Midnight Salivary Cortisol Levels Research Articles

FRI206 A Rare Case Of Coexisting Acromegaly And Adrenal Cushing’s Syndrome

Abstract Disclosure: T. Chamakkala: None. T. Gallagher: None. Introduction: Acromegaly has been associated with higher risk of cancer morbidity and mortality. Acromegaly coexisting with adrenal Cushing’s disease has been rarely described in literature. We present a patient who was found to have acromegaly during evaluation for Cushing’s syndrome. Clinical Case: A 50-year-old woman presented to the office for endocrinology evaluation at the referral of PCP for elevated 24h urine cortisol level 176ug/24h. She had noticed facial plethora over several years, fatigue, and easy bruising. She had recently been diagnosed with hypertension, poorly controlled on two medications at the time of evaluation. Repeat 24h urine cortisol and midnight salivary cortisol levels were elevated; dexamethasone suppression test was positive. ACTH was <1.5pg/mL, consistent with ACTH independent hypercortisolemia. Adrenal CT showed 2.6x3cm left adrenal adenoma. She underwent left adrenalectomy and pathology showed adrenal cortical adenoma. During evaluation for Cushing’s disease and new onset hypertension, IGF1 was evaluated and found to be elevated at 354ng/mL. She additionally endorsed symptoms of worsening carpal tunnel syndrome and increasing ring size. After adrenalectomy, IGF1 was repeated and remained elevated at 429ng/mL. Growth hormone suppression test showed nadir of 0.56ng/mL which is higher than <0.3ng/mL expected of high sensitivity GH assays. Pituitary MRI showed three suspected pituitary microadenomas, 4mm and 5mm in left gland, 7mm in right gland. Given difficulty with surgical approach and higher risk of hypopituitarism, she was started on lanreotide for treatment without surgery. She underwent genetic counseling and was offered genetic testing. Conclusion: This case highlights the rare coexistence of acromegaly and adrenal Cushing’s disease in a 50 year old woman. Though the relationship between acromegaly and cancer has been historically controversial, more recent studies have shown an increased risk of both benign and malignant tumors with acromegaly. Untreated Cushing’s Disease has been associated with mildly elevated IGF1 which then decreases after remission; it is unclear if the same pathological process is involved in other etiologies of hypercortisolemia like adrenal Cushing’s syndrome, but re-evaluation of IGF1 after treatment of Cushing’s should be considered. As Cushing’s and acromegaly share similar consequences such as worsening HTN, changing facial appearance, and worsening diabetes, it is prudent to consider each as differential diagnoses when signs do not remit after treatment. Acromegaly has additionally been associated with other endocrinopathies in syndromes including MEN1 syndrome, McCune Albright Syndrome, and Carney Complex. Evaluation for these syndromes and consideration for genetic testing should be considered in the evaluation of a patient with acromegaly and additional associated endocrinopathies. Presentation: Friday, June 16, 2023

SAT588 Cushing’s Syndrome Due To Ectopic ACTH Secretion From Ovarian Teratomas

Abstract Disclosure: Y. Kang: None. M.S. Gildenberg: None. B.J. Quade: None. R.A. Blair: None. Background: Approximately 9-18% of Cushing’s syndrome (CS) cases are secondary to ectopic ACTH secretion, most commonly from sources in the lung or mediastinum. However, ACTH-producing tumors are rarely found in distant organs, occasionally making the localization and management challenging. Clinical Case: A 32-year-old woman with class 3 obesity, hidradenitis suppurativa, anxiety, and depression experienced atraumatic pelvic and sacral fractures. DXA scan result showed Z-scores of -3.1 in the lumbar spine, -2.6 in the femur neck, and -0.5 in the total hip. She reported a steady weight-gain of 250 lbs over 7 years despite lifestyle modifications and liraglutide. On examination, she had a round face with plethora, acne, violaceous abdominal striae, and dorsocervical fat pad. Laboratory findings revealed elevated midnight salivary cortisol levels of 453 and 424 ng/dL (n: <100 ng/dL), elevated 24-hour urine cortisol levels of 254 and 741 (n: 3.5-45 mcg), and an abnormal 1 mg dexamethasone suppression test (DST) result at 15.1 ug/dL. AM plasma ACTH and cortisol levels were 190 pg/mL and 18.5 ug/dL, suggesting ACTH-dependent hypercortisolism. The plasma cortisol level after an 8 mg DST was unsuppressed at 13.1 ug/dL with a dexamethasone level of 3,380 ng/dL (n: >800 ng/dL). Abdominal CT and MRI scans showed large bilateral adnexal masses measuring up to 13.7 cm on the left and 9.3 cm on the right, with heterogeneous solid and cystic components, consistent with mature cystic ovarian teratomas. DOTATE-PET scan did not show any areas of increased uptake. The patient underwent a laparoscopic right cystectomy and left oophorectomy, with immediate drop in cortisol (1.6 ug/dL) and signs of adrenal insufficiency post-operatively, requiring hydrocortisone replacement. After holding hydrocortisone for 24 hours prior to laboratory assessment one week post-operatively, her ACTH and cortisol were undetectable, reflecting successful source removal. Pathology report showed neuroendocrine tumor with pituitary differentiation with positive ACTH immunohistochemical staining and Ki-67 proliferative index of 22.6% on the left adnexal mass, and a mature cystic teratoma on the right. Conclusion: Although rare, pituitary differentiation of ovarian teratomas should be considered as a possible source of ectopic ACTH secretion in CS patients without obvious sources identified in commonly involved organs. Presentation: Saturday, June 17, 2023

