Osilodrostat normalizes urinary free cortisol in Cushing’s disease for most at 72 weeks

Posted on September 19, 2022 by MaryO

More than 80% of adults with Cushing’s disease receiving osilodrostat had normalized mean urinary free cortisol levels at 72 weeks of treatment, according to findings from the LINC 3 study extension.

“Cushing’s disease is a chronic condition, and many patients require prolonged pharmacological treatment. Therefore, evaluating long-term efficacy and safety of drug therapies in clinical trials is essential,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland and a Healio | Endocrine Today co-editor, told Healio. “Our findings build on the positive results of the LINC 3 study core phase, and it was reassuring to see that continued treatment with osilodrostat for over 72 weeks provided long-term normalization of cortisol levels. Furthermore, continued treatment with osilodrostat also led to sustained improvements in clinical signs and physical manifestations of hypercortisolism, as well as health-related quality of life, which are all important factors in the management of these patients.”

Fleseriu and colleagues enrolled 106 adults with Cushing’s disease who were responders to osilodrostat (Isturisa, Recordati) at 48 weeks during the LINC 3 core study to enter the extension phase of the trial. Participants continued to receive open-label osilodrostat until 72 weeks or treatment discontinuation. Mean urinary free cortisol was collected every 12 weeks. Physical manifestations of hypercortisolism were rated at 48 and 72 weeks. Participants completed the Cushing’s Quality of Life questionnaire and Beck Depression Inventory II at 48 and 72 weeks. Adults were deemed to have completely responded to treatment if mean urinary free cortisol was less than the upper limit of normal and partially responded to treatment if mean urinary free cortisol was above the upper limit of normal but decreased more than 50% from baseline.

The findings were published in the European Journal of Endocrinology.

Of the 106 participants in the extension study, 98 completed 72 weeks of treatment. At 72 weeks, 81.1% of participants were complete responders to treatment, and reductions in mean urinary free cortisol from the core phase were maintained during the extension.

Improvements in most cardiovascular and metabolic-related parameters from the core study were maintained or improved in the extension phase. The cohort also had increases in quality of life score and improvements in Beck Depression Inventory II scores.

The proportion of participants with improvements in physical manifestation of hypercortisolism were maintained or improved in all areas at 72 weeks. For hirsutism in women, 86.4% had an improved or stable severe score at 72 weeks. Improved scores were observed in participants with mild, moderate and severe physical manifestations at baseline with few adults experiencing worse manifestations at the end of the extension study.

There were no new safety signals reported in the extension study. Of the extension study participants, 11.3% discontinued osilodrostat due to adverse events, a similar percentage to the 10.9% discontinuation rate during the core phase of the study.

Several hormone concentrations, including mean adrenocorticotropic hormone, 11-deoxycortisol and plasma aldosterone, stabilized during the extension phase after changes were observed in the core study compared with baseline. Mean testosterone in women decreased from 2.6 nmol/L at 48 weeks to 2.1 nmol/L at 72 weeks. There were no changes observed in mean testosterone levels for men.

“Patients should be regularly monitored and osilodrostat dose titrated as necessary, alongside adjustment of concomitant medications, to optimize outcomes,” the researchers wrote. “Taken together, these findings support osilodrostat as an effective and well-tolerated long-term treatment option for patients with Cushing’s disease.”

For more information:

Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu.

From https://www.healio.com/news/endocrinology/20220914/osilodrostat-normalizes-urinary-free-cortisol-in-cushings-disease-for-most-at-72-weeks

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Persistent vs Recurrent Cushing’s Disease Diagnosed Four Weeks Postpartum

Posted on September 9, 2022 by MaryO

Abstract

Background. Cushing’s disease (CD) recurrence in pregnancy is thought to be associated with estradiol fluctuations during gestation. CD recurrence in the immediate postpartum period in a patient with a documented dormant disease during pregnancy has never been reported. Case Report. A 30-year-old woman with CD had improvement of her symptoms after transsphenoidal resection (TSA) of her pituitary lesion. She conceived unexpectedly 3 months postsurgery and had no symptoms or biochemical evidence of recurrence during pregnancy. After delivering a healthy boy, she developed CD 4 weeks postpartum and underwent a repeat TSA. Despite repeat TSA, she continued to have elevated cortisol levels that were not well controlled with medical management. She eventually had a bilateral adrenalectomy. Discussion. CD recurrence may be higher in the peripartum period, but the link between pregnancy and CD recurrence and/or persistence is not well studied. Potential mechanisms of CD recurrence in the postpartum period are discussed below. Conclusion. We describe the first report of recurrent CD that was quiescent during pregnancy and diagnosed in the immediate postpartum period. Understanding the risk and mechanisms of CD recurrence in pregnancy allows us to counsel these otherwise healthy, reproductive-age women in the context of additional family planning.

1. Introduction

Despite a relatively high prevalence of Cushing’s syndrome (CS) in women of reproductive age, it is rare for pregnancy to occur in patients with active disease [1]. Hypercortisolism leads to infertility through impairment of the hypothalamic gonadal axis. Additionally, while Cushing’s disease (CD) is the leading etiology of CS in nonpregnant adults, it is less common in pregnancy, accounting for only 30–40% of the CS cases in pregnant women [2]. It has been suggested that in CD there is hypersecretion of both cortisol and androgens, impairing fertility to a greater extent, while in CS of an adrenal origin, hypersecretion is almost exclusively of cortisol with minimal androgen production [3]. Regardless of the cause, active CS in pregnancy is associated with a higher maternal and fetal morbidity, hence, prompt diagnosis and treatment are essential.

