Cardiometabolic Complications After Cushing’s Disease Remission

Posted on April 30, 2025 by MaryO

Abstract

Background and aim

Cushing’s disease (CD) is associated with phenotypic traits and comorbidities that may persist after the normalization of cortisol levels. Medical therapy is usually given in recurrent or persistent CD after transsphenoidal surgery. We aimed to investigate the impact of long-term normalization of daily cortisol secretion on clinical picture and cardiometabolic comorbidities, comparing surgical remission to medical treatment.

Methods

Monocentric retrospective study, two- and five-years observation. Sixty CD patients, with sustained normal 24-h urinary free cortisol (UFC) levels, divided group 1 (surgical remission, n = 36) and group 2 (medical remission, n = 24).

Results

Patients were different after achieving eucortisolism with surgery or medical treatment. Phenotypic traits: round face, dorsocervical fat pad, and bruisability persisted more prominently in the group 2, however abdominal obesity and muscle weakness persisted in both groups, especially in those patients with increased late-night salivary cortisol (LNSC). Hypertension: greater improvement was observed in group 1 (-31% vs. -5%, p = 0.04). Diabetes: less prevalent in group 1 after 2 years (2/36 vs. 9/24, p = 0.002), with a corresponding reduction in glucose-lowering treatments and persistence of impaired LNSC in diabetic patients (p < 0.001). Dyslipidemia: remained widespread in both groups, with minimal improvement over time (-22% in surgical and − 6% in medical cohort).

Conclusions

Surgical remission leads to faster and sustained improvements in clinical phenotype. However, obesity, arterial hypertension, and dyslipidemia do not completely revert in five years, especially during medical treatment. Most comorbidities persist despite UFC normalization, due to impaired LNSC: the recovery of cortisol rhythms confirms the remission of hypercortisolism.

Introduction

Cushing’s disease (CD) is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, resulting in persistent endogenous hypercortisolism. The cortisol excess leads to a typical clinical picture: round face, facial plethora, buffalo hump, cutaneous striae rubrae, easy bruising, proximal myopathy, weight gain with visceral obesity, hirsutism and acne [1,2,3]. Moreover, several comorbidities are cortisol-related: metabolic syndrome (visceral obesity, arterial hypertension, glucose intolerance or diabetes, and dyslipidemia), acquired thrombophilia, osteoporosis or vertebral fractures, immunological impairments with increased infection susceptibility, and psychiatric disorders [4]. The sum of physical changes and comorbidities leads to a reduced life expectancy and a worsening of the quality of life [5]. Pituitary trans-sphenoidal surgery (TSS) is the first-choice CD treatment [1]. Despite high remission rates (up to 90% in referral centers) [6], the risk of recurrence varies from 10 to 47% [7], especially in series with long-term follow-up. If surgery fails or is not feasible, cortisol excess can be managed with medical therapy. Not rarely, patients on cortisol-lowering therapy experience fluctuations of their cortisol levels, making outcome evaluations difficult and hardly standardized. The goals of CD treatment are to normalize cortisol levels, and to reduce the burden of comorbidities. The most used biochemical marker in clinical practice is urinary free cortisol (UFC), which estimates the cumulative daily secretion of cortisol, but does not offer information about cortisol rhythm [8].

In this study we compared two groups of CD patients with sustained normalization of 24-h UFC due either to post-surgical or medical cortisol-lowering therapy remission. The aim of the study was to analyze the impact of long-term normalization of hypercortisolism in terms of UFC, achieved with surgical or medical treatment, on endocrine parameters, cortisol-related clinical picture and comorbidities, in a five-years observation period of patients with CD.

Materials and methods

Subjects

Sixty CD patients were enrolled (75% female); the median age at diagnosis was 41 years (interquartile range [IQR] 32–52), followed at the Endocrinology Unit of Padua University Hospital from 2000 to 2021. This observational study was conducted in accordance with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines [9]. The study, following the guidelines in the Declaration of Helsinki, was approved by the ethics committee of Padova University Hospital (PITACORA, protocol No. AOP3318, ethics committee registration 5938-AO-24), and all patients gave informed consent. All data are included in the Repository of the University of Padova [10].

The first normalized UFC is considered as the starting point of observation at follow-up (two or five years). The cohort was divided into two cohorts: group 1 achieved CD remission after surgery, and group 2 achieved long-term eucortisolism during medical therapy. The inclusion criterion was 24-h UFC levels (mean of two collections) below the upper limit of normality during the observational period. Postoperative long-term adrenal insufficiency requiring substitutive glucocorticoid treatment (with hydrocortisone or cortisone acetate tablets) 12 months after surgery or new-onset hypopituitarism were considered exclusion criteria. The group 1 was made of 36 patients (69% female) in remission after successful TSS. The second group consisted of 24 patients (83% female) on long-term medical treatment for CD persistence (n = 17) or relapse (n = 4) after surgery and three patients in primary medical therapy for poor surgical eligibility, as shown in Fig. 1. Within group 2, nine patients underwent previous radiotherapy without efficacy, at least 5 years before reaching adequate biochemical control with medical treatment; none developed hypopituitarism. 14/24 patients (58%) were treated with a monotherapy and 11/24 (46%) with combined therapies during the observation period. Details on medical therapies are shown in Table 1. In particular, 3 patients were treated with metyrapone + pasireotide s.c., 1 with metyrapone + ketoconazole, 2 with ketoconazole and cabergoline, 1 with metyrapone + cabergoline, 1 with metyrapone + ketoconazole + cabergoline, 1 with metyrapone + ketoconazole + pasireotide s.c., 1 with metyrapone + ketoconazole + pasireotide s.c. + cabergoline. Metyrapone and ketoconazole were administered two/three times a day, pasireotide s.c. twice daily and cabergoline once daily in the evening.

Fig. 1
figure 1

Treatment and outcome of the described cohort. Light gray box indicates those patients in group 1 (surgical remission, n = 36), dark gray box indicates the patients in group 2 that achieved normalization of UFC with medical therapy (n = 24, either primary or after surgical failure)

Table 1 Cortisol-lowering drugs, dose, and time in treatment of subjects treated with a single and combined lines of therapy

All 60 patients completed at least 2 years of follow-up; a long-term 5-years evaluation was available in 43 patients of the original cohort (32 after surgery and 11 with medical therapy). Baseline characteristics of the two cohorts are reported in Table 2.

Table 2 Baseline characteristics of the two groups and previous treatment modalities

Data collection and study design

Two researchers retrieved clinical and biochemical data independently from the local digital medical records. We considered as baseline visit the clinical and endocrine evaluation performed with active hypercortisolism. Therefore, the baseline visit consists in the pre-surgical evaluation in group 1, and in the post-surgical confirmation of active hypercortisolism in those in medical treatment (or diagnosis in case of primary treatment, group 2).

We considered clinical and biochemical outcomes during routine follow-up at two- and five-years in each group, starting from surgical remission or the beginning of a stable normalization of UFC under medical therapy. CD diagnosis was based on at least two parameters among 24-h UFC above the upper normal limit (ULN, at least two collections), unsuppressed cortisol levels (> 50 nmol/L) after 1 mg overnight dexamethasone test (1 mg-DST) or late-night salivary cortisol (LNSC) > ULN (at least two samples). In all subjects, CD diagnosis was considered in case of normal-high ACTH levels, positive response to dynamic tests (corticotropin-releasing hormone or desmopressin test, high-dose dexamethasone test), and, two cases, with petrosal sinus sampling (BIPSS) [11]. Long-term remission after TSS was defined through normal UFC, combined with serum cortisol levels < 50 nmol/L in the first month after surgery and need of glucocorticoid replacement therapy. A relapse of CD was defined as the reappearance of the typical signs and symptoms of CD associated with the alteration of at least two first-line screening tests. Presence/absence of clinical signs of CD (round face, facial rubor, buffalo hump, bruising, cutaneous red striae, acne, hirsutism and oligo/amenorrhea in females) were evaluated during outpatient visits by expert endocrinologists. The presence of hirsutism in females was measured according to the Ferriman–Gallwey score > 8 (extent of hair growth in 9 locations was rated 0–4). Proximal muscle strength was diagnosed if patients were not able to stand up from a low seated position with anteriorly extended arms. Bodyweight, body mass index (BMI), waist and hip circumference, systolic (SBP), and diastolic blood pressure (DBP) were assessed with calibrated tools. Overweight was diagnosed in patients with BMI 25–30 kg/m2, obesity with BMI > 30 kg/m2. Visceral obesity was diagnosed as waist circumference ≥ 94 cm in men and ≥ 80 cm in women, or with a waist/hip ratio (WHR) ≥ 1 according to International Diabetes Federation criteria. Arterial hypertension was diagnosed for SBP above 140 mm Hg and/or DBP above 90 mm Hg and/or in patients on antihypertensive drugs. Diabetes mellitus (DM) was diagnosed according to American Diabetes Association criteria or when patients were taking antidiabetic medication. Dyslipidemia was diagnosed when low-density lipoprotein (LDL) calculated cholesterol was ≥ 100 mg/dL and hypertriglyceridemia when triglycerides were ≥ 150 mg/dL or when patients were on lipid-lowering medication. The presence of carotid vascular disease (CVD) has been assessed by supra-aortic vessels duplex ultrasound. Cushing’s cardiomyopathy (CCM) was diagnosed by doppler echocardiography with evidence of impaired relaxation and left ventricular filling pattern. The medical history was checked for cardiovascular disease (acute coronary syndrome, ACS) in all cases. A shortened activated partial thromboplastin time (aPTT < 29 s) defined pro-thrombotic status.

Assays

All biochemical analyses were carried out in an ISO15189:2012-accredited clinical laboratory [12], cortisol levels have been measured in urine or saliva with a mass-spectrometry home-made validated method. UFC was determined by a home-brew liquid chromatography-mass spectrometry (LC-MS/MS) method (intra-assay/interassay coefficient of variation [CV] < 6%/< 8%) since 2011 [13], previously by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%). The patients were instructed to discard the first morning urine void and to collect all urine for the next 24 h, so that the morning urine void on the second day was the final collection. The sample was kept refrigerated from collection time until it was analyzed: normal range for UFC is 16–168 nmol/24 h.

Salivary cortisol was measured by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%) until 2014 [14], after then by LC-MS/MS method (intra-assay/interassay CV < 6%/< 8% [15]). In order to prevent food or blood contamination, samples were collected at least 30 min after subjects had eaten, brushed their teeth, smoked or assumed liquorice; undertaken using Salivette® devices containing a cotton swab with or without citric acid (Sarstedt, Nümbrecht, Germany). The sample was stored at − 80 °C, before analyses [15].

The 1-mg DST test was performed orally assuming 1 mg of dexamethasone between 11 P.M. and midnight, sampling serum cortisol the next morning at 8 A.M. Serum dexamethasone levels, routinely evaluated since 2017, were adequate in all cases [16]. Serum cortisol (RRID: AB_2810257) and ACTH (RRID: AB_2783635) were determined by immune-chemiluminescence assay (Immulite 2000, Siemens Healthcare). Dynamic second-line tests and BIPSS were performed according to international standards.

Statistical analysis

Data were analyzed using SPSS Software for Windows, version 24.0 (SPSS Inc). Data are reported as medians and interquartile range or as percentages. The comparison between continuous variables was performed by non-parametric Wilcoxon test or Mann–Whitney test, as appropriate. The comparison between categorical variables was performed by the χ2 test. The correlation between continuous variables was performed by linear regression analysis. The level of significance for the overall difference between the groups was tested with one-way ANOVA. A p value < 0.05 was considered statistically significant.

