Withdrawal Study Details Effects of Levoketoconazole in Cushing’s Syndrome

Data presented at AACE 2022 detail levoketoconazole-specific effects observed among patients with endogenous Cushing’s syndrome from the phase 3 LOGICS trial.

New research presented at the American Academy of Clinical Endocrinology (AACE) annual meeting provides insight into the effects of treatment with levoketoconazole (Osilodrostat) among patients with endogenous Cushing’s syndrome.

An analysis of data from a double-blind, placebo-controlled, randomized withdrawal study, results of the study demonstrate levoketoconazole provided benefits across a range of etiologies and provide evidence of levoketoconazole-specific effects through the withdrawal and reintroduction of therapy during the trial.

“This LOGICS study showed that treatment with levoketoconazole benefitted patients with Cushing’s syndrome of different etiologies and a wide range in UFC elevations at baseline by frequent normalization of mUFC and concurrent improvements in serum cholesterol,” said Maria Fleseriu, MD, professor of medicine and neurological surgery and director of the Northwest Pituitary Center at Oregon Health and Science University, during her presentation. “The benefits observed were established as levoketoconazole-specific via the loss of therapeutic effect upon withdrawal to placebo and restoration upon reintroduction of levoketoconazole.”

An orally administered cortisol synthesis inhibitor approved by the US FDA for treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome considered ineligible for surgery, levoketoconazole received approval based on results of the phase 3 open-label SONICS trial, which demonstrated . Launched on the heels of SONICS, the current trial, LOGICS, was designed as phase 3, double-blind, placebo-controlled, randomized withdrawal study aimed at assessing the drug-specificity of cortisol normalization in adult patients with Cushing’s syndrome through a comparison of the effects of withdrawing levoketoconazole to placebo against continuing treatment.

The trial began with an open-label titration maintenance phase followed by a double-blind randomized withdrawal phase and a subsequent restoration phase, with the randomized withdrawal and restoration phase both lasting 8 weeks. A total of 89 patients with Cushing’s syndrome received levoketoconazole to normalize mUFC. Of these, 39 patients on a stable dose for 4 weeks or more were included in the randomized withdrawal stage of the study. These 39, along with 5 completers of the SONICS trial, were randomized in a 1:1 ratio to continue therapy with levoketoconazole or placebo therapy, with 22 patients randomized to each arm.

The primary outcome of interest in the study was the proportion of patients with loss of mean urinary free cortisol response during the randomized withdrawal phase of the study, which was defined as an mUFC 1.5 times the upper limit of normal or greater or an mUFC 40% or more above baseline. Secondary outcomes of interest included mUFC normalization at the end of the randomized withdrawal phase of the study and changes in comorbidity biomarkers.

Overall, 21 of the 22 patients randomized to placebo during the withdrawal stage met the primary endpoint of loss of mUFC compared to just 9 of 22 among the levoketoconazole arm of the trial (treatment difference: -54.5% [95% CI, -75.7 to -27.4]; P=.0002). Additionally, at the conclusion of the randomization phase, mUFC normalization was observed among 11 patients in the levoketoconazole arm of the trial compared to 1 patient receiving placebo (treatment difference: 45.5% [95% CI, 19.2 to 67.9]; P=.0015).

Further analysis indicated the restoration of levoketoconazole therapy was associated with a. Reversal of loss of contrail control in most patients who had been randomized to placebo. Investigators pointed out the mean change from randomized withdrawal baseline to the end of the randomized withdrawal period in total cholesterol was -0.04 mmol/L for levoketoconazole and 0.9 mmol/L for placebo (P=.0004) and the mean change in LDL-C was -0.006 mmol/L and 0.6 mmol/L, respectively (P=0.0056), with the mean increases in cholesterol observed among the placebo arm reversed during the restoration phase.

In safety analyses, results suggest the most commonly reported adverse events seen with levoketoconazole treatment, during all study phases combined were nausea and hypokalemia, which occurred among 29% and 26% of patients, respectively. Investigators also pointed out liver-related events, QT interval prolongation, and adrenal insufficiency, which were respecified adverse events of special interest occurred among 10.7%, 10.7%, and 9.5% of patients receiving levoketoconazole, respectively.

This study, “Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome: A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study,” was presented at AACE 2022.

Osilodrostat Improves Physical Manifestations of Hypercortisolism for Most Adults

Osilodrostat is associated with improvements in physical manifestations of hypercortisolism and reductions in mean body weight and BMI in adults with Cushing’s syndrome, according to a speaker.

