Association of IGF-1 Level with Low Bone Mass in Young Patients with Cushing’s Disease

Posted on July 28, 2023 by MaryO

Abstract

Purpose. Few related factors of low bone mass in Cushing’s disease (CD) have been identified so far, and relevant sufficient powered studies in CD patients are rare. On account of the scarcity of data, we performed a well-powered study to identify related factors associated with low bone mass in young CD patients.

Methods. This retrospective study included 153 CD patients (33 males and 120 females, under the age of 50 for men and premenopausal women). Bone mineral density (BMD) of the left hip and lumbar spine was measured by dual energy X-ray absorptiometry (DEXA). In this study, low bone mass was defined when the Z score was −2.0 or lower. Results. Among those CD patients, low bone mass occurred in 74 patients (48.37%). Compared to patients with normal BMD, those patients with low bone mass had a higher level of serum cortisol at midnight (22.31 (17.95-29.62) vs. 17.80 (13.75-22.77), ), testosterone in women (2.10 (1.33–2.89) vs. 1.54 (0.97–2.05), ), higher portion of male (32.43% vs. 11.54%, ) as well as hypertension (76.12% vs. 51.67%, ), and lower IGF-1 index (0.59 (0.43–0.76) vs. 0.79 (0.60–1.02), ). The Z score was positively associated with the IGF-1 index in both the lumbar spine (r = 0.35153, ) and the femoral neck (r = 0.24418, ). The Z score in the femoral neck was negatively associated with osteocalcin (r = −0.22744, ). Compared to the lowest tertile of the IGF-1 index (<0.5563), the patients with the highest tertile of the IGF-1 index (≥0.7993) had a lower prevalence of low bone mass (95% CI 0.02 (0.001–0.50), ), even after adjusting for confounders such as age, gender, duration, BMI, hypertension, serum cortisol at midnight, PTH, and osteocalcin.

Conclusions. The higher IGF-1 index was independently associated with lower prevalence of low bone mass in young CD patients, and IGF-1 might play an important role in the pathogenesis of CD-caused low bone mass.

1. Introduction

Cushing’s disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is a rare disease with approximately 1.2 to 2.4 new cases per million people each year [1].

Osteoporosis has been recognized as a serious consequence of endogenous hypercortisolism since the first description in 1932 [2]. The prevalence of osteoporosis is around 38–50%, and the rate of atraumatic compression fractures is 15.8% in CD patients [3]. After cortisol normalization and appropriate treatment, recovery of the bone impairment occurs slowly (6–9 years) and partially [4, 5]. Hypercortisolemia impairs bone quality through multiple mechanisms [6]. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play a crucial role in bone growth and development [7]. IGF-1 is considered essential for the longitudinal growth of bone, skeletal maturity, and bone mass acquisition not only during growth but also in the maintenance of bone in adults [8]. Previous research studies revealed that low serum IGF-1 levels were associated with a 40% increased risk of fractures [9, 10], and serum IGF-1 levels could be clinically useful for evaluating the risk of spinal fractures [11]. In Marl Hotta’s research, extremely low or no response of plasma GH to recombinant human growth hormone (hGRH) injection was noted in CD patients. This result suggested that the diminished hGRH-induced GH secretion in patients with Cushing’s syndrome might be caused by the prolonged period of hypercortisolemia [12]. Other surveys indicated that glucocorticoids, suppressing GH–IGF-1 and the hypothalamic-pituitary-gonadal axes, lead to decreased number and dysfunction of osteoblast [13].

However, the exact mechanism is still unclear, and few risk factors for osteoporosis in CD have been identified so far. Until now, relevant and sufficiently powered studies in CD patients have been rare [14, 15]. Early recognition of the changes in bone mass in CD patients contributes to early diagnosis of bone mass loss and prompt treatment, which could help minimize the incidence of adverse events such as fractures.

On account of the scarcity of data and pressing open questions concerning risk evaluation and management of osteoporosis, we performed a well-powered study to identify the related factors associated with low bone mass in young CD patients at the time of diagnosis.

2. Materials and Methods

2.1. Subjects

This retrospective study enrolled 153 CD patients (33 males and 120 females) from the Department of Endocrinology and Metabolism of Huashan Hospital between January 2010 and February 2021. All subjects were evaluated by the same group of endocrinologists for detailed clinical evaluation. This study, which was in complete adherence to the Declaration of Helsinki, was approved by the Human Investigation Ethics Committee at Huashan Hospital, Fudan University (No. 2017M011). We collected data on demographic characteristics, laboratory tests, and bone mineral density.

Inclusion criteria included the following: (1) willingness to participate in the study; (2) premenopausal women ≥18 years old, men ≥18 years old but younger than 50 years old, and young women (<50 years old) with menstrual abnormalities who were associated with CD after excluding menstrual abnormalities caused by other causes; (3) diagnosis of CD according to the updated diagnostic criteria [16]; and (4) pathological confirmation after transsphenoidal surgery (positive immunochemistry staining with ACTH). Exclusion criteria included Cushing’s syndrome other than pituitary origin.

2.2. Clinical and Biochemical Methods

IGF-1 was measured using the Immulite 2000 enzyme-labeled chemiluminescent assay (Siemens Healthcare Diagnostic, Surrey, UK). Other endocrine hormones, including cortisol (F), 24-hour urinary free cortisol (24hUFC), adrenocorticotropic hormone (ACTH), prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH), estrogen (E2), progesterone (P), testosterone (T), thyroid stimulating hormone (TSH), and free thyroxine (FT4), were carried out by the chemiluminescence assay (Advia Centaur CP). Intra-assay and interassay coefficients of variation were less than 8 and 10%, respectively, for the estimation of all hormones.

Bone metabolism markers included osteocalcin (OC), type I procollagen amino-terminal peptide (P1NP), parathyroid hormone (PTH), and 25-hydroxyvitamin D (25(OH)VD), measured in a Roche Cobas e411 analyzer using immunometric assays (Roche Diagnostics, Indianapolis, IN, USA).

The IGF-1 index was defined as the ratio of the measured value to the respective upper limit of the reference range for age and sex. Body mass index (BMI) was calculated using the following formula: weight (kg)/height2 (m2). The bone mineral density (BMD) measuring instrument was Discovery type W dual energy X-ray absorptiometry from the American HOLOGIC company. Quality control tests were conducted every working day. Before examination, the date of birth, height, weight, and menopause date of the examiner were accurately recorded, and then BMD (g/cm2) of the left hip and lumbar spine were measured by DEXA. Z value was used for premenopausal women and men younger than 50 years old, and Z-value = (measured value − mean bone mineral density of peers)/standard deviation of BMD of peers [17, 18]. In this study, low bone mass was defined as a Z-value of −2.0 or lower.

2.3. Statistical Analysis

The baseline characteristics were compared between CD patients with and without low bone mass by using the Student’s t-test for continuous variables and the χ2 test for category variables. Bone turnover markers, alanine aminotransferase (ALT), triglyceride (TG), IGF-1 index, thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), testosterone (T), 24 hours of urine cortisol (24 h UFC), and serum cortisol at 8 a.m. (F8 am) and at midnight (F24 pm) were not in normal distribution, so variables mentioned above were Log10-transformed, which could be used as continuous variables during statistical analysis. Participants were categorized into three groups according to tertiles of the IGF-1 index: <0.5986, 0.5986–0.8380, and >0.8380. The linear trend across IGF-1 index tertiles was tested using linear regression analysis for continuous variables and the Cochran–Armitage test for categorical variables. We used a multivariate logistic regression model to identify related factors that are independently associated with the risk of low bone mass. Variables included in the multivariate logistic regression model were selected based on the Spearman rank correlation analysis and established traditional low bone mass risk factors as priors. The results were presented as odds ratios (OR) and the corresponding 95% confidence intervals (CI). Significance tests were two-tailed, with  value <0.05 considered statistically significant for all analyses. Statistical analysis was performed using SAS version 9.3 (SAS Institute Inc, Cary, NC, USA).

3. Results

3.1. The Prevalence of Low Bone Mass in Young Cushing’s Disease Patients

From the inpatient system of Huashan hospital, a total of 153 CD patients under the age of 50 for men and premenopausal women (some with menstrual abnormalities were associated with CD) were included, aged from 13 to 49 years, with an average age of 34.25 ± 8.39 years. There were 33 males (21.57%) and 120 females (78.43%). These CD patients included newly diagnosed CD, recurrences of CD, and CD without remission after treatment. There were no differences in the prevalence of different statuses of CD between the two groups (Table 1).

Table 1 
Clinical and biochemical preoperative characteristics of young Cushing’s disease patients according to status of bone mineral density at diagnosis.

Among these CD patients, low bone mass occurred in 74 patients (48.37%), including 24 men and 50 women. The prevalence of low bone mass was 41.67% and 72.73% in female and male CD patients, respectively, and 42 (56.76%) patients suffered from low bone mass in the lumbar spine only, while 10 (13.51%) patients had low bone mass in the femoral neck only, and 22 (29.73%) patients had low bone mass in both parts.

In female patients with low bone mass, 27 (54%) had low bone mass in the lumbar region only, 9 (18%) in the femoral neck only, and 14 (28%) had low bone mass in both parts. For male patients with low bone mass, 16 (66.67%) patients had low bone mass only in the lumbar region, and the rest (8, 33.33%) had low bone mass in both parts.

Ten patients had a history of fragility fractures (6 ribs, 3 vertebrae, 1 femoral neck, and ribs), and all of them achieved low bone mass in BMD.

3.2. Baseline Characteristics of Cushing’s Disease Patients with and without Low Bone Mass

These CD patients were divided into two groups with and without low bone mass (Table 1). Compared to patients without low bone mass, those low bone mass patients had a higher level of diastolic blood pressure (DBP) (97.07 ± 13.69 vs. 89.76 ± 13.43, ), serum creatinine (66.15 ± 24.33 vs. 55.90 ± 13.35, ), uric acid (0.36 ± 0.10 vs. 0.32 ± 0.10, ), cholesterol (5.57 ± 1.30 vs. 5.06 ± 1.47, ), testosterone in women (2.10 (1.33–2.89) vs. 1.54 (0.97–2.05), ), F24 pm (22.31 (17.95–29.62) vs. 17.80 (13.75–22.77), ), and higher portion of male (32.43% vs. 11.54%, ), as well as hypertension (76.12% vs. 51.67%, ). The low bone mass group had a lower IGF-1 index (0.59 (0.43–0.76) vs. 0.79 (0.60–1.02), ) and FT3 level (3.54 (3.16–4.04) vs. 3.98 (3.47–4.45), ) than those without low bone mass. CD patients without low bone mass were more likely to have serum IGF-1 above the upper limit of the normal reference range (ULN) with age-adjusted (18, 26.87% vs. 3, 4.84%, ). No differences of bone turnover makers were found between the two groups.

3.3. Association between Baseline Characteristics and BMD

Spearman’s rank correlation analysis was used to explore the related factors of low bone mass in young CD patients (Table 2). The results indicated that the Z score in the lumbar spine was positively associated with age at diagnosis (r = 0.18801, ), IGF-1 index (r = 0.35153, ), FT3 level (r = 0.24117, ), estradiol in women (r = 0.2361, ), and occurrence of normal menstruation in females (r = 0.2267, ). Meanwhile, SBP (r = −0.21575, ), DBP (r = −0.32538, ), ALT (r = −0.17477, ), serum creatinine (r = −0.36072, ), cholesterol (r = −0.20205, ), testosterone in women (r = −0.2700, ), F8 am (r = −0.18998, ), and serum cortisol at midnight (r = −0.27273, ) were negatively associated with the Z-score in the lumbar spine. The results also illustrated that the Z-score in the femoral neck was positively associated with BMI (r = 0.33926, ), IGF-1 index (r = 0.24418, ), FT3 level (r = 0.20487, ), and occurrence of normal menstruation in females (r = 0.2393, ). Serum creatinine (r = −0.1932, ), osteocalcin (r = −0.22744, ), and testosterone in women (r = −0.2363, ) were negatively associated with the Z-score in the femoral neck.

