A retrospective analysis of endocirnopathies in 136 Chinese patients with POEMS syndrome

Background: POEMS syndrome is a rare multisystem disease but with a wide spectrum of clinical endocrinopathies. The patients with POEMS syndromes may present with one or more hormone disorders during disease course, but such phenomenon has usually been underestimated. In this report, the prevalence and clinical characteristics of Endocrine abnormalities in a large Chinese cohort with POEMS syndromes were summarized. Methods: Retrospective review of patients with a denite diagnosis of POEMS syndrome in our hospital between January 2000 and January 2020 were performed. The clinical data about endocrine abnormalities were extracted from their medical records and analysis. Results: This study comprised 136 patients (95 male, 41 female) with a median age of 48(40-56) years old. The endocrine abnormalities were more common (127 cases, 93.38%) in patients with POEMS syndromes. The prevalence of single endocrinopathy and multiple endocrinopathies was 12.60% (16/127 cases) and 87.40% (111/127) respectively. The most frequent endocrinopathy was hypogonadism (98/136, 72.06%), followed by hypothyroidism (83/136, 61.03%), hypocalcemia (50/136, 36.76%), hyperprolactinemia (47/136, 34.56%),abnormal glucose metabolism (41/136, 30.15%) and adrenal insuciency (41/136, 30.15%).In POEMS syndromes, nearly most of endocrine organs could be involved.In patients with multiple endocrinopathies, the percentage of 2, 3, 4, 5 and 6 kind of endocrine axes involved were 29.92%(38/127), 30.71%(39/127), 17.32%(22/127), 7.09%(9/127) and 2.36%(3/127), respectively. It results in complex clinical presentation of hormone disorders, including overt or sublinical situation. Conclusions: In Conclusion, this study overview of observed in a large series in China. frequent, clinical complicacy

Background POEMS syndrome is a really rare paraneoplastic syndrome due to plasma cell disorder, characterized by polyneuropathy, organomegaly, endocrinopathy,M protein, and skin changes [1] . Its prevalence is only 0.3 per 100,000 according to a national survey in Japan in 2003 [2] . In China, there have been some small series and many isolated case reports about this rare disorder, with limited information about systematically studies [3] .
The pathogenesis of POEMS syndrome has not been well understood, but more and more evidences indicate that the high levels of serum vascular endothelial growth factor (VEGF) correlates with disease activity. It can induce rapid and reversible increase in vascular permability, playing an important role in angiogenesis [4] .
Endocrinopathy is a very important feature of POEMS syndrome, which presented in about 84% patients with this paraneoplastic syndrome in some series. But usually it has been poorly understood.
Until now, there have been few reports about the prevalence and comprehensive clinical spectrum of endocrinopathy manifestations in POEMS syndrome in China. In this article, we reviewed such issues in a large Chinese cohort with POEMS syndromein our hospital in recent 20 years.

Participants
This retrospective observational study was conducted in PLA General hospital. A total of 136 with POEMS syndrome were included between January 2000 and January 2020. All the patients ful lled the diagnostic criteria de ned by Dispenzieri [1] , with two mandatory criteria (polyneuropathy and monoclonal plasma cell proliferating disorder), at least one major criterion (sclerotic bone lesion, Castleman disease or VEGF elevation) and one minor criterion (organomegaly, edema, endocrinology, skin change, papillary edema or thrombocytosis). Because of the high prevalence of diabetes mellitus (DM) and thyroid abnormalities, these diagnoses alone were not su cient to meet the minor criterion. We analyzed the medical records of these patients regarding their endocrinopathies at the time of diagnosis of POEMS syndrome. DM and hypothyroidism were not attributed to POEMS syndrome unless these reportedly occurred months to years after the onset of another or more features of POEMS syndrome.

Statistical analysis
Data are presented as number (%), mean ± standard deviation or median (interquartile range). SPSS (version 13.0, IBM Corporation, Somers, NY, USA) was used for statistical analysis.

Results
Totally, 136 patients with POEMS syndromes were enrolled in this report. The median age was 48(40-56) years and the ratio of male/female was 2.32 (95 cases/41 cases). It is showed the infomation about endocrinopathies evaluation was incomplete in many patients' medical record, so the true prevalence of endocrinopathies might be under underestimated.
The prevalence of primary adrenal insu ciency was 30.15% (41/136), including 8.82% (12/136) in overt group (elevated ACTH level and decreased free cortisone level) and 21.32% (29/136) in subclinical group (isolated elevated ACTH levels with cortisol rhythm disorder). ACTH stimulation test were not carried out in our series, which might omit some patients with adrenal insu ciency. Glucocorticoid were usually administrated in these patients with POEMS syndrome, meanwhile resulting in remission of adrenal insu ciency.
Parathyroid hormone(PTH) were not routinely measured in this series. In these 50 cases, availabe serum PTH levels in 14 cases were 48.04±21.17 (normal range 15.0-65.0 pmol/L) and other 36 cases had not serum PTH measured.This indicated that calcium abnormalities was also a characteristic endocrinopathy in POEMS, but such conditions had always been underestimated.