As Healio previously reported, in findings from the LINC 4 phase 3 trial, osilodrostat (Isturisa, Recordati) normalized mean urinary free cortisol level at 12 weeks in more than 75% of adults with Cushing’s disease. In new findings presented at the AACE Annual Scientific and Clinical Conference, most adults with Cushing’s syndrome participating in the LINC 3 phase 3 trial had improvements in physical manifestations of hypercortisolism 72 weeks after initiating osilodrostat, with more than 50% having no dorsal fat pad, supraclavicular fat pad, facial rubor, proximal muscle atrophy, striae, ecchymoses and hirsutism for women at 72 weeks.

Adrenal transparent _Adobe
Source: Adobe Stock

“Many patients with Cushing’s syndrome suffer from clinical manifestations related to hypercortisolism,” Albert M. Pedroncelli, MD, PhD, head of clinical development and medical affairs for Recordati AG in Basel, Switzerland, told Healio. “The treatment with osilodrostat induced a rapid normalization of cortisol secretion, and improvements in physical manifestations associated with hypercortisolism were observed soon after initiation of osilodrostat and were sustained throughout the study.”

Albert M. Pedroncelli

Pedroncelli and colleagues analyzed changes in the physical manifestations of hypercortisolism in 137 adults with Cushing’s syndrome (median age, 40 years; 77.4% women) assigned osilodrostat. Dose titration took place from baseline to 12 weeks, and therapeutic doses were administered from 12 to 48 weeks, with some participants randomly assigned to withdrawal between 26 and 34 weeks. An extension phase of the trial took place from 48 to 72 weeks. Investigators subjectively rated physical manifestations of hypercortisolism in participants as none, mild, moderate or severe. Participants were evaluated at baseline and 12, 24, 34, 48 and 72 weeks.

At baseline, the majority of the study cohort had mild, moderate or severe physical manifestations of hypercortisolism in most individual categories, including dorsal fat pad, central obesity, supraclavicular fat pad, facial rubor, hirsutism in women and striae. Central obesity was the most frequent physical manifestation rated as severe.

The percentage of participants with improvements in physical manifestations of hypercortisolism increased from week 12 on for all individual manifestations evaluated in the study, and improvements were maintained through week 72. At 72 weeks, the percentage of participants who had no individual physical manifestations was higher than 50% for each category except central obesity, where 30.6% of participants had no physical manifestations.

In addition to improvement in physical manifestations, the study cohort had decreases in body weight, BMI and waist circumference at weeks 48 and 72 compared with baseline.

“The main goal of treating patients with Cushing’s syndrome is to normalize cortisol secretion,” Pedroncelli said. “The rapid reduction and normalization of cortisol levels is accompanied by improvement in the associated clinical manifestations. This represents an important objective for patients.”

From https://www.healio.com/news/endocrinology/20220512/osilodrostat-improves-physical-manifestations-of-hypercortisolism-for-most-adults

Crinetics Pharmaceuticals (CRNX) Reports Positive Top-line Results Including Strong Adrenal Suppression from CRN04894 Phase 1 Study

Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX) today announced positive results from the multiple-ascending dose (MAD) portion of a first-in-human Phase 1 clinical study of CRN04894, the company’s first-in-class, investigational, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist that is being developed for the treatment of Cushing’s disease, congenital adrenal hyperplasia (CAH) and other conditions of excess ACTH. Following administration of CRN04894, results showed serum cortisol below normal levels and a marked reduction in 24-hour urine free cortisol excretion in the presence of sustained, disease-like ACTH concentrations.

“The design of our Phase 1 healthy volunteer study allowed us to demonstrate CRN04894’s potent pharmacologic activity in the presence of ACTH levels that were in similar range to those seen in CAH and Cushing’s disease patients,” said Alan Krasner, M.D., Crinetics’ chief medical officer. “The observation of dose-dependent reductions in serum cortisol levels to below the normal range even in the presence of high ACTH indicates that CRN04894 was effective in blocking the key receptor responsible for regulating cortisol secretion. We believe this is an important finding that may be predictive of CRN04894’s efficacy in patients.”

ACTH is the key regulator of the hypothalamic-pituitary adrenal (HPA) axis controlling adrenal activation. It is regulated by cortisol via a negative feedback loop that acts to inhibit ACTH secretion. This feedback loop is dysregulated in diseases of excess ACTH. In Cushing’s disease, a benign pituitary tumor drives excess ACTH secretion even in the presence of excess cortisol. While in CAH, an enzyme deficiency results in excess androgen synthesis without normal cortisol synthesis, allowing unchecked ACTH production and requiring lifelong glucocorticoid use. In both diseases, excess ACTH drives over-stimulation of the adrenal gland and leads to a host of symptoms including infertility, adrenal rest tumors, and metabolic complications in CAH and, in Cushing’s disease, symptoms include hypertension, central obesity, neuropsychiatric disorders and metabolic complications. To our knowledge, no other ACTH antagonists are currently in clinical development for diseases of ACTH excess such as Cushing’s disease or CAH.

