Endocrinopathy in POEMS Syndrome: The Mayo Clinic Experience

 
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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               edema, pleural effusion, or ascites; endocrinopathy; and
endocrinopathies at diagnosis of POEMS (p olyneuropathy,
organomegaly, endocrinopathy, M protein, and skin changes)                  skin changes.2 Individual patients may have some or all of
syndrome.                                                                   the features at the time of diagnosis or during follow-up.
PATIENTS AND METHODS: From January 1, 1960, through June 30,                Syndrome synonyms include osteosclerotic myeloma,
2006, we identified 170 patients with POEMS syndrome in the                 Crow-Fukase syndrome, Takatsuki syndrome, or plasma
Mayo Clinic dysproteinemia database. We abstracted information              cell dyscrasia, endocrinopathy, and polyneuropathy.3,4
about endocrine abnormalities from their medical records.
                                                                                Although a detailed understanding of the pathogenesis
RESULTS: Of the 170 patients with POEMS syndrome during the                 is lacking, increased levels of cytokines, particularly vas-
entire study period, the 64 patients seen after 2000 had more
complete endocrine evaluations; of these 64 patients, 54 (84%)              cular endothelial growth factor (VEGF), are a common
had a recognized endocrinopathy (38 men; median age, 50 years;              finding and may play an important role in the disorder.5-7
interquartile range, 43-59 years). Hypogonadism was the most                Vascular endothelial growth factor is a growth factor for
common endocrine abnormality; 26 (79%) of 33 men had subnor-
mal total testosterone levels, and 10 men had gynecomastia.                 endothelial cells that induces an increase in vascular per-
Among the 35 patients with measured prolactin levels, 7 men and             meability, is important in angiogenesis, and often de-
3 women had elevated levels. Hypothyroidism was noted in 17                 creases with successful therapy.8-11
men and 11 women. Abnormalities in glucose metabolism were
present in 24 (48%) of 50 patients; 16 patients had impaired                    Peripheral neuropathy is the dominant and frequently
fasting glucose levels, and 8 were diagnosed as having diabetes.            the presenting symptom. Because the characteristics of the
Adrenal insufficiency (defined by an abnormal response of cortisol          neuropathy are similar to those of chronic inflammatory
to stimulation with standard high-dose [250 µg] synthetic adreno-
corticotropic hormone) was noted in 6 of 9 patients tested.                 demyelinating polyneuropathy, patients are frequently
Fourteen (27%) of 51 patients tested had hypocalcemia. Twenty-              misdiagnosed as having chronic inflammatory demyelinat-
nine (54%) of 54 patients had evidence of multiple endocrinopa-             ing polyneuropathy or monoclonal gammopathy of unde-
thies in the 4 major endocrine axes (gonadal, thyroid, glucose,
and adrenal).                                                               termined significance–associated peripheral neuropathy.
CONCLUSION: The high prevalence of endocrinopathy in our study,
                                                                            Not until additional features of the POEMS syndrome are
to our knowledge the largest published series of POEMS cases,               recognized is the correct diagnosis made and effective
calls for a thorough endocrine investigation in patients presenting         therapies initiated.
with this syndrome.
                                                                                Endocrinopathy is a central feature of POEMS syn-
              Mayo Clin Proc. 2007;82(7):836-842                            drome. Several hormonal disorders have been described,
 ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hor-
                                                                            including hypogonadism, diabetes mellitus, hypothyroid-
 mone; POEMS = polyneuropathy, organomegaly, endocrinopathy, M              ism, hyperprolactinemia, adrenal insufficiency, gyneco-
 protein, and skin changes; PTH = parathyroid hormone; VEGF = vascular
 endothelial growth factor
                                                                            mastia in men, breast engorgement in women, hyperes-
                                                                            trogenemia, and hypoparathyroidism.1-3,12-14 The cause of
                                                                            endocrinopathies is unknown. Circulating antibodies di-
                                                                            rected against hormones or specific hormone receptors
I  n 1980, Bardwick et al1 coined the acronym POEMS to
   represent a rare multisystem syndrome characterized by
polyneuropathy, organomegaly, endocrinopathy, M pro-
                                                                            have not been found.1 At autopsy, endocrine glands appear

