Growth Hormone Deficiency Following Complicated Mild Traumatic Brain Injury

Posted on April 6, 2026 by MaryO

Traumatic brain injury (“TBI”) is considered the main cause of hypopituitarism in adults and growth hormone (“GH”)deficiency is the most common pituitary deficit associated with TBI.

According to Cedars-Sinai, even after we stop growing, adults need growth hormone. Growth hormone plays a role in healthy muscle, how our bodies collect fat (especially around the stomach area), the ratio of high density to low density lipoproteins in cholesterol levels, and bone density. In addition, growth hormone is needed for normal brain function.

A recent study aimed to assess pituitary function and GH deficiency in adult patients at different time durations following complicated mild TBI, according to the Glasgow Coma Scale (GCS). The study also aimed to evaluate whether mild TBI patients with GH deficiency had developed alterations in the glycolipid profile.

Forty-eight patients (34 men and 14 women) with complicated mild TBI were included in the study. Twenty-three patients were evaluated at 1 year (Group A), and 25 patients at 5 years or longer after the injury (Group B). All patients underwent basal hormonal evaluation for pituitary function. GH deficiency was investigated by the combined test (GH releasing hormone + arginine). The glycolipid profile was also evaluated.

Researchers report that GH deficiency occurred in 8/23 patients (34.7 percent) of Group A and in 12/25 patients (48 percent) of Group B. In addition, two patients, one in each group, showed evidence of central hypothyroidism. Patients examined one-year or several years after complicated mild TBI had a similarly high occurrence of isolated GH deficiency, which was associated with visceral adiposity and metabolic alterations.

These findings suggest that patients with complicated mild TBI should be evaluated for GH deficiency even if several years have passed since the underlying trauma.

From http://www.natlawreview.com/article/growth-hormone-deficiency-following-complicated-mild-traumatic-brain-injury

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Day 3: Cushing’s Awareness Challenge

Posted on April 3, 2026 by MaryO

me-tired

Sleep.  Naps.  Fatigue, Exhaustion.  I still have them all.  I wrote on my bio in 1987 after my pituitary surgery “I am still and always tired and need a nap most days. I do not, however, still need to take whole days off just to sleep.”

That seems to be changing back, at least on the weekends.  A recent weekend, both days, I took 7-hour naps each day and I still woke up tired. That’s awfully close to taking a whole day off to sleep again.

In 2006, I flew to Chicago, IL for a Cushing’s weekend in Rockford.  Someone else drove us to Lake Geneva, Wisconsin for the day.  Too much travel, too Cushie, whatever, I was too tired to stay awake.  I actually had put my head down on the dining room table and fallen asleep but our hostess suggested the sofa instead.  Amazing that I traveled that whole distance – and missed the main event 😦

This sleeping thing really impacts my life.  Between piano lessons, I take a nap.  I sleep as late as possible in the mornings and afternoons are pretty much taken up by naps.  I nod off at night during TV. One time I came home between church services and missed the third service because I fell asleep.

I only TiVo old tv shows that I can watch and fall asleep to since I already know the ending.

Since  mid-February, I have been doing physical therapy twice a week for 2 hours at a time for a knee injury (read more about that in Bees Knees).  I come home from that exhausted – and in more pain than I went.  I know it’s working and my knee is getting better, but it’s such a time and energy sapper.  Neither of which I can really spare.

Maybe now that I’m nearly 10  years out from my kidney cancer (May 9, 2006) I could theoretically go back on Growth Hormone again.  My surgeon says he “thinks” it’s ok.  I’m sort of afraid to ask my endo about it, though.  I want to feel better and get the benefits of the GH again but I don’t want any type of cancer again and I certainly can’t afford to lose another kidney.

I’ll probably just muddle through without it.  I always laugh when I see that commercial online for something called Serovital.  I saw it in Costco the other day and it mentions pituitary right on the package.  I wish I could take the people buying this, sit them down and tell them not to mess with their pituitary glands.  But I won’t.  I’ll take a nap instead because I’m feeling so old and weary today, and yesterday.

And tomorrow…

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Longer-Acting Growth Hormones Promising for Adult GH Deficiency

Posted on April 3, 2026 by MaryO

Two investigational long-acting growth-hormone (GH) replacement products hold potential for less frequent dosing and improved adherence among adult patients with proven growth-hormone deficiency.