ODP387 Hemihypertrophy: A Rare Clinical Presentation of Cushing's disease

Abstract Background Hemihypertrophy is a rare clinical presentation of Cushing's disease. It has been described in three newborns with massive enlargement of adrenal glands in presence of other congenital abnormalities and in a 17-year-old female with pituitary adenoma with a genetic diagnosis of Beckwith Weidman syndrome. We describe a case of Cushing's disease with lower extremity hemihypertrophy in the absence of features suggestive of an underlying syndrome. 1,2 Clinical Case: A 12-year-old male with no significant past medical history presented with poor growth and rapid weight gain. In addition, he had hemihypertrophy of left lower extremity interfering with his physical activity. Physical exam showed Tanner Stage 1 for pubic hair and testicular volume of 4 ml bilaterally, with no signs of hirsutism, bruising or purplish striae. Initial work up showed normal thyroid hormone and growth factor levels. Midnight salivary cortisol levels were 238 ng/dl and 51 ng/dl respectively (range <100 ng/dl). One mg dexamethasone suppression test showed suppressed cortisol level of 1 mcg/dl. At the subsequent visit seven months later, he had gained 13.8 kg and grown 0.9 cm in height. Physical exam showed facial plethora and buffalo hump, which had not been present at the initial visit. Left and right leg circumference above the knee were 22 inches and 20 inches respectively. Repeat midnight cortisol levels on two separate occasions were 251 ng/dl and 441 ng/dl respectively. Repeat 1 mg dexamethasone suppression test showed suppressed cortisol levels of 1.2 mcg/dl. Because of clinical picture consistent with Cushing syndrome and elevated salivary cortisol levels, 24-hour urine cortisol levels were ordered that were 145 mcg and 276 mcg/24h respectively (range 1-45 mcg/24hours). ACTH was elevated at 65 pg/ml. CT scan of abdomen and pelvis was normal. Left leg ultrasound was normal. MRI of brain showed a 4 mm hypoenhancing lesion in the pituitary gland to the left of midline. A peripheral DDAVP stimulation test showed elevated ACTH and cortisol levels suggestive of pituitary origin. MRI of legs showed asymmetric fat deposition causing hemihypertrophy. Patient underwent transsphenoidal resection of pituitary adenoma with postoperative remission (postop cortisol nadir <1 mcg/dl). At follow up visit after surgery, patient had lost 0.2 kg, buffalo hump had disappeared, and left leg circumference had slightly improved. Genetic testing ispending. Conclusion This case demonstrates that hemihypertrophy can be a presenting symptom of Cushing's disease.

ODP408 Elevated DHEAS and Acute Hair Loss in an Adult Male with Trichorhinophalangeal Syndrome Type 1: a Case of Male PCOS

Abstract Background Male androgenic alopecia is a common cause of hair loss in both men and women. Although genetic and hormonal factors likely play a role, the etiology is mostly unknown. PCOS is a highly heritable disease with elevated prevalence of reproductive abnormalities in first-degree relatives (FDRs) of patients with PCOS, which may be due to an underlying genetic defect in steroidogenesis. A recent meta-analysis revealed that male FDRs of patients with PCOS had significantly increased levels of DHEAS compared with controls. We present a young adult male who developed acute hair loss with biochemical evidence of hyperandrogenism. Clinical Case A 21-year-old man presented for evaluation of hyperandrogenism after experiencing progressive loss of posterior patch of hair over 3 weeks. He also endorsed acne, intermittent headaches, striae, and difficulty losing weight for the past 2 years. He denied facial rounding, vision changes, and use of glucocorticoids or supplements. Physical examination was notable for height of 67 inches, BMI 30.5 mg/m 2, BP 120/78, recession of the frontotemporal and occipital hairline, sparse posterior scalp hair, bulbous nose, long philtrum, mild facial acne, 2, 3 toe syndactyly, and thin purple striae on bilateral flanks and axillae. Labs revealed elevated DHEAS 1065.7 mcg/dL (ref. 238.4-539.3) and normal 8 AM total testosterone of 382 ng/dL (240-871). Cosyntropin stimulation test revealed baseline cortisol level of 10.6 mcg/dL with ACTH of 22.2 pg/mL (5-46) and 60-minute cortisol level of 24.8 mcg/dL, 17-OH progesterone level 81 ng/dL (18-164), and 17-OH pregnenolone 1040 ng/dL (55-455). Workup for Cushing's revealed multiple normal midnight salivary cortisol levels and mild intermittent elevation of 24-hour urinary free cortisol levels. CT scan of the adrenals was negative for a mass. Exome sequencing revealed a heterozygous de novo pathogenic variant (c.1614_1615delTCinsAT: p. C538X) in the TRPS1 gene (NM_0141112.2). Family history was significant for a 20-year-old sister with PCOS and elevated DHEAS of 443 ug/dL (51-321). Mid-parental height was 69.6 inches. Conclusion Trichorhinophalangeal syndrome Type 1 (TRPS1) is a rare genetic disorder characterized by hair, craniofacial, and skeletal abnormalities such as androgenetic alopecia, bulbous nasal tip, and cone-shaped epiphyses. To our knowledge, the hair findings in TRPS are not associated with hyperandrogenism which prompted further investigation. Evaluation for endocrine causes of hyperandrogenism such as Cushing's disease, congenital adrenal hyperplasia, and adrenal tumor were negative. However, our patient's elevated DHEAS is likely due to male PCOS, as previously described in male FDRs of patients with PCOS. Thus, genetic susceptibility to PCOS and rare genetic syndromes should be considered in the differential diagnosis of young men with clinical and biochemical evidence of hyperandrogenism. Reference: Shan D et al. Reproductive Health in First-degree relatives of Patients with Polycystic Ovarian Syndrome: a Review and Meta-analysis. JCEM. 2022 Jan;107(1); 273-295. Presentation: No date and time listed

