fibromyalgia is a chronic disorder characterized by widespread muscle pain that is often accompanied by fatigue or insomnia ( 1,2 ) . although the etiology of fibromyalgia remains unknown , endocrinological abnormalities , such as a disturbed hypothalamus - pituitary - adrenal axis and hypothyroidism , are thought to be triggering or exacerbating factors for this disorder ( 3 - 5 ) . in addition , fibromyalgia may occur after the withdrawal of supraphysiological doses of exogenous steroids ( 6 ) or after treatment for endogenous cushing 's syndrome ( 7,8 ) . however , few studies have so far investigated patients with fibromyalgia associated with untreated cushing 's syndrome . endogenous cushing 's syndrome is an endocrine disease resulting from chronic exposure to excessive glucocorticoids produced in the adrenal cortex ( 9 ) . it produces physical features , such as a rounded face , truncal obesity , thin skin , and proximal muscle weakness without pain . cushing 's disease is the most common form of endogenous cushing 's syndrome and it is caused by adrenocorticotropic hormone ( acth)-secreting pituitary adenomas . it is not uncommon for patients with cushing 's disease to exhibit central hypothyroidism regardless of whether their disease is due to acth - secreting macroadenomas or microadenomas ( 10 ) . we herein report a rare case of a patient who developed fibromyalgia during the course of cushing 's disease that was accompanied by central hypothyroidism . a 39-year - old japanese woman visited a local general hospital in february 2011 because of a 6-month history of widespread muscle pain . the patient 's family history was unremarkable other than her father 's sudden death ; furthermore , none of her relatives had any history of muscle or mitochondrial diseases . the patient had a personal history of iron deficiency anemia and had not taken any special health foods or any medications except for oral iron supplements . she had moved to niigata from the pacific side of japan 7 months before the visit , and the next month she developed spontaneous pain , tenderness , and exercise pain in her muscles that predominantly occurred in the extremities after the occurrence of a tingling sensation in her lower legs . magnetic resonance imaging ( mri ) revealed no apparent abnormalities in the cerebrum , cerebellum , brainstem or spinal cord . despite the administration of oral analgesics including non - steroidal anti - inflammatory drugs , her pain worsened , and she was referred to the neurology department of our hospital for a detailed examination in february 2011 . the patient was 165 cm tall , weighed 65 kg , and her body temperature was 36.3c . she presented with spontaneous , pressure , and exercise pain in the muscles of the neck , chest , bilateral upper and lower arms , and bilateral upper and lower legs ( visual analogue scale score : 6 of 10 ) . she experienced moderate fatigue and insomnia , waking unrefreshed , constipation , and an irregular menstrual cycle . she had mild weakness of the neck flexor muscles ( manual muscle testing score : 4 of 5 ) and had stiffness in the hands , but no joint swelling or pain . she had no cognitive impairment , hypoacusis , quadriplegia , extrapyramidal symptoms , or ataxia . laboratory tests showed a high - normal white blood cell count , normal serum creatine kinase , aldolase , and c - reactive protein levels , a normal blood lactic acid level , a slightly high erythrocyte sedimentation rate , and thyroid hormone level abnormalities ( table 1 ) . tests for rheumatoid factor , anti - nuclear antibody , anti - jo-1 antibody , and myeloperoxidase- or proteinase-3- anti - neutrophil cytoplasmic antibody were negative . a microscopic analysis of biopsy samples obtained from the left biceps brachii muscle revealed non - specific chronic myogenic changes , such as moderate fiber size variations ( fig . 1 ) . no necrotic or regenerated fibers , inflammatory cell infiltrate , atrophy or hypertrophy , predominance of type 1 or type 2 fibers , specific abnormal structure , ragged - red fibers , or increased expression of human leukocyte antigen class i were observed . taken together , these test results were not consistent with those of infectious myositis , collagen disease , or autoimmune or inflammatory myopathies including polymyalgia rheumatica , and mitochondrial myopathy . myopathy related to drug use , including statins , bisphosphonates , ciprofloxacin , and antidepressants were also ruled out due to the patient 's history of no medication , except for iron supplementation for her anemia . the patient began an analgesic medication