Adult growth-hormone deficiency is a rare disorder characterized by the inadequate secretion of the growth hormone from the pituitary gland. It can be hereditary; can be acquired as a result of trauma, infection, radiation therapy, or brain tumor growth; and can even emerge without a diagnosable cause. Currently, it is treated with once-daily injections of subcutaneous growth hormone.

The new results, from a 26-week phase 3 trial of Novo Nordisk’s once-weekly growth-hormone derivative somapacitan and a dose-finding phase 2 safety study of Versartis’s long-acting recombinant growth hormone somavaratan, both in adult patients with growth-hormone deficiency, were presented here at ENDO 2017: The Endocrine Society Annual Meeting.

“Compliance is often a problem with daily growth-hormone injections in children and even with adults,” session moderator Luma Ghalib, MD, assistant professor in the division of endocrinology, diabetes, and metabolism at Ohio State University Wexner Medical Center, Columbus, told Medscape Medical News.

“Patients will often stop taking the daily medications, sometimes because of the cost but also because the daily injections are cumbersome. So the two longer-acting agents that have been studied will be an amazing breakthrough if they get [US FDA]-approved.”

But, she cautioned, longer-term data are needed. “In the long term, we worry about the metabolic effects. We know growth hormone can increase insulin resistance and diabetes, so we have to keep an eye on the peaks.”

And, she added, there could be a small risk for regrowth of the pituitary adenoma that caused the growth-hormone deficiency. “The risk will probably be slim because we haven’t seen regrowth with the daily dosing, but it hasn’t been studied.”

Once-Weekly Somapacitan Found Safe, Well-Tolerated

Gudmundur Johannsson, MD, PhD, professor and chief physician at the University of Gothenburg, Sweden, reported findings from the 26-week multicenter, multinational, randomized open-label parallel-group trial of somapacitan, a reversible albumin-binding human GH derivative intended for once-weekly subcutaneous administration.

A total of 92 adults (aged 18-79 years) who had been previously treated with once-daily growth-hormone replacement for at least 6 months were randomized 2:1 (after a 1-day washout) to either once-weekly somapacitan or once-daily somatropin (Norditropin, Novo Nordisk). Doses of both were titrated for the first 8 weeks to achieve normal insulinlike growth factor (IGF)-1 levels (target 0–2 standard deviation scores) and remained fixed for the subsequent 18 weeks.

Patients were around 50 years of age, 45% female, with body mass index 28 kg/m2. After remaining stable in both arms following titration, mean serum IGF-1 standard-deviation scores at week 25 were 0.22 for somapacitan and 0.35 for somatropin.

The primary outcome, incidence of adverse events including injection-site reactions, was similar between the two groups. Total adverse events occurred in 53 of 61 (86.9%) with somapacitan vs 21 of 31 (67.5%) with somatropin and included nasopharyngitis, headache, fatigue, dizziness, and arthralgia. Serious adverse events occurred in four (6.6%) with somapacitan and two (6.5%) with somatropin.

Of more than 1500 somapacitan injections given, there were two mild, transient, injection-site reactions (hematoma and bruising). No antibodies to somapacitan or GH were detected.

At week 26, patients’ scores on the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) for convenience, effectiveness, and satisfaction all favored somapacitan over somatropin.

Additional phase 3 trials in adults with growth-hormone deficiency are ongoing, as well as a phase 2 trial in children, a Novo Nordisk spokesperson told Medscape Medical News.

Somavaratan Dose-Finding Study Yields 2-Week Response

Kevin CJ Yuen, MD, MBChB, medical director of the Swedish Pituitary Center, Swedish Neuroscience Institute, Seattle, Washington, presented findings from an open-label, multicenter phase 2 study of somavaratan, a novel long-acting form of recombinant human growth hormone. The study aimed to evaluate starting dose, dose titration plan, and safety and to determine the IGF-1 response with 30-day dosing.

Patients were allocated into three starting dose cohorts: 0.6 mg/kg/month for those aged 35 and older, 0.8 mg/kg/month for those younger than 35, and 1.0 mg/kg/month for women on oral estrogen, regardless of age. All received five monthly subcutaneous doses of somavaratan with a target IGF-1 standard deviation score of 0–1.5. In all, 32 of 49 patients completed the study.

The most common adverse events were injection-site reactions (19.4%) and headache (11.1%), mostly mild or moderate. No severe adverse events were deemed related to somavaratan.

Mean IGF-I SDS increased from -1.32 at baseline to +2.31 at 7 days after the first dose, with subjects within each cohort who received higher doses tending to have higher IGF-1 responses. Following the last study dose, IGF-1 standard-deviation scores returned to baseline by day 22.