Table 2 
Spearman rank correlation of BMD and various variables in Cushing’s disease patients.
3.4. IGF-1 Index and Low Bone Mass

Participants were categorized into the following three groups according to tertiles of the preoperative IGF-1 index: <0.5986 (tertiles 1), 0.5986–0.8380 (tertiles 2), and >0.8380 (tertiles 3). With the IGF-1 index increasing, the level of PTH decreased (54.85 (38.35–66.2), 38.9 (26.6–66.9), 36 (25.5–47.05), and ), while other bone metabolism makers, including PINP, osteocalcin, and 25 (OH) VD, showed no differences among the three groups (Figures 1(a)–1(d)). With the increase in the IGF-1 index level, the Z-score of both vertebra lumbalis (tertiles 1: −2.4 (−3.3∼−1.5); tertiles 2: −1.9 (−2.3∼−1.0); tertiles 3: −1.15 (−1.9∼−0.4), ) and the neck of femur (tertiles 1: −1.7 (−2.3∼−0.95); tertiles 2: −1.2 (−1.9∼−0.5); tertiles 3: −1.0 (−1.5∼−0.5), ) increased gradually (Figures 2(a) and 2(b)). Meanwhile, prevalence of low bone mass decreased (68.29%, 53.33%, 23.81%, ) (Figure 3(a)) both in the vertebra lumbalis (63.41%, 48.89%, 16.67%, ) and the neck of femur (32.5%, 11.11%, 11.19%, ), with the increasing of the IGF-1 index level (Figures 3(b) and 3(c)).

Figure 1 
Bone turnover makers in three groups according to tertiles of the preoperative IGF-1 index. Tertiles 1: <0.5986, tertiles 2: 0.5986–0.8380, and tertiles 3 >0.8380. a for PINP; b for osteocalcin; c for PTH; d for VD-OH25. (a) p for trend = 0.2601. (b) p for trend = 0.1310. (c) p for trend = 0.008. (d) p for trend = 0.7956.
Figure 2 
Z-score of both the neck of femur and the vertebra lumbalis in three tertiles of the IGF-1 index. a for the neck of femur; b for the vertebra lumbalis. Tertiles 1: <0.5986, tertiles 2: 0.5986–0.8380, and tertiles 3 >0.8380. (a) p for trend = 0.0148. (b) p for trend < 0.0001.
Figure 3 
Prevalence of low bone mass according to tertiles of the preoperative IGF-1 index. With increment of the IGF-1 index level, prevalence of low bone mass decreased, both in the vertebra lumbalis and neck of femur. Tertiles 1: <0.5986, tertiles 2: 0.5986–0.8380, and tertiles 3 >0.8380. (a) p for trend = 0.0002. (b) p for trend = 0.0169. (c) p for trend < 0.0001.

In the logistic regression analysis of the related factors of low bone mass, most of the potentially relevant factors were put into this model; only the IGF-1 index was still significantly negatively associated with the prevalence of low bone mass after adjusting for covariables. The results indicated that compared to the patients in the lowest tertile of the IGF-1 index (<0.5563), those with the highest tertile of the IGF-1 index (≥0.7993) had a lower prevalence of low bone mass (95% CI 0.16 (0.06–0.41), ). After adjusting for age, gender, and BMI, the patients in the highest tertile of the IGF-1 index still conferred a lower prevalence of low bone mass (95% CI 0.15 (0.06–0.42), ). The association between the IGF-1 index and low bone mass still existed (95% CI 0.02 (0.001–0.5), ) even after adjusting for age, gender, CD duration, BMI, hypertension, dyslipidemia, diabetes, ALT, Scr, FT3, F24 pm, PTH, and osteocalcin (Table 3). In comparison to the reference population, the participants in the middle tertile of the IGF-1 index (0.5563–0.7993) had no different risk of low bone mass.

Table 3 
Association between the preoperative IGF-1 index and the risk of low bone mass.

4. Discussion

Our results revealed that low bone mass occurred in around half of young CD patients, affecting more males than females, and mostly in the lumbar spine. The CD patients in our study had a high prevalence (48.37%) of low bone mass at the baseline. This was in accordance with the findings of previous research, and the reported prevalence of osteoporosis due to excess endogenous cortisol ranges from 22% to 59% [19–25]. In this study, CD patients’ lumbar vertebrae were more severely affected than the neck of the femur. It is reported that lumbar vertebrae, containing more trabecular bone than femur neck, were more vulnerable to endogenous cortisol [26].

Our results also indicated that men were more prone to low bone mass than women in CD, which was in accordance with several other studies [23, 27, 28]; possibly, the deleterious effect of cortisol excess on BMD might overrule the protective effects of sex hormones, and men were more often hypogonadal compared with women in CD patients. In our study, patients with low bone mass had a significantly higher level of F24 pm. Both cortisol levels in the morning and at midnight, were negatively associated with the Z-score of BMD in the lumbar spine at diagnosis. But these results were not seen in the femoral neck at diagnosis. This further indicated that lumbar vertebrae were more vulnerable to endogenous cortisol. BMI was considered to be associated with bone mass [29]. In our study, higher BMI was associated with higher BMD at diagnosis in the femur neck but not in the lumbar vertebrae, consistent with other studies [30].

Interestingly, besides the above known related factors, we also found that a higher level of the IGF-1 index was strongly associated with a lower prevalence of low bone mass, both in the vertebra lumbalis and the neck of the femur, independently of age, gender, duration, BMI, hypertension, dyslipidemia, diabetes, level of ALT, creatinine, FT3, and F24 pm. The IGF-1 index was also positively associated with the BMD Z-score, both in the lumbar spine and the femoral neck. So far, there have been few studies concerning the association between IGF-1 and low bone mass in Cushing’s disease patients. As we know, GH [31, 32] and IGF-1 [33] have been demonstrated to increase both bone formation (e.g., collagen synthesis) and bone resorption. However, in CD patients, glucocorticoids resulted in decreased number and dysfunction of osteoblasts by inhibiting GH-IGF-1 axes [34, 35]. In vitro studies suggested that at high concentrations of glucocorticoids, a decreased release of GHRH had been reported [36–38]; therefore, GH-IGF-1 axes were inhibited. IGF-1 possessed anabolic mitogenic actions in osteoblasts while reducing the anabolic actions of TGF-β [39]. The decrease in IGF-1 might be a risk factor for low bone mass in CD patients. In vitro studies had also indicated that the suppressive effects of glucocorticoids on osteoblast function can be partially reversed by GH or IGF treatment [8]. In recent years, some studies have also shown that patients with untreated Cushing’s disease may have elevated IGF-1, and mildly elevated IGF-1 in Cushing’s disease does not imply pathological growth hormone excess. Higher IGF-1 levels could predict better outcomes in CD [40, 41]. Possible mechanisms were not clear, which might involve changes in IGF binding proteins (IGFBPs), interference in IGFBP fragments, IGF-1 synthesis or clearance, and/or the effects of hyperinsulinism induced by excess glucocorticoids. In our study, the results also showed that IGF-1 was an independent protective factor for low bone mass in CD patients.

Our study was one of the few well-powered research studies on the association of IGF-1 levels with low bone mass in young CD patients. These represented important strengths of our study, especially given the rarity of CD. The main limitation of this study was its retrospective nature. This could not prove causality. A prospective study should be conducted to explore the causality between IGF-1 and osteoporosis in CD patients. In addition, this study lacked morphometric data for spinal fractures in all patients, which may underestimate the incidence of fractures and osteoporosis. However, our study indicated that a lower IGF-1 index level was significantly associated with low bone mass in young CD patients, which might provide a new aspect to understand the possible risk factors and mechanism of osteoporosis in CD patients.

In conclusion, our study found that a higher IGF-1 index was independently and significantly associated with decreased prevalence of low bone mass in young CD patients, drawing attention to the role of IGF-1 in the pathogenesis of CD-caused low bone mass and may support the exploration of this pathway in therapeutic agent development in antiosteoporosis in CD.

Data Availability

The data used to support the findings of the study are available on request from the authors.

Additional Points

Through a retrospective study of a large sample of Cushing’s disease (CD) patients from a single center, we found that a higher IGF-1 index was independently associated with a lower prevalence of low bone mass in young CD patients and IGF-1 might play an important role in the pathogenesis of CD-caused low bone mass.

Disclosure

Wanwan Sun and Quanya Sun were the co-first authors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Wanwan Sun analyzed the data and wrote the manuscript. Quanya Sun collected the data. Hongying Ye and Shuo Zhang conducted the study design and quality control. All authors read and approved the final manuscript. Wanwan Sun and Quanya Sun contributed equally to this work.

Acknowledgments

The present study was supported by grants from the initial funding of the Huashan Hospital (2021QD023). The study was also supported by grants from Multidisciplinary Diagnosis and Treatment (MDT) demonstration project in research hospitals (Shanghai Medical College, Fudan University, no: DGF501053-2/014).

References

  1. H. Nishioka and S. Yamada, “Cushing’s disease,” Journal of Clinical Medicine, vol. 8, no. 11, p. 1951, 2019.

    View at: Publisher Site | Google Scholar

  2. H. Cushing, “The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism),” Obesity Research, vol. 2, no. 5, pp. 486–508, 1994.

    View at: Publisher Site | Google Scholar

  3. R. A. Feelders, S. J. Pulgar, A. Kempel, and A. M. Pereira, “Management of endocrine disease: the burden of Cushing’s disease: clinical and health-related quality of life aspects,” European Journal of Endocrinology, vol. 167, no. 3, pp. 311–326, 2012.

    View at: Publisher Site | Google Scholar

  4. R. Pivonello, M. De Leo, A. Cozzolino, and A. Colao, “The treatment of Cushing’s disease,” Endocrine Reviews, vol. 36, no. 4, pp. 385–486, 2015.

    View at: Publisher Site | Google Scholar

  5. R. Pivonello, M. C. De Martino, M. De Leo, C. Simeoli, and A. Colao, “Cushing’s disease: the burden of illness,” Endocrine, vol. 56, no. 1, pp. 10–18, 2017.

    View at: Publisher Site | Google Scholar

  6. R. S. Hardy, H. Zhou, M. J. Seibel, and M. S. Cooper, “Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy,” Endocrine Reviews, vol. 39, no. 5, pp. 519–548, 2018.

    View at: Publisher Site | Google Scholar

  7. R. Bouillon and A. Prodonova, “Growth hormone deficiency and peak bone mass: laboratory for experimental medicine and Endocrinology, catholic university of leuven, gasthuisberg, leuven, Belgium,” Journal of Pediatric Endocrinology and Metabolism, vol. 13, no. s2, pp. 1327–1342, 2000.

    View at: Publisher Site | Google Scholar

  8. A. Giustina, G. Mazziotti, and E. Canalis, “Growth hormone, insulin-like growth factors, and the skeleton,” Endocrine Reviews, vol. 29, no. 5, pp. 535–559, 2008.

    View at: Publisher Site | Google Scholar

  9. T. Sugimoto, K. Nishiyama, F. Kuribayashi, and K. Chihara, “Serum levels of insulin-like growth factor (IGF) I, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures,” Journal of Bone and Mineral Research, vol. 12, no. 8, pp. 1272–1279, 1997.

    View at: Publisher Site | Google Scholar

  10. P. Garnero, E. Sornay-Rendu, and P. D. Delmas, “Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women,” The Lancet, vol. 355, no. 9207, pp. 898-899, 2000.