regimen that included oral gabapentin ( 1,800 mg / day ) , milnacipran hydrochloride ( 25 mg / day ) , and an extract from the cutaneous tissue of a rabbit inoculated with vaccinia virus ( 16 units / day ) and she was referred to our department for a further endocrine evaluation in march 2011 . anca : anti - neutrophil cytoplasmic antibody , ngsp : national glycohemoglobin standardization program microscopic findings from a biopsy specimen from the left biceps brachii muscle ( february 2011 ) . non - specific chronic myogenic changes , including moderate fiber size variations , were observed using hematoxylin and eosin staining . the patient 's blood pressure and pulse rate were 123/64 mmhg and 63 beats per minute , respectively . she presented with a rounded , ruddy face , supraclavicular fat accumulation , truncal obesity , and mild pretibial edema . laboratory findings confirmed decreased serum levels of thyroid - stimulating hormone ( tsh ) ( 0.50 u / ml ) , free triiodothyronine ( ft3 ) ( 1.5 pg / ml ) , and free thyroxine ( ft4 ) ( 0.8 ng / dl ) . she tested negative for pituitary antibody , thyroid peroxidase antibody , thyroglobulin antibody , and tsh receptor antibody . the patient began thyroid hormone replacement with 75 g / day levothyroxine . in parallel , an examination for her cushingoid features revealed acth - dependent hypercortisolemia ( table 2a ) . her urinary free cortisol excretion ( 214 g / day , reference range : 11.2 - 80.3 g / day ) was high . her morning plasma cortisol level was insufficiently suppressed by the oral administration of a low dose of dexamethasone , but it was appropriately suppressed following a high dose of dexamethasone ( table 2b ) . dynamic tests for the secretion of pituitary hormones revealed a certain acth release to a corticotropin - releasing hormone ( crh ) load , a reduced tsh response to a thyrotropin - releasing hormone ( trh ) load , and reduced growth hormone ( gh ) response to a growth hormone - releasing factor ( grf ) load ( table 2c ) . the patient 's serum insulin - like growth factor-1 ( igf-1 ) level ( 145 ng / ml , reference range : 100 - 250 ng / ml ) was normal . these results indicated a diagnosis of cushing 's disease accompanied by central hypothyroidism , and additionally , a decreased release of gh due to hypercortisolemia was suspected . a. plasma acth and cortisol levels during 1 day in july 2011 acth : adrenocorticotropic hormone b. morning plasma cortisol and acth levels following an overnight administration of low or high dose oral dexamethasone in july 2011 the patient received oral dexamethasone ( 0.5 mg or 8 mg ) at 11 pm , and blood samples were obtained the following morning at 8 am . c. crh / grf / trh / lhrh stimulation test in july 2011 the following were intravenously administered at 8 am : human corticotropin - releasing hormone ( crh ) , 100 g ; growth hormone - releasing factor ( grf ) , 100 g ; thyrotropin - releasing hormone ( trh ) , 500 g ; and gonadotropin - releasing hormone ( lhrh ) , 100 g . the patient underwent thyroid hormone replacement therapy with levothyroxine ( 75 g / day ) for her hypothyroidism and had normal serum levels of free thyroxine ( 1.3 ng / dl ) and free triiodothyronine ( 2.2 pg / ml ) . d. crh / grf / trh / lhrh stimulation test in march 2013 , 18 months after transsphenoidal surgery the following were intravenously administered at 8 am : crh , 100 g ; grf , 100 g ; trh , 500 g ; and lhrh , 100 g . the patient was euthyroid ( free thyroxine , 1.1 ng / dl ; free triiodothyronine , 3.1 pg / ml ) . e. growth hormone releasing peptide-2 stimulation test in february 2015 growth hormone releasing peptide-2 ( 100 g ) was intravenously administered at 8 am . gadolinium - enhanced t1-weighted magnetic resonance imaging ( a : coronal plane , b : sagittal plane ) revealed a 0.5 cm tumor on the right side of the pituitary gland ( arrows ) , and the hypophyseal stalk was observed to have slightly shifted to the left . the patient experienced specific decreases in her widespread muscle pain ( visual analogue scale score : 4 of 10 ) without any change in the region and behavior of the pain during the course of levothyroxine replacement for her hypothyroidism . the patient underwent endoscopic transsphenoidal surgery in september 2011 , and her pituitary tumor was completely removed . the histopathological features of the tumor were consistent with those of an acth - secreting pituitary microadenoma . the patient had undetectable basal plasma acth and cortisol levels after surgery , showed no acth or cortisol release to a crh load , and received maintenance replacement