Pregnancy is considered a physiological state of hypercortisolism, and the peripartum period is a common time for women to develop CD [3, 4]. A recent study reported that 27% of reproductive-age women with CD had onset associated with pregnancy [4]. The high rate of pregnancy-associated CD suggests that the stress of pregnancy and peripartum pituitary corticotroph hyperstimulation may promote or accelerate pituitary tumorigenesis [4–6]. During pregnancy, the circulating levels of corticotropin-releasing hormone (CRH) in the plasma increase exponentially as a result of CRH production by the placenta, decidua, and fetal membranes rather than by the hypothalamus. Unbound circulating placental CRH stimulates pituitary ACTH secretion and causes maternal plasma ACTH levels to rise [4]. A review of the literature reveals many studies of CD onset during the peripartum period, but CD recurrence in the peripartum period has only been reported a handful of times [7–10]. Of these, most cases recurred during pregnancy. CD recurrence in the immediate postpartum period has only been reported once [7]. Below, we report for the first time a case of CD recurrence that occurred 4 weeks postpartum, with a documented dormant disease throughout pregnancy.

2. Case Presentation

A 30-year-old woman initially presented with prediabetes, weight gain, dorsal hump, abdominal striae, depression, lower extremity weakness, and oligomenorrhea with a recent miscarriage 10 months ago. Diagnostic tests were consistent with CD. Results included the following: three elevated midnight salivary cortisols: 0.33, 1.38, and 1.10 μg/dL (<0.010–0.090); 1 mg dexamethasone suppression test (DST) with cortisol 14 μg/dL (<1.8); elevated 24 hr urine cortisol (UFC) measuring 825 μg/24 hr (6–42); ACTH 35 pg/mL (7.2–63.3). MRI of the pituitary gland revealed a left 4 mm focal lesion (Figure 1(a)). After transsphenoidal resection (TSA), day 1, 2, and 3 morning cortisol values were 18, 5, and 2 μg/dL, respectively. Pathology did not show a definitive pituitary neoplasm. She was rapidly titrated off hydrocortisone (HC) by six weeks postresection. Her symptoms steadily improved, including improved energy levels, improved mood, and resolution of striae. She resumed normal menses and conceived unexpectedly around 3 months post-TSA. Hormonal evaluation completed a few weeks prior to her pregnancy indicated no recurrence: morning ACTH level, 27.8 pg/mL; UFC, 5 μg/24 hr; midnight salivary cortisol, 0.085 and 0.014 μg/dL. Her postop MRI at that time did not show a definitive adenoma (Figure 1(b)). During pregnancy, she had a normal oral glucose tolerance test at 20 weeks and no other sequela of CD. Every 8 weeks, she had 24-hour urine cortisol measurements. Of these, the highest was 93 μg/24 hr at 17 weeks and none were in the range of CD (Table 1). Towards the end of her 2nd trimester, she started to complain of severe fatigue. Given her low 24 hr urine cortisol level of 15 μg/24 hr at 36 weeks gestation, she was started on HC. She underwent a cesarean section at 40 weeks gestation for oligohydramnios and she subsequently delivered a healthy baby boy weighing 7.6 pounds with APGAR scores at 1 and 5 minutes being 9 and 9. HC was discontinued immediately after delivery. Around four weeks postpartum she developed symptoms suggestive for CD. Diagnostic tests showed an elevated midnight salivary cortisol of 0.206 and 0.723 μg/dL, and 24-hour urine cortisol of 400 μg/24 hr. MRI pituitary illustrated a 3 mm adenoma in the left posterior region of the gland, which was thought to represent a recurrent tumor (Figure 1(c)). A discrete lesion was found and resected during repeat TSA. Pathology confirmed corticotroph adenoma with MIB-1 < 3%. On postoperative days 1, 2, and 3, the cortisol levels were 26, 10, and 2.8 μg/dL, respectively. She was tapered off HC within one month. Her symptoms improved only slightly and she continued to report weight gain, muscle weakness, and fatigue. Three months after repeat TSA, biochemical data showed 1 out of 2 midnight salivary cortisols elevated at 0.124 μg/dL and elevated urine cortisol of 76 μg/24 hr. MRI pituitary demonstrated a 3 × 5 mm left enhancement, concerning for residual or enlarged persistent tumor. Subsequent lab work continued to show a biochemical excess of cortisol, and the patient was started on metyrapone but reported no significant improvement of her symptoms and only mild improvement of excess cortisol. After a multidisciplinary discussion, the patient made the decision to pursue bilateral adrenalectomy, as she refused further medical management and opted against radiation given the risk of hypogonadism.

(a)
(a)
(b)
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(c)
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(a)(b)
(b)(c)
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Figure 1 
(a) Initial: MRI pituitary with and without contrast showing a coronal T1 postcontrast image immediately prior to our patient’s pituitary surgery. The red arrow points to a 3 × 3 × 5 mm hypoenhancing focus representing a pituitary microadenoma. (b) Postsurgical: MRI pituitary with and without contrast showing a coronal T1 postcontrast image obtained three months after transsphenoidal pituitary surgery. The red arrow shows that a hypoenhancing focus is no longer seen and has been resected. (c) Postpartum: MRI pituitary with and without contrast showing a coronal T1 postcontrast image obtained four weeks postpartum. The red arrow points to a 3 mm relatively hypoenhancing lesion representing a recurrent pituitary adenoma.
Table 1 
24-hour urine-free cortisol measurements collected approximately every 8 weeks throughout our patient’s pregnancy.

3. Discussion

The symptoms and signs of Cushing’s syndrome overlap with those seen in normal pregnancy, making diagnosis of Cushing’s disease during pregnancy challenging [1]. Potential mechanisms of gestational hypercortisolemia include increased systemic cortisol resistance during pregnancy, decreased sensitivity of plasma ACTH to negative feedback causing an altered pituitary ACTH setpoint, and noncircadian secretion of placental CRH during pregnancy causing stimulation of the maternal HPA axis [5]. Consequently, both urinary excretion of cortisol and late-night salivary cortisol undergo a gradual increase during normal pregnancy, beginning at the 11th week of gestation [2]. Cushing’s disease is suggested by 24-hour urinary-free cortisol levels greater than 3-fold of the upper limit of normal [2]. It has also been suggested that nocturnal salivary cortisol be used to diagnose Cushing’s disease by using the following specific trimester thresholds: first trimester, 0.25 μg/dL; second trimester, 0.26 μg/dL; third trimester 0.33, μg/dL [11]. By these criteria, our patient had no signs or biochemical evidence of CD during pregnancy but developed CD 4 weeks postpartum.