Discussion
The prevalence of POEMS is really much lower in China, as reported in other countries. To our knowledge, this series about patients with POEMS syndrome is the largest one in China. It showed that endocrinopathy is a central feature of this disorder and should be paid more attention to than before.
The proportion of each endocrinopathy and multiple endocinopathies in our Chinese series are slightly different compared with those data from Mayo Clinical report (Table 1) [5] . Of the 136 patients with POEMS syndrome, 93.38% of patients had one endocrinopathy, with hypogonadism as the most frequent endocrine abnormality, followed by hypothyroidism, hypocalcemia, hyperprolactinemia, abnormal glucose metabolism, and lastly by adrenal insu ciency. No other hypopituitarism was recorded in these patients, except for 7 patients with secondary hypogonadism and 15 patients with secondary hypothyroidism. The multiple endocrinopahties should also be emphasized. In POEMS syndromes, nearly most of endocrine axe had the possibility of being involved, resulting in complex clinical presentations of hormone disorders. The percentage of 2, 3, 4, 5 and 6 kind of endocrine axes involved were 29.92%, 30.71%, 17.32%, 7.09% and 2.36%, respectively. These endocrine abnormalities can seriously affect the patient's quality of life, and sometimes even lead to emergencies, if they cannot be diagnosed in time and treated properly. Endocrinopathy is a really central feature of POEMS syndrome, but the pathogenesis have not been well understood. Increased levels of cytokines, particularly VEGF, has been reported to be an important pathogenic factor of POMES syndrome [6] . However, antibodies against hormones in serum or special hormone receptors in endocrine gland have not been detected. In fact, the structure of endocrine glands is not impaired at autopsy, which indicates that endocrinopathy in POEMS syndrome maybe only functional disorder, rather than structure impairment [7] . It is hypothesized that overexpression of VEGF in POEMS syndrome might affect the endocrine axes because of a disruption of the local balance of angiogenic factors, which appears to be important in the regulation of hormone secretion in various endocrine glands.
Hypogonadism is the most common endocrine disorders in POEMS syndrome. In fact, Gonadal dysfunction is a serious problem that reduces patients' quality of life and interpersonal relationships. In this series, 83.16% male patients had hypogonadism and 88.61% reported erectile dysfunction. Gynecomastia (13.33%) was also a common nding in male patients with hypogonadism. The testosterone was much lower than that in same-aged male. In premenopausal female, irregular menses (94.74%) and even amenorrhea in some patients were the frequent symptoms. Mild hyperprolactinemia were detected both in male (32.63%) and female (39.02%). An increased intracranial pressure in patients with POEMS syndrome could be detected. It was presumed to disrupt hypothalamic function and inhibit dopaminergic pathways, resulting in hypoprolacteinemia [7] . Since patient with mild hyperprolactinemia had no special symptoms, administration with Bromocriptine maybe unnecessary.
7.35% patients (10/136) had impaired glucose tolerance, and 22.79% patients had overt DM. Since the insulin and C peptide secretion in fasting and postprandial were higher than normal range, which indicated that islet cell function were not obviously impaired. As for impaired glucose tolerance and mild type 2 DM, lifestyle interventions can keep blood glucose well controlled. Hypoglycemia medicines or/and insulin were administrated to diabetes mellitus with serious hyperglycemia. Usually, hyperglycemia would be more serious and high dose of insulin always needed when most of these POEM patients were treated with high dose of corticosteroids on POEMS syndrome. Peripheral neuropathy is the most obvious symptom of POEMS syndrome. Patients with POEMS syndrome always complain numbness and pain in limbs. If hyperglycemia also coexist at the same time, they are frequently misdiagnosed as diabetic peripheral neuropathy (DPN). In fact, there are some differences between neuropathy of POEMS syndrome and DPN. A longer process and slower progress are features of DPN with axonal degeneration alone, while there is a combination of axonal and demyelinating lesions in POEMS syndrome [8,9] .
Thyroid is the common organ involved in autoimmune associated disease. Hypothyroidism is also a common endocrine disorder in POEMS. 61.03% patients had hypothyroidism, overt or subclinical. Since the symptoms of hypothyroidism are always non-speici c, it is essencial to thoroughly evaluate thyroid function. Therapy with levothyroxine can relieve these symptoms gradually.Some patients with POEMS syndrome had obvious pleural effusion and peritoneal effusion, which should be distinguished from serious hypothyroidism.