therapy with 20 mg / day oral hydrocortisone . because the patient 's thyroid function was expected to improve , the levothyroxine replacement was discontinued just after surgery , and her basal serum thyroid hormone levels ( tsh , 1.52 u / ml ; ft3 , 3.2 pg / ml ; ft4 , 0.9 ng / dl ) normalized by 3 months after surgery . her cushing 's syndrome symptoms , including a rounded face , supraclavicular fat accumulation , and thin skin , resolved within 6 months after surgery , as did her neck muscle weakness ( manual muscle testing score : 5 of 5 ) . the patient experienced a decrease in her widespread muscle pain ( visual analogue scale score : 3 of 10 ) without any change in the region and behavior of the muscle pain , during the 6 months after surgery . however , her spontaneous , pressure , and exercise pain in the muscles of the neck , chest , and extremities remained unresolved . the patient met the diagnostic criteria for fibromyalgia ( widespread pain index : 10 of 19 and symptom severity scale score : 5 of 12 ) ( 1,2 ) . hydrocortisone replacement was discontinued in march 2013 , and dynamic tests showed normal acth and cortisol release to crh administration , but her gh release following grf administration remained low ( table 2d ) . mri performed in april 2013 revealed no abnormalities in the hypothalamus , hypophyseal stalk or pituitary gland , and no recurrence of pituitary tumors . her serum igf-1 level ( 90 ng / ml , reference range : 90 - 233 ng / ml ) was low - normal in february 2015 , and a growth hormone releasing peptide-2 load test showed a trend toward reduced gh release ( table 2e ) ( 11 ) , which was thought to be associated with fibromyalgia . the patient had no recurrent cushing 's disease or hypothyroidism during the postoperative follow - up period of > 4 years , but she suffered from prolonged fatigue , insomnia , and widespread muscle pain and was continuing treatment with oral analgesic drugs and sleeping pills for her persisting widespread myalgia and insomnia , respectively . in this case , the patient developed spontaneous , pressure , and exercise pain in the muscles of her neck , chest , and extremities along with fatigue and insomnia in the presence of cushing 's disease that was accompanied by central hypothyroidism . her widespread myalgia remained unresolved for more than 4 years after successful pituitary surgery to treat cushing 's disease . the patient experienced a decrease in her muscle pain ( visual analogue scale scores : from 6 to 3 of 10 ) during the recovery process from concomitant hypercortisolemia and hypothyroidism , but the region and behavior of her widespread myalgia remained almost completely unchanged during that period . these findings suggest that the patient developed fibromyalgia in association with concomitant untreated cushing 's disease and hypothyroidism , and the concomitant cushing 's disease and hypothyroidism also exacerbated her fibromyalgia . there are some reported cases of fibromyalgia symptoms that occurred , possibly in association with relative adrenal insufficiency , after withdrawal of supraphysiological doses of exogenous steroids ( 6 ) or after adrenal surgery to treat primary adrenal cushing 's syndrome ( 8) . an interesting case of severe fibromyalgia that occurred in association with hypopituitarism after a complete anterior hypophysectomy to treat cushing 's disease has been reported , in which a disturbed secretion of endogenous opioids and serotonin was also hypothesized to have triggered fibromyalgia ( 7 ) . to our knowledge , our patient is the first reported case of fibromyalgia associated with untreated cushing 's syndrome . in our case , the central hypothyroidism caused by cushing 's disease may have played an important role in triggering and exacerbating fibromyalgia . the mechanisms underlying the central hypothyroidism caused by cushing 's disease include mechanical compression of the hypophyseal stalk or pituitary gland by tumors ( 12 ) , and suppression of tsh secretion by excessive cortisol levels ( 13 ) , with or without non - thyroidal illness syndrome ( 14 ) . a rare case of isolated tsh deficiency coincidentally associated with cushing 's disease has also been reported ( 15 ) . our patient had central hypothyroidism in the absence of any marked mechanical compression of the hypophyseal stalk or pituitary gland by the acth - secreting pituitary microadenoma ( fig . 