Results

Endocrine evaluation

At baseline the two groups were similar for morning serum/salivary cortisol, LNSC, cortisol after 1 mg DST and morning ACTH levels (Table 3); UFC levels were higher in the surgical cohort (p < 0.001). Endocrine parameters were not influenced by sex and BMI. At baseline, all patients had impaired salivary cortisol rhythm with increased LNSC and inadequate cortisol suppression after 1-mg DST. At two years the recovery of salivary cortisol rhythm was observed in 97% of patients after surgery and 50% of patients during medical therapy. The only patient who did not show recovery of cortisol rhythm in the surgical cohort had LNSC of 5.4 nmol/L (range 0.5–2.6 nmol/L), with adequate cortisol suppression after 1-mg DST and sustained normal UFC: it was considered a false-positive due to residual minor depression state.

Table 3 Biochemical pattern at baseline and during the follow-up

Adequate cortisol suppression after 1-mg DST (both with normal UFC and LNSC) was observed in 34 out of 36 patients (94%) in the surgical cohort; the two patients who did not show complete cortisol suppression after 1-mg DST had cortisol levels of 60 and 119 nmol/l, respectively. On the contrary, as per selection criteria, none of the patients in group 2 presented suppressed cortisol after 1-mg DST.

At 5 years follow-up, all cases in the surgical cohort had suppressed cortisol after 1-mg DST and normal salivary cortisol rhythm, whereas in group 2 9% had suppressed cortisol after 1-mg DST and 36% recovered salivary cortisol rhythm. At 5 years, UFC and salivary cortisol levels (either morning or late night) were similar in the two groups, while the median value of serum cortisol after 1-mg DST remained not adequately suppressed (median 75 nmol/L, from 18 to 257 nmol/L) during medical therapy (See Table 3). In group 2, patients on combined therapy had higher UFC (102 vs. 76 nmol/24h p = 0.03) and LNSC (2.4 vs. 1.9 p = 0.05) at 5 years, compared to patients on monotherapy.

Hirsutism, abdominal obesity, round face and facial rubor were prevalent in group 1 at baseline. On the contrary, the abdominal obesity, facial rubor and easy bruising were most commonly found in the medical cohort. The prevalence of facial rubor, buffalo hump and bruisability was higher after medical than surgical remission after 2 years of eucortisolism; at 5 years the prevalence of buffalo hump and bruisability was higher in patients under drug therapy as well (Table 4; Fig. 2). Higher levels of UFC at baseline were observed in all patients with proximal myopathy (p < 0.001).

Table 4 Two- and five-years changes in clinical phenotype from baseline in group 1 and group 2
Fig. 2

figure 2

Signs and symptoms of hypercortisolism at baseline (grey bars), two-years (orange bars) and five-years (blue bars) follow up after surgical (TSS) or medical remission (MED)

Arterial hypertension

Arterial hypertension (AH) was the most frequent comorbidity in both groups at baseline, with similar distribution in the two groups (Table 5). The prevalence of AH decreased after two years in both groups, especially in the surgical cohort (64% vs. 44% in group 2, p < 0.001; 75% vs. 71% p = 0.003), with no further improvement after five years. Overall, hypertensive patients were older at diagnosis (45yrs vs. 31y; p < 0.001) and with larger BMI (29 vs. 25 kg/m2; p = 0.03). Median UFC, morning salivary cortisol and LNSC, and 1-mg DST were not different in patients with/without AH at baseline and at 2 years. SBP and DBP values were similar in the two cohorts and were not correlated to UFC, LNSC or 1-mg DST throughout the follow-up. At 2 years, hypertensive patients had higher levels of morning salivary cortisol and LNSC with impaired rhythm (respectively 10.4 vs. 6 nmol/L, p = 0.01 and 3.2 vs. 1 nmol/l, p = 0.007). SBP and DBP values did not change during the five-years observation time in both groups; however, the number of anti-hypertensive drugs was higher in group 2 than in group 1 (p = 0.007). Overall patients treated with metyrapone showed higher values of DBP at 2 years (mean 89.4 vs. 81.7 mmHg, p = 0.01), the prevalence of AH did not differ from patients with other medical treatments.

Table 5 Two- and five-years changes in cardio-metabolic cortisol-related comorbidities of CD from baseline in group 1 and group 2

Glucose metabolism

DM prevalence at baseline did not show a correlation with BMI and age at CD diagnosis. DM prevalence was similar in group 1 and 2 after two and five years of follow-up. The follow-up analysis of DM was performed excluding patients in pasireotide, since its known impact in glucose metabolism. In both groups, median UFC, morning salivary and LNSC, and 1-mg DST were similar in patients with/without DM at baseline. At 5 years, patients with diabetes had higher levels of morning salivary cortisol and LNSC with impaired cortisol rhythm (respectively 15 vs. 7 nmol/L, p < 0.001 and 5.4 vs. 1.5 nmol/l, p < 0.001). None of the explored hormonal parameters was correlated with HbA1c levels in both groups at any time point considered. The number of antidiabetic drugs was higher after medical than surgical remission (Table 5).

As expected, patients treated with pasireotide had higher incidence of newly onset DM at 2- and 5 years (p = 0.02 and p = 0.05 respectively) and required more antidiabetic drugs at 2- and 5 years (p = 0.002, p = 0.05) or insulin units at 5 years (p = 0.03). HbA1c levels during pasireotide were higher than patients treated with other drugs (55.6 vs. 38 nmol/l, p = 0.002), requiring a higher number of antidiabetic drugs (p = 0.008). Patients on combined therapy with pasireotide had higher rates of DM at 2- and 5 years (p < 0.001 and p = 0.01) and used more antidiabetic drugs at 2- and 5 years (p = 0.004, p = 0.01) than those on monotherapy.

Lipid metabolism

The prevalence of dyslipidemia was similar in the two groups at baseline and after two years, and higher in the medical remission cohort after five years (p = 0.01). Overall, dyslipidemic patients were older at diagnosis (46y vs. 36y; p = 0.006) and had higher BMI (30 vs. 25 kg/m2; p < 0.001). There was no correlation between hormone parameters and LDL or triglycerides levels. Lipid profile was similar between patients treated with different drugs.

Vascular disease and coagulative profile

There was no difference between the two groups, at baseline, in the prevalence of carotid vascular disease, history of ACS, and CCM; at 5 years, in both groups, no patient had a worsening of a previously diagnosed stenosis, or novel diagnosis of CVD, ACS and CCM.

The median aPTT value at baseline was in the pro-thrombotic range in both groups (25s), without sex and BMI differences. No correlation was observed between aPTT and UFC, LNSC and 1-mg DST levels. Patients who manifested easy bruising, had shorter aPTT at 2- and 5 years (median 24 vs. 27s, p = 0.03). aPTT does not increase within both groups at 2- and 5-years and aPTT was shorter during medical therapy compared to surgical remission both after 2 and 5 years (22.5s vs. 27s, p = 0.02 at 2y and 23.5s vs. 27.9s, p = 0.02 at 5y).

Discussion

The impact of CD remission on clinical picture and hypercortisolism-related comorbidities is still controversial. The current knowledge suggests that long-term CD surgical remission is associated with increased metabolic and vascular damage, not only if compared to active disease, but also even after long-term normalization of cortisol secretion [17]. If CD recurs after successful TSS, or if surgery fails/is not feasible, cortisol excess can be treated with medical therapy. Likewise, long-term studies (> 2 years) on the clinical effects of medical therapy on CD are lacking. Some prospective registry studies have been published [1], only one retrospective study on long-term use of ketoconazole described a multicentric cohort of CD patients without a control group [18].

In our study, we enrolled 60 patients with CD diagnosed and treated in a single tertiary care center, with sustained and long-term (2 and 5 years) UFC normalization after surgery or during medical therapy. As expected, UFC levels at baseline were different in the two groups, due to the distinct starting point of medical history: a patient with persistent-recurrent CD after pituitary surgery presents with lower UFC than the new diagnosis. After surgical remission, patients achieved the recovery of salivary cortisol rhythm and the complete suppression of cortisol after 1-mg DST (investigated after substitutive glucocorticoid treatment discontinuation) in almost all cases. On the contrary, if eucortisolism is achieved with long-term medical therapy the recovery of salivary cortisol rhythm was observed only in half of patients and only few of them showed cortisol suppression after 1-mg DST within the 5 years observation time. Patients who were more resistant to the recovery of cortisol rhythm were more likely to receive combined treatment, even if no treatment is superior to others in normalizing salivary cortisol rhythm, in line with previous reports [1, 18, 19].

Within 2 years, patients in the surgical remission group showed a marked improvement of all phenotypic traits common at CD diagnosis compared to those in medical therapy. As observed also in other series of CD patients in remission [20], abdominal obesity persisted more than other clinical features over time, leading to an impaired body composition especially in the medically treated group [21]. Considering hyperandrogenism, acne improvement was more relevant at 2 and 5-years of follow up, probably due to a differential effect of ACTH-dependent adrenal androgens compared to hirsutism.

The impaired cortisol rhythm was a predictor of the long-lasting of most CD phenotypic features, as round face, buffalo hump, facial rubor, abdominal obesity, proximal myopathy and bruisability. A more severe clinical phenotype at baseline can explain a reduced control of hypercortisolism in monotherapy, requiring drug combination, and signs or symptoms are likely to persist despite the normalization of UFC [22]. In this study, no medication outperformed the others in terms of recovery from the CD phenotype.

The aetiology of hypertension and dyslipidemia is known to be heterogeneous, since both are influenced also by age at diagnosis and BMI, causing low rates of remission after UFC normalization [23, 24]. Arterial hypertension showed a decreasing trend with the best response within 2 years after UFC normalization only after surgical remission. Patients with disrupted salivary cortisol rhythm were more likely to remain hypertensive during the 5 years follow-up. Likewise, DM persistence during follow up correlates to impaired salivary cortisol rhythm and not with UFC. This finding is in contrast with the observations of Schernthaner-Reiter et al. [25]. on CD remission, and, on the contrary, supports data described by Guarnotta et al. [22]. Newell-Price et al.. recently found that when UFC and LSNC are both normal in patients treated with pasireotide, the rise in HbA1c levels is less evident than in patients with normal UFC but uncontrolled LNSC [26]. This observation underlines the importance of the impaired cortisol rhythm in the glucose impairment pathogenesis in CD. During the 5 years observation time, a worsening of previously diagnosed cardiovascular conditions, or novel acute vascular events, was not observed in both groups. This finding suggested that normalized UFC and intensive treatment of cardio-metabolic CD comorbidities play a fundamental role in reducing cardiovascular mortality [27]. A minor impact of CD therapy was observed in dyslipidemia, which persisted in both groups, with minimal improvement over time (−22% in surgical and − 6% in medical cohort). The criterion of 100 mg/dL LDL cut-off identifies a moderate CV risk reflecting the main focus of the study: the assessment of cardiometabolic complication after CD remission, assuming that they present a lower cardiovascular risk compared to patients with overt hypercortisolism.

Plasma hypercoagulability, with shortened aPTT, was found in all patients with active hypercortisolism. In the 5 years observation time, this parameter showed latency in increasing in both groups and in none achieved normality (> 28s). As previously observed in other studies, no correlation is observed between aPTT and any of the explored hormonal parameters [22, 28]. At 2- and 5 years, instead, shorter aPTT was observed during medical treatment than after surgical remission cohort. In both groups a shorter aPTT was associated with bruisability, which is related to impaired LNSC, strengthening the role of the impaired cortisol rhythm as a major driver of hypercoagulability. Also, Ferrante et al.. observed the long latency of plasma hypercoagulability, persisting for years after biochemical remission of CD: in that series thrombophilia appeared to be reversible within 5 years [29], while in our cohort the recovery takes longer.