A recent study by Tang et al. proposed that there may be a higher risk of developing CD in the peripartum period, but did not test for CD during pregnancy, and therefore was not able to definitively say exactly when CD onset occurred in relation to pregnancy [4]. Previous literature suggests that there may be a higher risk of ACTH-secreting pituitary adenomas following pregnancy as there is a significant surge of ACTH and cortisol hormones at the time of labor. This increased stimulation of the pituitary corticotrophs in the immediate postpartum period may promote tumorigenesis [6]. It has also been suggested that the hormonal milieu during pregnancy may cause accelerated growth of otherwise dormant or small slow-growing pituitary corticotroph adenomas [4, 5]. However, the underlying mechanisms of CD development in the postpartum period have yet to be clarified. We highlight the need for more research to investigate not only the development, but also the risk of CD recurrence in the postpartum period. Such research would be helpful for family planning.

4. Conclusion

Hypothalamic-pituitary-adrenal axis activation during pregnancy and the immediate postpartum period may result in higher rates of CD recurrence in the postpartum period, as seen in our patient. In general, more testing for CS in all reproductive-age females with symptoms suggesting CS, especially during and after childbirth, is necessary. Such testing can also help us determine when CD occurred in relation to pregnancy, so that we can further understand the link between pregnancy and CD occurrence, recurrence, and/or persistence. Learning about the potential mechanisms of CD development and recurrence in pregnancy will help us to counsel these reproductive-age women who desire pregnancy.

Abbreviations

CD: Cushing’s disease
TSA: Transsphenoidal resection
DST: Dexamethasone suppression test
ACTH: Adrenocorticotropic hormone
MRI: Magnetic-resonance imaging
HC: Hydrocortisone
CTH: Corticotroph-releasing hormone
HPA: Hypothalamic-pituitary-adrenal.

Data Availability

The data used to support the findings of this study are included within the article.

Additional Points

Note. Peripartum refers to the period immediately before, during, or after pregnancy and postpartum refers to any period after pregnancy up until 1 year postdelivery.

Disclosure

This case report is a follow up to an abstract that was presented in ENDO 2020 Abstracts. https://doi.org/10.1210/jendso/bvaa046.2128.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank Dr. Puneet Pawha for his help in reviewing MRI images and his suggestions.

References

  1. J. R. Lindsay and L. K. Nieman, “The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment,” Endocrine Reviews, vol. 26, no. 6, pp. 775–799, 2005.View at: Publisher Site | Google Scholar
  2. W. Huang, M. E. Molitch, and M. E. Molitch, “Pituitary tumors in pregnancy,” Endocrinology and Metabolism Clinics of North America, vol. 48, no. 3, pp. 569–581, 2019.View at: Publisher Site | Google Scholar
  3. M. C. Machado, M. C. B. V. Fragoso, M. D. Bronstein, and M. Delano, “Pregnancy in patients with cushing’s syndrome,” Endocrinology and Metabolism Clinics of North America, vol. 47, no. 2, pp. 441–449, 2018.View at: Publisher Site | Google Scholar
  4. K. Tang, L. Lu, M. Feng et al., “The incidence of pregnancy-associated Cushing’s disease and its relation to pregnancy: a retrospective study,” Frontiers in Endocrinology, vol. 11, p. 305, 2020.View at: Publisher Site | Google Scholar
  5. S. K. Palejwala, A. R. Conger, A. A. Eisenberg et al., “Pregnancy-associated Cushing’s disease? an exploratory retrospective study,” Pituitary, vol. 21, no. 6, pp. 584–592, 2018.View at: Publisher Site | Google Scholar
  6. G. Mastorakos and I. Ilias, “Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum,” Annals of the New York Academy of Sciences, vol. 997, no. 1, pp. 136–149, 2003.View at: Publisher Site | Google Scholar
  7. G. F. Yaylali, F. Akin, E. Yerlikaya, S. Topsakal, and D. Herek, “Cushing’s disease recurrence after pregnancy,” Endocrine Abstracts, vol. 32, 2013.View at: Publisher Site | Google Scholar
  8. C. V. L. Fellipe, R. Muniz, L. Stefanello, N. M. Massucati, and L. Warszawski, “Cushing’s disease recurrence during peripartum period: a case report,” Endocrine Abstracts, vol. 70, 2020.View at: Publisher Site | Google Scholar
  9. P. Recinos, M. Abbassy, V. Kshettry et al., “Surgical management of recurrent Cushing’s disease in pregnancy: a case report,” Surgical Neurology International, vol. 6, no. 26, pp. S640–S645, 2015.View at: Publisher Site | Google Scholar
  10. A. Nakhleh, L. Saiegh, M. Reut, M. S. Ahmad, I. W. Pearl, and C. Shechner, “Cabergoline treatment for recurrent Cushing’s disease during pregnancy,” Hormones, vol. 15, no. 3, pp. 453–458, 2016.View at: Publisher Site | Google Scholar
  11. L. M. L. Lopes, R. P. V. Francisco, M. A. K. Galletta, and M. D. Bronstein, “Determination of nighttime salivary cortisol during pregnancy: comparison with values in non-pregnancy and cushing’s disease,” Pituitary, vol. 19, no. 1, pp. 30–38, 2015.View at: Publisher Site | Google Scholar

Copyright © 2022 Leena Shah et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

From https://www.hindawi.com/journals/crie/2022/9236711/

Filed under: Cushing's, pituitary, Rare Diseases, symptoms, Treatments | Tagged: , , , , | Leave a comment »

Altered Hippocampal Volume and Functional Connectivity in Patients with Cushing’s Disease

Posted on June 6, 2022 by MaryO

Abstract

Introduction

Stress-related brain disorders can be associated with glucocorticoid disturbance and hippocampal alteration. However, it remains largely unknown how cortisol affects the structure and function of hippocampus. Cushing’s disease (CD) provides a unique “hyperexpression model” to explore the effects of excessive cortisol on hippocampus as well as the relation between these effects and neuropsychological deficits.