tein, and skin changes. Two major criteria and at least 1                   From the Division of Endocrinology, Diabetes, Metabolism, and Nutrition (G.Y.G.,
minor criterion should be satisfied to differentiate this syn-              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.
drome from neuropathy associated with monoclonal
                                                                            Data were presented in part at the Endocrine Society’s 86th Annual Meeting;
gammopathy of undetermined significance, myeloma, pri-                      New Orleans, La; June 16-10, 2004; and at the Endocrine Society’s 89th
mary systemic amyloidosis, and Waldenström disease. The                     Annual Meeting; Toronto, Ontario; June 2-5, 2007.
major criteria include polyneuropathy and a clonal plasma                   Individual reprints of this article are not available. Address correspondence to
proliferative disorder (almost always λ). The minor criteria                Gunjan Y. Gandhi, MD, MSc, Division of Endocrinology, Diabetes, Metabo-
                                                                            lism, and Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-
include osteosclerotic bone lesions; Castleman disease;                     mail: gandhi.gunjan@mayo.edu).
papilledema; organomegaly, including lymphadenopathy;                       © 2007 Mayo Foundation for Medical Education and Research

836                           Mayo Clin Proc.     •   July 2007;82(7):836-842   •   www.mayoclinicproceedings.com

      For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
ENDOCRINOPATHY IN POEMS SYNDROME