2 ) , and the hypothyroidism resolved after the patient underwent surgical treatment for cushing 's disease . therefore , the central hypothyroidism of our patient was likely to have been caused by excessive cortisol production . hypothyroidism that induces reversible muscle pain and stiffness that is often associated with proximal muscle weakness is referred to as hypothyroid myopathy ( 16 ) . on the other hand , hypothyroidism per se may exacerbate muscle pain in patients with fibromyalgia ( 3,4 ) . our patient experienced decreased muscle pain during the 6 months of levothyroxine treatment before surgery to treat cushing 's disease with central hypothyroidism . she experienced a further decrease in her muscle pain during the 6 months after surgery . taken together , these findings suggest that our patient might have had hypothyroid myopathy that resolved over a 1-year period in the absence of muscle weakness in the extremities and elevations of serum myogenic enzymes . at the same time , because the region and behavior of her widespread myalgia remained almost completely unchanged before and after the surgery , her hypothyroidism probably increased the widespread myalgia via the exacerbation of the fibromyalgia . cushing 's syndrome can cause glucocorticoid - induced myopathy characterized by reversible proximal muscle weakness without pain ( 17 ) . our patient presented with neck muscle weakness that remained unchanged during the 6 months of levothyroxine treatment for hypothyroidism , but this resolved following treatment for cushing 's disease . therefore , she may have had glucocorticoid - induced myopathy in the presence of cushing 's disease . the patient 's muscle biopsy specimen was obtained from the left biceps brachii muscle prior to receiving treatment for hypothyroidism and cushing 's disease and revealed non - specific , chronic myogenic changes ( fig . such myogenic changes are often observed in patients with endocrine disorders , including both glucocorticoid - induced and hypothyroid myopathy ( 16 ) , and may be found in patients with fibromyalgia ( 18 ) . because a microscopic examination was not performed again after treatment for cushing 's disease , the causal factors underlying the patient 's myogenic changes remain unclear . however , the absence of muscle weakness in the extremities of our patient suggests that fibromyalgia was the most likely factor underlying the microscopic findings of chronic myogenic changes . the patient showed a persistent trend toward decreased gh secretion even after undergoing surgical treatment for cushing 's disease ( table 2d ) . additionally , although her acth and cortisol responses to crh administration were found to be normal , she presented with mildly decreased basal plasma acth and cortisol levels without any morphological defects in the pituitary gland 1.5 years after the resolution of her cushing 's disease . these endocrinological alterations in and of themselves do not cause muscle pain , but some studies have suggested that patients with fibromyalgia demonstrate some alterations in the hypothalamic - pituitary endocrine function , including decreased gh , acth , and cortisol secretion ( 19 - 21 ) . therefore , the altered pituitary function in the present patient may have borne a reciprocal relationship to fibromyalgia . a careful check of the pituitary function along with the clinical course of widespread muscle pain was therefore required in this case . in conclusion , this case study describes a patient who developed fibromyalgia in association with untreated cushing 's disease and central hypothyroidism . the central hypothyroidism caused by cushing 's disease probably played an important role in triggering and exacerbating the fibromyalgia . our case highlights the need to examine the endocrine function , including the pituitary , thyroid , and adrenal function , in conjunction with the assessment of characteristic physical findings , such as a cushingoid appearance , in patients who present with muscle pain .
a 39-year - old woman with a 3-year history of a rounded face developed widespread myalgia . 
 detailed examinations revealed no disorders that could explain the pain other than concomitant cushing 's disease and central hypothyroidism . 
 both the hypercortisolemia and hypothyroidism completely resolved after the patient underwent surgery to treat cushing 's disease , but she continued to experience unresolved myalgia and met the diagnostic criteria for fibromyalgia . 
 few studies have so far investigated patients with fibromyalgia associated with cushing 's syndrome . in our case , the hypothyroidism caused by cushing 's disease probably played an important role in triggering and exacerbating fibromyalgia . 
 this highlights the need to examine the endocrine function in patients with muscle pain .