The 49 healthy adults evaluated in the multiple ascending dose portion of the Phase 1 study were administered 40, 60 or 80 mg doses of CRN04894, or placebo, daily for 10 days. After 10 days of dosing was complete, evaluable participants were administered an ACTH challenge to stimulate adrenal activation to disease relevant levels. Safety and pharmacokinetic data were consistent with expectations from the single-ascending dose cohorts in the Phase 1 study. There were no discontinuations due to treatment-related adverse events and no serious adverse events reported. Glucocorticoid deficiency was the most common treatment-related adverse event in the MAD cohorts. This was an expected extension of pharmacology given the mechanism of action of CRN04894. CRN04894 showed consistent oral bioavailability in the MAD cohorts with a half-life of approximately 24 hours, which is anticipated to support once-daily dosing.

Participants in the MAD cohorts who were administered once nightly CRN04894 experienced a dose-dependent suppression of adrenal function as measured by suppression of serum cortisol production of 17%, 29% and 37% on average from baseline over 24 hours for the 40, 60 or 80 mg dosing groups respectively, (despite requirement for glucocorticoid supplementation in some of these subjects to prevent clinical adrenal insufficiency), compared to an average 2% increase in serum cortisol for individuals receiving placebo. The strong, dose-dependent suppression of serum and urine free cortisol was achieved despite ACTH levels in subjects in the 60 and 80 mg cohorts similar to those typically seen in patients with CAH and Cushing’s disease. Even when an additional exogenous ACTH challenge was administered on top of the already increased ACTH levels, cortisol levels remained below the normal range in subjects receiving CRN04894, indicating clinically significant suppression of adrenal activity.

“Due to its central position in HPA axis, ACTH is the obvious target for inhibiting excessive stimulation of the adrenal in diseases of ACTH excess. Even though the field of endocrinology has known about its clinical significance for more than 100 years, we are not aware of any other ACTH antagonist that has entered clinical development. This is an important milestone for endocrinology and for our company.” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “We are very excited to initiate patient studies in Cushing’s disease and CAH with CRN04894, which will be our third home-grown NCE to demonstrate pharmacologic proof-of-concept and enter patient trials.”

Crinetics plans to present additional details of safety, efficacy, and biomarker results from the CRN04894 Phase 1 study at an endocrinology-focused medical meeting in 2022.

Data Review Conference Call Crinetics will hold a conference call and live audio webcast today, May 25, 2022, at 8:00 a.m. Eastern Time to discuss results from the MAD cohorts of the Phase 1 study of CRN04894. To participate, please dial 1-877-407-0789 (domestic) or 1-201-689-8562 (international) and refer to conference ID 13730000. To access the webcast, click here. Following the live event, a replay will be available on the Events page of the Company’s website.

About the CRN04894 Phase 1 Study Crinetics has completed enrollment of the 88 healthy volunteers in this double-blind, randomized, placebo-controlled Phase 1 study. Participants were divided into multiple cohorts in the single ascending dose (n=39) and multiple ascending dose (n=49) portions of the study. In both the SAD and MAD portions of the study, safety and pharmacokinetics were assessed. In addition, pharmacodynamic responses were evaluated before and after challenges with injected synthetic ACTH to assess pharmacologic effects resulting from exposure to CRN04894.

From https://www.streetinsider.com/Corporate+News/Crinetics+Pharmaceuticals+(CRNX)+Reports+Positive+Top-line+Results+Including+Strong+Adrenal+Suppression+from+CRN04894+Phase+1+Study/20126484.html

Recurrent Metatarsal Fractures in a Patient With Cushing Disease

Published: May 15, 2022 (see history)

DOI: 10.7759/cureus.25015

Cite this article as: Iturregui J, Shi G (May 15, 2022) Recurrent Metatarsal Fractures in a Patient With Cushing Disease: A Case Report. Cureus 14(5): e25015. doi:10.7759/cureus.25015


Cushing syndrome (CS) can result from excess exposure to exogenous or endogenous glucocorticoids. The most common endogenous cause of CS is an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, known as Cushing disease (CD). Patients typically present with characteristics including truncal obesity, moon facies, facial plethora, proximal muscle weakness, easy bruising, and striae. Insufficiency fractures of the metatarsals are a rare presentation for CS. A 39-year-old premenopausal woman presented to the orthopedic outpatient clinic with recurrent metatarsal fractures and no history of trauma. A metabolic bone disease was suspected, and after further evaluation by endocrinology services, the CD was diagnosed. Surgical resection was performed, and pathology confirmed the presence of a pituitary adenoma. Multiple, recurrent, non-traumatic metatarsal fractures can be the initial presentation of CD in a premenopausal woman.