Methods

We acquired high-resolution T1-weighted and resting-state functional magnetic resonance imaging in 47 CD patients and 53 healthy controls. We obtained the volume and functional connectivity of the hippocampal rostral and caudal subregions in both groups. Relationships between hippocampal alterations, neuroendocrine, and neuropsychological assessments were identified.

Results

Relative to control subjects, the CD patients had smaller volumes of all four hippocampal subregions. Furthermore, whole brain resting-state functional connectivity analyses with these four different hippocampal regions as seeds revealed altered hippocampal functional connectivity with high-order networks, involving the DMN, frontoparietal, and limbic networks in CD patients. The intrinsic hippocampal functional connectivity was associated with the quality of life of the CD patients.

Conclusions

Our findings elucidate the cumulative effect of excess cortisol on the morphology and function of hippocampus and reinforce the need for effective interventions in stress-related brain disease to halt potential hippocampal damage.

1 INTRODUCTION

Converging evidence has pointed to a strong linkage between the cortisol and human brain and stress-related neuropsychiatry disorders, such as major depression disorder and posttraumatic stress disorder (de Kloet et al., 2005). However, it remains to be established how this stress hormone influences specific brain structures and functions, particularly in humans, which is of particular importance for both treatment of stress-related disorders and research on cortisol effects in the brain.

Cushing’s disease (CD) is caused by an adrenocorticotropic hormone pituitary adenoma and characterized by chronic hypercortisolism. This condition is therefore a unique and natural “hyperexpression model” to investigate the chronic effects of cortisol on brain physiology and cognition (Zhang et al., 2021). By applying multimodal neuroimaging techniques to CD patients, previous studies have observed that chronic hypercortisolism could cause a number of abnormalities in various brain phenotypes. Among these neural changes of CD patients, hippocampal anomalies are the most replicated findings. Studies on CD patients report hippocampal changes that converge with morphologic alterations such as reduction in volume (Burkhardt et al., 2015; Toffanin et al., 2011). Moreover, abnormal cerebral blood flow and glucose metabolism in hippocampus have also been found in CD patients. Both structural and functional alterations in the hippocampus might contribute to the psychotic symptoms in CD patients (Frimodt-Møller et al., 2019). However, it is well established that psychosis is better described as a brain connectional diaschisis rather than isolated regional dysfunctions (Matthews & Hampshire, 2016). These current hippocampus-related findings were mainly obtained by voxel-based or regional analyses of brain volume or metabolism properties, and researchers have not determined whether the organizational patterns of hippocampal functional connectivity are disrupted in CD patients.

The hippocampus is easily targeted by long-term hypercortisolism because this area is a part of the stress response system and is abundant in mineralocorticoid receptors and glucocorticoid receptors (McEwen et al., 2016). Also recently, studies on macaques and humans have observed that hippocampus is an anatomically and functionally heterogeneous region along the rostral/caudal-dorsal/ventral axis (Schultz & Engelhardt, 2014). Specifically, the rostral hippocampus has connections with prefrontal regions and relates to stress, emotion, and affect. In contrast, the caudal hippocampus mainly connects to sensory cortical areas and performs primarily cognitive functions (Fanselow & Dong, 2010). Therefore, the hippocampus should be studied in a set of separate structures with rostral and caudal hippocampus. Whether the hippocampal subregions exhibit differentially altered connectivity patterns responding to chronic hypercortisolism remains largely unknown.

The present study further extends this work by examining the relationship between hippocampal subregions and resting-state functional connectivity in large-scale brain networks, as measured by resting-state fMRI (rs-fMRI) (Park & Friston, 2013). We focus on default mode network (DMN), frontoparietal, and limbic networks, given their involvement in stress related psychiatric illnesses. The first is the DMN, which supports self-related cognitive functions. Complementing the DMN is the frontoparietal network, which supports the cognitive regulation of behavior and emotion. Finally, the limbic networks play a key role in emotion regulation.

In this study, first, to explore the structural changes of hippocampal subregions in CD patients, we performed a volumetric MRI analysis of the four subregions (left rostral hippocampus, left caudal hippocampus, right rostral hippocampus, and right caudal hippocampus). Given the known direct neurotoxic effects of cortisol on hippocampus, we predicted that chronic hypercortisolism caused smaller hippocampal volumes in CD patients. Second, we used these four subregions as seed regions separately and mapped whole-brain functional connectivity patterns associated with each subregion to examine alterations in hippocampal functional connectivity in CD patients. Considering the psychiatric symptoms in CD patients, it is reasonable to expect the presence of altered hippocampal functional connectivity with high-order networks.

2 MATERIAL AND METHODS

2.1 Participants

A total of 47 participants with a diagnosis of CD and 53 healthy control (HC) subjects were included in this study. The CD patients underwent transsphenoidal surgery at the Department of Neurosurgery, The First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital between May 2017 and November 2019. According to the clinical practice guideline (Nieman et al., 2015), CD was diagnosed by experienced endocrinologists and confirmed by postsurgical pathology. The detailed preoperative assessments of diagnostic criteria have been reported in our previous study. HCs were recruited from the local community and were controlled for any history of psychopathology abnormalities. All participants were right-handed and had normal vision and auditory sensation. The study was approved by the local ethics committee of the Chinese PLA General Hospital and written informed consent was obtained from each participant. The data of these 47 CD and 53 HC subjects have been partially used in our previous studies (Wang et al., 2019; Zhang et al., 2021).