Cushing’s Syndrome Associated With an Adrenal Cavernous Hemangioma

Introduction: Adrenal cavernous hemangiomas are rare benign tumors that arise from vascular endothelium and are often discovered incidentally on abdominal imaging. The majority are nonfunctioning; however, we present a case of adrenal Cushing’s syndrome in a patient with a cavernous adrenal hemangioma.Case: A 72-year-old woman was referred for an incidental right adrenal mass. On questioning, she endorsed abdominal pain, sixty-pound unintentional weight gain over five years, truncal obesity, and easy bruising. Past medical history was relevant for hypertension. Her surgical history was extremely complicated, having had a perforated peptic ulcer, open cholecystectomy complicated by injury to the right ureter, incisional hernia repair, appendectomy, and hysterectomy with bilateral salpingo-oophorectomy.She was first noted to have a right adrenal mass on a CT done eight years ago, measuring 3.8 x 3.2 cm. A repeat CT abdomen and pelvis now showed this mass to be 6.5 x 6.3 x 8.1 cm with unenhanced Hounsfield units of 29.6. Radiographically, this was a heterogeneous, solid, and cystic appearing mass with peripheral brisk arterial enhancement areas, which appeared to fill in on delayed imaging. The enhancement pattern of the lesion was consistent with an adrenal cavernous hemangioma. An MRI of the abdomen also demonstrated similar peripheral nodular enhancement favoring an adrenal cavernous hemangioma.Functional testing for the adrenal mass was undertaken. Morning cortisol was 23.4 mcg/dl with ACTH low at 5.3 pg/ml, and DHEA-S 3 mcg/dl. She failed to suppress with overnight 1 mg dexamethasone with AM cortisol of 3.6 mcg/dl. Midnight salivary cortisol levels were high at 0.237 mcg/dl and 0.419 mcg/dl while a 24-hour urine free cortisol was normal at 15.2 mcg/d. She tested negative for pheochromocytoma and primary aldosteronism.The patient was deemed a poor surgical candidate due to her history of multiple prior abdominal surgeries and a BMI of 46. Therefore, she underwent an IR angioembolization of the right adrenal mass instead. On follow-up CT, there was no significant change in the size of the lesion; however the degree of rim enhancement was slightly decreased. Post procedurally, her a.m. cortisol remained high-normal at 18.3 mcg/dL.. She is currently enrolled in a study for medical treatment of Cushing’s syndrome.Discussion: Adrenal cavernous hemangiomas usually present incidentally in the 6th-7th decade of life with a female predominance. These lesions are often asymptomatic; however, abdominal pain is the most common presenting symptom. The majority of adrenal cavernous hemangiomas are hormonally quiescent and mineralocorticoid excess and/or subclinical Cushing’s syndrome is exceedingly rare. Our patient is unique in her presentation of adrenal Cushing’s with this lesion and the novel use of angioembolization to decrease the size of this vascular tumor.