Cushing syndrome (CS) is a rare clinical and metabolic disorder caused by excessive exposure to glucocorticoids. In the United States, an estimated 10 to 15 people per million population are affected by CS each year, while studies in Europe report an incidence of 0.7 to 2.4 per million people affected annually [1,2]. Furthermore, CS more commonly affects women [2]. Common characteristics of CS include truncal obesity, moon facies, proximal muscle weakness, fatigue, facial plethora, supraclavicular fullness, peripheral edema, weight gain, striae, easy bruising, acne, hirsutism, amenorrhea, dorsocervical “buffalo” hump, depression, hypertension, impaired glucose tolerance, and osteoporosis [1,3,4].

The most common cause of CS is exogenous glucocorticoid therapy. Meanwhile, endogenous cortisol hypersecretion commonly results from either an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma or a cortisol-secreting adrenal tumor. When CS is caused by a pituitary adenoma, this is referred to as Cushing disease (CD). CD is the most common endogenous cause of CS, accounting for 80-85% of cases [1,5].

Whether a patient’s CS is caused by exogenous or endogenous sources, excessive exposure to steroids can have deleterious effects on the bones, resulting in secondary osteoporosis. The decrease in bone mass and microarchitectural changes increase the risk of fragility fractures, with reported rates as high as 30-67% [6]. The most commonly reported fracture site in CS patients is the vertebrae; however, other reported fracture sites include the ribs, sternum, wrist, elbow, shoulder, pelvis, hip, femoral condyles, tibia, fibula, calcaneus, metatarsals, and phalanges [4,6-16]. There are reports of metatarsal fractures occurring in patients diagnosed with endogenous CS [3,6,7,16-19]. However, to the best of our knowledge, there are no reports of multiple, recurrent, bilateral metatarsal fractures as the initial presentation in a pre-menopausal woman with CD. Here, we present a case of a premenopausal woman with recurrent metatarsal stress fractures who was diagnosed with CD after further evaluation.

Case Presentation

A 39-year-old premenopausal woman was evaluated by her primary care physician due to right foot pain after feeling a pop while walking. She reported swelling and some bruising along the lateral aspect of her foot. Her exercise regimen consisted of walking twice a week for 30 minutes at each session. She did not report any traumatic injuries to her foot. Imaging revealed a fifth metatarsal fracture (Figure 1). The patient was placed in a cast walker boot and referred to orthopedics for further evaluation. Orthopedic management included no weight bearing on her right foot and continuing using the cast walker boot or a postop shoe, with reevaluation in four weeks.

Figure 1: Oblique radiograph of the right foot demonstrating a mildly displaced transverse fracture of the proximal fifth metatarsal (arrow).

At the time of evaluation, the patient was 161.5 cm tall, weighed 101 kg, and had a BMI of 38.86 kg/m2. Her medical history included hypertension, hyperglycemia, hyperlipidemia, hypothyroidism, obesity, anxiety, obstructive sleep apnea, and colon polyps. The patient reported a history of metatarsal fractures in her left foot in 2008, which healed slowly and without surgical intervention. She also underwent bunion and bunionette surgery on her left foot. Her medications included alprazolam, levothyroxine, lisinopril, bimatoprost, ergocalciferol, meloxicam, and ondansetron. She was a former smoker (2007-2010), a daily wine drinker, and had an active job working as a nurse. Her family history included lung cancer and alcohol abuse in her father; hypertension, hypothyroidism, and alcohol abuse in her mother; and osteoporosis and end-stage renal disease secondary to polycystic kidney disease in her sister.

At the three-month follow-up visit, the fracture line remained clearly visible, and minimal callus had formed at the fracture site. Surgical fixation was recommended and performed four months after the fracture occurred. Six months after her right foot’s fifth metatarsal fracture, she developed new-onset swelling and tenderness over the middle metatarsals dorsally in her right foot with no history of trauma. Radiographs demonstrated new second and third metatarsal neck fractures (Figure 2). Conservative management with a postop shoe for six weeks and re-evaluation was recommended. In the interim between her initial right foot fifth metatarsal fracture and the new right foot second and third metatarsal fractures, the patient was diagnosed with diabetes mellitus type II, treated with a plant-based diet, hospitalized for urolithiasis, and diagnosed with depression. She was started on bupropion.