    View at: Publisher Site | Google Scholar

  11. C. Ohlsson, D. Mellström, D. Carlzon et al., “Older men with low serum IGF-1 have an increased risk of incident fractures: the MrOS Sweden study,” Journal of Bone and Mineral Research, vol. 26, no. 4, pp. 865–872, 2011.

    View at: Publisher Site | Google Scholar

  12. M. Hotta, T. Shibasaki, A. Masuda et al., “Effect of human growth hormone-releasing hormone on GH secretion in Cushing’s syndrome and non-endocrine disease patients treated with glucocorticoids,” Life Sciences, vol. 42, no. 9, pp. 979–984, 1988.

    View at: Publisher Site | Google Scholar

  13. L. T. Braun and M. Reincke, “The effect of biochemical remission on bone metabolism in Cushing’s syndrome: a 2-year follow-up study,” Journal of Bone and Mineral Research, vol. 36, no. 11, pp. 2281-2282, 2021.

    View at: Publisher Site | Google Scholar

  14. I. Kanazawa, T. Yamaguchi, M. Yamamoto, M. Yamauchi, S. Yano, and T. Sugimoto, “Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus,” Osteoporosis International, vol. 18, no. 12, pp. 1675–1681, 2007.

    View at: Publisher Site | Google Scholar

  15. A. Scillitani, G. Mazziotti, C. Di Somma et al., “Treatment of skeletal impairment in patients with endogenous hypercortisolism: when and how?” Osteoporosis International, vol. 25, no. 2, pp. 441–446, 2014.

    View at: Publisher Site | Google Scholar

  16. M. Fleseriu, R. Auchus, I. Bancos et al., “Consensus on diagnosis and management of Cushing’s disease: a guideline update,” Lancet Diabetes and Endocrinology, vol. 9, no. 12, pp. 847–875, 2021.

    View at: Publisher Site | Google Scholar

  17. J. M. Liu, D. L. Zhu, Y. M. Mu, and W. B. Xia, “Chinese Society of Osteoporosis and Bone Mineral Research, the Chinese Society of Endocrinology, Chinese Diabetes Society, Chinese Medical Association; Chinese Endocrinologist Association, Chinese Medical Doctor Association,” Management of fracture risk in patients with diabetes-Chinese Expert Consensus Journal of Diabetes, vol. 11, pp. 906–919, 2019.

    View at: Google Scholar

  18. P. M. Camacho, S. M. Petak, N. Binkley et al., “American association of clinical endocrinologists and American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal OSTEOPOROSIS-2020 update,” Endocrine Practice, vol. 26, no. 1, pp. 1–46, 2020.

    View at: Publisher Site | Google Scholar

  19. C. V. dos Santos, L. Vieira Neto, M. Madeira et al., “Bone density and microarchitecture in endogenous hypercortisolism,” Clinical Endocrinology, vol. 83, no. 4, pp. 468–474, 2015.

    View at: Publisher Site | Google Scholar

  20. N. Ohmori, K. Nomura, K. Ohmori, Y. Kato, T. Itoh, and K. Takano, “Osteoporosis is more prevalent in adrenal than in pituitary Cushing’s syndrome,” Endocrine Journal, vol. 50, no. 1, pp. 1–7, 2003.

    View at: Publisher Site | Google Scholar

  21. M. E. Randazzo, E. Grossrubatscher, P. Dalino Ciaramella, A. Vanzulli, and P. Loli, “Spontaneous recovery of bone mass after cure of endogenous hypercortisolism,” Pituitary, vol. 15, no. 2, pp. 193–201, 2012.

    View at: Publisher Site | Google Scholar

  22. L. Tauchmanovà, R. Pivonello, C. Di Somma et al., “Bone demineralization and vertebral fractures in endogenous cortisol excess: role of disease etiology and gonadal status,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 5, pp. 1779–1784, 2006.

    View at: Publisher Site | Google Scholar

  23. E. Valassi, A. Santos, M. Yaneva et al., “The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics,” European Journal of Endocrinology, vol. 165, no. 3, pp. 383–392, 2011.

    View at: Publisher Site | Google Scholar

  24. L. Trementino, G. Appolloni, L. Ceccoli et al., “Bone complications in patients with Cushing’s syndrome: looking for clinical, biochemical, and genetic determinants,” Osteoporosis International, vol. 25, no. 3, pp. 913–921, 2014.

    View at: Publisher Site | Google Scholar

  25. A. W. van der Eerden, M. den Heijer, W. J. Oyen, and A. R. Hermus, “Cushing’s syndrome and bone mineral density: lowest Z scores in young patients,” The Netherlands Journal of Medicine, vol. 65, no. 4, pp. 137–141, 2007.

    View at: Google Scholar

  26. P. G. Lacativa and M. L. F. Farias, “Office practice of osteoporosis evaluation,” Arquivos Brasileiros de Endocrinologia and Metabologia, vol. 50, no. 4, pp. 674–684, 2006.

    View at: Publisher Site | Google Scholar

  27. L. H. A. Broersen, F. M. van Haalen, T. Kienitz et al., “Sex differences in presentation but not in outcome for ACTH-dependent Cushing’s syndrome,” Frontiers in Endocrinology, vol. 10, p. 580, 2019.

    View at: Publisher Site | Google Scholar

  28. F. P. Giraldi, M. Moro, and F. Cavagnini, “Gender-related differences in the presentation and course of Cushing’s disease,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 4, pp. 1554–1558, 2003.

    View at: Publisher Site | Google Scholar

  29. S. Morin, J. F. Tsang, and W. D. Leslie, “Weight and body mass index predict bone mineral density and fractures in women aged 40 to 59 years,” Osteoporosis International, vol. 20, no. 3, pp. 363–370, 2009.

    View at: Publisher Site | Google Scholar

  30. M. Zilio, M. Barbot, F. Ceccato et al., “Diagnosis and complications of Cushing’s disease: gender-related differences,” Clinical Endocrinology, vol. 80, no. 3, pp. 403–410, 2014.

    View at: Publisher Site | Google Scholar

  31. G. Amato, C. Carella, S. Fazio, G. La Montagna, A. Cittadini, and D. Sabatini, “Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses,” Journal of Clinical Endocrinology and Metabolism, vol. 77, no. 6, pp. 1671–1676, 1993.

    View at: Publisher Site | Google Scholar

  32. S. A. Beshyah, E. Thomas, P. Kyd, P. Sharp, A. Fairney, and D. G. Johnston, “The effect of growth hormone replacement therapy in hypopituitary adults on calcium and bone metabolism,” Clinical Endocrinology, vol. 40, no. 3, pp. 383–391, 2010.

    View at: Publisher Site | Google Scholar

  33. P. R. Ebeling, J. D. Jones, W. M. O’Fallon, C. H. Janes, and B. L. Riggs, “Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women,” Journal of Clinical Endocrinology and Metabolism, vol. 77, no. 5, pp. 1384–1387, 1993.

    View at: Publisher Site | Google Scholar

  34. G. Mazziotti and A. Giustina, “Glucocorticoids and the regulation of growth hormone secretion,” Nature Reviews Endocrinology, vol. 9, no. 5, pp. 265–276, 2013.

    View at: Publisher Site | Google Scholar

  35. N. A. Tritos, “Growth hormone deficiency in adults with Cushing’s disease,” Best Practice and Research Clinical Endocrinology and Metabolism, vol. 35, no. 2, Article ID 101474, 2021.

    View at: Publisher Site | Google Scholar

  36. K. Nakagawa, T. Ishizuka, T. Obara, M. Matsubara, and K. Akikawa, “Dichotomic action of glucocorticoids on growth hormone secretion,” Acta Endocrinologica, vol. 116, no. 2, pp. 165–171, 1987.

    View at: Publisher Site | Google Scholar

  37. G. Fernández-Vázquez, L. Cacicedo, M. J. Lorenzo, R. Tolón, J. López, and F. Sánchez-Franco, “Corticosterone modulates growth hormone-releasing factor and somatostatin in fetal rat hypothalamic cultures,” Neuroendocrinology, vol. 61, no. 1, pp. 31–35, 1995.

    View at: Publisher Site | Google Scholar

  38. S. K. Fife, R. S. Brogan, A. Giustina, and W. B. Wehrenberg, “Immunocytochemical and molecular analysis of the effects of glucocorticoid treatment on the hypothalamic-somatotropic axis in the rat,” Neuroendocrinology, vol. 64, no. 2, pp. 131–138, 1996.

    View at: Publisher Site | Google Scholar

  39. T. L. McCarthy, M. Centrella, and E. Canalis, “Cortisol inhibits the synthesis of insulin-like growth factor-I in skeletal cells,” Endocrinology, vol. 126, no. 3, pp. 1569–1575, 1990.

    View at: Publisher Site | Google Scholar

  40. K. English, V. Chikani, G. Dimeski, and W. J. Inder, “Elevated insulin‐like growth factor‐1 in Cushing’s disease,” Clinical Endocrinology, vol. 91, no. 1, pp. 141–147, 2019.

    View at: Publisher Site | Google Scholar

  41. E. Gezer, B. Çetinarslan, A. Selek et al., “The association between insulin-like growth factor 1 levels within reference range and early postoperative remission rate in patients with Cushing’s disease,” Endocrine Research, vol. 46, no. 3, pp. 92–98, 2021.

    View at: Publisher Site | Google Scholar

Copyright © 2023 Wanwan Sun 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.

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High-resolution Contrast-enhanced MRI With Three-Dimensional Fast Spin Echo Improved the Diagnostic Performance for Identifying Pituitary Microadenomas In Cushing’s Syndrome

Posted on July 26, 2023 by MaryO

Abstract

Objectives

To assess the diagnostic performance of high-resolution contrast-enhanced MRI (hrMRI) with three-dimensional (3D) fast spin echo (FSE) sequence by comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with 2D FSE sequence for identifying pituitary microadenomas.

Methods

This single-institutional retrospective study included 69 consecutive patients with Cushing’s syndrome who underwent preoperative pituitary MRI, including cMRI, dMRI, and hrMRI, between January 2016 to December 2020. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources. The diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas was independently evaluated by two experienced neuroradiologists. The area under the receiver operating characteristics curves (AUCs) were compared between protocols for each reader by using the DeLong test to assess the diagnostic performance for identifying pituitary microadenomas. The inter-observer agreement was assessed by using the κ analysis.

Results

The diagnostic performance of hrMRI (AUC, 0.95–0.97) was higher than cMRI (AUC, 0.74–0.75; p ≤ .002) and dMRI (AUC, 0.59–0.68; p ≤ .001) for identifying pituitary microadenomas. The sensitivity and specificity of hrMRI were 90–93% and 100%, respectively. There were 78% (18/23) to 82% (14/17) of the patients, who were misdiagnosed on cMRI and dMRI and correctly diagnosed on hrMRI. The inter-observer agreement for identifying pituitary microadenomas was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively.

Conclusions

The hrMRI showed higher diagnostic performance than cMRI and dMRI for identifying pituitary microadenomas in patients with Cushing’s syndrome.

Key Points

• The diagnostic performance of hrMRI was higher than cMRI and dMRI for identifying pituitary microadenomas in Cushing’s syndrome.

• About 80% of patients, who were misdiagnosed on cMRI and dMRI, were correctly diagnosed on hrMRI.

• The inter-observer agreement for identifying pituitary microadenomas was almost perfect on hrMRI.