structurally normal and without defining characteristics.15                     TABLE 1. Criteria for Diagnosis of POEMS Syndrome2*
Therefore, it seems likely that the endocrine abnormalities               Criteria type                           Description
reflect a functional rather than structural disturbance of            Major                   Polyneuropathy
gland function.                                                                               Monoclonal plasma proliferative disorder
   Most of the information regarding endocrinopathies in              Minor                   Sclerotic bone lesions†
POEMS syndrome is from isolated case reports or small                                         Castleman disease†
                                                                                              Organomegaly (splenomegaly, hepatomegaly, or
case series that have not systematically studied the various                                   lymphadenopathy
endocrine manifestations in this disorder. To take advan-                                     Edema (pleural effusion or ascites)
tage of our institution’s experience with a large series                                      Endocrinopathy (adrenal, thyroid,‡ pituitary,
                                                                                               gonadal, parathyroid, pancreatic‡)
of patients, we sought to determine the prevalence and                                        Skin changes (hyperpigmentation, hypertrichosis,
characteristics of endocrinopathies at diagnosis of POEMS                                      plethora, hemangiomata, white nails)
syndrome to further our understanding of this enigmatic                                       Papilledema
disorder.                                                             Known                   Clubbing
                                                                       associations           Weight loss
                                                                                              Thrombocytosis
                                                                                              Polycythemia
               PATIENTS AND METHODS                                                           Hyperhidrosis
All patients with POEMS syndrome who met minimal                      Possible                Pulmonary hypertension
                                                                       associations           Restrictive lung disease
criteria for inclusion in the study were identified through                                   Thrombotic diatheses
the Mayo Clinic dysproteinemia database.2 From January                                        Arthralgias
1, 1960, through June 30, 2006, 170 patients (115 previ-                                      Cardiomyopathy (systolic dysfunction)
                                                                                              Fever
ously described2,16) met both major criteria and 1 minor                                      Low vitamin B12 values
criterion for the diagnosis of POEMS syndrome (Table 1).                                      Diarrhea
Because of the high prevalence of diabetes mellitus and               *Two major criteria and at least 1 minor criterion are required for diagno-
thyroid abnormalities, these diagnoses alone were not suf-             sis. POEMS = polyneuropathy, organomegaly, endocrinopathy, M pro-
ficient to meet the minor criterion. Using a standardized              tein, skin changes.
                                                                      †Osteosclerotic disease or Castleman disease is usually present.
data extraction form, we abstracted information from the              ‡Because of the high prevalence of diabetes mellitus and thyroid abnormali-
medical records of these patients regarding their endocrine            ties, these diagnoses alone are not sufficient to meet this minor criterion.
abnormalities at the time of diagnosis of POEMS syn-                  From Blood,2 with permission.
drome. Diabetes mellitus and hypothyroidism were not
attributed to POEMS syndrome unless these reportedly                  nized endocrinopathy (median age, 50 years; interquartile
occurred months to years after the onset of at least another          range, 43-59 years; 38 men).
feature of POEMS syndrome.
    As we conducted our investigation, we noticed a dif-              GONADAL AXIS
ference in the extent of endocrine evaluation over time.              Hypogonadism was the most common endocrine abnor-
Patients seen before 2000 had few endocrine tests, particu-           mality. Thirty-three (87%) of 38 men had testosterone
larly when they had no endocrine-related symptoms. Con-               levels measured; 26 (79%) had levels below the lower limit
versely, patients seen in 2000 or later had a more complete           of the normal range for total testosterone. Twenty-five
endocrine evaluation. Thus, we decided to focus our results           (96%) of these 26 patients had estimation of free testoster-
on the subset of patients seen in 2000 or later. The Mayo             one levels performed as well, which showed low levels in
Foundation Institutional Review Board approved the study              all cases. Twenty-three (61%) of 38 men reported erectile
in accordance with Minnesota state law that regulates re-             dysfunction. In 23 men with available data, 7 (30%) had
search from medical records.                                          evidence of primary hypogonadism, whereas 16 (70%) had
                                                                      secondary hypogonadism. Ten men (43%) had gynecomas-
                                                                      tia, of whom only 1 had elevated estrogen levels (of the 4
                        RESULTS
                                                                      men in whom estrogen levels were measured).
Of the 170 patients with POEMS syndrome, 106 were
treated before 2000, and 64 were treated in 2000 or later             PROLACTIN AXIS
(Table 2). A total of 118 patients (69%; 95% confidence               Among the 35 patients with measured prolactin levels, 10
interval, 62%-76%) had a recognized endocrinopathy (89                (29%; 7 men and 3 women) had levels higher than the upper
men; median age, 54 years, interquartile range, 47-63                 limit of the normal range. In most cases, prolactin concentra-
years). Fifty-four (84%) of the 64 patients treated in 2000           tions were noted to be mildly elevated. Two women had
or later (95% confidence interval, 73%-92%) had a recog-              irregular menses, 1 of whom also had galactorrhea.

                          Mayo Clin Proc.   •   July 2007;82(7):836-842     •    www.mayoclinicproceedings.com                                837

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ENDOCRINOPATHY IN POEMS SYNDROME