Additionally, sexual differences characterize patients with patients with Cushing’s syndrome and hypogonadism in hypercortisolism is known to further increase the cardiovascular risk [30, 31]. However, it was not an interfering factor in our study population since hypopituitarism was considered an exclusion criterion, no case of new-onset hypogonadism was reported (even in male patients treated with ketoconazole), and the menopause transition in six women during the observation was not considered relevant.

The limits of the present study are its retrospective design, the variability of concomitant treatments, the heterogenous combinations of medical therapy used in clinical practice, the presence of treatment-specific adverse events that mimic the effects of hypercortisolism (such as pasireotide-induced DM and hypertension with metyrapone), the unpredictable effect of previous treatments, including radiotherapy. We considered UFC and LNSC as markers of hypercortisolism remission; nonetheless we acknowledge that both of them present some limitations, especially during medical treatment. The former considers the whole cortisol secretion during the day, and albeit UFC normalization is the main outcome of all trials for medical treatment [32, 33] it does not detect mild hypercortisolism. On the other hand, a normal LNSC does not fully reflect a normal circadian rhythm: only high cortisol levels in the morning with a decline in the night are able to restore clock-related activities [34].

Its strengths are the complete patient characterization in a single tertiary care center, the comparative study design, and the standardized protocols for diagnosis and long-term follow-up. In particular, samples have been processed within a single laboratory with accurate methods (LC-MS for urinary and salivary steroids), and all endocrine aspects of hypercortisolism were considered (overall daily cortisol production by UFC, circadian cortisol rhythm, and the recovery of the hypothalamic-pituitary axis by 1-mg DST overnight test).

To conclude, despite UFC normalization in both groups during follow-up, surgical remission results in more rapid and relevant improvements in CD phenotype and comorbidities. During medical therapy the UFC levels can be higher than after surgery, although in the normal range, and the normalization of LNSC is not always achieved: both conditions suggests that stricter criteria should be considered to define eucortisolism in patients with CD under medical treatment. Conditions such as obesity, hypertension, dyslipidemia, and hypercoagulability are not completely reversible in a 5-year observation time even in the surgical remission group. This observation underlines that all the comorbidities, independently of the normalization of UFC, must be intensively treated. Moreover, UFC normalization should not be considered the only biochemical goal to be reached, since the persistence of comorbidities seems to be more related to an impaired cortisol rhythm rather than to the cortisol secretory burden.

References

  1. Fleseriu M et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update, Dec. 01, Elsevier Ltd. https://doi.org/10.1016/S2213-8587(21)00235-7

  2. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M Cushing’s syndrome. Dec 09 2023 Elsevier B V https://doi.org/10.1016/S0140-6736(23)01961-X

  3. Ceccato F et al (2024) Clinical and biochemical data for the diagnosis of endogenous hypercortisolism: the ‘cushingomic’ approach. J Clin Endocrinol Metab Jul. https://doi.org/10.1210/clinem/dgae517

    Article Google Scholar

  4. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A (2016) Complications of Cushing’s syndrome: state of the Art. Lancet Publishing Group. https://doi.org/10.1016/S2213-8587(16)00086-3

    Article Google Scholar

  5. Clayton RN et al (2016) Mortality in patients with Cushing’s disease more than 10 years after remission: A multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol 4(7):569–576. https://doi.org/10.1016/S2213-8587(16)30005-5

    Article PubMed Google Scholar

  6. Pivonello R, De Leo M, Cozzolino A, Colao A (2015) The treatment of Cushing’s disease. Endocr Soc. https://doi.org/10.1210/er.2013-1048

    Article Google Scholar

  7. Petersenn S et al (2015) Outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: Systematic review assessing criteria used to define remission and recurrence. BioScientifica Ltd. https://doi.org/10.1530/EJE-14-0883

    Article Google Scholar

  8. Broersen LHA, Jha M, Biermasz NR, Pereira AM, Dekkers OM (2018) Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary 21(6):631–641. https://doi.org/10.1007/s11102-018-0897-z

    Article CAS PubMed PubMed Central Google Scholar

  9. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP (2008) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 61(4): 344–349. https://doi.org/10.1016/j.jclinepi.2007.11.008

  10. Ceccato F (2024) The burden Of Cushing’s disease cardiometabolic comorbidities: comparison between surgical remission and long-term eucortisolism with medical treatment. Repository of the University of Padova. https://doi.org/10.25430/researchdata.cab.unipd.it.00001350

  11. Barbot M et al (2016) Second-line tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome. Pituitary 19(5):488–495. https://doi.org/10.1007/s11102-016-0729-y

    Article CAS PubMed Google Scholar

  12. ISO 15189:2012 Medical laboratories — Requirements for quality and competence. Published 2022. Accessed October 10 (2023) https://www.iso.org/standard/56115.html

  13. Ceccato F et al (2014) The diagnostic performance of urinary free cortisol is better than the cortisol: cortisone ratio in detecting de Novo Cushing’s syndrome: the use of a LC-MS/MS method in routine clinical practice. Eur J Endocrinol 171(1):1–7. https://doi.org/10.1530/EJE-14-0061

    Article CAS PubMed Google Scholar

  14. Ceccato F et al (2012) Assessment of glucocorticoid therapy with salivary cortisol in secondary adrenal insufficiency. Eur J Endocrinol 167(6):769–776. https://doi.org/10.1530/EJE-12-0534

    Article CAS PubMed Google Scholar

  15. Antonelli G, Ceccato F, Artusi C, Marinova M, Plebani M (2015) Salivary cortisol and cortisone by LC-MS/MS: Validation, reference intervals and diagnostic accuracy in Cushing’s syndrome. Clinica Chimica Acta 451:247–251. https://doi.org/10.1016/j.cca.2015.10.004

    Article CAS Google Scholar

  16. Ceccato F et al (2020) Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation. J Endocrinol Invest 43(8):1105–1113. https://doi.org/10.1007/s40618-020-01197-6

    Article CAS PubMed Google Scholar

  17. Pivonello R, Faggiano A, Lombardi G, Colao A (2005) The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. W.B. Saunders. https://doi.org/10.1016/j.ecl.2005.01.010

    Book Google Scholar

  18. Castinetti F et al (2014) Ketoconazole in Cushing’s disease: is it worth a try. J Clin Endocrinol Metab 99(5):1623–1630. https://doi.org/10.1210/jc.2013-3628

    Article CAS PubMed Google Scholar

  19. Barbot M et al (2014) Combination therapy for Cushing’s disease: Effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole? Pituitary 17(2):109–117. https://doi.org/10.1007/s11102-013-0475-3

    Article CAS PubMed Google Scholar

  20. Colao A et al (1999) Persistence of Increased Cardiovascular Risk in Patients with Cushing’s Disease after Five Years of Successful Cure,., [Online]. Available: https://academic.oup.com/jcem/article/84/8/2664/2864186

  21. Ceccato F et al (2017) Sep., Body Composition is Different after Surgical or Pharmacological Remission of Cushing’s Syndrome: A Prospective DXA Study, Hormone and Metabolic Research, vol. 49, no. 9, pp. 660–666. https://doi.org/10.1055/s-0043-115008

  22. Guarnotta V et al (2017) The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome. Endocrine 55(2):564–572. https://doi.org/10.1007/s12020-016-0914-9

    Article CAS PubMed Google Scholar

  23. Giordano R et al (2011) Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different aetiologies during active disease and 1 year after remission. Clin Endocrinol (Oxf) 75(3):354–360. https://doi.org/10.1111/j.1365-2265.2011.04055.x

    Article CAS PubMed Google Scholar

  24. Jha S, Sinaii N, McGlotten RN, Nieman LK (2020) Remission of hypertension after surgical cure of Cushing’s syndrome. Clin Endocrinol (Oxf), 92(20): 124–130. https://doi.org/10.1111/cen.14129

  25. Schernthaner-Reiter MH et al (2019) Factors predicting long-term comorbidities in patients with Cushing’s syndrome in remission. Endocrine 64(1):157–168. https://doi.org/10.1007/s12020-018-1819-6

    Article CAS PubMed Google Scholar

  26. Newell-Price J et al (2020) Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease. Eur J Endocrinol 182(2):207–217. https://doi.org/10.1530/EJE-19-0695

    Article CAS PubMed Google Scholar

  27. Mondin A et al (2023) Complications and mortality of Cushing’s disease: report on data collected over a 20-year period at a referral centre. Pituitary 26(5):551–560. https://doi.org/10.1007/s11102-023-01343-2

    Article PubMed PubMed Central Google Scholar

  28. Barbot M et al (2018) Effects of pasireotide treatment on coagulative profile: a prospective study in patients with Cushing’s disease. Endocrine 62(1):207–214. https://doi.org/10.1007/s12020-018-1669-2

    Article CAS PubMed Google Scholar

  29. Ferrante E et al (2022) Evaluation of procoagulant imbalance in Cushing’s syndrome after short- and long-term remission of disease. J Endocrinol Invest 45(1):9–16. https://doi.org/10.1007/s40618-021-01605-5

    Article CAS PubMed Google Scholar

  30. Zilio M, Barbot M, Ceccato F, Camozzi V, Bilora F, Casonato A, Frigo AC, Albiger N, Daidone V, Mazzai L, Mantero F, Scaroni C (2014) Diagnosis and complications of Cushing’s disease: gender-related differences. Clin Endocrinol (Oxf) 80(3):403–410. https://doi.org/10.1111/cen.12299

    Article CAS PubMed Google Scholar

  31. Detomas M, Deutschbein T, Tamburello M, Chifu I, Kimpel O, Sbiera S, Kroiss M, Fassnacht M, Altieri B (2024) Erythropoiesis in Cushing syndrome: sex-related and subtype-specific differences. Results from a monocentric study. J Endocrinol Invest 47(1):101–113. https://doi.org/10.1007/s40618-023-02128-x

    Article CAS PubMed Google Scholar

  32. Fleseriu M et al (2019) Long-term efficacy and safety of once-monthly pasireotide in Cushing’s disease: A Phase III extension study. Clin Endocrinol (Oxf) 91(6):776–785. https://doi.org/10.1111/cen.14081

    Article CAS PubMed Google Scholar

  33. Ceccato F et al (2018) Metyrapone treatment in Cushing’s syndrome: a real-life study. Endocrine 62(3):701–711. https://doi.org/10.1007/s12020-018-1675-4

    Article CAS PubMed Google Scholar

  34. Minnetti M, Hasenmajer V, Pofi R, Venneri MA, Alexandraki KI, Isidori AM (2020) Fixing the broken clock in adrenal disorders: Focus on glucocorticoids and chronotherapy. BioScientifica Ltd. https://doi.org/10.1530/JOE-20-0066

    Article Google Scholar

Download references

Funding

Open access funding provided by Università degli Studi di Padova within the CRUI-CARE Agreement.

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine-DIMED, University of Padova, Padova, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

  2. Endocrinology Unit, Department of Medicine DIMED, University Hospital of Padova, Via Ospedale Civile, 105, Padova, 35128, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

Corresponding author

Correspondence to Filippo Ceccato.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants involved in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cite this article

Tizianel, I., Lizzul, L., Mondin, A. et al. Cardiometabolic complications after Cushing’s disease remission. J Endocrinol Invest (2025). https://doi.org/10.1007/s40618-025-02572-x

Download citation

Share this article

Anyone you share the following link with will be able to read this content:

Get shareable linkProvided by the Springer Nature SharedIt content-sharing initiative

Keywords

From https://link.springer.com/article/10.1007/s40618-025-02572-x

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

Avascular Necrosis in Patients With Cushing Syndrome

Posted on March 12, 2025 by MaryO

Abstract

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, leading to a range of clinical manifestations including avascular necrosis (AVN), a rare complication of CS. Although AVN is often associated with exogenous glucocorticoid treatment, it can occur in endogenous CS but may be unrecognized because of its rarity and possibly from a subclinical presentation. We describe a case of a 71-year-old male with florid Cushing disease who initially presented with bilateral hip AVN and later developed bilateral shoulder AVN despite achieving biochemical remission following transsphenoidal surgery and adjuvant stereotactic photon radiosurgery. AVN in endogenous CS is underreported, and guidance on routine screening is lacking. Our case underscores the importance of considering AVN in patients with CS, especially in those with persistent or recurrent joint symptoms and markedly elevated cortisol levels. Early detection of AVN is crucial as it can lead to irreversible joint damage and disability if untreated. Screening strategies should be explored to identify high-risk patients who are diagnosed with CS for timely intervention, thereby preventing long-term morbidity associated with AVN.