SAT-266 Accelerated Osteoporosis - a Rare Presentation of Cushing’s Disease

Background:Osteoporosis in post-menopausal women is usually due to bone loss from estrogen deficiency and/or age. Secondary osteoporosis (SO) is less common. Up to 30% of postmenopausal women and 50% of men with osteoporosis may have an underlying cause. Cushing’s disease (CD) is one cause of SO but rarely the presenting symptoms. The prevalence of osteoporosis (69.6% vs 37.8%) is significantly higher in patients with adrenal rather than pituitary CD. Diagnosing CD remains a challenge to physicians in spite of advances in diagnostic techniques. We report a case of CD in a post-menopausal woman presenting as accelerated osteoporosis.Clinical CaseA 63-year-old Caucasian female with a history of hypertension and hysterectomy in her 50s on transdermal estrogen was referred to our Endocrine clinic for evaluation of osteoporosis and incidental finding of bilateral adrenal hyperplasia on CT spine. The patient rapidly developed kyphoscoliosis within the past 2 years. She was debilitated by pain and decreased mobility from compression fractures and spinal stenosis, and underwent thoracic and lumbar fusion surgery.On physical examination, her heart rate was 64 beats per minute, blood pressure 130/92 mmHg, weight 188 lbs. and Height 5.1 ft; a year ago it was 5.5 ft. Her face appeared round but not red. Buffalo hump and supraclavicular pad were noted. No striae or bruises noted. Healing surgical scars over the thoracic and lumbar spine were violaceous.The patient’s urine free cortisol levels, tested a month apart, were 190 mcg and 132 mcg (n 3.5-45 mcg/24h). Midnight salivary cortisol levels taken consecutive nights were 160 ng/dL and 513 ng/dL (n < 100 ng/dL). Morning Serum Cortisol and ACTH were 20.2 ug/dL and 14 pg/mL (n Cortisol 6.0-27.0 ug/dL and ACTH 7.2-63 pg/mL). Following low dose (1mg) dexamethasone suppression testing, her serum cortisol were 12.6 ug/dL, ACTH levels were 32 pg/mL and dexamethasone were 187 ng/dL (n < 30 ng/dL). 25-Hydroxy D total, TSH, Free T4, PTH intact, calcium, renin, aldosterone and SPEP levels were normal. Renal and liver functions were normal except alkaline phosphatase was 142 U/L (n 34-104 U/L). Pituitary MRI with contrast showed pituitary microadenoma. The patient was referred to a neurosurgeon and is planned for an inferior petrosal sinus sampling prior to transsphenoidal resection.ConclusionCushing’s disease as a cause of osteoporosis is rare. Diagnosis of Cushing’s can be challenging in patients without obvious signs, as in our patient who was referred to an endocrinologist due to incidental finding of bilateral adrenal hyperplasia. A high degree of clinical suspicion is needed when investigating CD, as initial test results can be indecisive. As in our patient, initial ACTH and cortisol levels were normal, the low dose dexamethasone suppression test helped us direct our diagnosis towards CD.

SAT-248 Cushing’s Disease with Two ACTH-Producing Pituitary Tumors

Objective: The objective of this case report is to discuss a case of Cushing’s disease with two ACTH-producing pituitary tumors and emphasize consideration of repeat surgery as a treatment modality for unsuccessful initial surgery. Methods: We present a case of a patient with Cushing’s disease with two ACTH-producing pituitary tumors and a literature review. Results: A 36 year-old female found to have left supraclavicular fossa swelling was screened for Cushing’s syndrome. Midnight salivary cortisol levels elevated at 0.636 ug/dL and 0.316 ug/dL (<0.010–0.090 ug/dL). 24-hour urine cortisol 162 ug/24 hr (0–50 ug/24 hr). 1-mg dexamethasone suppression test 14.0 ug/dL. Serum morning cortisol 26.4 ug/dL with corresponding ACTH 66.7 pg/mL (7.2–63.3 pg/mL). MRI brain with and without contrast showed a 7-mm relatively hypoenhancing lesion of the anterior pituitary gland. 8-mg dexamethasone suppression test 2.7 ug/dL. She underwent transsphenoidal surgery (TSS) and pathology was consistent with a pituitary adenoma staining positive for ACTH. No residual tumor was seen. Postoperative morning serum cortisol 17.0 ug/dL and ACTH 79 pg/mL (9–46 pg/mL). She had repeat TSS and the area of resection was clean with no residual tumor but a second adenoma was found that was not visualized on MRI and was distinct from the initial lesion. Postoperative morning cortisol 0.7 ug/dL and ACTH <9 pg/mL (9–46 pg/mL). Pathology was consistent with pituitary adenoma staining positive for ACTH. She is now on steroids for central adrenal insufficiency. Discussion: First-line treatment for Cushing’s disease is surgical resection of the primary lesion (Nieman LK, Biller BMK, et al. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015; 100(8):2807–2831). Remission rates are 73–76% for selectively resected microadenomas but 43% for macroadenomas (Nieman et al. 2015). For patients who undergo a noncurative surgery, second-line therapies include repeat TSS, radiotherapy, medical therapy, and bilateral adrenalectomy. Repeat TSS is recommended particularly in patients who had evidence of incomplete resection or a pituitary lesion on imaging although this was not the case with our patient. Repeat TSS is cited to be successful in about 50–60% of cases (Patil CG, Veeravagu A, et al. Outcomes after repeat transsphenoidal surgery for recurrent Cushing’s disease. Neurosurgery. 2008;63(2):266–270) but carries an increased risk of hypopituitarism and lower likelihood of remission compared to initial surgery. Remission can be achieved more rapidly compared to other second-line treatments. Conclusion: In Cushing’s Disease with unsuccessful initial surgery, consideration for repeat TSS may be considered when there is access to an expert pituitary surgeon.