      TABLE 2. Endocrine Abnormalities in the Recent Cohort                     low albumin, 14 (27%) of 51 patients had true hypocalce-
                         (2000-2006)*†
                                                                                mia. Parathyroid gland dysfunction was not routinely
                                                        No. (%) of patients     determined. Of those with low calcium levels, 2 of 6 pa-
                Characteristic                                (N=64)
                                                                                tients tested had high parathyroid hormone (PTH) levels
Patients with endocrinopathy                                 54 (84)            suggestive of secondary hyperparathyroidism. Two pa-
M/F                                                           38/16
Median age (y) (IQR)                                        50 (43-59)          tients with measured calcium levels had hypercalcemia,
Race                                                                            neither of whom had PTH levels measured. Phosphorus
    White                                                       48              levels were elevated in 12 (36%) of 33 patients. One of
    Hispanic                                                     5
    African American                                             1              the 64 patients had a low PTH level with a normal calcium
Mean body mass index (SD)                                      25 (4)           concentration.
Erectile dysfunction                                        23/38 (61)
Hypogonadism (men)                                          26/33 (79)
Gynecomastia (men)                                          10/38 (26)          MULTIPLE AXES
Hyperprolactinemia                                          10/35 (29)          Twenty-nine (54%) of 54 patients had evidence of multiple
Hypothyroidism                                              28/48 (58)          endocrinopathies in the 4 major endocrine axes (gonadal,
Glucose intolerance                                         24/50 (48)
Adrenal insufficiency                                         6/9 (67)          thyroid, glucose, and adrenal).
Hypocalcemia                                                14/51 (27)
Evidence of multiple endocrine abnormalities                29/54 (54)
                                                                                                         DISCUSSION
*Data are number (percentage) of patients unless otherwise indicated.
 IQR = interquartile range.                                                     KEY FINDINGS
†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;      Our series of patients with POEMS syndrome, to our
 fasting glucose, 70 to 100 mg/dL; calcium, 8.9 to 10.1 mg/dL; phospho-         knowledge the largest reported in the literature, confirms
 rus, 2.5 to 4.5 mg/dL; morning cortisol, 7 to 25 µg/dL; adrenocorticotro-      that endocrinopathy is a central feature of this disorder.
 pic 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      Hypogonadism in men is the most common endocrine ab-
 to 30 ng/mL for females.                                                       normality, whereas hypothyroidism and abnormalities of
                                                                                glucose metabolism were frequently noted at the time of
THYROID AXIS                                                                    diagnosis of POEMS syndrome. Of interest is the isolated
Elevated thyrotropin concentrations were noted in 28                            elevation of ACTH levels noted in these patients (pre-
(58%) of 48 patients (17 men and 11 women). Half of these                       sumed to be responsible for skin hyperpigmentation, but a
patients (14/28) had mild increases in thyrotropin levels                       clear correlation could not be established from these data).
(>5 but
ENDOCRINOPATHY IN POEMS SYNDROME

                     TABLE 3. Clinical Characteristics of Our Study Patients Compared With 2 Previous Series*
                                                                    Recent cohort
                                                                    (2000-2006)           Nakanishi et al3   Soubrier et al12
                               Characteristic                         (N=64)                 (N=102)            (N=25)
                Patients with endocrinopathy                           54 (84)                  NR                NR
                M/F                                                     38/16                  69/33              17/8
                Median or mean age (y) (IQR)                     50 (median) (43-59)         46 (mean)         51 (mean)
                Race                                                                                              NR
                    White                                                48
                    Hispanic                                              5
                    African American                                      1
                    Japanese                                                                    102
                Erectile dysfunction                                   23/38                   39/50                13/13
                Gynecomastia                                      10/38 (men only)             43/63                10/13
                Hyperprolactinemia                                     10/35                    NR                   4/17
                Hypothyroidism                                         28/48                    NR                  10/22
                Glucose intolerance                                    24/50                   26/93                 9/22
                Adrenal insufficiency                                    6/9                    NR                   NR
                Evidence of multiple endocrine abnormalities           29/54                    NR                   NR
                *Data are number (percentage) of patients unless otherwise indicated. IQR = interquartile range; NR = not
                 reported.
                Adapted from Blood,2 with permission.