2.2 Neuroendocrine and neuropsychological assessment

All participants underwent biochemical evaluation to assess their cortisol level. We quantified the levels of 24-h urinary free cortisol (24hUFC, nmol/24h); serum cortisol (nmol/L) at 0:00, 8:00, and 16:00. Cortisol was detected with an ADVIA Centaur Analyzer (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Cortisol levels at 8:00 as well as 24hUFC were also measured in 51 HC subjects.

All participants underwent a comprehensive neuropsychological assessment with an expert psychiatrist, including Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Mini-mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). Moreover, health-related quality of life and neuropsychiatric symptoms of CD patients were evaluated with the Cushing’s Quality-of-Life (CushingQoL) questionnaire (Nelson et al., 2013) and Chinese version of the neuropsychiatric inventory (CNPI) (Leung et al., 2001), respectively.

2.3 Image acquisition

Structural and functional MRI data were acquired on a 3.0-Tesla MR system (Discovery MR750, General Electric) with an 8-channel head coil. High-resolution structural 3D T1-weighted images were conducted using a sagittal Fast Spoiled Gradient-Echo (FSPGR) sequence with the following parameters: repetition time = 6.7 ms, echo time = 2.9 ms, flip angle = 7°, field of view = 250 × 250 mm2, number of slices = 192, voxel size = 1 × 1 × 1 mm3 with no gap. The functional images were acquired using an echo-planar imaging (EPI) sequence with repetition time = 2000 ms, echo time = 30 ms, flip angle = 90°, thickness/gap = 3.5 mm/0.5 mm, slices = 36, field of view = 224 × 224 mm2, voxel size = 3.5 × 3.5 × 3.5 mm3, number of total volumes = 240. Soft earplugs were used to attenuate scanner noise and head motion was restrained with foam padding. During functional scanning, all participants were requested to keep their eyes closed and stay awake.

2.4 rs-fMRI data preprocessing

Preprocessing of the rs-fMRI images was conducted using SPM12 and Data Processing Assistant for Resting-State fMRI (DPABI, http://www.restfmri.net/forum/DPARSF). The first 10 volume of the functional images were removed to avoid initial steady-state problems. Then functional images were spatially realigned to the first image for motion correction, and reslicing for acquisition temporal delay. The head motion of all participants in this study had no more than 2-mm translation or 2° rotation in any direction. Next, functional images were coregistered to each participant’s segmented gray matter T1 image, and then spatially normalized to the MNI space, resampled to 3-mm isotropic voxels. Subsequently, the global signal, white matter signal, cerebrospinal fluid signal and 24-motion vectors were regressed from the data. Finally, linear detrending and bandpass filter (0.01−0.08 Hz) were carried out to reduce the effects of low-frequency drift and high-frequency physiological noise.

2.5 Hippocampal functional connectivity

The hippocampus has been functionally parcellated into four subregions (left rostral hippocampus, left caudal hippocampus, right rostral hippocampus, and right caudal hippocampus) based on Human Brainnetome Atlas (Fan et al., 2016). On each hippocampal subregion, we performed seed-based functional connectivity analysis. Briefly, hippocampal functional connectivity maps were obtained by computing the Pearson correlation coefficient for each voxel’s time course with the average time course inside the region of interest. Notably, the computation was constrained within a gray-matter mask which was generated by thresholding (a threshold of 0.2) a prior gray-matter probability map in SPM12. The resulting correlation coefficients were further converted to z scores using Fisher’s r-to-z transform to improve normality. For each subject, we obtained 4 z-score maps indicative of the intrinsic functional connectivity patterns of the four hippocampal subregions. To exclude the possible confounding effect of hippocampal volume in CD patients, we performed a voxel-based morphometry analysis on structural MRI images and took the volume of hippocampal subregions as a covariate in the functional connectivity statistical analyses.

2.6 Statistical analysis

All demographic and clinical variables including neuroendocrine and neuropsychological scores were compared by two-sample t-tests. Sex composition of the two groups was compared using a Pearson’s chi-square test (two-tailed). To explore differences in hippocampal functional connectivity between CD patients and HCs, general linear models were performed in a voxel-wise fashion. To exclude the possible confounding effects of age, gender, education level, and volume of hippocampal subregions, we used these measures as covariates in the general linear models. Multiple comparison correction was performed using a FDR of 0.05 within the grey matter mask.

In CD patients group, a linear regression analysis was further performed to explore the relationship between functional connectivity of the clusters showing significant group differences and neuropsychological scores as well as the endocrinological indicators (cortisol and 24hUFC). Multiple comparisons were also corrected using the FDR method with a corrected threshold of q < 0.05.

3 RESULTS

3.1 Demographic, endocrinological, and neuropsychological results

Table 1 shows the demographic characteristics of the CD patients and the HCs. There were no significant differences in terms of age, sex distribution, and years of education between groups. Compared with HCs, CD patients had significantly lower MoCA scores and higher SDS and SAS scores (Table 1). As expected, the CD patients had significantly higher levels of serum cortisol and 24hUFC (p < .001). Moreover, we calculated the volumes of the four hippocampal subregions and found smaller volumes of all four hippocampal subregions in the CD patients.