Thus, Dr Yuen said, twice-monthly administration will be studied going forward. Starting somavaratan dose and administration frequency are being investigated further in the extension study and then will be carried forward in a new phase 3 study.

Speaking about both products, Dr Ghalib told Medscape Medical News: “We are waiting. Less frequent dosing will make our lives and definitely the patients’ lives a lot easier.”

Dr Johannsson is a consultant and/or speaker for Viropharma, Shire, AstraZeneca, Novartis, Otsuka, Novo Nordisk, Merck, Serono, Pfizer, and Ipsen. Dr Yuen is an investigator and/or medical advisory board member for Pfizer, Opko, Novo Nordisk, Versartis, and Sandoz. Dr Ghalib has no relevant financial relationships.  

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ENDO 2017. April 1, 2017; Orlando, Florida. Abstract OR22-1, Abstract OR22-2

From http://www.medscape.com/viewarticle/878088

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Disease Remission and Surgical Outcomes of Endoscopic Transsphenoidal Surgery for Cushing Disease: A Single Center Experience

Posted on February 1, 2026 by MaryO

Introduction

Transsphenoidal surgery is the primary treatment for patients with Cushing disease (CD). This study assessed the surgical and endocrinologic outcomes of patients with CD following endoscopic pituitary surgery using strict biochemical criteria to guide surveillance in patients not achieving early remission.

Methods

The medical records of all patients with CD who underwent endoscopic transsphenoidal surgery at a single institution between 2004 and 2025 were reviewed. Remission was defined as a fasting serum cortisol level <50 nmol/L (1.8 μg/dL) either basal or after 1 mg dexamethasone.

Results

A total of 125 patients were diagnosed with CD and had a primary endoscopic transsphenoidal surgery during the study period (median age 48 years [range: 14–79 years; M:F 93:32). Fifty-seven patients (45.6%) had a microadenoma, 41 (32.8%) had a macroadenoma, and 26 (20.8%) had no demonstrable focal lesion on pituitary magnetic resonance imaging (MRI) (MRI-negative CD). The median length of follow-up was 3.1 years (range: 1 month to 16.7 years). Initial remission rates 3 months after surgery were: 72.0% for patients with MRI-negative CD, 77.2% for microadenomas, and 48.7% for macroadenomas. Age, male sex, MRI-negative, and single operation were predictors of remission. Patients who achieved remission at 3 months were significantly more likely to be in remission at last follow-up after accounting for patient and tumor characteristics. The 5-year recurrence rate following remission was 6.9%.

Conclusion

Endoscopic transsphenoidal surgery is an effective first-line treatment for patients with CD but a significant minority will relapse. Close biochemical surveillance of patients who fail to achieve remission may support the use of early adjuvant radiotherapy.

Key words

Cushing disease
Endoscopic transsphenoidal surgery
Remission

Abbreviations

CD

Cushing’s Disease
CSF

Cerebrospinal fluid
DI

Diabetes insipidus
MRI

Magnetic Resonance Imaging

Introduction

Cushing disease (CD) is a rare endocrine disease caused by the circulation of excess cortisol due to hypersecretion of adrenocorticotrophic hormone from a pituitary adenoma. The annual incidence of CD is estimated to be between 1.2 and 2.4 million cases per year1, 2, 3 although it may be higher in selected patient populations such as those with poorly controlled diabetes and young patients with osteoporosis or hypertension.4 Untreated CD is associated with a very poor prognosis and a significantly reduced 5-year survival mandating prompt and effective treatment.5 Nevertheless, long-term management of patients with CD remains challenging.
In most cases of CD, the pituitary adenoma is benign and excellent remission rates have been reported with surgical treatment.6, 7, 8 Comparable remission rates of around 80% have been reported with both microscopic and endoscopic transsphenoidal pituitary surgery,7,8 however the basal serum cortisol level used to define remission varies significantly in the literature (50–138 nmol/L). Several previous studies have also excluded macroadenomas and invasive tumors from longitudinal analysis. As such, there is a paucity of long-term clinical data for an unselected population undergoing endoscopic transsphenoidal pituitary surgery for CD. Furthermore, there is little evidence concerning the optimal management of patients who fail to enter complete biochemical remission (basal serum cortisol level <50 nmol/L [1.8 μg/dL]) following their initial surgical treatment.
The aim of this study was to assess the treatment pathway and long-term outcomes of consecutive patients treated at a regional treatment center over a 20-year period. All surgical cases were performed using a purely endoscopic approach and we evaluated the impact surgical experience on clinical outcomes. We assessed biochemical remission rates immediately following surgery (within 2 weeks of surgery), at 3 months and at the patient’s most recent follow-up appointment and analyzed predictors of successful remission in our patient group. For those who did not achieve biochemical remission, we detail the treatment course of patients placed under surveillance and those who underwent adjuvant therapy. In doing so, we illustrate a complete picture of the surgical outcomes and subsequent management of an unselected population that may be encountered during the treatment of patients with CD at a dedicated regional center.