Introduction

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, either from exogenous glucocorticoids or endogenous sources. In endogenous CS, hypercortisolism may be due to an ACTH-dependent process, most often from a corticotroph adenoma in Cushing disease (CD) or from ectopic ACTH secretion from neuroendocrine tumors or other solid tumors such as small cell lung carcinoma. On the other hand, ACTH-independent CS is mainly driven from adrenal pathology including adrenal adenomas, adrenocortical carcinomas, adrenal hyperplasia, and primary pigmented micronodular disease [1]. The presenting symptoms and signs of CS include hypertension, diabetes mellitus, weight gain, facial plethora, dorsocervical fat pads, muscle weakness, and osteoporosis, most of which may be detected on physical examination or diagnosed biochemically. A less common symptom is avascular necrosis (AVN) of bone tissue [1, 2], which can present with pain or point tenderness of the hip or other joints as well as present subclinically [3].

AVN of the hip results from compromised blood supply to the bone tissue and usually impacts the hips and shoulders. This leads to necrosis of hematopoietic cells, adipocytes, and osteocytes. Subsequently, bone repair processes are activated, with differentiation of mesenchymal cells into osteoblasts to build new bone and hematopoietic stem cells into osteoclasts to remove necrotic tissue. However, because of impaired bone resorption and formation, subchondral fractures eventually occur [4]. Exogenous glucocorticoid treatment is 1 of the most common causes of AVN and may account for up to 38% of atraumatic AVN and is dose dependent [5]. Glucocorticoid treatment is theorized to cause AVN through increased systemic lipids, leading to compromised perfusion to the femoral head resulting from fat emboli or external lipocyte compression, as well as alterations in the inflammatory cytokines resulting in osteoclast activation and osteoblast apoptosis [4, 6]. Compared to exogenous glucocorticoid treatment, AVN caused by endogenous hypercortisolism is not frequently reported nor is it screened for on diagnosis of CS.

We describe a patient who presented with bilateral hip AVN in the context of florid CD. We aim to highlight this presenting feature to heighten awareness for screening for this progressive condition, which can potentially lead to joint damage, loss of mobility, and long-term disability.

Case Presentation

A 71-year-old male with medical history of active tobacco use and obstructive sleep apnea was diagnosed with new-onset hypertension during an annual health visit. He was started on antihypertensive medications (losartan, hydrochlorothiazide, and spironolactone) by his primary care doctor, but the hypertension remained uncontrolled. Over the course of 2 months, the patient developed progressive lower extremity edema and was started on furosemide, which led to hypokalemia and was subsequently discontinued. He clinically deteriorated, with progressive anasarca and dyspnea, and then developed acute left eye ptosis and diplopia and was admitted to the hospital. The patient also endorsed irritability, mood swings, easy bruising, low libido, increased appetite, 30-lb weight gain, and bilateral hip pain.

Diagnostic Assessment

Physical examination was significant for oral candidiasis, dorsocervical fat pad, facial plethora, proximal muscle weakness, and bilateral hip tenderness. Testing confirmed ACTH-dependent CS with elevated 24-hour urine free cortisol of 1116 μg/24 hours (30788.21 nmol/24 hours) and 1171.9 μg/24 hours (32330.38 nmol/24 hours) (normal reference range, 3.5-45 μg/24 hours; 96.56-1241.46 nmol/24 hours) and ACTH of 173 pg/mL (38.06 pmol/L) and 112 pg/mL (24.64 pmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L) on 2 separate occasions. He had hypogonadotropic hypogonadism with total testosterone levels of 41 ng/dL (1.42 nmol/L) (normal reference range, 250-1100 ng/dL; 8.68-38.17 nmol/mL) and suppressed LH and FSH at <0.2 mIU/mL (<0.2 IU/L) (normal reference range, 0.6-12.1; 0.6-12/1.1 IU/L) and 0.2 mIU/mL (<0.2 IU/L) (normal reference range, 1.0-12.0 2 mIU/mL; 1.0-12.0 2 IU/L) respectively, whereas the remaining pituitary hormones were normal, although IGF-1 was low normal at 66 ng/mL (8.65 nmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L). He also had new-onset diabetes mellitus with glycated hemoglobin of 8% (<5.7%) (Table 1). Imaging of the lungs showed a 15-mm solid noncalcified nodule in the posterior right upper lobe concerning for neoplasm. Pituitary magnetic resonance imaging (MRI) revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (Fig. 1). Additionally, pelvis computed tomography (CT) scan demonstrated bilateral avascular necrosis of the capital femoral epiphysis without evidence of fracture or subchondral collapse (Fig. 2A and 2B).

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Figure 1.

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Figure 2.

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Table 1.

Laboratory evaluation of the patient at presentation

Lab Value Reference Range
Conventional units (Système International units)
ACTH 173 pg/mL (38.06 pmol/L) 7.2-63 pg/mL (1.58-13.86 pmol/L)
24-h urine free cortisol 1116 μg/24 h (30,788.21 nmol/24 h) 4.0-55.0 μg/24 h (110.35-1517.34 nmol/24 h)
Total testosterone 41 ng/mL (1.42 nmol/L) 250-1100 ng/mL (8.68-38.17 nmol/L)
Free testosterone 12.3 pg/mL (0.07 nmol/L) 30.0-135.0 pg/mL (0.17-0.79 nmol/L)
LH <0.2 mIU/mL (<0.2 IU/L) 0.6-12.1 mIU/mL (0.6-12.1 IU/L)
FSH 0.2 mIU/mL (0.2 IU/L) 1-12 mIU/mL (1-12 IU/L)
Prolactin 9.6 ng/mL (9.6 μg/L) 3.5-19.4 ng/mL (3.5-19.4 μg/L)
TSH 0.746 mIU/L 0.450-5.330 mIU/L
Free T4 0.66 ng/dL (8.49 pmol/L) 0.61-1.60 ng/dL (7.85-20.59 pmol/L
IGF-1
Z score		 66 ng/mL (8.65 nmol/L)
−0.9		 34-245 ng/mL (4.45-32.09 nmol/L)
−2.0 to +2.0
HbA1c 8.2% <5.7%

Abbreviations: Hb A1c, hemoglobin A1C.

Treatment

Prophylactic treatment was started with subcutaneous heparin for anticoagulation and trimethoprim-sulfamethoxazole for opportunistic infections. Orthopedic evaluation did not recommend acute intervention for the hip AVN. Given the pituitary macroadenoma on imaging and left cranial nerve VI palsy, it was determined that the patient likely had CD, so he underwent transsphenoidal surgery. Surgical pathology confirmed the adenoma was ACTH positive, sparsely granulated, with Ki-67 index of 4%, and without increased mitotic activity (Fig. 3).

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Figure 3.

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Outcome and Follow-up

Due to ongoing hypercortisolism (Table 2) and residual tumor in the left cavernous sinus, the patient underwent adjuvant treatment with stereotactic photon radiosurgery at a dose of 13 Gy targeted to the left cavernous sinus and was started on osilodrostat, an oral, reversible inhibitor of 11β-hydroxylase that drives the final step of cortisol synthesis and aldosterone synthase, which converts 11-deoxycorticosterone to aldosterone [7]. The starting dose of osilodrostat was 2 mg twice per day. As the patient developed nausea, lack of appetite, and malaise with decreasing cortisol levels, osilodrostat was reduced to 1 mg daily, and he was started on hydrocortisone replacement therapy on week 11 postoperatively (Table 3). Ultimately, both osilodrostat and hydrocortisone were discontinued following normalization of cortisol levels. Regarding the rest of the hormonal deficiencies, his total testosterone and IGF-1 levels improved to levels of 483 ng/dL (16.76 nmol/L) and 99 (12.97 nmol/L), respectively, and he did not require hormone replacement therapy. Clinically, the patient improved with resolution of his hypertension and diabetes and achieved a 38-lb weight loss. Additionally, his diplopia improved and his hip pain resolved without any restriction in mobility. However, 1 year postoperatively, the patient developed bilateral shoulder pain. MRI of the shoulders demonstrated subchondral changes in the right humeral head (Fig. 2C) and a linear area of subchondral change involving the left humeral head (Fig. 2D) consistent with AVN, as well as a bilateral high-grade supraspinatus tear and acromioclavicular joint osteoarthritis. He was treated with an intraarticular methylprednisolone 40-mg injection to both shoulders, with subsequent improvement of the pain and joint mobility. He also underwent a coronary artery bypass graft surgery for 3-vessel disease. The patient has otherwise maintained normal urine and salivary cortisol levels off osilodrostat or hydrocortisone, and 1 year after surgery, the ACTH (cosyntropin) stimulation test was normal. The pulmonary nodule has remained stable on serial imaging.

Table 2.

Postoperative cortisol and ACTH levels

Postoperative day
Lab Reference Range Conventional units (Système International units) 1 2 2 3 4 5
Morning cortisol 3.7-19.4 μg/dL (102.08- 535.21 nmol/L) 26 μg/dL (717.29 nmol/L) 21.5 μg/dL (593.14 nmol/L) 6 μg/dL (165.53 nmol/L) 8.1 μg/dL (223.46 nmol/L) 16.4 μg/dL (452.44 nmol/L) 21.5 μg/dL (593.14 nmol/L)
ACTH 7.2-63.3 pg/mL (1.58- 13.93 pmol/L) 72 pg/mL (15.84 pmol/L) 62 pg/mL (13.64 pmol/L)

Table 3.

Titration of osilodrostat treatment based on cortisol levels

Postoperative week
Lab Reference range Conventional units (Système International units) 8 9 11 13 15 18 22 24
ACTH 7.2-63.3 pg/mL (1.58-13.93 pmol/L) 95.6 pg/mL (21.03 pmol/L) 131 pg/mL (28.82 pmol/L) 58.8 pg/mL (12.94 pmol/L) 79.3 pg/mL (17.45 pmol/L) 79.9 pg/mL (17.58 pmol/L) 73.4 pg/mL (16.15 pmol/L) 62 pg/mL (13.64 pmol/L) 71.5 pg/mL (15.73 pmol/L)
Morning cortisol 3.7-19.4 μg/dL (102.08-535.21 nmol/L) 23.9 μg/dL (659.35 nmol/L) 18.8 μg/dL (518.65 nmol/L) 6.6 μg/dL (182.08 nmol/L) 4.5 μg/dL (124.15 nmol/L) 3.3 μg/dL (91.04 nmol/L) 2.4 μg/dL (66.21) nmol/L 8.2 μg/dL (226.22. nmol/L) 4.1 μg/dL (113.11 nmol/L)
LNSC <0.010-0.090 μg/dL (0.28-2.48 nmol/L) 0.615 μg/dL (16.97 nmol/L) 0.058 μg/dL (1.60 nmol/L) 0.041 μg/dL (1.13 nmol/L) 0.041 μg/dL (1.13 nmol/L)
UFC, 24-h 5-64 μg/24 h (137.94-1765.63 nmol/24 h) 246 μg/24 h (6786.65 nmol/24 h) 226 μg/24 h (6234.89 nmol/24 h) 2 μg/24 h (55.18. nmol/24 h)
Osilodrostat dose 2 mg BID 2 mg BID 2 mg AM
3 mg PM		 2 mg BID 2 mg AM
1 mg PM		 1 mg BID 1 mg daily Oslidrostat discontinued

Abbreviations: BID, twice per day; LNSC, late night salivary cortisol; UFC, urine free cortisol.

