels may be prudent. Interestingly, Nakanishi et al3 reported hypercalcemia in 7 of 23 patients, although it is unclear if this was accurate because none had a serum calcium level greater than 10 mg/dL. The elevated phosphate levels in our patients suggest impaired renal function or increased bone loss of calcium and phosphate as possible mechanisms. STUDY LIMITATIONS Overall, the prevalence of endocrinopathy in our series is likely an underestimate because most patients, especially those seen before the turn of the century, had incomplete endocrine evaluations. To enable us to gain a better understanding of asymptomatic endocrine laboratory changes seen early in the disease, we separately studied and describe patients seen in the last 6 years, who appear to be better characterized. This was a retrospective medical record review with all its inherent biases. Thus, no standardized means were available for ensuring when and what laboratory tests were performed and if they were necessarily repeated to confirm an abnormal test result. Cortisol, testosterone, glucose, and prolactin samples were in most cases obtained in the early morning. Because this is an extremely rare disorder, a retrospective review has been the preferred method of study until now. Most of the patients seen at our institution were white. This is an extension of the first large North American patient population reported,2 but with an emphasis on endocrine findings. We have no follow-up information regarding progression of endocrine abnormalities or new development of endocrine disorders. However, in the future, we plan to develop a systematic method to track and obtain follow-up information on these patients. Although we believe that this report is helpful in guiding the evaluation today, future knowledge about the natural history of endocrinopathies in POEMS syndrome may be particularly helpful to the frontline cliniMayo Clin Proc.

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TABLE 5. Suggested Endocrine Review of Systems and Laboratory Tests During Initial Evaluation of POEMS Syndrome* Endocrine axis Thyroid

Glucose metabolism

Gonadal

Prolactin

Adrenal

Calcium regulation

Review of systems

Initial laboratory tests

Change in energy level Skin and hair changes Menstrual irregularities Heat or cold intolerance Change in bowel habits Weight change Mood changes Polyuria Polydipsia Polyphagia Weight change Change in libido Erectile dysfunction Menstrual irregularities

Thyrotropin, free thyroxine

Gynecomastia Galactorrhea Breast engorgement Menstrual irregularities Headaches Visual changes Weight change Change in energy level Skin color changes Salt craving Muscle aches Paresthesias Muscle cramps

Fasting glucose (early morning)

Total and bioavailable testosterone (early morning), FSH, luteinizing hormone, estradiol (in women) Prolactin (early morning)

Cortisol, ACTH (early morning)

Calcium

*ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.

cian following up these patients over time, especially after treatment. SUGGESTED APPROACH TO EVALUATING ENDOCRINOPATHIES IN POEMS SYNDROME We suggest that all patients with POEMS syndrome have a thorough and systematic endocrine evaluation at diagnosis of this syndrome. Clinicians should complete an endocrine review of systems during the initial evaluation and obtain total and bioavailable testosterone, prolactin, fasting glucose, cortisol and ACTH specimens (all early morning) and thyrotropin and calcium specimens (Table 5). An endocrinologist should see patients with concerns or abnormal levels for further assessment and treatment. FUTURE DIRECTIONS To gain a better understanding of the pathogenesis of endocrinopathies in POEMS syndrome, researchers should focus on studies that assess the role of cytokines and VEGF, especially related to endocrine dysfunction. Whether endocrine disorders associated with POEMS syndrome improve

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after successful treatment of the disease is unknown. Follow-up studies to better understand the evolution of endocrine disorders in these patients are needed. CONCLUSION The high prevalence of endocrinopathies in our study, to our knowledge the largest published series of POEMS cases, calls for a thorough endocrine investigation in patients who present with this syndrome and vigilance in monitoring for treatable hormonal disorders that may emerge during the disease. We are grateful to Rebecca Bahn, MD, for contributing to our reporting of the potential association between VEGF overexpression and endocrine manifestations in patients with POEMS syndrome.

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