Midnight salivary cortisol for the diagnosis of Cushing's syndrome in a Chinese population.

Cushing's syndrome is defined as chronic excess free cortisol in circulation. According to recent studies, midnight salivary cortisol is an accurate and non-stress method for screening and diagnosing Cushing's syndrome. However, there is limited data on midnight salivary cortisol for diagnosing Cushing's syndrome in the Chinese population. Among 61 suspected Chinese patients, 48 patients were confirmed to have Cushing's syndrome. We evaluated the midnight salivary cortisol, midnight serum cortisol and 24-hour urine free cortisol excretion for diagnosis. Midnight salivary cortisol was collected from 21 healthy volunteers for control purposes. In the patient group, mean urine free cortisol excretion and midnight salivary cortisol levels were 296.50 ± 47.99 µg/day and 10.18 ± 1.29 ng/mL, respectively. Among the control group and normal participants, mean midnight salivary cortisol level was 0.53 ± 0.13 ng/mL and 0.50 ± 0.12 ng/mL, respectively. The cut-off value for midnight salivary cortisol was 1.7 ng/mL for diagnosing Cushing's syndrome, with a sensitivity of 98% and specificity of 100%. The diagnostic performance of midnight salivary cortisol (area under the curve [AUC] = 0.99) was superior to that of urine free cortisol (AUC = 0.89). Our study confirmed the good diagnostic performance of midnight salivary cortisol for diagnosing Cushing's syndrome in a Chinese population. Correlation between midnight salivary cortisol and either urine free cortisol or midnight serum cortisol was good. Midnight salivary cortisol is a convenient and precise tool for diagnosing Cushing's syndrome and can be the screening test of choice for Chinese populations.

MON-412 Subclinical Cushing's Disease and the Importance of Broad Differential Diagnoses

Introduction: Cushing disease is the most common cause of endogenous Cushing syndrome, and if undiagnosed, carries significant morbidity including diabetes, obesity, infertility, and osteoporosis. Physical exam findings commonly seen include violaceous abdominal striae, supraclavicular fat pads, facial plethora, and proximal muscle weakness. Here, we discuss a case of a rare presentation of Cushing disease in a patient whose chief complaint was fatigue with none of the aforementioned physical manifestations. Case: A 43 year old female with a medical history of multinodular goiter status post hemithyroidectomy presented with persistent fatigue and weight gain over a one year period. Physical exam revealed normal body habitus, no thyroid nodules, no supraclavicular fat pad, abdominal striae, or proximal muscle weakness. Thyroid studies were normal, and despite lifestyle modifications, the patient's symptoms persisted. Laboratory workup revealed elevated midnight salivary cortisol levels, an elevated 24 hour urine free cortisol measurement, and on dexamethasone suppression testing, elevated ACTH levels, confirming Cushing disease. Pituitary MRI was significant for pituitary macroadenoma with cystic changes measuring 1.1x1.9cm and mild compression of the optic chiasm. The patient was transferred for surgical resection, where pathology was consistent with an ACTH-secreting adenoma. Discussion: Subclinical Cushing's disease is defined by an adrenocorticotrophic hormone (ACTH)-induced mild hypercortisolism without typical features of Cushing's disease. In a 2016 cohort study, the prevalence of subclinical and silent corticotroph adenomas was approximately 40%, making it imperative for practitioners to have a broad differential when evaluating patients with non-specific complaints. Additional studies show that clinically silent adenomas (adenomas with normal cortisol secretion and ACTH-immunopositive staining without autonomous ACTH secretion) have the risk of progressing to Cushing's disease, thereby carrying the risk of increased morbidity secondary to the metabolic derangements due to hypercortisolism. Finally, should surgical resection be warranted, the size of the adenoma has been associated not only with the level of difficulty of surgical resection, but also with the risk of recurrence. Ultimately, it behooves the medical community to obtain detailed histories, conduct thorough physical, and maintain broad differentials of rare conditions to allow for better screening.