CAUSE OF ENDOCRINOPATHIES                                                 agents might have a role in the treatment of the endocrine
The cause of POEMS syndrome is unknown. Although the                      manifestations of POEMS syndrome.11 Interestingly, pro-
high prevalence of λ light chains (>95% of cases) is sug-                 lactin levels were elevated in several of our patients. Thus,
gestive of a key role in the pathogenesis, histopathologic                VEGF could potentially account for organomegaly, skin
review of affected organs and nerves does not support that                lesions, edema, and possibly polyneuropathy and endo-
it is a form of deposition disorder.3,17 Antibodies to human              crinopathies in POEMS syndrome.
herpesvirus were reported in 78% of patients who have                         Many of the endocrine abnormalities seen in patients
POEMS syndrome with Castleman disease and 22% of                          with POEMS syndrome could be due to chronic illness or
those with POEMS syndrome without Castleman disease.18                    illnesses commonly observed in this age population. Un-
No circulating antibodies against hormones or hormone                     fortunately, no studies have assessed endocrinopathies in
receptors seem to be present.1,12 No characteristic findings              patients with POEMS syndrome compared with an age-
are seen in endocrine organ studies at autopsy.15                         and sex-matched population or patients with chronic dis-
    Considerable interest has been demonstrated in the role               ease. Although previous studies have compared cytokines5
of cytokines (chiefly interleukin 1β, interleukin 6, and                  and VEGF8 levels in patients with POEMS syndrome to
tumor necrosis factor α) as mediators of POEMS syn-                       other causes of polyneuropathy (multiple myeloma, chron-
drome.5,19 The site of activation of the cytokine network is              ic inflammatory demyelinating polyneuropathy), they did
not yet known, but macrophages, not T cells, are assumed                  not specifically report on endocrine laboratory or clinical
to be activated. Compared with patients with multiple my-                 abnormalities. As indicated in Table 4, the prevalence of
eloma, patients with POEMS syndrome had higher serum                      hypogonadism, diabetes, and hypothyroidism is signifi-
levels of proinflammatory cytokines (interleukin 1β, tumor                cantly greater in patients with POEMS syndrome com-
necrosis factor α, and interleukin 6) and lower levels of an              pared with population-based longitudinal cohorts.20-22
antagonistic cytokine (transforming growth factor β1),
suggesting a loss of balance between proinflammatory and                  HYPOGONADISM
anti-inflammatory cytokines.5 Vascular endothelial growth                 We confirmed the high prevalence of hypogonadism in
factor is the leading candidate as a pathogenic factor in                 patients with POEMS syndrome.2,3,12 Hypogonadism was
POEMS syndrome and often decreases with successful                        secondary (hypogonadotropic hypogonadism) in most
treatment.8-10 Also, VEGF plays a critical role in angiogen-              cases. In comparison, Soubrier et al12 reported an equal
esis.11 One might hypothesize that overexpression of                      incidence of primary (hypergonadotropic hypogonadism)
VEGF in POEMS syndrome might affect several of the                        (5/9) and secondary (4/9) hypogonadism in these patients.
endocrine axes because of a disruption of the local balance               In our series, a significant proportion of men who did not
of angiogenic factors that appears to be important in the                 report erectile dysfunction had low testosterone levels. We
regulation of hormone secretion in many endocrine glands.                 also noted gynecomastia in men and irregular menses in
Because dopamine agonists disrupt VEGF signaling, these                   women, which others have described.1,3,12

                           Mayo Clin Proc.      •   July 2007;82(7):836-842   •     www.mayoclinicproceedings.com                  839

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ENDOCRINOPATHY IN POEMS SYNDROME

                            TABLE 4. Prevalence of Common Endocrine Disorders in the General Population
                                               Compared With POEMS Syndrome20-22*
                                                                                         Prevalence (%)
                                                                        General population
                                                                                                                 Patients with
                        Endocrine disorder                 Overall             Men               Women         POEMS syndrome
                    Hypogonadism                                           12 (50-59 y)                              79
                    Diabetes (diagnosed)                6.6 (40-59 y)      7.5 (40-59 y)       5.7 (40-59 y)         16
                    Impaired fasting glucose                 29.9               37.2                22.9             32
                    Hypothyroidism
                      (clinical plus subclinical)             4.6                                                    58
                    *POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.