Discussion

Our patient exhibited pronounced hypercortisolism secondary to CD, with bilateral hip AVN as 1 of the presenting symptoms. Despite achieving biochemical remission of the disease and resolution of other associated symptoms, the patient was later diagnosed with bilateral shoulder AVN.

AVN caused by endogenous hypercortisolism is seldom documented, and routine screening for it is not typically conducted during the diagnosis of CS. However, AVN has been reported to be a presenting symptom in several case reports or may manifest years after the initial diagnosis [8]. Reported causes of AVN in endogenous CS include pituitary adenomas, adrenal adenomas or carcinomas, adrenal hyperplasia, or neuroendocrine tumors [8‐23] (Table 4), with some cases of AVN associated with severe hypercortisolism [10, 15]. Other risk factors associated with AVN include hip trauma, femoral fractures, hip dislocation, systemic lupus erythematosus in the setting of concomitant corticosteroid treatments, or vasculitis, sickle cell disease, hypercoagulability, Gaucher disease, hyperlipidemia or hypertriglyceridemia, hyperuricemia, hematological malignancies, antiretroviral medications, alcohol use, and exogenous steroid treatment [4]. Our patient had no history of hip trauma or other aforementioned comorbidities. Furthermore, during presentation, his lipid levels were normal, with low-density lipoprotein cholesterol of 89 mg/dL (<130 mg/dL) and triglycerides of 97 mg/dL (<150 mg/dL). Therefore, it is likely that his bilateral hip and shoulder AVN was caused by severe endogenous hypercortisolism.

Table 4.

Published cases of avascular necrosis in patients with endogenous hypercortisolism

First author, year Age (y)/sex Time of diagnosis in relation to CS diagnosis AVN related symptoms Imaging modality Imaging description Diagnosis Treatment
Salazar D, 2021 [15] 38 F 3 y prior to diagnosis Right hip pain MRI
  • Right hip joint effusion and synovitis
  • Flattening of the femoral head-Subcortical edema
 Adrenal adenoma Right hip arthroplasty
Madell SH, 1964 [16] 41 F 1 month before diagnosis Right shoulder pain X-ray
  • Increased density of the right humeral head with spotty areas of radiolucency
  • Early flattening and beginning of fragmentation
 Adrenal adenoma Osteotomy
Anand A, 2022 [21] 47 M Bilateral hip pain MRI
  • Necrosis of bilateral femur heads
 adrenocortical carcinoma
Belmahi N, 2018 [9] 28 F Progressive limping and right hip pain MRI
  • Right femoral head AVN
 Pituitary adenoma Right total hip replacement
Wicks I, 1987 [10] 39 M 18 months before diagnosis Progressive hip pain and stiffens X-ray
Bone scan
  • Lucent and sclerotic regions within flattened femoral heads
  • Some loss of articular cartilage
 Pituitary adenoma Conservative management
Koch C, 1999 [11] 30 F Sudden onset of severe left hip pain MRI
  • Abnormal high intensity signal changes in the bone marrow of the left femoral head
  • Joint effusion
  • Stage 2 AVN
 Pituitary adenoma Immediate core decompression surgery with decongestion of the left femoral head
Premkumar M, 2013 [12] 26 F 2 y after pituitary surgery for Cushing, while on replacement steroid therapy Progressive bilateral hip pain resulting in difficulty in walking MRI
  • Bilateral multiple bony infarcts in the proximal femur and distal femur
  • Femoral head collapse fractures -Stage 2 avascular necrosis
 Pituitary adenoma
Bauddh N, 2022 [13] 24 M 2 y prior to diagnosis Progressive left hip pain and difficulty in walking X-ray
MRI
  • Left femoral head AVN
 Pituitary adenoma Planned for surgery of hip AVN
Joseph A, 2022 [14] 21 F 1 y prior to diagnosis Bilateral hip joint pain X-ray
MRI
  • Ill-defined mixed sclerotic and lytic pattern of the femoral heads
  • Cortical disruption of the round contour
  • Low signal intensity in the subchondral region of the femoral necks on T1-weighted images
 Pituitary adenoma Planned for total hip replacement.
Bisphosphonates.
Pazderska A, 2016 [19] 36 F Right leg pain MRI
  • Bilateral AVN of the femoral heads
  • Left femoral head with early bone fragmentation
 Bilateral primary pigmented micronodular adrenal disease Spontaneous healing of AVN after adrenalectomy.
Papadakis G, 2017 [22] 55 F MRI
PET/CT 68Ga-DOTATATE
  • Bilateral AVN
  • Bone marrow edema extending to the intertrochanteric area
  • Mild subchondral femoral head collapse of the left hip
  • Increased activity in bilateral femoral heads and in the bone marrow consistent with edema
  • Mild left femoral head collapse
 Ectopic ACTH- secreting tumor
Phillips K, 1986 [8] 24 F 4.5 y after diagnosis Right femoral AVN X-ray
  • Flattening and sclerosis of femoral head
 Cushing disease
25 F 4 y after diagnosis Right femoral AVN
  • Subchondral lucency
43 F 8 mo after diagnosis Right humeral AVN
  • Sclerosis and flattening of articular surface of humeral head
61 F 11 y after diagnosis Left femoral AVN and bilateral humeral heads
  • Cortical indistinctness and subchondral lucency
  • Left humeral head flattening and sclerosis
Cerletty J, 1973 [20] 54 M 3 mo before diagnosis Right femoral head fracture X-ray
  • Bilateral subchondral sclerosis of the femoral heads
  • Some narrowing of the joint space on the left
  • Infraction of the margin of the right femoral head
  • Femoral neck fracture.
 Bilateral adrenal cortical hyperplasia Total hip joint arthroplasty
Ha J-S, 2019 [18] 36 F 2 y before diagnosis 2 mo left hip restricted range of motion X-ray
MRI
  • Right femoral head with areas of hyperlucency and surrounding sclerosis
  • Subtle changes in the shape of the articular surface
  • Bilateral femoral head osteonecrosis -Increased amount of joint fluid and bone marrow edema in the left hip
  • Right femoral head necrosis
 Adrenal cortical adenoma Total hip replacement
Takada, J, 2004 [17] 55 F Intense right hip pain and a limp MRI
  • Low-intensity band on T1-weighted images
  • Stage 2 AVN.
 Adrenal adenoma Total hip arthroplasty
Modlinger RS, 1972 [23] 69 F Increased pain of right shoulder X-ray
  • Bilateral shoulders with aseptic necrosis of the humeral heads
 Ectopic ACTH secretion NET form pancreatic tumor

Abbreviations: AVN, avascular necrosis; F, female; M, male; MRI, magnetic resonance imaging; NET, neuroendocrine tumor.

AVN can result in irreversible femoral head collapse, leading to severe limitation in movement, reduced joint functionality, and decreased quality of life [24]. Initially, patients may be asymptomatic or endorse nonspecific pain when presenting with AVN and may not be diagnosed until an advanced stage when they develop more severe pain and disability [25]. In a meta-analysis assessing the prevalence of AVN in patients with systemic lupus erythematosus, including those who received corticosteroid treatment, asymptomatic AVN was detected in 29% of patients and symptomatic disease was noted in 9% [26]. AVN can diagnosed with MRI or CT imaging. Although noncontrast MRI has higher sensitivity and specificity in detecting early stages of the disease, CT is comparable to MRI in more advanced stages. Ancillary imaging modalities include plain radiography, positron emission tomography, and bone scan [27].

Staging of AVN relies on radiologic features and size of lesions. In earlier stages, imaging can be normal (stage 0) or with subtle abnormalities on MRI or bone scan and normal radiography (stage 1). As the disease progresses, structural changes, including cystic and sclerotic changes (stage 2), subchondral collapse (stage 3), flattening of the femoral head (stage 4), joint narrowing and acetabular changes (stage 5), and, finally, advanced degenerative changes (stage 6) can be detected on most imaging modalities.

Management of early stages of AVN includes observation or conservative weight-bearing management, medical therapy with bisphosphonates, anticoagulation therapy, statins, and vasodilators. Invasive procedures such as mesenchymal stem cells implantation, osteotomy, surgical joint decompression, and total hip replacement are reserved for more advanced stages [28]. Indeed, AVN accounts for approximately 10% of total hip replacements in the United States [29]. Staging has prognostic implications for treatment options and disease outcomes. Early-stage disease, when diagnosed and treated, can often regress, and be cured. Conservative measures, medical treatment, biophysical stimulation, extracorporeal shockwave therapy, or core decompression, can prevent femoral head collapse and further hip arthroplasty. On the other hand, late-stage disease, characterized by joint collapse, is irreversible and often requires joint replacement [30].

Although actual prevalence rates of AVN in endogenous CS is unknown, one should consider screening for AVN in this high-risk population, particularly in patients showing markedly elevated cortisol levels, as in our case. Such an approach would facilitate the early identification of individuals who would benefit from earlier medical or surgical interventions, thereby preventing permanent joint destruction and chronic disability.

Learning Points

  • AVN can be a complication of endogenous hypercortisolism.
  • AVN may present asymptomatically or with nonspecific symptoms such as joint pain.
  • AVN can affect multiple joints, including hips and shoulders, and its early diagnosis relies on MRI or CT imaging.
  • Early detection and intervention for AVN are crucial to prevent irreversible joint damage and disability.
  • Screening for AVN in patients with CS should be considered to enable timely intervention and prevent long-term complications, particularly in patients with hip or shoulder pain and severe hypercortisolism.

Contributors

All authors made individual contributions to authorship. N.T. and O.C. were involved in the diagnosis and management of the patient and manuscript submission. S.B. was involved in the histopathology section and preparation of histology images. T.L. was involved in the interpretation and preparation of the radiology images. A.N.M. was responsible for the patient’s surgery and treatment plan. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

Dr. Odelia Cooper is an Editorial Board member for JCEM Case Reports and played no role in the journal’s evaluation of the manuscript. There are no other disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

  • AVN

    avascular necrosis

  • CD

    Cushing disease

  • CS

    Cushing syndrome

  • CT

    computed tomography

  • MRI

    magnetic resonance imaging

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

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

Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

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

From Knee Pain Consultation to Pituitary Surgery: The Challenge of Cushing Disease Diagnosis

Posted on April 24, 2024 by MaryO

Abstract

Cushing syndrome (CS) is a rare endocrinological disorder resulting from chronic exposure to excessive cortisol. The term Cushing disease is used specifically when this is caused by excessive secretion of adrenocorticotropic hormone (ACTH) by a pituitary tumor, usually an adenoma. This disease is associated with a poor prognosis, and if left untreated, it has an estimated 5-year survival rate of 50%. We present the case of a 66-year-old female patient who received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. Taking into consideration her age, she was screened for osteoporosis, with results that showed diminished bone density. Considering this, combined with other clinical features of the patient, suspicion turned toward hypercortisolism. Laboratory findings suggested that the CS was ACTH-dependent and originated in the pituitary gland. After a second look at the magnetic resonance imaging results, a 4-mm lesion was identified on the pituitary gland, prompting a transsphenoidal resection of the pituitary adenoma.