Figure 2: Anteroposterior radiograph of bilateral feet demonstrating second and third metatarsal neck fractures of the right foot (arrows).

Due to the recurrent metatarsal stress fractures with no associated trauma, the patient was referred to endocrinology for workup of metabolic bone disease. Her physical exam revealed no abnormalities, and her overall workup was negative. Bone mineral density results demonstrated osteopenia in the lumbar spine (T-score: -1.8) and left femoral neck (T-score: -1.0), and normal bone density in the left total hip (T-score: -0.80).

Six months following her right foot’s second and third metatarsal fractures, the patient developed right great toe and second toe swelling and bruising. Two months later, after trying supportive tennis shoes and reducing weightbearing on her right foot, she did not notice any improvement and sought orthopedic care. Radiographs revealed a new subacute fracture of the right second proximal phalanx (Figure 3). A magnetic resonance imaging (MRI) scan was ordered, which revealed a first metatarsal shaft stress fracture as well (Figure 4). She underwent conservative management with a Cam walker boot and was referred to endocrinology for re-evaluation for suspected endocrinopathy.

Figure 3: AP radiograph of bilateral feet demonstrating a subacute fracture of the second proximal phalanx of the right foot (arrow).
Figure 4: T1-weighted sagittal MRI of the right foot demonstrating a first metatarsal shaft stress fracture (arrow).

At her endocrinology visit, a physical exam revealed some facial hair, frontal hair loss, and a significant dorsocervical and anterior cervical fat pad. A Cushingoid face shape, facial redness, acne, oligomenorrhea, incremental weight gain over the last decade, centripetal adiposity, easy bruising, and lower leg swelling were also reported. Bone mineral density results reported spine and hip Z-scores within the expected range for age, indicating no osteoporosis. Since she had features of hypercortisolism, labs to evaluate for Cushing syndrome were ordered. The 11:00 pm salivary cortisol levels were elevated to 173 ng/dL and 168 ng/dL in two samples. The 1 mg dexamethasone suppression test failed to suppress her cortisol levels, with an elevated cortisol value of 29 mcg/dL. The 24-hour urine-free cortisol level was elevated at 135 mcg/24 hours. These lab results confirmed a diagnosis of Cushing syndrome. Her ACTH was elevated at 86 pg/mL, which indicated an ACTH-dependent CS. Pituitary MRI demonstrated a 1.1 cm × 1.5 cm × 1.1 cm pituitary lesion, representing a pituitary macroadenoma (Figure 5). The patient underwent endoscopic endonasal transsphenoidal pituitary tumor resection with the goal of treating her Cushing disease and preventing further fragility fractures. Pathology evaluation confirmed a pituitary adenoma.

Figure 5: T1-weighted coronal MRI of the pituitary demonstrating a 1.1 cm × 1.5 cm × 1.1 cm cystic sellar mass which represents a pituitary macroadenoma (arrow).


This is a case of a 39-year-old woman who presented with recurrent metatarsal fractures with no history of trauma, raising suspicion of a metabolic bone disease. The patient also developed centripetal weight gain, glucose intolerance, kidney stones, depression/anxiety, and Cushingoid features. A laboratory workup performed by endocrinology services confirmed a diagnosis of ACTH-dependent CS. An MRI revealed a pituitary lesion which represented a pituitary macroadenoma, for which surgical resection was performed. Pathology confirmed a pituitary adenoma. The association of multiple, non-traumatic metatarsal fractures occurring in premenopausal women with endogenous CS has been reported in the literature [3,7,19]. However, to the best of our knowledge, this is the first report presenting a premenopausal woman with multiple, recurrent metatarsal fractures as the initial manifestation of CD.