Introduction

Cushing’s syndrome, caused by excessive exposure to glucocorticoids, is associated with considerable morbidity and increased mortality [1]. Cushing’s syndrome has diverse manifestations, including central obesity, moon facies, purple striae, and hypertension [2]. Cushing’s disease, due to adrenocorticotropic hormone (ACTH) hypersecretion from pituitary adenomas, is the most common etiology of ACTH-dependent Cushing’s syndrome [1, 2]. According to the Endocrine Society Clinical Practice Guideline, transsphenoidal surgery is the first-line treatment for Cushing’s disease [3]. The identification of pituitary adenomas on preoperative MRI can significantly increase the postoperative remission rate from 50 to 98% [4]. Therefore, it is critical to identify pituitary adenomas on MRI before surgery.

However, there are considerable challenges in identifying ACTH-secreting pituitary adenomas. This is because about 90% of the tumors are microadenomas (less than 10 mm in size) and the median diameter at surgery is about 5 mm [5, 6]. Conventional contrast-enhanced MRI (cMRI) using a two-dimensional (2D) fast spin echo (FSE) sequence has been routinely used to acquire images with 2- to 3-mm slice thickness, but some microadenomas are difficult to be identified on cMRI, resulting in false negatives reported in up to 50% of patients with Cushing’s disease [7]. Dynamic contrast-enhanced MRI (dMRI) increases the sensitivity of identifying pituitary adenomas to 66% [8], but it also increases false positives at the same time [9, 10]. The 3D spoiled gradient recalled (SPGR) sequence has been introduced in high-resolution contrast-enhanced MRI (hrMRI) to acquire images with 1- to 1.2-mm slice thickness. It is reported that the 3D SPGR sequence is superior to the 2D FSE sequence in the identification of pituitary adenomas with a sensitivity of up to 80% [11,12,13], but it cannot satisfy the clinical needs that about 20% of the lesions are still missed. Therefore, techniques are needed that can help better identify pituitary adenomas, particularly microadenomas. Previously, the 3D FSE sequence was recommended in patients with hyperprolactinemia [14]. Recently, the 3D FSE sequence has developed rapidly and can provide superior image quality with diminished artifacts [15]. Sartoretti et al demonstrated in a very effective fashion that the 3D FSE sequence is a reliable alternative for pituitary imaging in terms of image quality [16]. However, to our knowledge, few studies have investigated the diagnostic performance of 3D FSE sequences for identifying ACTH-secreting pituitary adenomas, particularly microadenomas.

The aim of our study was to assess the diagnostic performance of hrMRI with 3D FSE sequence by comparison with cMRI and dMRI with 2D FSE sequence for identifying ACTH-secreting pituitary microadenomas in patients with Cushing’s syndrome.

Materials and methods

This single-institutional retrospective study was approved by the Institutional Review Board of our hospital. The study was conducted in accordance with the Helsinki Declaration. The informed consent was waived due to the retrospective nature of the study.

Study participants

We retrospectively reviewed the medical records and imaging studies of 186 consecutive patients with ACTH-dependent Cushing’s syndrome, who underwent a combined protocol of cMRI, dMRI, and hrMRI from January 2016 to December 2020. Postoperative patients with Cushing’s disease (n = 97), patients with ectopic ACTH syndrome who underwent pituitary exploration (n = 2), and patients with macroadenomas (n = 5) or lack of pathology (n = 13) were excluded from the study. Finally, 69 patients with ACTH-dependent Cushing’s syndrome were included in the current study (Fig. 1) and the patients included were all surgically confirmed.

Fig. 1
figure 1

Flowchart of patient inclusion/exclusion process and image analysis. ACTH adrenocorticotropic hormone, CD Cushing’s disease, EAS ectopic ACTH syndrome, T1WI T1-weighted imaging, T2WI T2-weighted imaging

MRI protocol

All the patients were imaged on a 3.0 Tesla MR scanner (Discovery MR750w, GE Healthcare) using an 8-channel head coil. The MRI protocol included coronal T2-weighted imaging, coronal T1-weighted imaging, and sagittal T1-weighted imaging before contrast injection. After contrast injection of gadopentetate dimeglumine (Gd-DTPA) at 0.05 mmol/kg (0.1 mL/kg) with a flow rate of 2 mL/s followed by a 10-mL saline solution flush, dMRI and cMRI with 2D FSE sequence were obtained first, and hrMRI with 3D FSE sequence using variable flip angle technique was performed immediately afterward. Detailed acquisition parameters are presented in Table S1.

Image analysis: diagnostic performance

Image interpretation was independently conducted by two experienced neuroradiologists (F.F. and H.Y. with 25 and 16 years of experience in neuroradiology, respectively), who were blinded to patient information. The evaluation order of cMRI, dMRI, and hrMRI sequences was randomized. The identification of pituitary microadenomas on images was scored based on a three-point scale (0 = poor; 1 = fair; 2 = excellent). Scores of 1 or 2 represented the identification of the lesion. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources, with a multidisciplinary team approach.

Image analysis: image quality

Two readers (Z.L. and B.H. with 4 years of experience in radiology, respectively) were asked to assess the image quality of cMRI, dMRI, and hrMRI. Before exposure to images used in the current study, these readers underwent a training session to make sure that they were comparable to the experienced neuroradiologists in terms of image quality assessment. Images were presented in a random order. Image quality was assessed by using a 5-point Likert scale [17], including overall image quality (1 = non-diagnostic; 2 = poor; 3 = fair; 4 = good; 5 = excellent), sharpness (1 = non-diagnostic; 2 = not sharp; 3 = a little sharp; 4 = moderately sharp; 5 = satisfyingly sharp), and structural conspicuity (1 = non-diagnostic; 2 = poor; 3 = fair; 4 = good; 5 = excellent). An example of image quality assessment is shown in Table S2. Final decision was made through a consensus agreement.

The mean signal intensity of pituitary microadenomas, pituitary gland, and noise on cMRI, dMRI, and hrMRI was measured using an operator-defined region of interest. For noise, a 10-mm2 region of interest was placed in the background, and noise was defined as the standard deviation of the signal intensity of the background [17]. For pituitary microadenomas and pituitary gland, the region of interest should include a representative portion of the structure. The mean signal intensity of the pituitary microadenoma was replaced with that of the pituitary gland when no microadenoma was identified. A signal-to-noise ratio (SNR) was defined as the mean signal intensity of the pituitary microadenoma divided by noise. A contrast-to-noise ratio (CNR) was defined as the absolute difference of the mean signal intensity between the normal pituitary gland and pituitary microadenomas divided by noise [17]. Supplementary Fig. 1 shows how to measure the SNR and CNR with the region of interest in a contrast-enhanced pituitary MRI. Supplementary Fig. 2 shows the selection of images for the SNR and CNR calculation.

Statistical analysis

The κ analysis was conducted to assess the inter-observer agreement for identifying pituitary microadenomas. The κ value was interpreted as follows: below 0.20, slight agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, substantial agreement; greater than 0.80, almost perfect agreement.

To assess the diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas, the receiver operating characteristic curves were plotted and the area under curves (AUCs) were compared between MR protocols for each reader by using the DeLong test. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The Mann–Whitney U test was used to evaluate the difference in image quality scores and the Wilcoxon signed-rank test was used to evaluate SNR and CNR measurements between MR protocols. A p value of less than 0.05 was considered statistically significant. Statistical analysis was performed using MedCalc Statistical Software (version 20.0.15; MedCalc Software) and SPSS Statistics (version 22.0; IBM).

Results

Clinical characteristics

A total of 69 patients (median age, 39 years; interquartile range [IQR], 29–54 years; 38 women [55%]) with ACTH-dependent Cushing’s syndrome were included in the study and their clinical characteristics are shown in Table 1. Among the 69 patients, 60 (87%) patients were diagnosed with Cushing’s disease and 9 (13%) were ectopic ACTH syndrome. The median disease course was 36 months (IQR, 12–78 months). The median serum cortisol, ACTH, and 24-h urine free cortisol level before surgery were 33.0 μg/dL (IQR, 25.1–40.1 μg/dL; normal range 4.0–22.3 μg/dL), 77.2 ng/L (IQR, 55.0–124.0 ng/L; normal range 0–46 ng/L), and 422.0 μg (IQR, 325.8–984.6 μg; normal range 12.3–103.5 μg), respectively. The median serum cortisol and 24-h urine free cortisol level after surgery were 3.0 μg/dL (IQR, 1.8–18.4 μg/dL) and 195.6 μg (IQR, 63.5–1240.3 μg), respectively. The median diameter of pituitary microadenomas was 5 mm (IQR, 4–5 mm), ranging from 3 to 9 mm.

Table 1 Clinical characteristics of the patients

Diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas

The inter-observer agreement for identifying pituitary microadenomas by κ statistic between two readers was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively.

The diagnostic performance for identifying pituitary microadenomas on cMRI, dMRI, hrMRI, and combined cMRI and dMRI is summarized in Table 2. For reader 1, the diagnostic performance of hrMRI (AUC, 0.95; 95%CI: 0.87, 0.99) was higher than that of cMRI (AUC, 0.75; 95%CI: 0.63, 0.85; p = 0.002), dMRI (AUC, 0.59; 95%CI: 0.47, 0.71; p < 0.001), and combined cMRI and dMRI (AUC, 0.65; 95%CI: 0.53, 0.76; p = 0.001). For reader 2, the diagnostic performance of hrMRI (AUC, 0.97; 95%CI: 0.89, 1.00) was higher than that of cMRI (AUC, 0.74; 95%CI: 0.63, 0.84; p = 0.001), dMRI (AUC, 0.68; 95%CI: 0.56, 0.79; p = 0.001), and combined cMRI and dMRI (AUC, 0.70; 95%CI: 0.58, 0.80; p = 0.003).

Table 2 Diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas

For reader 1, 23 of the 69 patients (33%) were misdiagnosed on both cMRI and dMRI, but 18 of the 23 misdiagnosed patients (78%) were correctly diagnosed on hrMRI. For reader 2, 17 of the 69 patients (25%) were misdiagnosed on both cMRI and dMRI, but 14 of the 17 misdiagnosed patients (82%) were correctly diagnosed on hrMRI.

Figure 2 shows that a 5-mm pituitary microadenoma was identified on preoperative pituitary MRI. The margin of the lesion was fully delineated on hrMRI, but not on cMRI and dMRI. Figure 3 shows that a 3-mm pituitary microadenoma was missed on cMRI, but identified on dMRI and hrMRI. Figure 4 shows that a 5-mm pituitary microadenoma was correctly diagnosed on hrMRI, but missed on cMRI or dMRI. Figure 5 shows that a 4-mm pituitary microadenoma was evident on coronal images as well as reconstructed axial and reconstructed sagittal images on hrMRI.