SUN-380 A Case of Cushing Syndrome

Introduction: Cushing's syndrome is characterized by over-secretion of cortisol. Etiologies of Cushing’s syndrome can be ACTH dependent or independent. This highlights a case of ACTH independent Cushing’s secondary to an adrenal lesion. Clinical case: A 28 year old lady presents to Endocrine clinic for evaluation of secondary amenorrhea for 2 years. She was previously evaluated by a gynecologist who performed a progesterone challenge test with no response. The patient reports mild acne during adolescence but denies excess hair growth, or voice deepening. She notes weight gain primarily distributed in her abdomen and face. She reports fatigue, anxiety, easy bruising, intermittent headaches as well as some polydipsia and polyuria. She is not experiencing peripheral muscle weaknessm galactorrhea, or problems with peripheral vision. Her medications are fish oil, multivitamin, and probiotic. Physical exam is notable for BMI of 21.7 kg/m2, round face with increased facial plethora, and an increased posterior fat pad. Significant labs include DHEA sulfate 15mcg/dL (18-391mcg/dL), FSH 6.3mlU/mL, estradiol <15pg/mL for a non-premenopausal woman (19-357pg/mL), total testosterone 3ng/dL (2-45ng/dL), prolactin 25.9 ng/dL (3.0-30 ng/dL). Her ACTH is <5pg/mL (6-50pg/mL) and AM cortisol followed by 1 mg dexamethasone of 22.9mcg/dL (<2.0mcg/dL). Repeat low dose dexamethasone suppression test is significant for AM cortisol 20.7 mcg/dL (4-22mcg/dL) and dexamethasone 258ng/dL. CT Abdomen is performed revealing a left sided adrenal mass. The patient undergoes unilateral adrenalectomy with pathology demonstrating an adrenal cortical adenoma. Her post-operative midnight salivary cortisol levels are appropriately low. Given some symptoms of adrenal insufficiency of dizziness and weakness she undergoes a slow hydrocortisone taper. Her menstrual cycles gradually return, facial plethora and sites of abnormal fat deposition resolve. She reports a significant improvement in her psychological wellbeing with decreased anxiety and increased functionality. Conclusion: The signs and symptoms of Cushing’s syndrome are attributable to the presence of hypercortisolism. While there are signs highly suggestive of Cushing’s syndrome including central obesity with wasting of the extremities, increased dorsocervical fat pad, easy bruising and wide purple striae, symptoms can be subtle, leading to a delay in diagnosis. Our patient presented with a complaint of amenorrhea. Menstrual irregularities are very common in women with Cushing’s syndrome. These symptoms are due to suppression of gonadotropin-releasing hormone secretion secondary to hypercortisolemia, with resultant decrease in levels of FSH and LH. A high level of suspicion is important in order to diagnose Cushing’s syndrome as curative treatment leads to a significant improvement in morbidity and the patient’s quality of life.

Visual Vignette

Case Presentation: A 55-year-old female presented with a 5-year history of progressive weight gain, fatigue, easy bruising, abdominal striae, and central obesity; she appeared cushingoid. Her medical history included hypertension, gout, diabetes mellitus, and restrictive lung disease. Endocrine evaluation revealed: 24-hour urine free cortisol 124.2 mg (20-100), 2 consecutive elevated midnight salivary cortisol levels of 541 and 459 ng/dL (<100), and a random adrenocorticotrophic hormone (ACTH) level of 65 pg/mL (5-50). Two 8 am serum cortisol measurements were 28.6 and 15.1 mg/dL after 1-mg low-dose and 8-mg high-dose overnight dexamethasone suppression tests, respectively. Magnetic resonance imaging of the sella did not reveal a sellar or parasellar adenoma, and the pituitary appeared normal (Fig. 1A, black arrow); incidentally, a soft tissue mass (Fig. 1A, white arrow) was identified in the sphenoid sinus. On noncontrast computed tomographic (CT) scanning of the sinuses, an isointense lesion with areas of punctate calcification was re-identified (Fig. 1B, white arrow); the sellar floor was intact and there was no evidence of bony destruction. Inferior petrosal sinus sampling demonstrated more than a 3-fold increase in the central to peripheral gradient of ACTH after administration of corticotrophic-releasing hormone, which was consistent with Cushing’s disease. A 4 x 4 mm pituitary microadenoma was identified and resected during transsphenoidal exploration. Postoperatively, the patient became hypocortisemic consistent with remission, and replacement hydrocortisone was administered. The pituitary adenoma was immunohistochemically positive for ACTH. The sphenoid mass was also removed completely during surgery. What is the diagnosis?

Depression, smoking, physical inactivity and season independently associated with midnight salivary cortisol in type 1 diabetes.

BackgroundDisturbances of the circadian rhythm of cortisol secretion are associated with depression, coronary calcification, and higher all-cause and cardiovascular mortality.The primary aim of this study was to test the associations between midnight salivary cortisol (MSC), depression and HbA1c, and control for behavioural, environmental and intra individual factors with possible impact on cortisol secretion, like smoking, physical inactivity, season, medication, diabetes duration, severe hypoglycemia episodes, age and gender in patients with type 1 diabetes. Secondary aims were to present MSC levels for a reference group of non-depressed type 1 diabetes patients with a healthy life style (physically active and non-smoking), and to explore seasonal variations.MethodsA cross-sectional population based study of 196 patients (54% men and 46% women) aged 18–59 years that participated in a randomized controlled trial targeting depression in type 1 diabetes. Depression was assessed by the Hospital Anxiety and Depression Scale-depression subscale. MSC, HbA1c, serum-lipids, blood pressure, waist circumference and data from medical records and the Swedish National Diabetes Registry were collected.ResultsThirty four patients (17%) had MSC ≥9.3 nmol/L, which was associated with smoking (AOR 5.5), spring season (AOR 4.3), physical inactivity (AOR 3.9), self-reported depression (AOR 3.1), and older age (per year) (AOR 1.08). HbA1c >70 mmol/mol (>8.6%) (AOR 4.2) and MSC ≥9.3 nmol/L (AOR 4.4) were independently linked to self-reported depression. Season was strongly associated with MSC levels and no other variables studied showed seasonal variations. In a reference group of 137 non-depressed patients with a healthy life style (physically active, non-smoking) the median MSC level was 4.6 nmol/L (range 1.9–23.0).ConclusionsIn this study of patients with type 1 diabetes high MSC was linked to smoking, physical inactivity, depression, season and older age. Thus a high cortisol value identified three major targets for treatment in type 1 diabetes.