    Although estrogen was not routinely checked in our                           quency of impaired fasting glucose levels and diabetes
patients, other investigators have proposed hyperestro-                          mellitus in the general population, the number of patients
genemia as a unifying hypothesis for endocrinopathy.23 In                        with POEMS syndrome taking corticosteroids at diagnosis,
those patients, an accelerated conversion of androgens into                      and stress hyperglycemia from severe illness. We estab-
estrogens was found. Increased estrogen could potentially                        lished a clear temporal relationship between glucose intol-
also cause hyperprolactinemia either directly or by modify-                      erance and POEMS syndrome and ruled out corticosteroid
ing the estrogen-testosterone ratio.24                                           use at the time of testing in our series of patients.
    The cause of hyperprolactinemia remains unclear. An
increased intracranial pressure in patients with POEMS                           HYPOTHYROIDISM
syndrome may result in disturbed hypothalamic function,                          After carefully establishing that at least 1 of the features of
loss of inhibitory dopaminergic pathways, and hyper-                             POEMS syndrome preceded hypothyroidism months to
prolacteinemia.1 Although hyperprolactinemia may cause                           years after the onset of hypothyroidism, we noted that a
hypogonadism, normalization of prolactin with bromo-                             significant proportion of patients had hypothyroidism.
criptine had no effect on androgen and gonadotropin lev-                         Most patients had mild primary hypothyroidism, which
els.1 Treatment of hypothyroidism when present did not                           is consistent with other reports.1,2,12,13,26,27 Interestingly,
resolve the hyperprolactinemia. Also, 2 eugonadal men                            Soubrier et al described secondary (central) hypothyroid-
with POEMS syndrome were noted to have primary fol-                              ism in 2 of 10 patients with hypothyroidism in their series
licle-stimulating hormone (FSH) hypersecretion, suggest-                         of 25 patients. Although the cause remains elusive, specific
ing that primary FSH hypersecretion in the absence of                            antibody-binding activity directed against pituitary tissue
primary testicular failure should be added to the list of                        was demonstrated in a patient with POEMS syndrome and
endocrinopathies of POEMS syndrome.25 An isolated el-                            hypothyroidism.28 However, the thyrotropin levels were
evation of FSH levels with normal levels of FSH and                              high. Thyroid microsomal antibodies or thyroglobulin anti-
testosterone can also occur in Sertoli cell–only syndrome,                       bodies have not been found.1
which has a wide variety of causes, including antineoplas-
tic therapy with radiation and chemotherapy. It is not                           ADRENAL INSUFFICIENCY
routine practice at our institution to obtain fertility data,                    Adrenal insufficiency has been described infrequently in
perform sperm analyses, or consider cryopreservation                             patients with POEMS syndrome.2,14,26 We noted an abnor-
of sperm before chemotherapy or radiotherapy in these                            mal ACTH stimulation test result in most of those tested.
patients.                                                                        However, data are insufficient to comment on whether this
                                                                                 was primary or secondary adrenal insufficiency. Previous
GLUCOSE ABNORMALITIES                                                            case reports describing adrenal insufficiency in this disor-
An abnormality in glucose metabolism was a common                                der have noted it to be a primary adrenal disorder,14,26 but
endocrine manifestation in our series, a finding that is                         none measured adrenal autoantibodies. Bardwick et al1 did
consistent with previously reported large series.2,3,12 Most                     not detect circulating inhibitors of ACTH in the serum of
patients have impaired fasting glucose levels and need                           the 2 patients described. The isolated elevation in ACTH
lifestyle interventions. Patients with diabetes tend to have                     levels with a normal cortisol level (seen in 7 of 13 patients)
modest insulin requirements.1 Antibodies to pancreatic is-                       could indicate “compensated” cortisol levels; the fact that
let cells were not demonstrated in 2 patients with POEMS                         we saw this in more than half the patients tested (7/13)
syndrome.1 Potential confounders to the high incidence of                        indicates that this is unlikely to be attributable to assay or
glucose abnormalities to remember are the increased fre-                         biological variability.