Fig. 2

figure 2

Images in a 56-year-old man with Cushing’s disease. The 5-mm pituitary microadenoma (arrow) can be identified on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence, but the margin is not fully delineated. The lesion (arrow) is well delineated on (c) coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence. d Intraoperative endoscopic photograph during transsphenoidal surgery after exposure of the sellar floor shows a round pituitary microadenoma (arrow)

Fig. 3

figure 3

Images in a 34-year-old woman with Cushing’s disease. No tumor is identified on (a) coronal contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. The 3-mm pituitary microadenoma (arrow) with delayed enhancement is identified on the left side of the pituitary gland on (b) coronal dynamic contrast-enhanced T1-weighted image obtained with 2D FSE sequence and (c) coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence. d Intraoperative endoscopic photograph during transsphenoidal surgery shows a 3-mm pituitary microadenoma (arrow)

Fig. 4

figure 4

Images in a 43-year-old man with Cushing’s disease. The lesion is missed on (a) coronal contrast-enhanced T1-weighted image and (b) coronal dynamic contrast-enhanced T1-weighted image obtained with two-dimensional (2D) fast spin echo (FSE) sequence. c Coronal contrast-enhanced T1-weighted image on high-resolution MRI obtained with 3D FSE sequence shows a round pituitary microadenoma (arrow) measuring approximately 5 mm with delayed enhancement on the left side of the pituitary gland. d Intraoperative endoscopic photograph for microsurgical resection of the 5-mm pituitary microadenoma (arrow)

Fig. 5

figure 5

Images in a 48-year-old woman with Cushing’s disease. Preoperative high-resolution contrast-enhanced MRI using three-dimensional fast spin echo sequence shows a 4-mm pituitary microadenoma (arrow) with delayed enhancement is well delineated on the left side of the pituitary gland on (a) coronal, (b) reconstructed axial, and (c) reconstructed sagittal contrast-enhanced T1-weighted images. d Intraoperative endoscopic photograph during transsphenoidal surgery after exposure of the sellar floor shows a round pituitary microadenoma (arrow)

Image quality of cMRI, dMRI, and hrMRI

Image quality scores of cMRI, dMRI, and hrMRI are presented in Table 3. Scores for overall image quality, sharpness, and structural conspicuity on hrMRI (overall image quality, 5.0 [IQR, 5.0–5.0]; sharpness, 5.0 [IQR, 4.5–5.0]; structural conspicuity, 5.0 [IQR, 5.0–5.0]) were higher than those on cMRI (overall image quality, 4.0 [IQR, 3.5–4.0]; sharpness, 4.0 [IQR, 3.0–4.0]; structural conspicuity, 4.0 [IQR, 4.0–4.0]; p < 0.001 for all) and dMRI (overall image quality, 4.0 [IQR, 4.0–4.0]; sharpness, 4.0 [IQR, 4.0–4.0]; structural conspicuity, 4.0 [IQR, 4.0–4.5]; p < 0.001 for all).

Table 3 Image quality scores on cMRI, dMRI, and hrMRI

The SNR and CNR measurements are shown in Table 4. The SNR of the pituitary microadenomas on hrMRI (67.5 [IQR, 51.2–92.1]) was lower than that on cMRI (82.3 [IQR, 61.8–127.2], p < 0.001), but higher than that on dMRI (53.9 [IQR, 35.2–72.6], p = 0.001). The CNR on hrMRI (26.2 [IQR, 15.1–41.0]) was higher than that on cMRI (10.6 [IQR, 0–42.6], p = 0.023) and dMRI (11.2 [IQR, 0–29.8], p < 0.001).

Table 4 SNR and CNR on cMRI, dMRI, and hrMRI

Discussion

The identification of pituitary microadenomas is considerably challenging but critical in patients with ACTH-dependent Cushing’s syndrome. Our study demonstrated that hrMRI with 3D FSE sequence had higher diagnostic performance (AUC, 0.95–0.97) than cMRI (AUC, 0.74–0.75; p ≤ 0.002) and dMRI (AUC, 0.59–0.68; p ≤ 0.001) for identifying pituitary microadenomas. To our knowledge, there are no previous studies specifically evaluating the identification of pituitary microadenomas on hrMRI with 3D FSE sequence by comparison with cMRI and dMRI in patients with ACTH-dependent Cushing’s syndrome, and this is the largest study conducted in ACTH-secreting microadenomas with a sensitivity of more than 90%.

Recently, techniques for pituitary evaluation have developed rapidly. Because of false negatives and false positives on cMRI and dMRI using 2D FSE sequence [7, 9, 10], a 3D SPGR sequence was introduced for identifying pituitary adenomas. Previous studies demonstrated that the 3D SPGR sequence performed better than the 2D FSE sequence in the identification of pituitary adenomas with a sensitivity of up to 80% [11,12,13]. In patients with hyperprolactinemia, the 3D FSE sequence was recommended [14] and the 3D FSE sequence has rapidly developed recently with superior image quality [15, 16], suggesting that the 3D FSE sequence may be a reliable alternative for identifying pituitary adenomas. However, to our knowledge, few studies have investigated the diagnostic performance of the 3D FSE sequence for identifying ACTH-secreting pituitary adenomas. To fill the gaps, we conducted the current study and revealed that images obtained with the 3D FSE sequence had higher sensitivity (90–93%) in identifying pituitary microadenomas, than that in previous studies using the 3D SPGR sequence [8, 11,12,13].

There is a trade-off between spatial resolution and image noise. The reduced slice thickness can overcome the partial volume averaging effect, but it is associated with increased image noise [17]. Strikingly, our study showed that hrMRI had higher image quality scores than cMRI and dMRI, in terms of overall image quality, sharpness, and structural conspicuity. The SNR of the pituitary microadenomas on cMRI was slightly higher than that on hrMRI in our study. This is because the SNR was calculated as the mean signal intensity of the pituitary gland (instead of the pituitary microadenoma) divided by noise when no microadenoma was identified, and the mean signal intensity of the pituitary gland is higher than that of the pituitary microadenoma. About 40% of pituitary microadenomas were missed on cMRI, whereas less than 10% of pituitary microadenomas were missed on hrMRI. Given the situation mentioned above, the SNR on hrMRI was lower than that on cMRI. However, the CNR on hrMRI was significantly higher than that on cMRI and dMRI. Therefore, hrMRI in our study can dramatically improve the spatial resolution with high CNR, enabling the better identification of pituitary microadenomas.

The identification of pituitary adenomas on preoperative MRI in patients with ACTH-dependent Cushing’s syndrome could help the differential diagnosis of Cushing’s syndrome and aids surgical resection of lesions. It should be noted that most of the pituitary adenomas in patients with Cushing’s disease are microadenomas [5, 6]. In our study, all the tumors are microadenomas with a median diameter of 5 mm (IQR, 4–5 mm), making the diagnosis more challenging. The sensitivity of identifying pituitary adenomas decreased from 80 to 72% after excluding macroadenomas in a previous study [12], whereas the sensitivity of identifying pituitary microadenomas in our study was 90–93% on hrMRI. In the current study, hrMRI performed better than cMRI, dMRI, and combined cMRI and dMRI, with high AUC (0.95–0.97), high sensitivity (90–93%), and high specificity (100%), superior to previous studies [8, 11,12,13]. The high sensitivity of hrMRI for identifying pituitary adenomas will help surgeons improve the postoperative remission rate [4]. The high specificity of hrMRI will assist clinicians to consider ectopic ACTH syndrome, and then perform imaging to identify ectopic tumors. Besides, the inter-observer agreement for identifying pituitary microadenomas was almost perfect on hrMRI (κ = 0.91), which was moderate on cMRI (κ = 0.50) and dMRI (κ = 0.57). Therefore, hrMRI using the 3D FSE sequence is a potential alternative that can significantly improve the identification of pituitary microadenomas.

Limitations of the study included its retrospective nature and the relatively small sample size in patients with ectopic ACTH syndrome as negative controls. The bias may be introduced in the patient inclusion process. Only those patients who underwent all the cMRI, dMRI, and hrMRI scans were included. In fact, some patients will bypass hrMRI when obvious pituitary adenomas were detected on cMRI and dMRI. These patients were not included in the current study because of lack of hrMRI findings. Given the situation, the sensitivity of identifying pituitary adenomas will be higher with the enrollment of these patients. Besides, the timing of the sequence acquisition after contrast injection is essential [16] and bias may be introduced due to the postcontrast enhancement curve of both the pituitary gland and the microadenoma [14]. In the future, a prospective study with different sequence acquisition orders is needed to minimize possible interference caused by the postcontrast enhancement curve. Moreover, a larger sample size is also needed to verify the diagnostic performance of hrMRI using 3D FSE sequence for identifying pituitary microadenomas and to determine whether it can replace 2D FSE or 3D SPGR sequences for routinely evaluating the pituitary gland.

In conclusion, hrMRI with 3D FSE sequence showed higher diagnostic performance than cMRI and dMRI for identifying pituitary microadenomas in patients with Cushing’s syndrome.

Abbreviations

ACTH:
Adrenocorticotropic hormone
AUC:
Area under the receiver operating characteristics curve
cMRI:
Conventional contrast-enhanced MRI
CNR:
Contrast-to-noise ratio
dMRI:
Dynamic contrast-enhanced MRI
FSE:
Fast spin echo
hrMRI:
High-resolution contrast-enhanced MRI
IQR:
Interquartile range
SNR:
Signal-to-noise ratio
SPGR:
Spoiled gradient re

called

References

  1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015) Cushing’s syndrome. Lancet 386:913–927

    Article CAS PubMed Google Scholar

  2. Loriaux DL (2017) Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med 376:1451–1459

    Article CAS PubMed Google Scholar

  3. Nieman LK, Biller BM, Findling JW et al (2015) Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 100:2807–2831

    Article CAS PubMed PubMed Central Google Scholar

  4. Yamada S, Fukuhara N, Nishioka H et al (2012) Surgical management and outcomes in patients with Cushing disease with negative pituitary magnetic resonance imaging. World Neurosurg 77:525–532

    Article PubMed Google Scholar

  5. Vitale G, Tortora F, Baldelli R et al (2017) Pituitary magnetic resonance imaging in Cushing’s disease. Endocrine 55:691–696

    Article CAS PubMed Google Scholar

  6. Jagannathan J, Smith R, DeVroom HL et al (2009) Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease. J Neurosurg 111:531–539

    Article PubMed PubMed Central Google Scholar

  7. Boscaro M, Arnaldi G (2009) Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab 94:3121–3131

    Article CAS PubMed Google Scholar

  8. Kasaliwal R, Sankhe SS, Lila AR et al (2013) Volume interpolated 3D-spoiled gradient echo sequence is better than dynamic contrast spin echo sequence for MRI detection of corticotropin secreting pituitary microadenomas. Clin Endocrinol (Oxf) 78:825–830

    Article CAS PubMed Google Scholar

  9. Lonser RR, Nieman L, Oldfield EH (2017) Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg 126:404–417

    Article PubMed Google Scholar

  10. Potts MB, Shah JK, Molinaro AM et al (2014) Cavernous and inferior petrosal sinus sampling and dynamic magnetic resonance imaging in the preoperative evaluation of Cushing’s disease. J Neurooncol 116:593–600

    Article PubMed Google Scholar

  11. Grober Y, Grober H, Wintermark M, Jane JA, Oldfield EH (2018) Comparison of MRI techniques for detecting microadenomas in Cushing’s disease. J Neurosurg 128:1051–1057

    Article PubMed Google Scholar

  12. Fukuhara N, Inoshita N, Yamaguchi-Okada M et al (2019) Outcomes of three-Tesla magnetic resonance imaging for the identification of pituitary adenoma in patients with Cushing’s disease. Endocr J 66:259–264

    Article PubMed Google Scholar

  13. Patronas N, Bulakbasi N, Stratakis CA et al (2003) Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors. J Clin Endocrinol Metab 88:1565–1569

    Article CAS PubMed Google Scholar

  14. Magnaldi S, Frezza F, Longo R, Ukmar M, Razavi IS, Pozzi-Mucelli RS (1997) Assessment of pituitary microadenomas: comparison between 2D and 3D MR sequences. Magn Reson Imaging 15:21–27

    Article CAS PubMed Google Scholar

  15. Lien RJ, Corcuera-Solano I, Pawha PS, Naidich TP, Tanenbaum LN (2015) Three-Tesla imaging of the pituitary and parasellar region: T1-weighted 3-dimensional fast spin echo cube outperforms conventional 2-dimensional magnetic resonance imaging. J Comput Assist Tomogr 39:329–333

    PubMed Google Scholar

  16. Sartoretti T, Sartoretti E, Wyss M et al (2019) Compressed SENSE accelerated 3D T1w black blood turbo spin echo versus 2D T1w turbo spin echo sequence in pituitary magnetic resonance imaging. Eur J Radiol 120:108667

    Article PubMed Google Scholar

  17. Kim M, Kim HS, Kim HJ et al (2021) Thin-slice pituitary MRI with deep learning-based reconstruction: diagnostic performance in a postoperative setting. Radiology 298:114–122

    Article PubMed Google Scholar

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Acknowledgements

We thank Dr. Kai Sun, Medical Research Center, Peking Union Medical College Hospital, for his guidance on the statistical analysis in this study.