TABLE 1. Participant characteristics
CDs (n = 47) HCs (n = 53) p Value
Age (years) 37.38 ± 10.61 (20–59) 34.79 ± 10.72 (21–63) .113
Gender (male/female) 4/43 4/49 .859
Education (years) 11.00 ± 4.11 11.74 ± 3.10 .311
Illness duration (months) 41.62 ± 53.71 — —
Neuropsychological tests
MoCA 22.47 ± 3.98 (n = 45) 27.72 ± 2.00 <.001
SDS 40.18 ± 9.96 (n = 45) 27.13 ± 4.42 <.001
SAS 38.27 ± 7.90 (n = 45) 26.98 ± 4.47 <.001
CNPI 11.93 ± 9.68 (n = 45) — —
Cushing QOL 37.76 ± 8.29 (n = 45) — —
Endocrinological tests
Serum cortisol (nmol/L)
0:00 am 633.81 ± 237.59 (n = 46) — —
8:00 am 735.34 ± 279.44 (n = 47) 358.51 ± 107.43 (n = 51) <.001
16:00 pm 671.05 ± 273.56 (n = 47) — —
24hUFC (nmol/24 h) 2381.59 ± 1653.16 (n = 41) 252.03 ± 119.47 (n = 47) <.001
Volume of hippocampal subregions (mm3)
Left rostral hippocampus 343.75 ± 39.15 (257.18–423.27) 365.69 ± 27.19 (313.21–442.06) .001
Left caudal hippocampus 272.69 ± 32.74 (206.63–339.04) 296.39 ± 23.13 (249.62–347.61) <.001
Right rostral hippocampus 305.10 ± 33.71 (229.67–396.89) 336.76 ± 25.98 (274.95–415.16) <.001
Right caudal hippocampus 320.42 ± 32.60 (238.16–396.58) 347.87 ± 27.16 (294.00–415.80) <.001
  • Abbreviations: 24hUFC, 24-h urinary free cortisol.; CDs, Cushing’s disease patients; CNPI, Chinese version of neuropsychiatric inventory; Cushing QOL, Cushing Quality of Life Scale; HCs, healthy controls; MoCA, Montreal Cognitive Assessment; SAS, Self-Rating Anxiety Scale; SDS, Self-Rating Depression Scale.
  • Note: All values are expressed as mean ± SD. Group differences in sex between CDs and HCs were examined using chi-square test. Group differences in the other demographic and clinical characteristics between CDs and HCs were examined using two-sample t-tests (two-tailed).

3.2 Spatial distribution of hippocampal functional connectivity

The hippocampal functional connectivity maps of both CD patients and HCs are presented in Figure 1. Visually, the spatial distributions of hippocampal functional connectivity were highly similar between groups, in spite of some differences in strength. We observed that the brain regions significantly positively connecting to hippocampus were primarily distributed in several limbic network regions (the orbital frontal cortex, bilateral medial temporal regions, and temporal pole) and DMN regions (bilateral medial frontal cortex, posterior cingulate gyrus/precuneus, and anterior cingulate cortex). Brain regions with negative connectivity to hippocampus were chiefly distributed in the frontoparietal network regions (dorsolateral prefrontal cortex, supramarginal gyrus, and angular gyrus).

Details are in the caption following the image

Between-group differences in functional connectivity of the hippocampal subregions. The first column shows the hippocampal functional connectivity subregions. The second and third columns show the hippocampal functional connectivity maps within CD and HC groups, respectively. Further between-group comparisons showed that CD patients had significantly altered hippocampal functional connectivities relative to HCs, with a corrected statistical threshold of p < .05. ROI1, left rostral hippocampus; ROI2, left caudal hippocampus; ROI3, right rostral hippocampus; ROI4, right caudal hippocampus; ROI, region of interest; CD, Cushing’s disease; HC, healthy control

3.3 Altered hippocampal functional connectivity in CD patients

The significant differences in functional connectivity with each hippocampal subregion between the CD patients and HCs groups are illustrated in third column of Figure 1. Both the right and left rostral hippocampus exhibited significantly decreased functional connectivity with the superior parietal lobe (SPL), a component of the frontoparietal network. Moreover, right rostral hippocampus exhibited additional increased functional connectivity with right inferior frontal gyrus, a component of DMN. For the left caudal hippocampus, significantly altered functional connectivity was found to the DMN regions, including (bilateral medial frontal cortex, angular gyrus, anterior, and posterior cingulate cortex). We also observed decreased functional connectivity between the right caudal hippocampus and anterior cingulate cortex. Additionally, the right caudal hippocampus exhibited increased functional connectivity with some limbic regions including the right orbital frontal cortex and temporal pole (Table 2).

TABLE 2. Brain regions showing changed RSFC between CDs and HCs groups
Peak MNI coordinate
Brain regions BA Cluster size (voxels) x y z Peak T
ROI-based RSFC
ROI1 R IFG 48 219 57 21 —3 4.598
L angular 39 423 −27 −72 51 −5.530
RIO2 R thalamus − 114 9 −6 3 −5.905
L angular 39 195 −27 −72 54 −4.830
R angular 39 384 36 −66 48 −5.607
ROI3 R MTG 20 633 39 6 −21 4.410
L angular 39 195 −27 −72 54 −4.830
R angular 39 384 36 −66 48 −5.607
MFG/ACC 10/32 572 −3 42 −3 −4.033
PCC/PreCUN 26/23 709 12 −45 27 −4.502
ROI4 MFG/ACC 32 465 3 48 6 −4.670
R MTG/OFC 48/21 747 30 3 −21 4.208
  • Note: Statistical threshold was set at p < .05, corrected.
  • Abbreviations: CDs, Cushing’s disease patients; HCs, healthy controls; ROI, regions of interest; BA, Brodmann areas; MNI, Montreal Neurological Institute; RSFC, resting-state functional connectivity; SFG, superior frontal gyrus; MFG, middle frontal gyrus; dMFG, dorsal medial frontal gyrus; IPL, inferior parietal lobule; AG, angular gyrus; ROL, rolandic operculum; Ins, insular; PrCG, precentral gyrus; L, left; R, right; ROI1, left rostral hippocampus; ROI2, left caudal hippocampus; ROI3, right rostral hippocampus; ROI4, right caudal hippocampus.

3.4 Brain–behavior relationships in the CD patients

In the correlation analyses of CD patients, the mean values of the functional connectivity between the left caudal hippocampus and anterior cingulate cortex correlated positively with the Cushing’s QoL scores (r = .327, p < .05) (Figure 2). No other correlations were found for volumes and functional connectivity of the four hippocampal subregions with neuroendocrine and neuropsychological assessment in the CD patients.