Methods

Study Population

We analyzed the medical records of all patients diagnosed with CD who underwent primary surgical treatment at King’s College Hospital, London, between January 2004 and January 2025. Patients were identified from our prospective pituitary multidisciplinary database and cross-referenced with data from the hospital’s clinical coding department and operative database.

Preoperative Investigations

Serum cortisol was measured by chemiluminescent assay (Siemens ADVIA Centaur XP) with a sensitivity of 0.0362 nmol/L. A diagnosis of Cushing syndrome was confirmed by a serum cortisol measurement of >50 nmol/L after administering a 1-mg low-dose dexamethasone suppression test. Additional 24-hour urinary free cortisol measurements (>50 μg/24 hours), late night salivary cortisol measurements (>4 nmol/L), plasma adrenocorticotrophic hormone levels (pg/mL), and 48-hour 2-mg low-dose dexamethasone suppression tests were performed as required. All patients with confirmed Cushing syndrome underwent magnetic resonance imaging (MRI) of the pituitary gland and in equivocal cases patients also underwent corticotrophin-releasing hormone stimulation, high-dose dexamethasone suppression test, and/or inferior petrosal sinus sampling before proceeding to surgery.

Surgical Procedure

Surgery was performed via an endoscopic transnasal transsphenoidal approach in all study patients as described by Jho9 and Cappabianca.10 Image guidance was used in patients with complex or atypical sinus or vascular anatomy, those with very small microadenomas, and in patients undergoing repeat surgery. Complete hypophysectomy (sellar clearance) was performed for patients with MRI-negative Cushing disease. The histological pseudocapsular technique was employed to permit wide exposure of the sella, pituitary, and parasellar region.11,12 If a cerebrospinal fluid (CSF) leak was identified intraoperatively, an autologous adipose tissue graft was positioned in the pituitary fossa and sphenoid sinus and in selected cases a vascularized naso-septal flap was also positioned over the defect.

Postoperative Investigations and Follow-up

Our postoperative protocol included endocrinologic assessment in the early postoperative period, within 72 hours of surgery, and again within the first 2 weeks following surgery. The patient’s initial treatment strategy was defined as any surgical management within 30 days of the patient’s first surgical procedure. If a postoperative CSF leak was suspected, samples of fluid were sent for confirmatory testing of β-2-transferrin. Management of the CSF leak was determined by its severity and included observation alone, insertion of a lumbar drain and a period of bed rest, and surgical repair. Postoperative diabetes insipidus was defined as patients with polyuria requiring ongoing desmopressin therapy 6 months after surgery.
Long-term biochemical assessment of cortisol status was performed on an annual basis, or more frequently depending on the patient’s individual status. A routine postoperative MRI scan was also performed 3 months postoperatively. Remission was defined as an early morning serum cortisol of <50 nmol/L (1.8 μg/dL) requiring substitutive therapy at 3 months postoperatively. Patients who failed to enter remission were considered for further pituitary surgery, radiotherapy, medical treatment, and/or bilateral adrenalectomy. Recurrence was defined as the re-emergence of clinical features of cortisol excess supported by biochemical evidence of cortisol excess as described above. Persistent disease was defined as such was defined as a postoperative basal cortisol(s) > 50 nmol/.

Data Collection

We reviewed the biochemical, radiologic, medical, and surgical records of all study patients. The following data were collected: demographic features, preoperative endocrinologic measurements, radiologic MRI features of the tumor (including tumor visibility on MRI and size), procedural complications (including CSF leak, meningitis, diabetes insipidus [DI], hematoma, visual complications, or new cranial nerve deficits), postoperative endocrinologic assessments, and any further treatments performed.