Funding

This study has received funding from the National Natural Science Foundation of China (grant 82071899), the National Key Research and Development Program of China (grants 2016YFC1305901, 2020YFA0804500), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grants 2017-I2M-3–008, 2021-I2M-1–025), the Beijing Natural Science Foundation (grant L182067) and National High Level Hospital Clinical Research Funding (2022-PUMCH-B-067, 2022-PUMCH-B-114).

Author information

Author notes

  1. Zeyu Liu and Bo Hou contributed equally to this work and share first authorship
  2. Hui You and Feng Feng contributed equally to this work and share corresponding authorship

Authors and Affiliations

  1. Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Zeyu Liu, Bo Hou, Hui You, Mingli Li & Feng Feng

  2. Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Lin Lu, Lian Duan & Huijuan Zhu

  3. Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Kan Deng & Yong Yao

  4. State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan Wangfujing Dongcheng Distinct, Beijing, 100730, China

    Yong Yao, Huijuan Zhu & Feng Feng

Corresponding authors

Correspondence to Hui You or Feng Feng.

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Guarantor

The scientific guarantor of this publication is Feng Feng.

Conflict of interest

The authors of this manuscript declare no conflict of interest.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was waived by the Institutional Review Board.

Ethical approval

Institutional Review Board approval was obtained.

Methodology

• retrospective

• diagnostic or prognostic study

• performed at one institution

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Seliciclib for the Treatment of Cushing’s Disease Targeting Pituitary

Posted on June 1, 2023 by MaryO

The following is a summary of “Treatment of Cushing Disease With Pituitary-Targeting Seliciclib,” published in the March 2023 issue of Endocrinology & Metabolism by Liu, et al.

Seliciclib (R-roscovitine) has been shown in preclinical studies to inhibit neoplastic corticotroph proliferation and the production of adrenocorticotropic hormone (ACTH) in the pituitary gland. Therefore, for a study, researchers sought to investigate the effectiveness of seliciclib as a pituitary-targeting treatment for patients with Cushing’s disease (CD).

Two prospective, open-label, phase 2 trials were conducted at a tertiary referral pituitary center. Adult patients with de novo, persistent, or recurrent CD received oral seliciclib 400 mg twice daily for four consecutive days each week for four weeks. The primary endpoint in the single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at the end of the study, and in the multicenter study, the primary endpoint was UFC normalization or a ≥ 50% reduction in UFC from baseline to the end of the study.

Of the 16 patients who consented, 9 were treated with seliciclib. The mean UFC decreased by 42% from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours at the end of the study. The longitudinal model showed significant reductions in UFC from baseline to each treatment week. Three patients achieved a ≥ 50% reduction in UFC (range, 55%-75%), and two exhibited a 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients with ≥48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within four weeks of seliciclib discontinuation.

The results suggested that seliciclib may target pituitary corticotrophs in CD and reverse hypercortisolism. Although potential liver toxicity of seliciclib resolves with treatment withdrawal, a further determination is required to establish the lowest effective dose.

Source: academic.oup.com/jcem/article-abstract/108/3/726/6754906?redirectedFrom=fulltext

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Cushing’s Syndrome in the Elderly

Posted on March 6, 2023 by MaryO

Abstract

Objective

To evaluate whether age-related differences exist in clinical characteristics, diagnostic approach and management strategies in patients with Cushing’s syndrome included in the European Registry on Cushing’s Syndrome (ERCUSYN).

Design

Cohort study.

Methods

We analyzed 1791 patients with CS, of whom 1234 (69%) had pituitary-dependent CS (PIT-CS), 450 (25%) adrenal-dependent CS (ADR-CS) and 107 (6%) had an ectopic source (ECT-CS). According to the WHO criteria, 1616 patients (90.2%) were classified as younger (<65 years) and 175 (9.8%) as older (>65 years).

Results

Older patients were more frequently males and had a lower BMI and waist circumference as compared with the younger. Older patients also had a lower prevalence of skin alterations, depression, hair loss, hirsutism and reduced libido, but a higher prevalence of muscle weakness, diabetes, hypertension, cardiovascular disease, venous thromboembolism and bone fractures than younger patients, regardless of sex (p<0.01 for all comparisons). Measurement of UFC supported the diagnosis of CS less frequently in older patients as compared with the younger (p<0.05). An extra-sellar macroadenoma (macrocorticotropinoma with extrasellar extension) was more common in older PIT-CS patients than in the younger (p<0.01). Older PIT-CS patients more frequently received cortisol-lowering medications and radiotherapy as a first-line treatment, whereas surgery was the preferred approach in the younger (p<0.01 for all comparisons). When transsphenoidal surgery was performed, the remission rate was lower in the elderly as compared with their younger counterpart (p<0.05).

Conclusions

Older CS patients lack several typical symptoms of hypercortisolism, present with more comorbidities regardless of sex, and are more often conservatively treated.

From https://academic.oup.com/ejendo/advance-article-abstract/doi/10.1093/ejendo/lvad008/7030701?redirectedFrom=fulltext&login=false

 

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Ketogenic Diet Initially Masks Symptoms of Hypercortisolism in Cushing’s Disease

Posted on November 30, 2022 by MaryO

Abstract

Cushing’s syndrome (CS) is a diagnosis used to describe multiple causes of serum hypercortisolism. Cushing’s disease (CD), the most common endogenous subtype of CS, is characterized by hypercortisolism due to a pituitary tumor secreting adrenocorticotropic hormone (ACTH). A variety of tests are used to diagnose and differentiate between CD and CS. Hypercortisolism has been found to cause many metabolic abnormalities including hypertension, hyperlipidemia, impaired glucose tolerance, and central adiposity. Literature shows that many of the symptoms of hypercortisolism can improve with a low carb (LC) diet, which consists of consuming <30 g of total carbohydrates per day. Here, we describe the case of a patient with CD who presented with obesity, hypertension, striae and bruising, who initially improved some of his symptoms by implementing a LC diet. Ultimately, as his symptoms persisted, a diagnosis of CD was made. It is imperative that practitioners realize that diseases typically associated with poor lifestyle choices, like obesity and hypertension, can often have alternative causes. The goal of this case report is to provide insight on the efficacy of nutrition, specifically a LC diet, on reducing metabolic derangements associated with CD. Additionally, we will discuss the importance of maintaining a high index of suspicion for CD, especially in those with resistant hypertension, obesity and pre-diabetes/diabetes.

1. Introduction

Cushing’s syndrome (CS) is a rare disorder of hypercortisolism related to exposure to high levels of cortisol (>20 mcg/dL between 0600–0800 or >10 mcg/dL after 1600) for an extended period [1,2]. CS affects 10 to 15 people per million and is more common among those with diabetes, hypertension, and obesity [3]. The metabolic derangements associated with CS include visceral obesity, elevated blood pressure, dyslipidemia, type II diabetes mellitus (T2DM) and insulin resistance [4]. CS physical exam findings include round face, dorsal fat pad, central obesity, abdominal striae, acne, and ecchymosis [3]. Other symptoms associated with CS include low libido, headache, change in menses, depression and lethargy [2,3,5]. The most common features of CS are weight gain, which is found in 82% of cases, and hypertension, which is found in 50–85% of cases [6]. CS can be caused by exogenous glucocorticoids, known as iatrogenic CS, ectopic ACTH secretion (EAS) from sources like a small cell lung cancer or adrenal adenoma, known as EAS CS, or excess production of ACTH from a pituitary tumor, known as CD [3]. In CD, ACTH subsequently causes increased production of cortisol from the adrenal glands. CD accounts for 80–85% of endogenous cases of CS [3]. Other conditions including alcoholism, depression, severe obesity, bulimia and anorexia nervosa can lead to a Cushing-like state, although are not considered true CS [3]. Many studies have demonstrated that LC diets can ameliorate some of the most common metabolic derangements seen in CD, namely hyperglycemia, weight gain, hypertension and insulin resistance.
A LC diet is a general term for diets which lower the total carbohydrates consumed per day [4]. A ketogenic diet is a subtype of LC that is described as having even fewer carbohydrates, typically less than 30 g/day. By reducing carbohydrate intake and thus limiting insulin production, the body achieves ketosis by producing an elevated number of ketones including β-hydroxybutyric acid, acetoacetic acid, and acetone, in the blood [7]. A carnivore diet, a specific type of a ketogenic diet, is defined as mainly eating animal food such as meat, poultry, eggs and fish. Contrarily, a standard American diet (SAD) is defined as a diet high in processed foods, carbs, added sugars, refined fats, and highly processed dairy products [8]. There are several therapeutic applications for LC diets that are currently supported by strong evidence. These include weight loss, cardiovascular disease, T2DM, and epilepsy. LC diets have clinical utility for acne, cancer, polycystic ovary syndrome (PCOS), and neurologic deficits [9].
In this case report, the patient endorsed initially starting a LC diet to address weight gain and high blood sugars that he noted on a glucometer. The patient noted a 35 pounds (lbs.) weight loss over the first 1.5 years on his LC diet, as well as improved blood pressure and in his overall health. He then adopted a carnivore diet but found that weight loss was difficult to maintain, although his body composition continued to improveand his clothes fit better. Later, he noted that his blood pressure would at times be poorly controlled despite multiple medications and strict dietary adherence. The patient reported “being in despair” and “not trusting his doctors” because they did not understand how much his diet had helped him. Despite strict adherence, his symptoms of insulin resistance and hypertension persisted. In this report, we will describe how his symptoms of CD were ameliorated by the ketogenic diet. This case report also highlights that when patients are unable to overcome hormonal pathology, clinicians should not blame patients for lack of adherence to a diet, but instead understand the need to evaluate for complex pathology.