Several mechanisms play a role in glucocorticoid-induced bone loss, which is more prominent in trabecular bone compared to cortical bone [3,4,6,8]. Normally, trabecular bone has a greater bone turnover rate than cortical bone. In the presence of excess glucocorticoids, trabecular bone has greater sensitivity to glucocorticoids and undergoes slower bone turnover. The most significant effects of excess glucocorticoids on bones are decreased osteoblast function and quantity, which explain the reduced trabecular bone turnover rate [4,10]. The proposed mechanisms for this are glucocorticoid-induced inhibition of osteoblast proliferation and genesis, as well as induction of osteoblast and osteocyte apoptosis [4,10,11]. Furthermore, glucocorticoids decrease bone protein synthesis (e.g., osteocalcin), type I collagen formation, and alkaline phosphatase activity [4]. Additional effects include greater bone resorption, inhibition of intestinal calcium absorption, inhibition of renal calcium reabsorption, and decreased secretion of gonadal steroids and growth hormones [8]. Glucocorticoids also induce protein catabolism, which can result in muscle weakness, decreased bone stimulation from weakened muscle contraction, and further bone loss and debility [4].

Multiple fragility fractures in the foot with no history of trauma or overuse are uncommon. When evaluating a patient with this presentation, secondary causes for these fractures need to be investigated. Differential diagnoses include osteoporosis, Charcot foot, multiple myeloma, celiac disease, avascular necrosis, and endocrine disorders such as hyperthyroidism, primary hyperparathyroidism, or CS, among others [3,6,7].

There is a high rate of fragility fractures due to secondary osteoporosis in CS patients, with the vertebrae being most commonly affected [6]. LiYeung and Lui [7] and Albon et al. [19] each reported a case of a pre-menopausal woman who initially presented with multiple metatarsal fractures secondary to an adrenal adenoma causing CS. In each case, the patient’s densitometry indicated osteoporosis. However, in our case and the case reported by Molnar et al. [3] of a pre-menopausal woman with multiple fractures due to CD (recurrent fractures were not reported), the bone densitometries performed did not indicate osteoporosis.

The patients reported by LiYeung and Lui [7], Albon et al. [19], and Molnar et al. [3] did not demonstrate marked clinical characteristics of CS. In comparison to our patient, she did have multiple Cushingoid features upon her second evaluation by endocrinology. Furthermore, in all our cases, the patients were first evaluated for metatarsal fractures as the initial presentation, which resulted in a diagnosis of endogenous CS after further evaluation.

Finally, early recognition and treatment of CS are important, as there is an increased risk of morbidity and mortality as the condition progresses [20]. In addition, the treatment of CS can reverse the bone loss that occurs with excess glucocorticoid exposure [4,10]. This case also highlights the importance of collaboration between physicians in the different branches of medicine.


Excess glucocorticoid exposure can have deleterious effects on the bones, increasing the risk for secondary osteoporosis and fragility fractures. There needs to be an index of suspicion for metabolic bone disease, including endogenous CS caused by CD, as the underlying etiology of multiple, recurrent, atraumatic metatarsal fractures in pre-menopausal women. Early diagnosis and management of CD can lower the risk of morbidity and mortality as well as reverse bone loss.


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From https://www.cureus.com/articles/91295-recurrent-metatarsal-fractures-in-a-patient-with-cushing-disease-a-case-report

Intermittent Blurry Vision: An Unexpected Presentation of Cushing’s Syndrome Due to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH)

Published: May 15, 2022 (see history)

DOI: 10.7759/cureus.25017

Cite this article as: Fernandez C, Bhatia S, Rucker A, et al. (May 15, 2022) Intermittent Blurry Vision: An Unexpected Presentation of Cushing’s Syndrome Due to Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). Cureus 14(5): e25017. doi:10.7759/cureus.25017


Cushing’s syndrome (CS) is an uncommon endocrine disorder resulting from prolonged exposure to elevated glucocorticoids, with 10-15 million annual cases per the American Association of Neurological Surgeons. Exogenous and endogenous causes can further be divided into adrenocorticotropic hormone (ACTH) dependent (i.e Cushing’s Disease) or ACTH independent. ACTH-independent CS can be caused by primary bilateral macronodular adrenal hyperplasia (PBMAH) representing less than 1% cases of CS. We report a case of a woman presenting with chronic resistant hypertension, episodic blurry vision, weight gain and wasting of extremities. She was diagnosed with Cushing’s syndrome due to PBMAH.

Our patient’s presentation was unusual as she presented at 40 years old, 10 years earlier than expected for PBMAH; and primarily with complaints of episodic blurry vision. Her symptoms also progressed rapidly as signs and symptoms largely presented over the course of 12 months, however responded well to surgical resection.