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ENDOCRINOPATHY IN POEMS SYNDROME

CALCIUM ABNORMALITIES                                                         TABLE 5. Suggested Endocrine Review of Systems and
                                                                          Laboratory Tests During Initial Evaluation of POEMS Syndrome*
Although experts have not associated calcium abnormali-
ties to POEMS syndrome, we noted that approximately                       Endocrine
                                                                            axis          Review of systems          Initial laboratory tests
one third of patients in our series had low calcium levels.
Although parathyroid function was not routinely measured              Thyroid           Change in energy level     Thyrotropin, free thyroxine
                                                                                        Skin and hair changes
in these patients, no evidence was available of primary                                 Menstrual irregularities
hypoparathyroidism in those cases in which PTH levels                                   Heat or cold intolerance
were measured. To our knowledge, there has been only 1                                  Change in bowel habits
                                                                                        Weight change
report of established primary hypoparathyroidism (low                                   Mood changes
calcium, high phosphate, and undetectable PTH levels)                 Glucose           Polyuria                   Fasting glucose (early
in association with vitamin D deficiency.13 Another case               metabolism       Polydipsia                  morning)
report described a patient with hypocalcemia, hyperphos-                                Polyphagia
                                                                                        Weight change
phatemia, low-normal vitamin D levels, and an inappropri-
                                                                      Gonadal           Change in libido           Total and bioavailable
ately normal PTH level, suggestive of an abnormal para-                                 Erectile dysfunction         testosterone (early
thyroid response.26 Routine measurement of calcium and                                  Menstrual irregularities     morning), FSH, luteinizing
phosphate levels and, if abnormal, measurement of PTH,                                                               hormone, estradiol (in
                                                                                                                     women)
creatinine, and vitamin D levels may be prudent. Interest-
                                                                      Prolactin         Gynecomastia               Prolactin (early morning)
ingly, Nakanishi et al3 reported hypercalcemia in 7 of 23                               Galactorrhea
patients, although it is unclear if this was accurate because                           Breast engorgement
none had a serum calcium level greater than 10 mg/dL. The                               Menstrual irregularities
                                                                                        Headaches
elevated phosphate levels in our patients suggest impaired                              Visual changes
renal function or increased bone loss of calcium and phos-            Adrenal           Weight change              Cortisol, ACTH (early
phate as possible mechanisms.                                                           Change in energy level      morning)
                                                                                        Skin color changes
                                                                                        Salt craving
STUDY LIMITATIONS                                                                       Muscle aches
Overall, the prevalence of endocrinopathy in our series is            Calcium           Paresthesias               Calcium
likely an underestimate because most patients, especially              regulation       Muscle cramps
those seen before the turn of the century, had incomplete             *ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hor-
endocrine evaluations. To enable us to gain a better under-            mone; POEMS = polyneuropathy, organomegaly, endocrinopathy, M
standing of asymptomatic endocrine laboratory changes                  protein, skin changes.
seen early in the disease, we separately studied and de-
scribe patients seen in the last 6 years, who appear to be            cian following up these patients over time, especially after
better characterized. This was a retrospective medical                treatment.
record review with all its inherent biases. Thus, no stan-
dardized means were available for ensuring when and what              SUGGESTED APPROACH TO EVALUATING ENDOCRINOPATHIES IN
laboratory tests were performed and if they were necessar-            POEMS SYNDROME
ily repeated to confirm an abnormal test result. Cortisol,            We suggest that all patients with POEMS syndrome have a
testosterone, glucose, and prolactin samples were in most             thorough and systematic endocrine evaluation at diagnosis
cases obtained in the early morning. Because this is an               of this syndrome. Clinicians should complete an endocrine
extremely rare disorder, a retrospective review has been the          review of systems during the initial evaluation and obtain
preferred method of study until now. Most of the patients             total and bioavailable testosterone, prolactin, fasting glu-
seen at our institution were white. This is an extension of           cose, cortisol and ACTH specimens (all early morning) and
the first large North American patient population reported,2          thyrotropin and calcium specimens (Table 5). An endocri-
but with an emphasis on endocrine findings. We have no                nologist should see patients with concerns or abnormal
follow-up information regarding progression of endo-                  levels for further assessment and treatment.
crine abnormalities or new development of endocrine dis-
orders. However, in the future, we plan to develop a sys-             FUTURE DIRECTIONS
tematic method to track and obtain follow-up information              To gain a better understanding of the pathogenesis of endo-
on these patients. Although we believe that this report is            crinopathies in POEMS syndrome, researchers should fo-
helpful in guiding the evaluation today, future knowledge             cus on studies that assess the role of cytokines and VEGF,
about the natural history of endocrinopathies in POEMS                especially related to endocrine dysfunction. Whether endo-
syndrome may be particularly helpful to the frontline clini-          crine disorders associated with POEMS syndrome improve