2. Detailed Case Description

A male patient in his thirties, of Asian descent, had a past medical history of easy bruising, central obesity, headaches, hematuria, and hypertension and past family medical history of hypertension in his father and brother. In 2015, he was at his heaviest weight of 179 lbs. with a body mass index (BMI) of 28 kg/m2, placing him in the overweight category (25.0–29.9 kg/m2). At that time the patient reported he was following a SAD diet and was active throughout the day. The patient stated he ate a diet of vegetables, fruits and carbohydrates, but he was not able to lose weight. The patient stated that he switched to a LC diet, to address weight gain and hyperglycemia, and he reported that he lost approximately 35 lbs. in 1.5 years. The patient described his LC diet as eating green leafy vegetables, low carb fruits, fish, poultry, beef and dairy products. The patient then later switched to a carnivore diet. He noted despite aggressively adhering to his diet, that his weight-loss had plateaued, although his waist circumference continued to decrease. The patient noted his carnivore diet consisted of eating a variety of different meats, poultry, fish and eggs.
The metabolic markers seen in Table 1 were obtained after the patient had started a carnivore diet. The patient’s blood glucose levels decreased overtime despite impaired glucose metabolism being a known side effect of hypercortisolism [4]. The patient’s high-density lipoprotein (HDL) remained in a healthy range (40–59 mg/dL) and his triglycerides stayed in an optimal range (<100 mg/dL), despite dyslipidemia being a complication of CD [4]. When the patient was consuming a SAD diet, he was not under the care of a physician and was unable to provide us with previous biomarkers.
Table 1. Patient’s metabolic markers on a carnivore diet. Glucose (70 to 99 mg/dL), total cholesterol (desirable <200 mg/dL, borderline high 200–239 mg/dL, high >239 mg/dL), triglycerides (optimal: <100 mg/dL), HDL (low male: <40 mg/dL), low density lipoprotein (LDL) (Optimal: <100 mg/dL).
Table
Despite strict adherence to his diet and initial improvement in his weight, his blood pressure and his blood sugar levels, in October of 2021 the patient was admitted to the hospital for hypertensive urgency, with a blood pressure of 216/155. His complaints at the time were unexplained ecchymosis, hematuria and significant headaches that were resistant to Excedrin (acetaminophen-aspirin-caffeine) use. At the hospital, the patient underwent a computed tomography (CT) scan of the head and radiograph of the chest, and both images were negative for acute pathology. During his hospital admission, the patient denied any changes in vision, chest pain or edema of the legs. Ultimately, the patient was told to eat a low-salt diet and to follow-up with a cardiologist. At discharge, the patient was placed on hydrochlorothiazide, labetalol, amlodipine and lisinopril. The patient was then seen by his primary care physician in November of 2021 and his urinalysis at that time showed 30 mg/mL (Negative/Trace) of protein in his urine, without hematuria. The patient’s primary care physician discontinued his hydrochlorothiazide and started the patient on furosemide. Additionally, the primary care physician reinforced cutting out salt and limiting his calories to prevent any further weight gain, which his physician explained would contribute further to his hypertension. He was referred to hematology and oncology in November of 2021 for his symptoms of hematuria and abnormal ecchymosis to his abdomen, thighs and arms. The patient’s coagulation and platelet counts were normal, and his symptoms were noted to be improving. His hematuria and ecchymosis were attributed to his significant Excedrin use from the past 1–2 months, secondary to his headaches, and their anti-platelet effect. It was noted that the patient had significant hemolysis during his hospital admission. However, in his follow up examination, there were no signs of hemolysis, and it was attributed to his hypertensive urgency. Again, a low-salt, calorie-limited diet was recommended. The patient was referred to cardiology where he was evaluated for secondary hypertension, because despite his weight loss and his strict adherence to his diet, his blood pressure was still uncontrolled on multiple medications. He had a normal echocardiogram and renal ultrasound which showed no signs of renal artery stenosis bilaterally. At that time the patient’s serum renin, aldosterone and urine metanephrine levels were all normal. His cardiologist increased his lisinopril, and continued him on amlodipine, furosemide and labetalol and reinforced the recommendations of lowering his salt and preventing weight gain.
The patient first contacted our office in January of 2022. At that time his blood pressure was noted to be 160/120 despite being compliant with current blood pressure medications. The patient reported strict adherence to his carnivore diet by sharing his well-documented meals on his social media accounts. Given the persistent symptoms, despite his significant change in diet and weight loss, we were concerned that a hormonal etiology may be driving his symptoms. The patient was seen in-person, in our office, in March of 2022. At the request of the patient, we again reviewed his social media profile to assess his meal choices and diet. While the patient was eager to show us his carnivore meals, what we incidentally noted in his photos was despite weight loss and strict diet adherence, he had developed moon facies (Figure 1a,b). On the physical exam, we noted his prominent abdominal striae (Figure 2). Several screening tests for Cushing’s syndrome were ordered. A midnight salivary cortisol was ordered, with values of 0.884 ug/dL (<0.122 ug/dL) and 0.986 ug/dL (<0.122 ug/dL) and a urinary free cortisol excretion (UFC) was ordered, with values of 8.8 ug/L (5–64 ug/L). At this point our suspicion was confirmed that the patient had inappropriately elevated cortisol.
Metabolites 12 01033 g001 550
Figure 1. The patient’s progression of moon facies, (a) photo from 2019 after initial weight loss (b) photo from office visit in 2022.
Metabolites 12 01033 g002 550
Figure 2. The arrows demonstrate early striae visualized on the lower abdomen bilaterally, unclear in image due to poor office lighting.
Based on screening tests and significant physical exam findings, we referred the patient to endocrinology for a low dose dexamethasone suppression test (DST). They performed a low dose DST revealing a dehydroepiandrosterone (DHEA) of 678 ug/dL (89–427 ug/dL) and ACTH of 23.9 pg/mL (7.2–63.3 pg/mL). The low dose DST and midnight salivary cortisol were both positive indicating hypercortisolism. To begin determining the source of hypercortisolism, the plasma ACTH was evaluated and was 27.2 pg/mL (7.2–63.3 pg/mL). While ACTH was within normal range, a plasma ACTH > 20 pg/mL is suggestive of ACTH-dependent CS, so a magnetic resonance imaging (MRI) of the brain was ordered [2]. The MRI revealed a 4 mm heterogeneous lesion in the central pituitary gland which is suspicious of a cystic microadenoma. To confirm that a pituitary tumor was the cause of the patient’s increased cortisol, the patient was sent for inferior petrosal sinus sampling (IPSS). The results of the IPSS indicated an increase in ACTH in both inferior petrosal sinuses and peripheral after corticotropin-releasing hormone (CRH) stimulation (Figure 3a–c), which was consistent with hypercortisolism.
Metabolites 12 01033 g003a 550Metabolites 12 01033 g003b 550
Figure 3. (a) Right IPS venous sampling values for ACTH and prolactin after CRH stimulation over multiple time intervals. (b) Left IPS venous sampling values for ACTH and prolactin after CRH stimulation over multiple time intervals. (c) Peripheral sampling values for ACTH and prolactin after CRH stimulation over multiple time intervals.
Lab results from the patient’s IPSS venous sampling can be seen above. The graphs depict the lab values of ACTH (7.2–63.3 pg/mL) and prolactin (PRL) (2.1–17.7 ng/mL) before and after CRH stimulation during IPSS. PRL acts as a baseline to indicate successful catheterization in the procedure [10].
Using the ACTH levels from our patient’s IPSS we calculated a ratio of inferior petrosal sinus to peripheral (IPS:P). These results can be seen below (Table 2). The right IPS:P was calculated as 3.60 at 10 min and the left IPS:P as 7.65 at 10 min. These ratios confirmed that the hypercortisolism was due to the pituitary tumor, as it is higher than the 3:1 ratio necessary for diagnosis of CD [11]. The patient is currently scheduled to undergo surgical resection of the pituitary microadenoma.
Table 2. Right and left petrosal sinus to peripheral serum ACTH ratios.
Table

3. Clinical Evaluation for CS

In this case, the patient presented with uncontrolled hypertension, weight gain despite a strict diet, hyperglycemia, abdominal striae and moon facies. Despite evaluation, both inpatient and outpatient, a diagnosis of CS was not yet explored. When CS is suspected based on clinical findings, the use of exogenous steroids must first be excluded as it is the most common cause of hypercortisolism [3]. If there is still concern for CS, there are three screening tests that can be done which are sensitive but not specific for hypercortisolism. The screening tests include: a 24-h UFC, 2 late night salivary cortisol tests, low dose (1 g) DST [3]. To establish the preliminary diagnosis of hypercortisolism two screening tests must be abnormal [2].
The first step to determine the cause of hypercortisolism is to measure the plasma level of ACTH. Low values of ACTH < 5 pg/mL indicate the cause is likely ACTH-independent CS and imaging of the adrenal glands is warranted as there is a high suspicion of an adrenal adenoma [2,3]. When the serum ACTH is elevated >/20 pg/mL it is likely an ACTH-dependent form of CS [2]. To further evaluate an ACTH-dependent hypercortisolism, an MRI should be obtained as there is high suspicion that the elevated cortisol is coming from a pituitary adenoma. If there is a pituitary mass >6 mm there is a strong indication for the diagnosis of CD [2]. However, pituitary tumors can be quite small and can be missed on MRIs in 20–58% of patients with CD [2]. If there is still a high suspicion of CD with an inconclusive MRI, a high dose DST (8 g) is done. Patients with CD should not respond and their ACTH and DHEA, a steroid precursor, should remain high. Similarly, CRH stimulation test is done and patients with CD should have an increase in ACTH and/or cortisol within 45 min of CRH being given. If the patient has a positive high-dose DST, CRH-stimulation test and an MRI with a pituitary tumor >6 mm no further testing is needed as it is likely the patient has CD [2]. If either of those tests are abnormal, the MRI shows a pituitary tumor < 6 mm, or there is diagnostic ambiguity, the patient should undergo IPSS with ACTH measurements before and after the administration of CRH [4]. IPSS is the gold standard for determining the source of ACTH secretion and confirming CD. In this invasive procedure, ACTH, prolactin, and cortisol levels are sampled prior to CRH stimulation and after CRH stimulation. PRL acts as a baseline to indicate successful catheterization in the procedure [12]. To confirm CD, a ratio of IPS:P is calculated for values prior to and after CRH stimulation. A peak ratio greater than 2.0 before CRH stimulation or a peak ratio greater than 3.0 after CRH stimulation is indicative of CD. In comparing the right and left petrosal sinus sample, an IPS:P ratio greater than 1.4 suggests adenoma lateralization. However, due to high variability, IPSS should not be used for diagnosing lateralization [13].