Cushing’s syndrome (CS) is an uncommon endocrine disorder caused by prolonged exposure to elevated glucocorticoids [1]. There are exogenous or endogenous causes. The National Institute of Health’s (NIH) Genetic and Rare Diseases Information Center (GARD) estimated the prevalence of endogenous CS to be 1 in 26,000 [2]. According to a large study, the annual incidence of CS in individuals less than 65 years old was nearly 49 cases per million [3]. Cushing’s disease (CD), which is defined as Cushing’s syndrome caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, accounts for approximately 80% of patients with CS; whereas ACTH-independent CS accounts for the remaining 20% [4]. Among the causes of pituitary ACTH-independent CS is bilateral macronodular adrenal hyperplasia which is rare, comprising less than 1% of patients with CS [5]. Herein is a case of rapid onset Cushing’s syndrome due to PBMAH initially presenting as episodes of bilateral blurry vision.

Case Presentation

The patient is a 40-year-old female with a past medical history of resistant hypertension (on four agents), and recently diagnosed type 2 diabetes mellitus (started on insulin regimen). Patient was recently seen by her primary care provider, with complaints of intermittent episodes of blurry vision going on for months.

As part of evaluation in December 2020, the patient underwent a renal ultrasound as part of evaluation by the primary physician for uncontrolled hypertension. The doppler incidentally showed an indeterminate hypoechoic mass on the right kidney and presumably located within the right adrenal gland, measuring 3.4 x 5.4 cm, without sonographic evidence of renal artery stenosis. The left kidney appeared normal. She was recommended to have further evaluation with contrast enhanced MR or CT with adrenal protocol.

In January 2021, the patient was sent from her PCP’s office to the ED as the patient was having blurred vision. She had a plain CT scan of the brain that was unremarkable. The patient’s systolic blood pressure was in the 160s-170s mm Hg upon arrival to ED compliance with home medications of 5mg of amlodipine daily, 25mg of metoprolol succinate daily, 100mg of losartan daily, and 25mg of hydrochlorothiazide daily. Physical exam reported obesity without evidence of abdominal striae. Blood work in the ED showed elevated blood glucose level over 600 (mg/dL) despite being on a regimen of lantus 60 units, metformin 1000mg twice a day, and semaglutide SQ weekly. Hemoglobin A1c was greater than 15.5%, and vitamin D was low (15.6 ng/mL). The morning ACTH was low (<5pg/mL) (nAM levels: 7.2 – 63.3 pg/mL), AM cortisol was high at 26.1 ug/ml (normal: 5.0 – 23.0 ug/mL), plasma aldosterone was normal at 4.2 ng/dL with a normal plasma renin at 1.96 (0.25 – 5.82 ng/mL/h). 24-hour urine free cortisol (UFC) was high at 1299.5 (4.0-50.0 mcg/24h). CT of the abdomen/pelvis with and without contrast showed low-attenuation masses (less than 5 Hounsfield units) present in both adrenal glands measuring 6.9 x 5.3 cm on the right and 4.5 x 3.9 cm on the left, and did not demonstrate significant arterial enhancement (Figure 1). MR imaging of the abdomen without and with contrast was also obtained and showed the same masses of the bilateral adrenal glands, with largest on the left measured 3.6 cm and largest on the right measured 3.7 cm, as well as mild fatty infiltration of the liver. General surgery and hematology/oncology were consulted and recommendations were made for outpatient follow-up with PCP and endocrinology.

Figure 1: CT of the abdomen/pelvis with contrast showing low-attenuation masses present in both adrenal glands measuring 6.9 x 5.3 cm on the right (dark gray arrow) and 4.5 x 3.9 cm on the left (light gray arrow)

In early February 2021, the patient again presented to the ED complaining of recurrent episodes of bilateral blurry vision. Examination was unremarkable, including an ophthalmological exam with slit lamp exam. Blurred vision was suspected to be due to osmotic swelling in the setting of severe hyperglycemia as the patient had persistently uncontrolled blood sugars. Recommendations were for tighter control of blood glucose, and follow-up with primary care and ophthalmology.

Patient followed up with the endocrinologist in mid-February to which the patient reported first noticing a difference in her energy and changes to her weight around one year prior. She communicated a weight gain of 30 to 40 lbs over the past year. Patient had a reported history of gestational hypertension diagnosed five years ago when she gave birth to her daughter, which was steadily worsening over the past year. She reported intermittent myalgias and easy bruising. Patient had no family history or any apparent features to suggest multiple endocrine neoplasia (MEN) syndrome. Blood work revealed ACTH less than 1.5 pg/mL, AM cortisol was high at 24.5 mcg/dL, and normal aldosterone at 3.6 ng/dL, with normal renin and metanephrine levels. Physical examination revealed truncal obesity as well as a round face, cushingoid in appearance, and relatively thin extremities and abdominal striae.