Detecting post-surgical recurrence in a patient with Cushing’s disease

To the Editor, Cushing’s disease (CD), a rare disorder of chronic hypercortisolism caused by an adrenocorticotropic (ACTH)-secreting pituitary adenoma, is associated with increased mortality and complications including central obesity, diabetes mellitus, osteoporosis, and cardiovascular disease [1]. Transsphenoidal adenomectomy is generally first-line treatment for CD but confirmation of surgical success and diagnosis of recurrence can prove challenging [1]. We endeavor to raise awareness of the complex, insidious nature of CD recurrence through this illustrative case report. A 17-year-old female presented in 2006 with signs and symptoms of CD including facial rounding and rubor, hirsutism, alopecia, proximal muscle weakness, acne, stretch marks, weight gain, fatigue, insomnia, emotional fluctuations, headaches, and heartburn. She had elevated 24-hour urinary free cortisol [UFC; 126.5 μg/24 h (normal, <80)], and plasma ACTH [61 pg/mL (normal <48)]. Her dexamethasone suppression/corticotropin-releasing hormone stimulation test (Dex/CRH) was positive (serum cortisol 6.0 μg/dL 15 min after CRH) and magnetic resonance imaging (MRI) showed a 1.1-cm hypoenhancing pituitary lesion, confirming CD diagnosis (Fig. 1a). Fig. 1 a Initial (2006) pre-operative T1 dynamic contrast-enhanced MRI (field strength 1.5 T) showing a 1.1-cm pituitary lesion. b Follow-up (2011) MRI with no lesion noted. c ACTH immunostain confirming recurrent CD After transsphenoidal surgery in December 2006, corticotroph adenoma was histologically confirmed. Consistent with CD remission, nadir serum cortisol measurement of 1.1 μg/dL (normal range 7.0–23.0) was recorded at 8 a.m. within 72 h post-surgery. Over the ensuing months, the patient reported decreased acne, heartburn, and proximal muscle weakness. Her face thinned and she lost 55 pounds. Beginning 6 months after surgery, she reported that her previous symptoms began to return episodically several times per year. In February 2011, her symptoms (weight gain, acne, fatigue, and proximal muscle weakness) became unremitting. At this time, however, 24-h UFC and Dex/CRH tests were normal. She was noted to have elevated morning serum cortisol (peak, 31.5 μg/dL), but levels normalized after oral estrogen was discontinued. A follow-up MRI showed no pituitary lesion (Fig. 1b). Despite consistently normal biochemical assessments (13 salivary cortisol tests, seven 24-h UFCs, three Dex/CRH tests, and one overnight Dex suppression test) over the 5-year period since pituitary surgery, the patient’s Dex/CRH levels ultimately became strongly positive (7.9 μg/dL 15 min after CRH; Dex level: 571 ng/dL) in late 2011. Based on the positive Dex/CRH result plus strong symptomatic and physical features of recurrent CD, the patient underwent repeat pituitary surgery. Corticotroph adenoma was again identified, removed, and confirmed by positive immunohistochemical staining for ACTH (Fig. 1c). Post-surgery, serum cortisol was measured every 6 h and, consistent with remission and possible complete removal of the adenoma, levels decreased to 0.9 μg/dL (normal 6.2–19.0) within 72 h. Her CD symptoms resolved and follow-up biochemistry was negative. This case study illustrates the complexities of identifying patients with post-surgical recurrent CD. Within 4 years of apparent surgical remission, the patient experienced returning symptoms despite normal UFC and Dex/CRH tests. Ultimately, however, once she had biochemical evidence of CD recurrence (i.e., positive Dex/CRH despite continued normal UFC), she underwent repeat pituitary surgery and corticotroph adenoma was histologically confirmed. While subnormal immediate post-operative serum cortisol (as detected in this patient after her initial surgery) generally portends lasting remission, recurrence is still a possibility and occurs in approximately 6–12 % of such cases [2]. Similarly, normal UFC and/or midnight salivary cortisol levels are not reliable predictors of sustained remission per se. Careful follow up is required for all post-surgical CD patients and, if recurrence is suspected, biochemical test results should be interpreted in the context of clinical signs and symptoms. CD has been associated with a 1.84- to 4.8-fold increase in mortality compared with the general population [3, 4]. However, many features of cortisol excess (e.g., obesity, depression, diabetes, hypertension, dyslipidemia) are common in the general population [1]. Given that 10-year post-surgical recurrence rates for CD may be as high as 56 % [5], postoperative CD patients should be meticulously monitored for persistence and recurrence of disease. When this patient presented, no medical therapies were yet indicated for treatment of recurrent CD. Since that time, however, treatment options have expanded and clinicians have more choices for treating refractory cases. The US FDA has approved mifepristone (a glucocorticoid receptor antagonist) for treatment of hyperglycemia associated with Cushing’s syndrome [6], and pasireotide (a multireceptor-targeted somatostatin analog) for treatment of adults with CD who are not surgical candidates [7]. Choice of therapy depends on several factors including the patient’s overall surgical risk, severity of hypercortisolism, and patient preferences—particularly with respect to fertility. Regardless of treatment choice, special attention should be given to recurring symptoms as these may indicate early signs of disease even before biochemical evidence is present. Appropriate management is crucial, even when conflicting results make clinical decisions challenging.