Statistical Analysis

Categorical data are summarized using frequencies and percentages and continuous data are described using means, standard deviations, medians, and ranges. Associations between categorical variables were assessed using Fisher’s Exact test. Multivariable logistic regression models were performed in which remission statuses at (i) 3 months and (ii) last follow-up were used as outcome variables. The list of predictors of each outcome included patient characteristics (sex, age), tumor category, number of operations performed, and the presence of postoperational complications, which were decided a priori. Subgroup analyses were also performed based on tumor category—microadenomas, macroadenomas, and MRI-negative CD.
Data were collated in Microsoft Excel (Microsoft, Redmond, WA). All statistical analyses were performed using R software version 4.2.1 (R Foundation for Statistical Computing, 2022; r-project.org). P-values less than 0.05 were considered statistically significant.

Ethics Statement

This study was approved by King’s College Hospital’s research committee without the need for informed consent. The study was conducted in accordance with the ethics standards of the institution’s research committee and with the 1964 Helsinki declaration and its later amendments.

Results

Baseline Characteristics

A total of 125 patients including 93 (74.4%) female patients and 32 (25.6%) male patients were diagnosed with CD and had primary endoscopic transsphenoidal surgery during the study period. The median age was 48 years (range: 14–79 years). Fifty-seven patients (45.6%) had a microadenoma, 41 (32.8%) had a macroadenoma, and 26 (20.8%) had no demonstrable focal lesion on pituitary MRI (MRI-negative CD). The median length of follow-up was 3.1 years (range: 1 month to 16.7 years). Of the 125 patients included in our study, 88 patients (70.4%) had a single operation during their initial treatment strategy. Thirty-seven patients (29.6%) had more than 1 operation; 4 patients (3.2%) had 3 operations during the study period. A summary of the baseline characteristics of our patients can be found in Table 1.

Table 1. Baseline Characteristics of the Study Population

Number of Patients 125
Patient variables
 Age Median 48 (range: 14–79) years
 Male 32 (25.6%)
Pituitary characteristics
 Microadenoma 57 (45.6%)
 Macroadenoma 41 (32.8%)
 No focal lesion on pituitary MRI (MRI-negative Cushing’ disease) 26 (20.8%)
Operative variables
 Single operation 88 (70.4%)
 More than 1 operation 33 (26.4%)
 3 operations 4 (3.2%)

Perioperative Complications

Forty patients (32.0%) had a complication following their surgery (Table 2). The overall complication rate for patients undergoing a single procedure was 23.9% (21 of 88) and was significantly lower than the complication rate in patients who had multiple operations: 51.3% (19 of 37) (P = 0.002). The complication rates for different tumor types were not significantly different: microadenoma 33.3% (19 of 57), macroadenoma 36.6% (15 of 41), MRI-negative CD 23.1% (6 of 26) (P = 0.274). There was a significant difference between complications in the second period; Period 1: 8.7% (2 of 23) and Period 2: 37.3% (38 of 102) (P = 0.008).

Table 2. Procedural Complications Encountered in Our Series

Complication N (%)
Any complication 40 (32.0%)
Persistent diabetes insipidus 18 (14.4%)
Cerebrospinal fluid leak 17 (13.6%)
Meningitis 2 (1.6%)
Ventriculitis 1 (0.8%)
Bleeding/haematoma 4 (3.2%)
Visual deterioration 2 (1.6%)
Death 3 (2.4%)
Eighteen patients (14.4%) developed persistent DI following surgery (requiring treatment for more than 6 months which we considered as a complication). Separately, in 12 patients (9.6%) the DI was transient and resolved spontaneously within 6 months of surgery, and 34 patients (27.2%) recovered from transient DI before discharge.
A confirmed postoperative CSF leak occurred in 17 patients (13.6%) and was significantly higher in patients who had multiple procedures; the CSF leak rate was 16.2% (6 of 37) in patients who had multiple procedures versus 12.5% (11 of 88) in those who only had a single procedure (P = 0.004). The type of tumor did not affect the CSF leak rate (P = 0.737). In 3 (2.4%) patients, the leak settled with observation alone. Three (2.4%) patients were managed with only a lumbar drain and 11 (8.8%) patients underwent surgical repair either as an executive decision or after failed lumbar drain. There were 2 (1.6%) cases with new cranial nerve deficits following surgery presenting with visual deterioration and a partial sixth nerve palsy. Two patients developed meningitis (1.6%), 1 (0.8%) developed ventriculitis. Four patients (3.2%) developed postoperative bleeding or hematoma requiring surgical attention.
Three (2.4%) patients died in the immediate perioperative period. One (0.8%) patient developed acute respiratory failure and suffered a cardiac arrest. Significant intraoperative bleeding was encountered in the other 2 cases (1.6%); 1 (0.8%) subsequently died of acute cardiorespiratory instability and the other (0.8%) died because of multiorgan failure following a prolonged stay on the intensive care unit.