Adrenal insu ciency has ever been reported infrequently in patients with POEMS syndrome. In our report, The prevalence of primary adrenal insu ciency was 30.15% (41/136), including 8.82% (12/136) in overt group (elevated ACTH level and decreased free cortisone level) and 21.32% (29/136) in subclinical group (isolated elevated ACTH levels with cortisol rhythm disorder). However, ACTH stimulation test were not routinely carried out in our series, which might omit some patients with adrenal insu ciency. Systematic administration with glucocorticoid on POEMS syndrome can relieve the symptoms of adrenal insu ciency.
Simple hypocalcaemia were also common in POEMS in this series, with a prevalence of 36.76%. This indicated that calcium abnormalities was also a frequent characteristic endocrinopathy in POEMS, but had always been underestimated for a long time. Unfortunately, Serum PTH were not routinely measured. The available serum PTH in 14 cases with hypocalcemia was in normal range, which indicated that the parathyroid function were not impaired. In Mayo clinic report, that approximately one third of patients in our series had low calcium levels.
According to the ndings in our series and other large series, We can see that POEMS syndrome is a rare multisystem disease but with a wide spectrum of clinical endocrinopathies. In fact, the evaluation of endocrinopathies always incomplete and delayed for a long time. During the disease course, the various endocrinopathies may occur in different stage [5] . Also, several hormones disorders may present at the same time. All these disorders results in the complicated clinical presentations, which is susceptive to be misdiagnosed. So we suggest that all patients with POEMS syndrome should have a thorough and systematic endocrine evaluation at diagnosis of this syndrome.
After patients with POEMS syndrome were hospitalized, the de nite diagnosis always need the clinical consultation of various specialists from neurology department, endocrinology department, hematology department, et al. We recommend that the multiple discipline teams should be united in management of POEMS syndrome. With this approach, the endocrinopathies can be toughly analyzed, correctly treated and timely monitored in the follow up [7] .
The present study had several limitations. As a retrospective medical record review, the inherent biases could not be precluded. The prevalence of endocrinopathy in our series is likely underestimated because some patients had incomplete endocrine evaluations, which had been reported in Mayo clinical series [5] .
The actual prevalence of endocrinopathies may be much higher than the data reported in this article, which must attract our more attention.
For patients with a dominant sclerotic plasmacytoma, rst line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement should receive systemic therapy. Current systematic therapies include high-dose chemotherapy with autologous stem cell transplantation (ASCT), alkylator-based therapy, and therapy with novel agents. All three treatments can achieve acceptable remission rates and survival [10][11][12] .
Besides therapies on POEMS syndrome, the treatment on endocrinopathies should be aimed at hormone supplement and/or recti ng the disorder in hypogonadism, hypothyroidism, glucose metabolism, and calcium metabolism. To those with subclinical endocrinopathies, the intensive monitoring or low dose of corresponding hormones should also be prescribed. With improvement of endocrinopathies the clinical satiation will also improve, resulting in a good base for future treatment on POEMS syndromes.
It reported that endocrine abnormalities can also improve after chemotherapy, including successful tapering off of thyroid replacement, androgen replacement, and corticosteroid replacement in at least one-third of the patients. In a single-center prospective study in China, 35 patients with newly diagnosed POEMS syndrome were treated with Lenalidomide and dexamethasone for 12 cycles. After treatment, the mean total female sexual function index (FSFI) score increased from 17.1 to 23.7 and the mean international index of erectile function (IIEF) scores increased from 12.9 to 20.5. Meanwhile the total testosterone levels in male increased from 55 ng/dl to 624 ng/dl [6].

Conclusions
Endocrinopathies manifestation is an important component of the POEMS syndrome. This study provides an overview of the abnormalities observed in a large series in China. These ndings should serve as a reminder for physicians caring for patients with POEMS syndrome that endocrinopathy manifestations in POEMS syndromes are more frequent, and its clinical complicacy should be paid more attention to. To patients with de nite diagnosis of POEMS syndromes, early and thorough endocrine evaluation should be performed.

Declarations
Ethics approval and consent to participate The study was approved by the Ethics Committee of PLA General Hospital.

Consent for publication
Informed consents were obtained from all the patients prior to the use of their data and images for publication.

Availability of data and materials
The datasets used or analysed during the current study are available from the corresponding author on reasonable request.