Introduction

Chronic excessive exposure to glucocorticoids leads to the diverse clinical manifestations of Cushing syndrome (CS), which has an annual incidence ranging from 1.8 to 3.2 cases per million individuals [1]. The syndrome’s signs and symptoms are not pathognomonic, and some of its primary manifestations, such as obesity, hypertension, and glucose metabolism alterations, are prevalent in the general population [2], making diagnosis challenging. Endogenous CS falls into 2 categories: adrenocorticotropic hormone (ACTH)-dependent (80%-85% of cases), mostly due to a pituitary adenoma, or ACTH-independent (15%-20% of cases), typically caused by adrenal adenomas or hyperplasia [3]. Cushing disease (CD) represents a specific form of CS, characterized by the presence of an ACTH-secreting pituitary tumor [1]. Untreated CD is associated with high morbidity and mortality compared to the general population [1], with a 50% survival rate at 5 years [2]. However, surgical removal of a pituitary adenoma can result in complete remission, with mortality rates similar to those of the general population [2]. This article aims to highlight the challenges of suspecting and diagnosing CD and to discuss the current management options for this rare condition.

Case Presentation

A 66-year-old woman received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. During physical examination, she exhibited a body mass index of 34.3 kg/m2, blood pressure of 180/100, a history of non-insulin-requiring type 2 diabetes mellitus with glycated hemoglobin (HbA1c) of 6.9% (nondiabetic: < 5.7%; prediabetic: 5.7% to 6.4%; diabetic: ≥ 6.5%) and hypertension. Additionally, the patient complained of proximal weakness in all 4 limbs.

Diagnostic Assessment

Upon admission, densitometry revealed osteoporosis with T scores of −2.7 in the lumbar spine and −2.8 in the femoral neck. Hypercortisolism was suspected due to concomitant arterial hypertension, central obesity, muscle weakness, and osteoporosis. Physical examination did not reveal characteristic signs of hypercortisolism, such as skin bruises, flushing, or reddish-purple striae. Late-night salivary cortisol (LNSC) screening yielded a value of 8.98 nmol/L (0.3255 mcg/dL) (reference value [RV] 0.8-2.7 nmol/L [0.029-0.101 mcg/dL]) and ACTH of 38.1 pg/mL (8.4 pmol/L) (RV 2-11 pmol/L [9-52 pg/mL]). A low-dose dexamethasone suppression test (LDDST) was performed (cutoff value 1.8 mcg/dL [49 nmol/L]), with cortisol levels of 7.98 mcg/dL (220 nmol/L) at 24 hours and 20.31 mcg/dL (560 nmol/L) at 48 hours. Subsequently, a high-dose dexamethasone suppression test (HDDST) was conducted using a dose of 2 mg every 6 hours for 2 days, for a total dose of 16 mg, revealing cortisol levels of 0.0220 nmol/L (0.08 ng/mL) at 24 hours and 0.0560 nmol/L (0.0203 ng/mL) at 48 hours, alongside 24-hour urine cortisol of 0.8745 nmol/L (0.317 ng/mL) (RV 30-145 nmol/24 hours [approximately 11-53 μg/24 hours]) [4].

These findings indicated the presence of endogenous ACTH-dependent hypercortisolism of pituitary origin. Consequently, magnetic resonance imaging (MRI) was requested, but the results showed no abnormalities. Considering ectopic ACTH production often occurs in the lung, a high-resolution chest computed tomography scan was performed, revealing no lesions.

Treatment

Upon reassessment, the MRI revealed a 4-mm adenoma, prompting the decision to proceed with transsphenoidal resection of the pituitary adenoma.

Outcome and Follow-Up

The histological analysis revealed positive staining for CAM5.2, chromogranin, synaptophysin, and ACTH, with Ki67 staining at 1%. At the 1-month follow-up assessment, ACTH levels were 3.8 pmol/L (17.2 pg/mL) and morning cortisol was 115.8621 nmol/L (4.2 mcg/dL) (RV 5-25 mcg/dL or 140-690 nmol/L). Somatomedin C was measured at 85 ng/mL (RV 70-267 ng/mL) and prolactin at 3.5 ng/mL (RV 4-25 ng/mL). At the 1-year follow-up, the patient exhibited a satisfactory postoperative recovery. However, she developed diabetes insipidus and secondary hypothyroidism. Arterial hypertension persisted. Recent laboratory results indicated a glycated hemoglobin (HbA1c) level of 5.4%. Medications at the time of follow-up included prednisolone 5 milligrams a day, desmopressin 60 to 120 micrograms every 12 hours, losartan potassium 50 milligrams every 12 hours, and levothyroxine 88 micrograms a day.

Discussion

CD is associated with high mortality, primarily attributable to cardiovascular outcomes and comorbidities such as metabolic and skeletal disorders, infections, and psychiatric disorders [1]. The low incidence of CD in the context of the high prevalence of chronic noncommunicable diseases makes early diagnosis a challenge [2]. This case is relevant for reviewing the diagnostic approach process and highlighting the impact of the availability bias, which tends to prioritize more common diagnoses over rare diseases. Despite the absence of typical symptoms, a timely diagnosis was achieved.

Once exogenous CS is ruled out, laboratory testing must focus on detecting endogenous hypercortisolism to prevent misdiagnosis and inappropriate treatment [5]. Screening methods include 24-hour urinary free cortisol (UFC) for total cortisol load, while circadian rhythm and hypothalamic-pituitary-adrenal (HPA) axis function may be evaluated using midnight serum cortisol and LNSC [5]. An early hallmark of endogenous CS is the disruption of physiological circadian cortisol patterns, characterized by a constant cortisol level throughout the day or no significant decrease [2]. Measuring LNSC has proven to be useful in identifying these patients. The LNSC performed on the patient yielded a high result.

To assess HPA axis suppressibility, tests such as the overnight and the standard 2-day LDDST [5] use dexamethasone, a potent synthetic corticosteroid with high glucocorticoid receptor affinity and prolonged action, with minimal interference with cortisol measurement [6]. In a normal HPA axis, cortisol exerts negative feedback, inhibiting the secretion of corticotropin-releasing-hormone (CRH) and ACTH. Exogenous corticosteroids suppress CRH and ACTH secretion, resulting in decreased synthesis and secretion of cortisol. In pathological hypercortisolism, the HPA axis becomes partially or entirely resistant to feedback inhibition by exogenous steroids [5, 6]. The LDDST involves the administration of 0.5 mg of dexamethasone orally every 6 hours for 2 days, with a total dose of 4 mg. A blood sample is drawn 6 hours after the last administered dose [6]. Following the LDDST, the patient did not demonstrate suppression of endogenous corticosteroid production.

After diagnosing CS, the next step in the diagnostic pathway involves categorizing it as ACTH-independent vs ACTH-dependent. ACTH-independent cases exhibit low or undetectable ACTH levels, pointing to adrenal origin. The underlying principle is that excess ACTH production in CD can be partially or completely suppressed by high doses of dexamethasone, a response not observed in ectopic tumors [6]. In this case, the patient presented with an ACTH of 38.1 pg/mL (8.4 pmol/L), indicative of ACTH-dependent CD.

Traditionally, measuring cortisol levels and conducting pituitary imaging are standard practices for diagnosis. Recent advances propose alternative diagnostic methods such as positron emission tomography (PET) scans and corticotropin-releasing factor (CRF) tests [7]. PET scans, utilizing radioactive tracers, offer a view of metabolic activity in the adrenal glands and pituitary region, aiding in the identification of abnormalities associated with CD. Unfortunately, the availability of the aforementioned tests in the country is limited.

Once ACTH-dependent hypercortisolism is confirmed, identifying the source becomes crucial. A HDDST is instrumental in distinguishing between a pituitary and an ectopic source of ACTH overproduction [2, 6]. The HDDST involves administering 8 mg of dexamethasone either overnight or as a 2-day test. In this case, the patient received 2 mg of dexamethasone orally every 6 hours for 2 days, totaling a dose of 16 mg. Simultaneously, a urine sample for UFC is collected during dexamethasone administration. The HDDST suppressed endogenous cortisol production in the patient, suggesting a pituitary origin.

In ACTH-dependent hypercortisolism, CD is the predominant cause, followed by ectopic ACTH syndrome and, less frequently, an ectopic CRH-secreting tumor [3, 5]. With the pretest probability for pituitary origin exceeding 80%, the next diagnostic step is typically an MRI of the pituitary region. However, the visualization of microadenomas on MRI ranges from 50% to 70%, requiring further testing if results are negative or inconclusive [5]. Initial testing of our patient revealed no pituitary lesions. Following a pituitary location, ACTH-secreting tumors may be found in the lungs. Thus, a high-resolution chest computed tomography scan was performed, which yielded negative findings. Healthcare professionals must keep these detection rates in mind. In instances of high clinical suspicion, repeating or reassessing tests and imaging may be warranted [3], as in our case, ultimately leading to the discovery of a 4-mm pituitary adenoma.

It is fundamental to mention that the Endocrine Society Clinical Practice Guideline on Treatment of CS recommends that, when possible, all patients presenting with ACTH-dependent CS and lacking an evident causal neoplasm should be directed to an experienced center capable of conducting inferior petrosal sinus sampling to differentiate between pituitary and nonpituitary or ectopic cause [8]. However, in this instance, such a referral was regrettably hindered by logistical constraints.

Regarding patient outcomes and monitoring in CD, there is no consensus on defining remission criteria following tumor resection. Prolonged hypercortisolism results in suppression of corticotropes, resulting in low levels of ACTH and cortisol after surgical intervention. Typically, remission is identified by morning serum cortisol values below 5 µg/dL (138 nmol/L) or UFC levels between 28 and 56 nmol/d (10-20 µg/d) within 7 days after surgical intervention. In our case, the patient’s morning serum cortisol was 115.8621 nmol/L (4.2 µg/dL), indicating remission. Remission rates in adults are reported at 73% to 76% in selectively resected microadenomas and at 43% in macroadenomas [8], highlighting the need for regular follow-up visits to detect recurrence.

Following the surgery, the patient experienced diabetes insipidus, a relatively common postoperative occurrence, albeit usually transient [8]. It is recommended to monitor serum sodium levels during the first 5 to 14 days postsurgery for early detection and management. Additionally, pituitary deficiencies may manifest following surgery. In this patient, prolactin levels were compromised, potentially impacting sexual response. However, postoperative somatomedin levels were normal, and gonadotropins were not measured due to the patient’s age group, as no additional clinical decisions were anticipated based on those results. Secondary hypothyroidism was diagnosed postoperatively.

Moving forward, it is important to emphasize certain clinical signs and symptoms for diagnosing CD. The combination of low bone mineral density (Likelihood Ratio [LR] +21.33), central obesity (LR +3.10), and arterial hypertension (LR + 2.29) [9] has a higher positive LR than some symptoms considered “characteristic,” such as reddish-purple striae, plethora, proximal muscle weakness, and unexplained bruising [2, 10]. It is essential to give relevance to the signs the patient may present, emphasizing signs that have been proven to have an increased odds ratio (OR) such as osteoporosis (OR 3.8), myopathies (OR 6.0), metabolic syndrome (OR 2.7) and adrenal adenoma (OR 2.4) [9‐11]. The simultaneous development and worsening of these conditions should raise suspicion for underlying issues. Understanding the evolving nature of CD signs highlights the importance of vigilance during medical examinations, prioritizing the diagnostic focus, and enabling prompt initiation of treatment.

Recognizing the overlap of certain clinical features in CS is fundamental to achieving a timely diagnosis.

Learning Points

  • CS diagnosis is challenging due to the absence of pathognomonic signs and symptoms and the overlap of features present in many pathologies, such as metabolic syndrome.
  • Early detection of CS is crucial, given its association with high morbidity and mortality resulting from chronic exposure to glucocorticoids.
  • Recognizing the combination of low bone mineral density, obesity, hypertension, and diabetes as valuable clinical indicators is key in identifying CS.
  • Interdisciplinary collaboration is essential to achieve a comprehensive diagnostic approach.