Disease Remission

The overall remission rate 2 weeks following surgery was 59.0% (72 of 122), increasing to 60.7% (74 of 122) at 3 months. The remission rate 3 months following surgery was 72.0% (18 of 25) for patients with MRI-negative CD, 77.2% (44 of 57) for microadenomas, and 48.7% (19/39) for macroadenomas. Following adjuvant treatment and further surgery, the overall remission rate at last follow up was 68.0% (85 of 125).
Age, patient sex, tumor category and the number of operations were significant predictors of remission at three months. Age (adjusted odds ratio [aOR]: 1.04, 95% CI: 1.01–1.07, P = 0.009), male sex (aOR: 4.15, 95% CI: 1.64–10.53, P = 0.003), MRI-negative CD (aOR: 2.25, 95% CI: 1.24–4.07, P = 0.008), and single operation (aOR: 3.87, 95% CI: 1.56–9.61, P = 0.004), were predictors of remission at 3 months (Table 3).

Table 3. Multivariable Logistic Regression for Predictors of Remission at Last Follow-up

Outcome Predictor Multivariable Analysis
Adjusted OR (95% CI) P Value
Remission at 3 months Age 1.04 (95%CI: 1.01–1.07) 0.009
Sex† 3.31 (95%CI: 1.31–8.40) 0.011
MRI-negative Cushing disease‡ 1.88 (95%CI: 1.06–3.35) 0.031
Single operation§ 3.87 (95%CI: 1.56–9.61) 0.004
Remission at last follow-up Age 1.00 (95%CI: 0.97–1.04) 0.904
Sex† 2.92 (95%CI: 0.89–9.62) 0.003
MRI-negative Cushing disease‡ 1.84 (95%CI: 0.89–3.79) 0.008
Single operation§ 1.24 (95%CI: 0.36–4.24) 0.730
Remission at 3 months∗ 27.0 (95%CI: 8.47–83.33) <0.001
∗
No remission is used as the reference group.
†
Female is used as the reference group.
‡
Microadenoma is used as the reference group.
§
Multiple operation is used as the reference group.
Additionally, patients were more likely to be in remission at last follow-up if they had achieved remission at 3 months, compared with those who had not (aOR: 31.25, 95% CI: 11.2–90.9, P < 0.001). On multivariable analysis, this remained significant (aOR: 27.0, 95% CI: 8.47–83.33, P < 0.001).
Of the 72 patients who entered remission following surgery, 5 patients (6.9%) had relapsed at their last follow-up. Further intervention was performed/planned in all patients exhibiting recurrence, including repeat surgery and radiotherapy. Four of the 5 recurrences (80.0%) happened within the first 5 years.

Growth Hormone Replacement Therapy

In total, 48.0% (60 of 125) and 40.8% (51 of 125) patients required growth hormone replacement therapy at three months and at last endocrine follow up. Nine (15.0%) patients who initially needed growth hormone replacement, no longer required it at last endocrine follow-up.

Secondary Intervention

Patients with persistent disease are very likely to require a secondary intervention within a short time after initial surgery. The rate of secondary endoscopic transsphenoidal surgery was more common in patients with persistent disease (22 of 53, 41.5%) than those in initial remission (15 of 72, 20.8%) (aOR: 3.52, 95% CI: 1.48–8.38, P = 0.004). The ongoing management of patients with active disease with was tailored to the patient and included medical therapy with metyrapone, chemotherapy (temozolamide), bilateral adrenalectomy, and radiotherapy; either alone or in combination.

DISCUSSION

In one of the largest modern series in the literature, we reviewed the treatment pathway and long-term outcomes of consecutive patients treated for CD at a single regional treatment center over a 20-year period. Several previous studies have examined the surgical outcomes of patients undergoing microscopic surgery and a recent meta-analysis compared the early clinical outcomes of patients undergoing endoscopic surgery.7 However, there remains little evidence concerning the optimal long-term management of CD patients who do not immediately enter remission following surgery. Given the potential complications of CD and the challenges in managing recurrent disease, our center considers treating any patient with a cortisol of >50 nmol/L (1.8 μg/dL).