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease

To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. Laboratory tests included morning and midnight serum cortisol levels, 24h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.

The Association between Midnight Salivary Cortisol and Metabolic Syndrome in Korean Adults

BackgroundThe common characteristics of metabolic syndrome (MetS) and Cushing's syndrome suggest that excess cortisol may be involved in the pathogenesis of MetS. Salivary cortisol measurements are simple and can be surrogates for plasma free cortisol, which is the most biologically active form. We evaluated the association between levels of midnight salivary cortisol and MetS in Korean adults.MethodsA total of 46 subjects, aged 20 to 70 years, who visited the Health Care Center at Konkuk University Hospital from August 2008 to August 2009 were enrolled. We compared the levels of midnight salivary cortisol in subjects with MetS with those in subjects without MetS. We analyzed the associations between midnight salivary cortisol levels and components of MetS.ResultsMidnight salivary cortisol levels were higher in the MetS group (70±42.4 ng/dL, n=12) than that in the group without MetS (48.1±36.8 ng/dL, n=34) (P=0.001). Positive correlations were observed between midnight salivary cortisol levels and waist circumference, fasting blood glucose, and homeostasis model assessment of insulin resistance. The risk for MetS was significantly higher in subjects with midnight salivary cortisol levels ≥100 ng/dL than in those with levels <50 ng/dL (odds ratio, 5.9; 95% confidence interval, 2.35 to 36.4).ConclusionThe results showed a positive correlation between midnight salivary cortisol levels and MetS, suggesting that hypercortisolism may be related to MetS.

The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma

The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma

The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma

The criteria for defining subclinical hypercortisolism (SH) are debated and a real gold standard test or combination of tests is lacking. Recently, late-night salivary cortisol (MSC) has been described as a sensitive and easy-to-perform marker for diagnosing overt hypercortisolism. No data are available on the role of MSC in the diagnosis of SH. The aim of this study was to evaluate the sensitivity and specificity of MSC levels in the diagnosis of SH in patients with adrenal incidentalomas (AI). In 103 (females/males, 69/34) patients with AI, MSC levels were studied. One milligram overnight dexamethasone suppression test (DST), urinary-free cortisol (UFC), and ACTH plasma levels were also evaluated. Patients were defined as affected by SH if they showed two of the following criteria: DST>83 nmol/l, ACTH <2.2 pmol/l, and UFC >193 nmol/24 h. No difference in MSC levels in patients with SH (3.1+/-3.1 nmol/l) compared with patients without SH (2.2+/-2.8 nmol/l) was observed. In patients with SH, MSC levels were significantly correlated with DST (r=0.4, P<0.05). Using the cut-off of 5.1 nmol/l, the sensitivity and specificity of MSC levels for diagnosis of SH is 22.7 and 87.7% respectively. In patients with AI, normal levels of MSC do not exclude SH, whereas high levels may suggest the presence of SH identified by conventional tests. Thus, MSC is not suitable as a screening test, although it may be used in conjunction with other tests as the confirming test in selected patients.

Reversibles metabolisches Syndrom hormoneller Ursache

A 52-year-old male patient was admitted to the emergency department with dyspnea and hypertensive urgency. During the previous 6 months, the patient had noticed leg edema, weight gain (particularly in the face and abdomen), and impotence. 1.5 years ago, he was diagnosed with hypertension resistant to medication. After an accident at work 1 year ago, osteoporosis was diagnosed with vertebral and rib fractures. Measurement of sleeping midnight salivary cortisol levels together with 24-h urine free cortisol excretion and an overnight low-dose 1-mg dexamethasone suppression test proved overt hypercortisolism. The high-dose 8-mg dexamethasone suppression suggested an adrenal or ectopic source of hypercortisolism. By contrast, elevated adreno-corticotropic hormone (ACTH) levels and a corticotropin-releasing hormone stimulation test gave evidence for a pituitary source of hypercortisolism. However, pituitary magnetic resonance imaging failed to reveal a pituitary adenoma. Moreover, computed tomography scans of thorax and abdomen were negative. In this situation, an inferior petrosal vein sampling was performed and revealed an ACTH gradient (central-systemic) >3 with lateralization to the right side. The patient underwent a selective, partial, transsphenoidal resection and was cured from clinical signs and symptoms caused by hypercortisolism. Subsequent hormonal replacement therapy of postoperative pituitary insufficiency was necessary.