Acknowledgments

We extend our gratitude to Pontificia Universidad Javeriana in Bogotá for providing essential resources and facilities that contributed to the successful completion of this case report. Special acknowledgment is reserved for the anonymous reviewers, whose insightful feedback significantly enhanced the quality of this manuscript during the peer-review process. Their contributions are sincerely appreciated.

Contributors

All authors made individual contributions to authorship. A.B.O. was involved in the diagnosis and management of this patient. M.A.G., J.M.H., and A.B.O. were involved in manuscript drafting and editing. All authors reviewed and approved the final draft.

Funding

This research received no public or commercial funding.

Disclosures

The authors declare that they have no conflicts of interest related to the current study.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.

Data Availability Statement

Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.

References

1

Hakami
OA

,

Ahmed
S

,

Karavitaki
N

.

Epidemiology and mortality of Cushing’s syndrome

.

Best Pract Res Clin Endocrinol Metab

.

2021

;

35

(

1

):

101521

.

2

Nieman
LK

,

Biller
BMK

,

Findling
JW

, et al.

The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline

.

J Clin Endocrinol Metab

.

2008

;

93

(

5

):

1526

‐

1540

.

3

Gutiérrez Restrepo
J

,

Latorre Sierra
G

,

Campuzano Maya
G

.

Síndrome de cushing

.

Med Lab

.

2009

;

15

:

411

‐

430

.

4

Petersenn
S

,

Newell-Price
J

,

Findling
JW

, et al.

High variability in baseline urinary free cortisol values in patients with Cushing’s disease

.

Clin Endocrinol (Oxf)

.

2014

;

80

(

2

):

261

‐

269

.

5

Lila
AR

,

Sarathi
V

,

Jagtap
VS

,

Bandgar
T

,

Menon
P

,

Shah
NS

.

Cushing’s syndrome: stepwise approach to diagnosis

.

Indian J Endocrinol Metab

.

2011

;

15

(

Suppl4

):

S317

‐

S321

.

6

Dogra
P

,

Vijayashankar
NP

.

Dexamethasone suppression test. In: StatPearls StatPearls Publishing; 2024

. Accessed January 29, 2024. http://www.ncbi.nlm.nih.gov/books/NBK542317/

7

Müller
OA

,

Dörr
HG

,

Hagen
B

,

Stalla
GK

,

von Werder
K

.

Corticotropin releasing factor (CRF)-stimulation test in normal controls and patients with disturbances of the hypothalamo-pituitary-adrenal axis

.

Klin Wochenschr

.

1982

;

60

(

24

):

1485

‐

1491

.

8

Nieman
LK

,

Biller
BMK

,

Findling
JW

, et al.

Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline

.

J Clin Endocrinol Metab

.

2015

;

100

(

8

):

2807

‐

2831

.

9

Aron
DC

.

Cushing’s syndrome: why is diagnosis so difficult?
Rev Endocr Metab Disord

.

2010

;

11

(

2

):

105

‐

116

.

10

Braun
LT

,

Vogel
F

,

Zopp
S

, et al.

Whom should we screen for cushing syndrome? the Endocrine Society practice guideline recommendations 2008 revisited

.

J Clin Endocrinol Metab

.

2022

;

107

(

9

):

e3723

‐

e3730

.

11

Schneider
HJ

,

Dimopoulou
C

,

Stalla
GK

,

Reincke
M

,

Schopohl
J

.

Discriminatory value of signs and symptoms in Cushing’s syndrome revisited: what has changed in 30 years?
Clin Endocrinol (Oxf)

.

2013

;

78

(

1

):

153

‐

154

.

Abbreviations

 

  • ACTH

    adrenocorticotropic hormone

  • CD

    Cushing disease

  • CRH

    corticotropin-releasing hormone

  • CS

    Cushing syndrome

  • HDDST

    high-dose dexamethasone suppression test

  • HPA

    hypothalamic-pituitary-adrenal

  • LDDST

    low-dose dexamethasone suppression test

  • LNSC

    late-night salivary cortisol

  • MRI

    magnetic resonance imaging

  • OR

    odds ratio

  • RV

    reference value

  • UFC

    urinary free cortisol

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Navigating the Surgical Landscape: A Comprehensive Analysis of Endoscopic vs. Microscopic Transsphenoidal Pituitary Surgery Outcomes

Posted on February 6, 2024 by MaryO

Abstract

Pituitary surgery, a critical intervention for various pituitary disorders, has sparked ongoing debates regarding the preference between endoscopic and microscopic transsphenoidal approaches. This systematic review delves into the outcomes associated with these techniques, taking into account the recent advancements in neurosurgery. The minimally invasive nature of endoscopy, providing improved visualization and reduced morbidity, stands in contrast to the well-established track record of the conventional microscopic method. Examining outcomes for disorders such as Cushing’s disease and acromegaly, the review synthesizes evidence from Denmark, Bulgaria, and China. Noteworthy advantages of endoscopy encompass higher resection rates, shorter surgery durations, and fewer complications, endorsing its effectiveness in pituitary surgery. While emphasizing the necessity for prospective trials, the review concludes that endoscopic approaches consistently showcase favorable outcomes, influencing the ongoing discourse on the optimal surgical strategies for pituitary disorders.

Introduction & Background

Pituitary surgery is a critical intervention for various pituitary disorders, and the choice between endoscopic and microscopic transsphenoidal approaches has been a subject of ongoing debate within the medical community. This systematic review aims to explore and analyze the outcomes associated with endoscopic and microscopic transsphenoidal pituitary surgery. As advancements in surgical techniques continue to shape the field of neurosurgery, understanding the comparative effectiveness of these two approaches becomes imperative. The endoscopic approach, characterized by its minimally invasive nature, has gained popularity for pituitary surgery in recent years [1]. Proponents argue that it provides enhanced visualization, improved maneuverability, and reduced patient morbidity. On the other hand, traditional microscopic transsphenoidal surgery has been the conventional method for decades, known for its familiarity among surgeons and established track record [2].

Several studies have investigated the outcomes of these approaches in treating pituitary disorders, including but not limited to Cushing’s disease, pituitary adenomas, and other tumors. For instance, a systematic review and meta-analysis by Chen et al. compared endoscopic and microscopic transsphenoidal surgery specifically for Cushing’s disease, shedding light on the effectiveness of these approaches in managing this specific condition [3]. Moreover, Møller et al. reported promising results for endoscopic pituitary surgery based on the experiences of experienced microscopic pituitary surgeons, indicating a potential shift towards the adoption of the endoscopic technique [1]. Guo et al. conducted a meta-analysis comparing the effectiveness of microscopic and endoscopic surgery for treating pituitary disorders, contributing valuable insights into the overall efficacy of these approaches [4].

This review aims to contribute to the ongoing discourse on pituitary surgery by providing a comprehensive analysis of the outcomes associated with endoscopic versus microscopic transsphenoidal approaches. By synthesizing the existing evidence, we strive to offer valuable insights that can guide both clinicians and researchers in making informed decisions regarding the optimal surgical approach for pituitary disorders.

Review

Materials and methods

This systematic review strictly adheres to the established Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, employing a comprehensive approach to investigate the outcomes of endoscopic versus microscopic transsphenoidal pituitary surgery. The subsequent sections delineate the criteria for study inclusion, the search strategy utilized, and the methodology employed for data synthesis.

Search Strategy

We conducted a meticulous search across prominent electronic databases, including PubMed, Embase, and the Cochrane Library, to identify pertinent articles. Our search strategy comprised a combination of Medical Subject Headings (MeSH) terms and keywords related to pituitary surgery, encompassing both endoscopic and microscopic approaches. Boolean operators (AND, OR) were strategically employed to refine the search and identify studies meeting our predetermined inclusion criteria. The search string used for PubMed was (“Outcomes” OR “Treatment Outcome” OR “Surgical Outcome”) AND (“Endoscopic Transsphenoidal Pituitary Surgery” OR “Endoscopic Pituitary Surgery” OR “Endoscopic Hypophysectomy”) AND (“Microscopic Transsphenoidal Pituitary Surgery” OR “Microscopic Pituitary Surgery” OR “Microscopic Hypophysectomy” OR “Endoscopy”[Mesh] OR “Endoscopy, Surgical”[Mesh] OR “Transsphenoidal Hypophysectomy”[Mesh] OR “Microsurgery”[Mesh] OR “Microscopic Hypophysectomy”[Mesh]).

Eligibility Criteria

Stringent inclusion criteria were predefined to ensure the selection of high-quality and relevant studies. The included studies focused on investigating the outcomes of endoscopic versus microscopic transsphenoidal pituitary surgery. Only articles published in peer-reviewed journals within the timeframe from the inception of relevant databases until October 2023 were considered. Exclusion criteria encompassed studies on other interventions, those lacking sufficient data on surgical outcomes, and studies solely involving animal cells. Additionally, only studies in the English language with full-text availability were included, and gray literature was not considered eligible.

Data Extraction and Synthesis

Two independent reviewers meticulously screened titles and abstracts to identify potentially eligible studies. Subsequently, full-text articles were retrieved and evaluated for adherence to inclusion criteria. Discrepancies between reviewers were resolved through discussion and consultation with a third reviewer. Relevant data, including study design, patient characteristics, interventions, and surgical outcomes, were systematically extracted using a predefined data extraction form.

Data Analysis

A narrative synthesis approach was employed to summarize findings from included studies due to anticipated heterogeneity in study designs and outcome measures. Key themes and patterns related to the outcomes of endoscopic versus microscopic transsphenoidal pituitary surgery were identified and presented.

Results

Study Selection Process

Following four database searches, 97 articles were initially identified. After eliminating eight duplicates, the titles and abstracts of the remaining 89 publications were evaluated. Subsequently, 17 potential studies underwent eligibility verification through a thorough examination of their full texts. Ultimately, three articles satisfied the inclusion criteria. No additional studies meeting the eligibility criteria were found during the examination of references in the selected articles. The entire process is visually depicted in the PRISMA flowchart (Figure 1).

PRISMA-flow-diagram-of-the-selection-of-studies-for-inclusion-in-the-systematic-review.
Figure 1: PRISMA flow diagram of the selection of studies for inclusion in the systematic review.

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Characteristics of Selected Studies

Overall, three papers met the inclusion criteria. Two studies were randomized controlled trials (RCTs), one each from Bulgaria and China. One study was an observational study from Denmark. The main findings and characteristics of the included studies are mentioned in the following tables (Table 1 and Table 2).

Author Year Country Study type Sample size No. of participants in the endoscopic group No. of participants in the microscopic group Main findings
Møller et al. [1] 2020 Denmark Observational study 240 45 195 The study comparing endoscopic and microscopic transsphenoidal pituitary surgery revealed that the endoscopic technique exhibited advantages, achieving a higher rate of gross total resection (39% vs. 22%) and shorter surgery duration (86 minutes vs. 106 minutes). Complications within 30 days were lower with the endoscope (17% vs. 27%), and grade II complications or higher were significantly reduced (4% vs. 20%) compared to the microscopic approach. Pituitary function outcomes favored the endoscope, with fewer new deficiencies in the HPA axis (3% vs. 34%) and TSH-dependent deficiencies (15% vs. 38%). The HPG axis also showed better normalization in the endoscopic group (32% vs. 19%). Visual field impairment and postoperative improvement did not significantly differ between the two techniques. Overall, the findings suggest that endoscopic transsphenoidal pituitary surgery may offer superior outcomes compared to the microscopic approach, particularly in terms of resection rates and complication profiles.
Vassilyeva et al. [5] 2023 Bulgaria RCT 83 43 40 The study compared endoscopic and microscopic transsphenoidal pituitary surgery in acromegaly patients, revealing comparable demographic profiles between the groups. Endoscopic surgery demonstrated advantages with shorter anesthesia and surgery times, as well as a reduced postoperative hospital stay. Complete tumor removal was more frequent with endoscopic adenomectomy, while microscopic surgery showed a higher rate of sub-total removal. Both techniques led to a tendency for somatic improvement, with more pronounced visual function improvement in the endoscopic group. Complications, such as liquorrhea and endocrine disorders, were generally low, with endoscopic surgery showing mainly mild complications. Disease remission rates were similar between the groups at various follow-up intervals. In conclusion, while both techniques proved effective in achieving remission, endoscopic surgery exhibited favorable outcomes in terms of efficiency and some aspects of complication profiles.
Zhang et al. [6] 2021 China RCT 46 23 23 Endoscopic transsphenoidal pituitary surgery for the treatment of Cushing’s disease showed comparable efficacy to microscopic transseptal pituitary surgery but with the added benefits of shorter operative time, reduced estimated blood loss, shorter hospital stays, and fewer complications.
Table 1: Summary of the studies included in this systematic review.