She was then referred to a surgical specialist, and it was decided that she would undergo laparoscopic bilateral adrenalectomy due to severe Cushing’s syndrome. The surgical pathology report revealed macro-nodular cortical hyperplasia of both left and right adrenal gland masses with random endocrine atypia. The largest nodule on the left measured 4.5 cm and the largest nodule on the right measured 6.6 cm. Post-operatively she was started on hydrocortisone 20 mg every morning and 10 mg every evening, and fludrocortisone 0.1 mg twice a day as part of her steroid replacement regimen. Eventually she changed to hydrocortisone 10 mg three times a day and fludrocortisone 0.1 mg once a day. For her diabetes, her insulin glargine decreased from 60 units to 20 units. Amlodipine and hydrochlorothiazide were discontinued from her antihypertensive medications; she continued losartan and metoprolol. Follow up blood work showed stable electrolytes with potassium 4.2 mmol/L (3.5-5.2 mmol/L), sodium 137 mmol/L (134-144mmol/L), chloride 100 mmol/L (96-106 mmol/L), and carbon dioxide 23 mmol/L (20-29mmol/L).


ACTH-independent Cushing’s syndrome due to bilateral cortisol-secreting nodules is rare, accounting for 2% of CS cases. The majority of causes include primary bilateral macronodular adrenal hyperplasia (PBMAH), primary pigmented nodular adrenocortical disease (PPNAD), and bilateral adrenocortical adenomas (BAA). In PBMAH, typically patients are diagnosed within the fifth or sixth decade of life [4]. The usual age of onset for PPNAD is within the first to third decade of life, with median age in the pediatric population at age 15 years [6]. BAA is such a rare entity that there exists little epidemiological data with less than 40 reported cases until 2019 [7]. A small subset of patients present with overt clinical symptoms of CS, as hypercortisolism often follows an insidious course that can delay diagnosis from years to decades, with one series reporting a diagnostic delay of approximately eight years [8]. Serum and urine hormone screening in the right clinical setting can provide clues to these endocrine disorders, however diagnosis of ACTH-independent CS often occurs incidentally wherein a radiographic study was done for reasons other than to identify adrenal disease [9]. CT or MRI alone are not able to differentiate these disease entities, requiring pathological examination for final determination [7]. Adrenal venous sampling (AVS) and I-6B-iodomethyl-19-norcholesterol (I-NP-59) can aid in identifying hormone-secreting status of each adrenal lesion, however usefulness is debated among experts [10-12].

In all cases the end goal is to normalize adrenocortical hormones, and PBMAH primarily involves surgical resection with exogenous hormone replacement. Bilateral adrenalectomy is generally the treatment of choice with overt Cushing syndrome regardless of cortisol level. These patients require lifelong steroid administration [9,13]. Another approach is unilateral adrenalectomy of the larger or more metabolically active gland, which can be identified after AVS or I-NP-59 testing. This has been proposed in order to preserve some autonomous hormonal production and prevent adrenal crisis, however remission rates of Cushing syndrome as high as 84% have been reported with eventual need for bilateral adrenalectomy [7,8,14]. Steroid enzyme inhibition to control cortisol secretion has been used as an adjunct before surgery. In some patients with identified aberrant adrenal hormone receptors, targeted pharmacological inhibition remains an alternative medical approach [8]. Despite these alternatives to surgery, surgical resection remains the optimal approach [1].


ACTH-independent Cushing’s syndrome due to PBMAH usually presents as an indolent course, with typical diagnosis in the fifth to sixth decade. As the use of imaging for other non-endocrine related investigations becomes more utilized, PBMAH being less of a rare entity. Clinical presentation usually dictates the timing of and type of surgical intervention. Although there are some reports of unilateral resection resulting in a cure, many of these cases eventually proceed to staged bilateral resection. Our patient’s presentation as her primary complaint was recurrent episodes of blurry vision that were suspected to be due to osmotic swelling because of her uncontrolled hyperglycemia. Her case was also unusual as she presented at 40 years old, an average of 10 years earlier than is typically diagnosed for PBMAH. Her symptoms also progressed rapidly over the course of 12 months with development of resistant hypertension and insulin-dependent diabetes requiring high basal insulin. Following surgical resection, her antihypertensive regimen was de-escalated and had significant reduction in insulin requirements, and was maintained on adrenocorticoid therapy.


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From https://www.cureus.com/articles/90069-intermittent-blurry-vision-an-unexpected-presentation-of-cushings-syndrome-due-to-primary-bilateral-macronodular-adrenal-hyperplasia-pbmah

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