Remission

A postoperative cortisol of <50nmol/L is a good predictor of remission but not a guarantee and patients should be advised accordingly. The most conclusive finding of our study was that patients who achieved remission at 3 months were 3 times as likely to still be in remission at their last follow-up, having accounted patient and tumor characteristics. The overall initial 3-month remission rate for patients in our series was 60.7% and is comparable to other studies that have used a similarly low early morning serum cortisol level of <50 nmol/L (1.8 μg/dL) to define remission.13, 14, 15 Despite this, patients achieving early remission remain at risk of relapse with a 5-year recurrence rate of 6.9%. In addition, those with persistent disease are very likely to require a secondary intervention within a short time after initial surgery.
Using an early morning serum cortisol level of 50 nmol/L(1.8 μg/dL). to define remission enabled us to label a subgroup of patients with moderately lowered cortisol levels (50–150 nmol/L [1.8–5.4 μg/dL]) that were placed under close surveillance. It has been demonstrated that patients with postoperative cortisol of 55–137nmol/L (equivalent to 2–5.4 μg/dL) have a higher risk of late recurrence.12 We considered patients with a cortisol of greater than 150 nmol/L to be candidates for early secondary intervention without delay.
Radiotherapy, delivered by conventional external beam radiotherapy or via stereotactic radiosurgery, is typically used as a second-line treatment in CD patients after failure of initial or repeat pituitary surgery.8 In other centers, patients with similar moderately lowered cortisol level would have been labeled as being in remission and would not have been offered adjuvant radiotherapy. However, by closely observing the biochemical trends of these patients in the months following surgery we were able to offer further intervention at an earlier stage, thus avoiding the potentially harmful sequelae of untreated CD. In future work, it would be helpful to compare the long-term clinical outcomes of patients with moderately lowered serum cortisol levels who received early adjuvant therapy with patients who had similar biochemical results but did not receive adjuvant treatment.
Finally, we observed a statistically and clinically significant association between patient sex and tumor type on remission—a finding not previously reported. The underlying reasons for this result are unclear but further work should examine if, and how, the biology and histologic characteristics of adenomas changes with sex and age.9,16, 17, 18

Complications

Previous studies elected not to report the overall complication rate, hence at first sight, our overall complication rate of 32.0% may appear high even though the rate of individual specific complications are similar to those previously reported (Table 2).7, 8,15, 19 Postoperative complications were significantly higher in patients who underwent more procedures.
The overall perioperative mortality rate of 2.4% (n = 3) observed in this series is comparable with other published studies.7,8 One patient developed acute respiratory failure in the early postoperative period and died on day 3 following surgery. In the other cases significant intracavernous and intracranial bleeding was encountered and controlled; one patient subsequently developed acute cardiorespiratory instability and died on day 5; the other developed multiorgan failure and died following a prolonged stay on the intensive care unit. Following an internal review of these deaths we lowered our threshold for giving preoperative medical treatment such as ketoconazole or metyrapone in potential high-risk cases, particularly in those patients presenting with more severe clinical features at diagnosis. Preoperative medical treatment improves the quality of the tissues and increases the patient’s physiological reserve in preparation for surgery.14 In the ERCUSYN study, patients with severe clinical features who were treated preoperatively experienced comparable outcomes to those patients with milder features who were not treated with medical treatment before surgery. This justifies our approach to treat the more severe cases medically in the first instance. Nevertheless, preoperative medical treatment may confound the interpretation of early postoperative serum cortisol levels so close monitoring of these patients is required in the first few months following surgery.14 Since this change in practice, no deaths have occurred in patients undergoing surgery for CD at our unit.

Limitations

CD is a rare disease, and this study offers one of the larger modern series with practical illustrations of multidisciplinary practice at a tertiary pituitary center. Despite its size, this study did confirm that patients who achieved remission at 3 months were more likely to be in remission at the last follow-up. Patient and tumor characteristics were also important factors to consider. This study is nonetheless limited by lack of data on residual tumors found in postoperative MRIs. As such, we were unable to investigate further on the subgroup of patients without biochemical remission who had residual tumors. Furthermore, we do not fully know the proportion of MRI-negative patients who harbored an adenoma on histopathology, which may have skewed our findings. Further multi-institutional research is required to determine if patients with moderately lowered serum cortisol levels who receive early adjuvant radiotherapy have improved long-term clinical outcomes.