                          Mayo Clin Proc.   •   July 2007;82(7):836-842     •   www.mayoclinicproceedings.com                               841

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ENDOCRINOPATHY IN POEMS SYNDROME

after successful treatment of the disease is unknown. Fol-                        11. Goth MI, Hubina E, Raptis S, Nagy GM, Toth BE. Physiological and
                                                                                pathological angiogenesis in the endocrine system. Microsc Res Tech. 2003;
low-up studies to better understand the evolution of endo-                      60:98-106.
crine disorders in these patients are needed.                                     12. Soubrier MJ, Dubost JJ, Sauvezie BJ, French Study Group on POEMS
                                                                                Syndrome. POEMS syndrome: a study of 25 cases and a review of the litera-
                                                                                ture. Am J Med. 1994;97:543-553.
                                                                                  13. Cabezas-Agricola JM, Lado-Abeal JJ, Otero-Anton E, Sanchez-Leira J,
                            CONCLUSION                                          Cabezas-Cerrato J. Hypoparathyroidism in POEMS syndrome. Lancet. 1996;
                                                                                347:701-702.
The high prevalence of endocrinopathies in our study, to                          14. Mauvais-Jarvis F, Bertherat J, Ravaud H, Thomopoulos P, Luton JP.
our knowledge the largest published series of POEMS                             POEMS syndrome with primary adrenocortical insufficiency [in French].
                                                                                Presse Med. 1998;27:15-17.
cases, calls for a thorough endocrine investigation in pa-                        15. Gherardi R, Baudrimont M, Kujas M, et al. Pathological findings in three
tients who present with this syndrome and vigilance in                          non-Japanese patients with the POEMS syndrome. Virchows Arch A Pathol
monitoring for treatable hormonal disorders that may                            Anat Histopathol. 1988;413:357-365.
                                                                                  16. Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood
emerge during the disease.                                                      stem cell transplantation in 16 patients with POEMS syndrome, and a review of
                                                                                the literature. Blood. 2004 Nov 15;104:3400-3407. Epub 2004 Jul 27.
                                                                                  17. Bergouignan FX, Massonnat R, Vital C, et al. Uncompacted lamellae in
We are grateful to Rebecca Bahn, MD, for contributing to our                    three patients with POEMS syndrome. Eur Neurol. 1987;27:173-181.
reporting of the potential association between VEGF over-                         18. Belec L, Authier FJ, Mohamed AS, Soubrier M, Gherardi RK. Antibod-
expression and endocrine manifestations in patients with POEMS                  ies to human herpesvirus 8 in POEMS (polyneuropathy, organomegaly, endo-
syndrome.                                                                       crinopathy, M protein, skin changes) syndrome with multicentric Castleman’s
                                                                                disease. Clin Infect Dis. 1999;28:678-679.
                                                                                  19. Gherardi RK, Belec L, Fromont G, et al. Elevated levels of interleukin-
                                                                                1β (IL-1β) and IL-6 in serum and increased production of IL-1β mRNA in
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