Details are in the caption following the image

Significant correlations between left hippocampal functional connectivity and the quality of life in CD patients. CD, Cushing’s disease; Hip, hippocampus; ACC, anterior cingulate cortex

4 DISCUSSION

Using a cohort of CD patients and HCs, the present study performed a comprehensive investigation to reveal how the chronic hypercortisolism affects the morphology and connectivity of hippocampal subregions and their relationships with neuroendocrine and neuropsychological assessment. Compared with the HCs, the CD patients had smaller volumes of all four hippocampal subregions. Furthermore, CD patients exhibited differential patterns of altered hippocampal functional connectivity with high-order networks, involving the DMN, frontoparietal, and limbic networks. The intrinsic hippocampal functional connectivity was associated with the quality of life of the CD patients. Together, these findings elucidate the cumulative effect of cortisol on the morphology and function of hippocampus and provide important information to further understand the role of hippocampus in stress-related brain disease.

Cortisol, the end product of the hypothalamic–pituitary–adrenal axis, plays a critical role in the body’s response to stress and maintenance of homeostasis (Sapolsky et al., 2000); however, chronic hypercortisolism is known to impair neurons in the hippocampus. CD patients naturally demonstrate chronic excessive amounts of cortisol; therefore these patients serve as a natural “hyperexpression model” to investigate the chronic effects of cortisol on human hippocampus. Importantly, we showed the CD patients are associated with smaller hippocampal volumes in all four subregions. In line with our study, previous structural imaging studies have shown hippocampal volume decreases in CD patients (Frimodt-Møller et al., 2019; Toffanin et al., 2011). Furthermore, Brown et al. found that healthy volunteers were associated with a significant reduction in hippocampal volume following only 3-day stress doses of corticosteroid administration, strongly suggesting the effects of cortisol on hippocampal size. It is important to note that chronic hypercortisolism can affect the hippocampus in at least two ways: by direct neurotoxic effects on the hippocampus (Lupien et al., 2018; Uno et al., 1994) and by reduction in hippocampal neurogenesis (Saaltink & Vreugdenhil, 2014). Moreover, cortisol stimulates the release of excitatory amino acids glutamate on hippocampal cells (de Kloet et al., 2005). On the other hand, chronic elevations of cortisol also reduce neurotrophic factors that includes nerve growth factor and brain-derived neurotrophic factor (McEwen et al., 2015).

The different patterns of functional connectivity in rostral hippocampus versus caudal hippocampus might be associated to the specific cytoarchitecture along the rostral/caudal hippocampus. Accumulated evidence from both animal and human studies suggests that different parts of the hippocampus display distinctive gene expression and anatomical projections patterns (Fanselow & Dong, 2010). In detail, gene expression in the rostral hippocampus correlates with regions involved in emotion and stress (amygdala and hypothalamus). Moreover, the rostral hippocampus has connections with prefrontal regions, exerts strong regulatory control of the hypothalamic–pituitary–adrenal axis with a negative feedback (Toffanin et al., 2011). Accordingly, as demonstrated in this study, chronic hypercortisolism predominantly disrupted the functional connectivity in rostral hippocampus.

Another major finding in this study was altered hippocampal functional connectivity with DMN, frontoparietal, and limbic networks in CD individuals relative to that in HCs. Emerging evidence proposes that interactions within and between these large-scale brain networks play important roles on brain functions and may be affected in multiple psychiatric disorders (Menon, 2011; Sha et al., 2019). Among these brain networks, the DMN is anchored in the medial prefrontal cortex and posterior cingulate cortex and is implicated in internally directed attention and self-referential processing (Raichle, 2015), while the frontoparietal and limbic networks support the cognitive regulation of emotion, attention, and behavior (Buhle et al., 2014; Kohn et al., 2014). The engagement of these high-level functional networks may suggest the linkage of abnormal stress hormone cortisol to cognitive deficits in CD patients. In line with our study, previous studies have shown stress-induced cortisol increase was associated with altered connectivity within the major brain networks (Zhang et al., 2019, 2020, 2020). Meanwhile, structural and functional alterations in these brain systems are also found in CD patients. For example, many functional imaging studies have consistently demonstrated altered brain activities and functional connectivity involving in DMN, frontoparietal, and limbic networks (Jiang et al., 2017; Wang et al., 2019; Zhang et al., 2021), even in the patients with long-term remission of CD (van der Werff et al., 2015). Importantly, previous studies have shown that the CD patients had widespread reductions of white matter integrity, which provide further evidence for the structural substrate for the persistence of these functional deficits (Pires et al., 2015; van der Werff et al., 2014). Here, we propose that by altering hippocampal processes via the abundant glucocorticoid and mineralocorticoid receptors, exposure to hypercortisolism disrupts the interactions with DMN, frontoparietal, and limbic networks in CD patients, thus engender vulnerability for emotional and cognitive problems. In line with this view is evidence that altered hippocampal functional connectivity is associated with the quality of life in CD patients. Because impaired quality of life is a persistent complaint from CD patients (Webb et al., 2018), it is important to accurately assess which aspects of QoL are affected in order to better understand the severity of hypercortisolism on patients and the potential efficacy of treatment. CushingQoL questionnaire has proven to be a valuable resource for assessing health-related QoL in CD patients, based on the combination of psychosocial issues and physical problems (Nelson et al., 2013). A better understanding of the neuroplasticity and continuing quality of life change may in turn facilitate advances in management and intervention.

Several issues need to be addressed further. First, although the sample size of this study was relatively large, the findings still need to be further replicated in an independent sample. Second, the cross-sectional, observational nature of our study design precludes any causal conclusions. Therefore, studies tracking dynamic changes in hippocampal functional connectivity following the remission of hypercortisolism are needed. We are currently following up participants as part of a longitudinal study. Finally, a combined analysis of multimodal imaging including structural and metabolic data would provide integrated information on the effect of cortisol excess on human brain.