Conclusions

Despite good initial remission rates following endoscopic transsphenoidal surgery, this study demonstrated significant recurrence of CD. Nevertheless, patients who achieved initial biochemical remission (serum cortisol <50 nmol/L [1.8 μg/dL]) at 3 months were significantly more likely to achieve long-term biochemical remission. Selected patients with moderately lowered serum cortisol (serum cortisol 50–150 nmol/L [1.8–5.4 μg/dL]) responded well to early adjuvant radiotherapy but further research is required to determine their long-term clinical outcomes.

CRediT authorship contribution statement

Jonathan Shapey: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. Keng Siang Lee: Data curation, Formal analysis, Visualization, Writing – original draft. Vanitha Karunakaran: Formal analysis, Visualization, Writing – review & editing. Mohamed Okasha: Data curation, Writing – review & editing. Proma Dey: Data curation. Sabina Pate: Data curation. Mariusz T. Grzeda: Formal analysis, Writing – review & editing. Jackie Gilbert: Data curation, Writing – review & editing. Paul V. Carroll: Data curation, Writing – review & editing. Benjamin Whitelaw: Data curation, Writing – review & editing. Konstantinos Barkas: Data

curation, Writing – review & editing. Eleni Maratos: Data curation, Writing – review & editing. Sinan Barazi: Data curation, Writing – review & editing. Simon Aylwin: Data curation, Methodology, Supervision, Writing – original draft, Writing – review & editing. Nick WM. Thomas: Conceptualization, Data curation, Methodology, Supervision, Writing – review & editing.

References

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BIPSS Diagnostic Method May Cause False Positive in Some Cases of Cyclic Cushing’s Syndrome

Posted on January 31, 2026 by MaryO

A diagnostic technique called bilateral inferior petrosal sinus sampling (BIPSS), which measures the levels of the adrenocorticotropic hormone (ACTH) produced by the pituitary gland, should only be used to diagnose cyclic Cushing’s syndrome patients during periods of cortisol excess, a case report shows.

When it is used during a spontaneous remission period of cycling Cushing’s syndrome, this kind of sampling can lead to false results, the researchers found.

The study, “A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome,” was published in BMC Endocrine Disorders.

Cushing’s syndrome is caused by abnormally high levels of the hormone cortisol. This is most often the result of a tumor on the pituitary gland that produces too much ACTH, which tells the adrenal glands to increase cortisol secretion.

However, the disease may also occur due to adrenal tumors or tumors elsewhere in the body that also produce excess ACTH — referred to as ectopic Cushing’s syndrome.

Because treatment strategies differ, doctors need to determine the root cause of the condition before deciding which treatment to choose.

BIPSS can be useful in this regard. It is considered a gold standard diagnostic tool to determine whether ACTH is being produced and released by the pituitary gland or by an ectopic tumor.

However, in people with cycling Cushing’s syndrome, this technique might not be foolproof.

Researchers reported the case of a 43-year-old woman who had rapidly cycling Cushing’s syndrome, meaning she had periods of excess cortisol with Cushing’s syndrome symptoms — low potassium, high blood pressure, and weight gain — followed by normal cortisol levels where symptoms resolved spontaneously.

In general, the length of each period can vary anywhere from a few hours to several months; in the case of this woman, they alternated relatively rapidly — over the course of weeks.

After conducting a series of blood tests and physical exams, researchers suspected of Cushing’s syndrome caused by an ACTH-producing tumor.

The patient eventually was diagnosed with ectopic Cushing’s disease, but a BIPSS sampling performed during a spontaneous remission period led to an initial false diagnosis of pituitary Cushing’s. As a result, the woman underwent an unnecessary exploratory pituitary surgery that revealed no tumor on the pituitary.

Additional imaging studies then identified a few metastatic lesions, some of which were removed surgically, as the likely source of ACTH. However, the primary tumor still hasn’t been definitively identified. At the time of publication, the patient was still being treated for Cushing’s-related symptoms and receiving chemotherapy.

There is still a question of why the initial BIPSS result was a false positive. The researchers think that the likely explanation is that BIPSS was performed during an “off phase,” when cortisol levels were comparatively low. In fact, a later BIPSS performed during a period of high cortisol levels showed no evidence of ACTH excess in the pituitary.

This case “demonstrates the importance of performing diagnostic tests only during the phases of active cortisol secretion, as soon as first symptoms appear,” the researchers concluded.

From https://cushingsdiseasenews.com/2020/01/02/cushings-syndrome-case-study-shows-drawback-in-bipss-method/

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