RCT: randomized controlled trial; HPA: hypothalamic-pituitary-adrenal; TSH: thyroid-stimulating hormone; HPG: hypothalamic-pituitary-gonadal

Technique Møller et al. [1] Vassilyeva et al. [5] Zhang et al. [6]
Male-to-female ratio (endoscopic) 25:20 17:26 13:10
Male-to-female ratio (microscopic) 107:88 16:24 12:11
Mean age in years (endoscopic) 61 43.26 55.6
Mean age in years (microscopic) 58 44.12 53.2
Functional tumors (endoscopic) 15 All functional All functional
Non-functional tumors (endoscopic) 29 – –
Functional tumors (microscopic) 69 All functional All functional
Non-functional tumors (microscopic) 115 – –
Microadenoma size (mm) (endoscopic) – 4 19
Macroadenoma size (mm) (endoscopic) – 39 4
Microadenoma size (mm) (microscopic) – 3 18
Macroadenoma size (mm) (microscopic) – 37 5
Mean operative time (min) (endoscopic) 86 142 108
Mean operative time (min) (microscopic) 106 176 174
Mean hospital stay (days) (endoscopic) – 5 2.8
Mean hospital stay (days) (microscopic) – 7 5.1
Postoperative complications (endoscopic) 2 15 3
Postoperative complications (microscopic) 39 10 8
Table 2: Summary of demographics, tumor characteristics, and postoperative outcomes of the studies included in this systematic review.

The quality assessment of the selected studies was done using the Newcastle-Ottawa Quality Assessment Scale. All three studies included in this study turned out to be of high quality with a rating of 9/9 stars (Table 3).

Author Selection Comparability Outcome Total stars
Møller et al. [1] ★★★★ ★★ ★★★ ★★★★★★★★★
Vassilyeva et al. [5] ★★★★ ★★ ★★★ ★★★★★★★★★
Zhang et al. [6] ★★★★ ★★ ★★★ ★★★★★★★★★
Table 3: Quality assessment of the included studies using the Newcastle-Ottawa Quality Assessment Scale.

Discussion

This systematic review thoroughly assesses the effectiveness and results of endoscopic transsphenoidal pituitary surgery in comparison to microscopic transsphenoidal surgery, with a specific focus on pituitary adenomas, including Cushing’s disease and acromegaly. The results contribute significant insights into the evolving landscape of pituitary surgery, highlighting the benefits and limitations of both surgical techniques.

The selected studies offer valuable insights into the comparative outcomes. Møller et al.’s observational study in Denmark suggests that endoscopic surgery exhibits superior outcomes with higher gross total resection rates, shorter surgery duration, and fewer complications [1]. Vassilyeva et al.’s RCT in Bulgaria, focusing on acromegaly patients, indicates endoscopic advantages such as shorter anesthesia and surgery times, reduced postoperative stay, and comparable remission rates [5]. Zhang et al.’s RCT in China, specifically for Cushing’s disease, suggests comparable efficacy with added benefits favoring endoscopy [6].

The endoscopic approach has been advocated for its panoramic visualization and superior mobility, which are crucial in resecting tumors while preserving normal structures [7,8]. Studies have shown a higher remission rate in endoscopic procedures for endocrine-active tumors, like growth hormone or adrenocorticotropic hormone (ACTH)-secreting adenomas, compared to the microscopic approach [9,10]. Patient comfort and recovery play a significant role in evaluating surgical methods. The endoscopic technique, by avoiding submucosal excision of nasal tissues, typically results in less postoperative pain and rhinological dysfunction. Studies, including ours, have reported shorter operative times and hospital stays with endoscopic surgery, attributed to fewer intraoperative and postoperative complications and a reduced need for wound management [11-13].

Safety is paramount to any surgical intervention. The endoscopic method has shown a decrease in common complications such as cerebrospinal fluid (CSF) leak, pituitary hormone dysfunction, and diabetes insipidus. Additionally, the endoscopic procedure exhibited fewer complications, which could be attributed to the enhanced visualization allowing for more precise tumor excision and preservation of vital structures [14-16].

In the context of acromegaly patients, the endoscopic technique has demonstrated increased radicality in tumor removal. Our review aligns with these findings, showing a higher rate of total tumor resection in endoscopic patients compared to those undergoing microscopic surgery. This improved outcome is likely due to better illumination and a wider angle of vision provided by endoscopic operations [5,17].

The endoscopic technique has shown a statistically significant improvement in visual function post surgery compared to the microscopic method. However, the frequency of certain postoperative complications, such as intraoperative liquorrhea, was higher in microscopic surgery. These differences underline the importance of the surgical technique in influencing the outcomes and complications of pituitary surgery [5,18].

Despite these findings, it is important to recognize the limitations inherent in these studies. Factors such as tumor size, density, and localization significantly influence surgical outcomes and procedure times. Additionally, the retrospective nature of many studies introduces potential biases, underscoring the need for more prospective, randomized trials for a comprehensive understanding of the long-term outcomes of these techniques.

Conclusions

This systematic review comparing endoscopic and microscopic transsphenoidal pituitary surgery outcomes indicates consistent evidence favoring the endoscopic approach. Notable studies from Denmark, Bulgaria, and China reveal superior results with endoscopic surgery, demonstrating higher resection rates, shorter surgery duration, and fewer complications. Endoscopy’s benefits extend to patient comfort, as evidenced by shorter operative times and hospital stays. Safety considerations also support endoscopy, showing a decrease in common complications such as CSF leaks and hormonal dysfunction. Despite these strengths, the review underscores the need for prospective, randomized trials to address limitations and provide a comprehensive understanding of long-term outcomes.

References

  1. Møller MW, Andersen MS, Glintborg D, Pedersen CB, Halle B, Kristensen BW, Poulsen FR: Endoscopic vs. microscopic transsphenoidal pituitary surgery: a single centre study. Sci Rep. 2020, 10:21942. 10.1038/s41598-020-78823-z
  2. Gao Y, Zhong C, Wang Y, et al.: Endoscopic versus microscopic transsphenoidal pituitary adenoma surgery: a meta-analysis. World J Surg Oncol. 2014, 12:94. 10.1186/1477-7819-12-94
  3. Chen J, Liu H, Man S, et al.: Endoscopic vs. microscopic transsphenoidal surgery for the treatment of pituitary adenoma: a meta-analysis. Front Surg. 2022, 8:806855. 10.3389/fsurg.2021.806855
  4. Guo S, Wang Z, Kang X, Xin W, Li X: A meta-analysis of endoscopic vs. microscopic transsphenoidal surgery for non-functioning and functioning pituitary adenomas: comparisons of efficacy and safety. Front Neurol. 2021, 12:614382. 10.3389/fneur.2021.614382
  5. Vassilyeva N, Mena N, Kirov K, Diatlova E: Comparative effectiveness of endoscopic and microscopic adenoma removal in acromegaly. Front Endocrinol (Lausanne). 2023, 14:1128345. 10.3389/fendo.2023.1128345
  6. Zhang T, Zhang B, Yuan L, Song Y, Wang F: Superiority of endoscopic transsphenoidal pituitary surgery to microscopic transseptal pituitary surgery for treatment of Cushing’s disease. Rev Assoc Med Bras (1992). 2021, 67:1687-91. 10.1590/1806-9282.20210732
  7. Yadav Y, Sachdev S, Parihar V, Namdev H, Bhatele P: Endoscopic endonasal trans-sphenoid surgery of pituitary adenoma. J Neurosci Rural Pract. 2012, 3:328-37. 10.4103/0976-3147.102615
  8. Louis RG, Eisenberg A, Barkhoudarian G, Griffiths C, Kelly DF: Evolution of minimally invasive approaches to the sella and parasellar region. Int Arch Otorhinolaryngol. 2014, 18:S136-48. 10.1055/s-0034-1395265
  9. Broersen LH, Biermasz NR, van Furth WR, de Vries F, Verstegen MJ, Dekkers OM, Pereira AM: Endoscopic vs. microscopic transsphenoidal surgery for Cushing’s disease: a systematic review and meta-analysis. Pituitary. 2018, 21:524-34. 10.1007/s11102-018-0893-3
  10. Torales J, Halperin I, Hanzu F, et al.: Endoscopic endonasal surgery for pituitary tumors. Results in a series of 121 patients operated at the same center and by the same neurosurgeon. Endocrinol Nutr. 2014, 61:410-6. 10.1016/j.endoen.2014.07.002
  11. Zubair A, M Das J: Transsphenoidal hypophysectomy. StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL); 2023.
  12. Pan X, Ma Y, Fang M, Jiang J, Shen J, Zhan R: Improvement in the quality of early postoperative course after endoscopic transsphenoidal pituitary surgery: description of surgical technique and outcome. Front Neurol. 2020, 11:527323. 10.3389/fneur.2020.527323
  13. Aiyer RG, Upreti G: Endoscopic endo-nasal trans-sphenoidal approach for pituitary adenomas: a prospective study. Indian J Otolaryngol Head Neck Surg. 2020, 72:36-43. 10.1007/s12070-019-01725-8
  14. Oertel J, Gaab MR, Linsler S: The endoscopic endonasal transsphenoidal approach to sellar lesions allows a high radicality: the benefit of angled optics. Clin Neurol Neurosurg. 2016, 146:29-34. 10.1016/j.clineuro.2016.04.016
  15. Hanson M, Li H, Geer E, Karimi S, Tabar V, Cohen MA: Perioperative management of endoscopic transsphenoidal pituitary surgery. World J Otorhinolaryngol Head Neck Surg. 2020, 6:84-93. 10.1016/j.wjorl.2020.01.005
  16. Qiao N: Endocrine outcomes of endoscopic versus transcranial resection of craniopharyngiomas: a system review and meta-analysis. Clin Neurol Neurosurg. 2018, 169:107-15. 10.1016/j.clineuro.2018.04.009
  17. Nie D, Fang Q, Wong W, Gui S, Zhao P, Li C, Zhang Y: The effect of endoscopic transsphenoidal somatotroph tumors resection on pituitary hormones: systematic review and meta-analysis. World J Surg Oncol. 2023, 21:71. 10.1186/s12957-023-02958-2
  18. Butenschoen VM, Schwendinger N, von Werder A, Bette S, Wienke M, Meyer B, Gempt J: Visual acuity and its postoperative outcome after transsphenoidal adenoma resection. Neurosurg Rev. 2021, 44:2245-51. 10.1007/s10143-020-01408-x

From https://www.cureus.com/articles/213241-navigating-the-surgical-landscape-a-comprehensive-analysis-of-endoscopic-vs-microscopic-transsphenoidal-pituitary-surgery-outcomes#!/

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

« Previous Page — Next Page »