In short, we demonstrate that CD patients present atypical morphology and functional connectivity of hippocampus. Here we observed the chronic hypercortisolism caused smaller volumes of all hippocampal subregions. This volume change was in line with the preclinical research that excess cortisol cause dendritic shrinkage and loss of spines in the hippocampus. Functionally, CD patients demonstrated altered hippocampal connectivity whose nodes include key components of the DMN, frontoparietal, and limbic networks. These multimodal results reinforce the need for effective therapeutic interventions in stress-related brain disease to halt possible hippocampal damage.

ACKNOWLEDGMENTS

This study was supported by the National Natural Science Foundation of China (No. 82001798 and No. 81871087), Military Young Scholar Medical Research Fund of Chinese PLA General Hospital (No. QNF19071), and Medical Big Data and Artificial Intelligence Development Fund of Chinese PLA general Hospital (No. 2019MBD-039).

CONFLICT OF INTEREST

The authors report no biomedical financial interests or potential conflicts of interest.

Read more, including references, at https://onlinelibrary.wiley.com/doi/10.1002/brb3.2507

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

Posted on May 26, 2022 by MaryO

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

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Recurrent Metatarsal Fractures in a Patient With Cushing Disease

Posted on May 23, 2022 by MaryO

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

Abstract

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.

Introduction

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.

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

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

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

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).
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).

Discussion

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.

Conclusions

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.

References

  1. Guaraldi F, Salvatori R: Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012, 25:199-208. 10.3122/jabfm.2012.02.110227
  2. Valassi E, Santos A, Yaneva M, et al.: The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol. 2011, 165:383-92. 10.1530/EJE-11-0272
  3. Molnar V, Zekan P, Dušek T, Ivković A: Multiple metatarsal fractures: the first manifestation of Cushing’s disease—a case report. J Am Podiatr Med Assoc. 2021, 111:10.7547/19-024
  4. Han JY, Lee J, Kim GE, et al.: A case of cushing syndrome diagnosed by recurrent pathologic fractures in a young woman. J Bone Metab. 2012, 19:153-8. 10.11005/jbm.2012.19.2.153
  5. Barahona MJ, Sucunza N, Resmini E, et al.: Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing’s syndrome. J Bone Miner Res. 2009, 24:1841-6. 10.1359/jbmr.090505
  6. Papadakis G, Uebelhart B, Goumaz M, Zawadynski S, Rizzoli R: An unusual case of hypercortisolism with multiple weight-bearing bone fractures. Clin Cases Miner Bone Metab. 2014, 10:213-7.
  7. LiYeung LL, Lui TH: Bilateral adrenal adenoma presented as multiple metatarsal and phalangeal fractures. J Orthop Case Rep. 2015, 5:77-8. 10.13107/jocr.2250-0685.353
  8. Trementino L, Appolloni G, Ceccoli L, Marcelli G, Concettoni C, Boscaro M, Arnaldi G: Bone complications in patients with Cushing’s syndrome: looking for clinical, biochemical, and genetic determinants. Osteoporos Int. 2014, 25:913-21. 10.1007/s00198-013-2520-5
  9. Abdel-Kader N, Cardiel MH, Navarro Compan V, Piedra Priego J, González A: Cushing’s disease as a cause of severe osteoporosis: a clinical challenge. Reumatol Clin. 2012, 8:278-9. 10.1016/j.reuma.2011.11.004
  10. Lee HJ, Je JH, Seo JH, Na YJ, Yoo HJ: Multiple spontaneous rib fractures in patient with Cushing’s syndrome. J Bone Metab. 2014, 21:277-82. 10.11005/jbm.2014.21.4.277
  11. Poonuru S, Findling JW, Shaker JL: Lower extremity insufficiency fractures: an underappreciated manifestation of endogenous Cushing’s syndrome. Osteoporos Int. 2016, 27:3645-9. 10.1007/s00198-016-3712-6
  12. Belaya ZE, Hans D, Rozhinskaya LY, et al.: The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing’s syndrome. Arch Osteoporos. 2015, 10:44. 10.1007/s11657-015-0244-1
  13. Tajika T, Shinozaki T, Watanabe H, Yangawa T, Takagishi K: Case report of a Cushing’s syndrome patient with multiple pathologic fractures during pregnancy. J Orthop Sci. 2002, 7:498-500. 10.1007/s007760200087
  14. Baron E, Sheinfeld M, Migdal EA, Hardoff R: Multiple pathologic fractures mimicking bone metastases in a patient with Cushing’s syndrome. Clin Nucl Med. 1996, 21:506-8. 10.1097/00003072-199606000-00027
  15. Bosch S, Bogaerts S: Pituitary adenoma presenting with bilateral calcaneal stress fracture: a case report. JOSPT Cases. 2021, 1:109-111.
  16. Kostoglou-Athanassiou I, Spiliotis G, Athanassiou L, Myriokefalitakis I: Cushing’s syndrome in a patient with systemic lupus erythematosus. Endocrine Abstracts. 2018, 56:106. 10.1530/endoabs.56.P106
  17. Kaur K, Findling JW: Cushing’s disease. A Case-Based Guide to Clinical Endocrinology. Davies TF (ed): Humana Press, Totowa; 2008. 27-33. 10.1007/978-1-60327-103-5_3
  18. Ontell FK, Shelton DK: Multiple stress fractures. An unusual presentation of Cushing’s disease. West J Med. 1995, 162:364-6.
  19. Albon L, Rippin J, Franklyn J: “My feet are killing me!” An unusual presentation of Cushing’s syndrome. Endocrine Abstracts. 2003, 5:26.
  20. Nieman LK: Recent updates on the diagnosis and management of Cushing’s syndrome. Endocrinol Metab (Seoul). 2018, 33:139-46. 10.3803/EnM.2018.33.2.139

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

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