4. Discussion

Surgical intervention remains the primary treatment for CD [4]. However, remission is not guaranteed as symptoms and metabolic diseases have been shown to persist afterwards. In the literature it has been shown that nutrition can have a powerful impact on suppressing, or even reversing metabolic disorders and comorbidities associated with CD. A LC diet has been shown to promote significant weight loss, reduce hypertension, improve dyslipidemia, reverse T2DM and improve cortisol levels (2, 14–15, 18–21).
There are reports of weight loss on a LC diet in the literature. A LC significantly reduced weight and BMI of 30 male subjects [14]. In a group of 120 participants over 24 weeks who followed a LC versus low fat (LF) diet, showed a greater weight loss in the LC group vs. the LF group [15]. Patients diagnosed and treated for CD found that their weight remained largely unchanged even after treatment [6]. In many cases, surgical treatment does not always resolve the associated comorbidity of central adiposity in CD. In such cases, a LC diet can be used before, during and after treatment, as an adjunct, to decrease associated weight gain and comorbidities.
Nutritional intervention can be a powerful adjunct to reduce comorbidities associated with CD. As seen in this case report, the patient’s symptoms of CD, especially hypertension and weight gain, improved with dietary changes despite him having a pituitary microadenoma. Multiple studies showed that a LC diet was able to decrease blood pressure parameters. In a group of 120 participants over 24 weeks who followed a LC versus a LF diet showed a greater decrease in both systolic and diastolic blood pressure in the LC group vs. the LF group [15]. Other literature which studied the effect of a LC diet on hypertension demonstrated the reduction of blood pressure and is thought to be due to ketogenesis. It is thought the production of ketones have a natriuretic effect on the body therefore lowering systemic blood pressure [16].
A LC diet improves lipid profiles and inflammatory markers associated with metabolic syndrome [14]. Literature shows that a LC diet has a greater impact on decreasing triglyceride levels and increasing HDL levels, when compared to a LF diet [15]. Triglyceride levels in patients in CD remission remained high [17]. Therefore, it can be hypothesized that a LC diet would be beneficial, in addition to standard CD treatment, to lower the associated comorbidity of hypertriglyceridemia and metabolic syndrome.
Insulin resistance, a precursor to T2DM, is a common comorbidity of hypercortisolism which can be treated with a LC diet. One study showed that in subjects with T2DM, a decrease in A1c and a reduction in antidiabetic therapy were seen with consumption of a LC diet [18]. Additionally, a cohort of 9 participants following a LC diet were able to collectively lower their A1c on average by 1% while concurrently discontinuing various antidiabetic therapies including insulin [19].
Literature shows that a LC diet can minimize systemic cortisol levels through various mechanisms. Current treatment of CD includes medications which block cortisol production and/or cortisol secretion [2]. LC can imitate similar results seen through medication intervention for CD. Carbohydrate restriction can lower cortisol levels, as carbohydrates stimulate adrenal cortisol secretion and extra-adrenal cortisol regeneration [4]. A ketogenic diet can lower the level of ghrelin, a peptide produced in the stomach that has orexigenic properties [20,21]. Literature shows that ghrelin increases levels of serum cortisol [22]. Therefore, implementing a ketogenic diet would decrease ghrelin, and subsequently minimize the effects of increased ghrelin on serum cortisol. A LC diet decreases visceral fat which itself is an endocrine organ and can increase the synthesis of cortisol [14]. Therefore, decreasing visceral fat also decreases the production of cortisol. A LC was shown to significantly reduced weight, BMI and cortisol levels of 30 obese male subjects [14]. Further, a LC diet excludes foods with a high glycemic index which cause increased stress on the body which subsequently leads to the activation of the hypothalamic-pituitary-axis which causes increased levels of cortisol [14].
This case report illustrated how a LC diet was initially successful at ameliorating the patient’s associated symptoms of hypertension and obesity, making his diagnosis of CD go undetected. Literature shows that while the prevalence of CS on average is a fraction of a percent, it is much higher among patients with poorly controlled diabetes, hypertension and early onset osteoporosis [3]. Two hundred patients with diabetes mellitus were studied and 5.5% were found to have CS [23]. Another study discovered that in subjects with CD, 36.4% were found to have hyperlipidemia, 73.1% with hypertension, and 70.2% with impaired glucose metabolism [17]. It can be concluded that a higher index of suspicion and lower threshold for screening for CS may be necessary in obese and diabetic patient populations. A lower threshold for screening can allow for earlier diagnosis for many patients, and therefore provide better outcomes for those diagnosed with CS.
It is important for clinicians to consider alternative pathology for patients combating metabolic derangements. As depicted in this case, the patient lost 35 lbs. while on a LC diet, despite having hypercortisolism, presumably for months to years prior to the diagnosis of his condition. The patient noted a tendency to gain weight, have elevated blood sugar and blood pressure which prompted him to begin self-treatment with increasingly strict carbohydrate restriction. The patient was able to keep his symptoms of hypercortisolism managed, potentially making the diagnosis difficult for his team of clinicians. From a diagnostic perspective, it’s important to understand that strict dietary adherence can have profound impacts on even the most severe hormonal pathology. Ultimately, this case serves as a reminder of the power of nutrition to address metabolic derangements and simultaneously as a reminder to diagnosticians to never rely on lack of dietary adherence as a reason for persistent metabolic symptoms. The reflexive advice to “not gain weight” and “lower salt intake” in retrospect appears both dogmatic and careless. In this case, the patient had seen several doctors and was even hospitalized and yet his disease state remained unclear and the dietary messaging cursory.

5. Conclusions

Many chronic diseases, including diabetes, hypertension and obesity, are generally thought to be caused by dietary and lifestyle choices. However, as exemplified in this report underlying medical problems, such as endocrine disorders, can be the cause of such metabolic derangements. It is critical that practitioners consider other causes of metabolic derangements, as assuming that they are due to poor dietary adherence, can allow them to go undiagnosed. While there is extensive literature on LC diets and their effect on the metabolic derangements associated with hypercortisolism, there needs to be further research on LC as an adjunctive therapy to conventional CD treatment. Ultimately, nutrition can have a powerful impact on suppressing, or even reversing metabolic disorders. As depicted in this case study, a LC diet is powerful enough to temporarily suppress symptoms of CD.

Author Contributions

M.K.D., E.-C.P.-M. and T.K. equally contributed to this case report. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Written informed consent has been obtained from the patient to publish this paper.

Data Availability Statement

The data presented in this study are available in article.

Acknowledgments

We would like to thank our patients and the Society of Metabolic Health Practitioners.

Conflicts of Interest

T.K. is an unpaid member of the Board of Directors of the Society of Metabolic Health Practitioners and a producer of podcasts on health and nutrition, with all proceeds donated to humanitarian charities; his spouse has ownership interest in a food company. The other author reports no conflicts of interest.

References

  1. Nieman, L.K. UpToDate. Available online: https://www.uptodate.com/contents/measurement-of-cortisol-in-serum-and-saliva?search=cortisol%20level&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 (accessed on 27 September 2022).
  2. Feelders, R.; Sharma, S.; Nieman, L. Cushing’s Syndrome: Epidemiology and Developments in Disease Management. Clin. Epidemiol. 2015, 7, 281. [Google Scholar] [CrossRef] [PubMed]
  3. Guaraldi, F.; Salvatori, R. Cushing Syndrome: Maybe Not so Uncommon of an Endocrine Disease. J. Am. Board Fam. Med. 2012, 25, 199–208. [Google Scholar] [CrossRef] [PubMed]
  4. Guarnotta, V.; Emanuele, F.; Amodei, R.; Giordano, C. Very Low-Calorie Ketogenic Diet: A Potential Application in the Treatment of Hypercortisolism Comorbidities. Nutrients 2022, 14, 2388. [Google Scholar] [CrossRef] [PubMed]
  5. Nieman, L.K. UpToDate. Available online: https://www.uptodate.com/contents/epidemiology-and-clinical-manifestations-of-cushings-syndrome?search=cushings%20diagnosis%20symptoms&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2 (accessed on 27 September 2022).
  6. Schernthaner-Reiter, M.H.; Siess, C.; Gessl, A.; Scheuba, C.; Wolfsberger, S.; Riss, P.; Knosp, E.; Luger, A.; Vila, G. Factors Predicting Long-Term Comorbidities in Patients with Cushing’s Syndrome in Remission. Endocrine 2018, 64, 157–168. [Google Scholar] [CrossRef] [PubMed]
  7. Giordano, C.; MarchiÃ2, M.; Timofeeva, E.; Biagini, G. Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets. Front. Neurol. 2014, 5, 63. [Google Scholar] [CrossRef]
  8. Standard American Diet (SAD). Available online: https://piviohealth.com/knowledge-bank/glossary/standard-american-diet-sad/ (accessed on 2 October 2022).
  9. Paoli, A.; Rubini, A.; Volek, J.S.; Grimaldi, K.A. Beyond Weight Loss: A Review of the Therapeutic Uses of Very-Low-Carbohydrate (Ketogenic) Diets. Eur. J. Clin. Nutr. 2013, 67, 789–796. [Google Scholar] [CrossRef] [PubMed]
  10. Sharma, S.T.; Nieman, L.K. Is Prolactin Measurement of Value during Inferior Petrosal Sinus Sampling in Patients with ACTH-Dependent Cushing’s Syndrome? J. Endocrinol. Investig. 2013, 36, 1112–1116. [Google Scholar] [CrossRef]
  11. Kline, G.; Chin, A.C. Chapter 5—Adrenal disorders. In Endocrine Biomarkers: Clinical Aspects and Laboratory Determination; Elsevier: Amsterdam, The Netherlands, 2017; Available online: https://www.sciencedirect.com/science/article/pii/B9780128034125000057 (accessed on 18 October 2022).
  12. Ghorbani, M.; Akbari, H.; Griessenauer, C.J.; Wipplinger, C.; Dastmalchi, A.; Malek, M.; Heydari, I.; Mollahoseini, R.; Khamseh, M.E. Lateralization of Inferior Petrosal Sinus Sampling in Cushing’s Disease Correlates with Cavernous Sinus Venous Drainage Patterns, but Not Tumor Lateralization. Heliyon 2020, 6, e05299. [Google Scholar] [CrossRef]
  13. Knecht, L. Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing’s Disease. Available online: https://csrf.net/doctors-articles/inferior-petrosal-sinus-sampling-diagnosis-cushings-disease/ (accessed on 18 October 2022).
  14. Polito, R.; Messina, G.; Valenzano, A.; Scarinci, A.; Villano, I.; Monda, M.; Cibelli, G.; Porro, C.; Pisanelli, D.; Monda, V.; et al. The Role of Very Low Calorie Ketogenic Diet in Sympathetic Activation through Cortisol Secretion in Male Obese Population. J. Clin. Med. 2021, 10, 4230. [Google Scholar] [CrossRef] [PubMed]
  15. Yancy, W.S.; Olsen, M.K.; Guyton, J.R.; Bakst, R.P.; Westman, E.C. A Low-Carbohydrate, Ketogenic Diet versus a Low-Fat Diet to Treat Obesity and Hyperlipidemia. Ann. Intern. Med. 2004, 140, 769. [Google Scholar] [CrossRef] [PubMed]
  16. Khan, S.S.; Ning, H.; Wilkins, J.T.; Allen, N.; Carnethon, M.; Berry, J.D.; Sweis, R.N.; Lloyd-Jones, D.M. Association of Body Mass Index with Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. JAMA Cardiol. 2018, 3, 280–287. [Google Scholar] [CrossRef]
  17. Sun, X.; Feng, M.; Lu, L.; Zhao, Z.; Bao, X.; Deng, K.; Yao, Y.; Zhu, H.; Wang, R. Lipid Abnormalities in Patients with Cushing’s Disease and Its Relationship with Impaired Glucose Metabolism. Front. Endocrinol. 2021, 11, 600323. [Google Scholar] [CrossRef] [PubMed]
  18. Bolla, A.; Caretto, A.; Laurenzi, A.; Scavini, M.; Piemonti, L. Low-Carb and Ketogenic Diets in Type 1 and Type 2 Diabetes. Nutrients 2019, 11, 962. [Google Scholar] [CrossRef] [PubMed]
  19. Norwitz, N.G.; Soto-Mota, A.; Kalayjian, T. A Company Is Only as Healthy as Its Workers: A 6-Month Metabolic Health Management Pilot Program Improves Employee Health and Contributes to Cost Savings. Metabolites 2022, 12, 848. [Google Scholar] [CrossRef] [PubMed]
  20. Ebbeling, C.B.; Feldman, H.A.; Klein, G.L.; Wong, J.M.W.; Bielak, L.; Steltz, S.K.; Luoto, P.K.; Wolfe, R.R.; Wong, W.W.; Ludwig, D.S. Effects of a Low Carbohydrate Diet on Energy Expenditure during Weight Loss Maintenance: Randomized Trial. BMJ 2018, 363, k4583. [Google Scholar] [CrossRef] [PubMed]
  21. Marchiò, M.; Roli, L.; Lucchi, C.; Costa, A.M.; Borghi, M.; Iughetti, L.; Trenti, T.; Guerra, A.; Biagini, G. Ghrelin Plasma Levels after 1 Year of Ketogenic Diet in Children with Refractory Epilepsy. Front. Nutr. 2019, 6, 112. [Google Scholar] [CrossRef] [PubMed]
  22. Kärkkäinen, O.; Farokhnia, M.; Klåvus, A.; Auriola, S.; Lehtonen, M.; Deschaine, S.L.; Piacentino, D.; Abshire, K.M.; Jackson, S.N.; Leggio, L. Effect of Intravenous Ghrelin Administration, Combined with Alcohol, on Circulating Metabolome in Heavy Drinking Individuals with Alcohol Use Disorder. Alcohol. Clin. Exp. Res. 2021, 45, 2207–2216. [Google Scholar] [CrossRef] [PubMed]
  23. Catargi, B.; Rigalleau, V.; Poussin, A.; Ronci-Chaix, N.; Bex, V.; Vergnot, V.; Gin, H.; Roger, P.; Tabarin, A. Occult Cushing’s Syndrome in Type-2 Diabetes. Available online: https://academic.oup.com/jcem/article/88/12/5808/2661485 (accessed on 27 September 2022).
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