Helping others learn more about Cushing’s/Acromegaly

Posted on November 28, 2025 by MaryO

I found this article especially interesting.  This question was asked of a group of endos at an NIH conference a few years ago – if you saw someone on the street who looked like they had symptoms of fill-in-the disease, would you suggest that they see a doctor.  The general answer was no.  No surprise there.

Patients, if you see someone who looks like s/he has Cushing’s, give them a discrete card.

Spread The Word! Cushing’s Pocket Reference

Robin Writes:

This has been a concern of mine for some time. Your post spurred me on to do something I’ve been meaning to do. I’ve designed something you can print that will fit on the business cards you can buy just about anywhere (Wal-mart included). You can also print on stiff paper and cut with a paper cutter or scissors. I’ve done a front and a back.

Cushing's Pocket Reference

Here are the links:

• Front: This card is being presented by a person who cares.
• Back (The same for everyone)

This Topic on the Message Boards

~~~~~~~~~~~~~~~~~~

And now, the article from http://www.guardian.co.uk/lifeandstyle/2009/nov/03/doctor-diagnosis-stranger:

Are doctors ever really off duty?

Which potentially serious symptoms would prompt them to stop and advise a stranger on a bus?

By Lucy Atkins

Bus

Passengers on a London bus. Photograph: David Levene

A Spanish woman of 55, Montse Ventura, recently met the woman she refers to as her “guardian angel” on a bus in Barcelona. The stranger – an endocrinologist – urged Ventura to have tests for acromegaly, a rare disorder involving an excesss of growth hormone, caused by a pituitary gland tumour. How had the doctor made this unsolicited diagnosis on public transport? Apparently the unusual, spade-like shape of Ventura’s hands was a dead giveaway.

But how many off-duty doctors would feel compelled to alert strangers to symptoms they spot? “If I was sitting next to someone on a bus with a melanoma, I’d say something or I wouldn’t sleep at night,” says GP Mary McCullins. “We all have a different threshold for interfering and you don’t want to terrify people, but this is the one thing I’d urge a total stranger to see a doctor about.” So what other symptoms might prompt a doctor to approach someone on the street?

Moon face

Cushing’s syndrome is another rare hormone disorder which can be caused by a non-cancerous tumour in the pituitary gland. “A puffy, rounded ‘moon face’ is one of the classic signs of Cushing’s,” says Dr Steve Field, chair of the Royal College of GPs. “In a social situation, I wouldn’t just say, ‘You’re dangerously ill’ but I’d try to elicit information and encourage them to see a doctor.”

Different-sized pupils

When one pupil is smaller than the other, perhaps with a drooping eyelid, it could be Horner’s syndrome, a condition caused when a lung tumour begins eating into the nerves in the neck. This can be the first obvious sign of the cancer. “I’d encourage someone to get this checked out,” says Dr Simon Smith, consultant in emergency medicine at the Oxford Radcliffe Hospitals Trust. “People often have an inkling that something’s wrong, and you might spur them to get help sooner.”

Clubbing fingers

Some people are born with club-shaped fingers, but if, over time, they become “drumstick-like”, this could signify serious problems such as lung tumours, chronic lung infections or congenital heart disease. “Because it happens gradually, some people disregard clubbing,” says Smith. “But I’d say something because it can be an important symptom in many serious illnesses.”

Lumpy eyelids

Whitish yellowy lumps around the eyelids can be a sign of high cholesterol, a major factor in heart disease. Sometimes you also get a yellow circle around the iris. “I would suggest they got a cholesterol test with these symptoms,” says Smith. “They can do something about it that could save their life.”

Suntan in unlikely places

A person with Addison’s disease, a rare but chronic condition brought about by the failure of the adrenal glands, may develop what looks like a deep tan, even in non sun-exposed areas such as the palms. Other symptoms (tiredness, dizziness) can be non-specific so the condition is often advanced by the time it is diagnosed. Addison’s is treatable with lifelong steroid replacement therapy. “If someone was saying they hadn’t been in the sun but had developed a tan, alarm bells would ring and I’d probably ask how they were feeling,” says McCullins.

Trench mouth

Putrid smelling breath – even if the teeth look perfect – can be a sign of acute necrotising periodontitis. “I’d be able to tell when someone walks through the door,” says dentist Laurie Powell. “But people become accustomed to it and don’t notice.” Untreated, the condition damages the bones and connective tissue in the jaw. It can also be a sign of other diseases such as diabetes or Aids.

Filed under: adrenal, Cushing's, General Health, pituitary, Rare Diseases | Tagged: , , , , , | 2 Comments »

A Preliminary Model to Tailor Osilodrostat In Patients With Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s syndrome

Posted on October 10, 2025 by MaryO

Abstract

Over the past 10 years, osilodrostat has become one of the most commonly used steroidogenesis inhibitors in patients with Cushing’s syndrome. The starting dose is usually determined based on the product characteristics, the prescriber’s experience, and cortisol levels. However, no study has attempted to determine whether there was a dose–response relationship between osilodrostat and cortisol reduction. In this study, we developed a preliminary kinetic–pharmacodynamic model to tailor osilodrostat in patients with Adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. We first analyzed the decrease in cortisol 48 hours after initiation or dose change of osilodrostat in 18 patients. Simulations were then performed for different doses of osilodrostat to evaluate the variation in cortisol concentrations. Our results report the first dose–response relationship between osilodrostat dose and cortisol levels, which should be helpful in identifying the optimal dosing regimen in patients with Cushing’s syndrome and in individualizing treatment to approximate a nychthemeral rhythm.

osilodrostat, Cushing’s syndrome, Cushing’s disease, cortisol, adrenal insufficiency
Issue Section:

Brief Report

Significance

The current preliminary study is a first step in trying to better understand the effect of osilodrostat on cortisol, which should help determine the optimal dose for each patient.

Introduction

Cushing’s syndrome is a rare condition in which increased cortisol levels lead to a wide range of comorbidities and increased mortality. Surgery is usually regarded as the first-line and most effective treatment.1 In some cases, cortisol-lowering drugs are necessary, mainly after failed surgery.2,3 Among several steroidogenesis inhibitors such as ketoconazole and metyrapone,4,5 osilodrostat, which acts through inhibition of 11β-hydroxylase, is now being considered an effective drug in controlling cortisol hypersecretion. Initially designed as a CYP11B2 inhibitor, the study by Ménard et al.6 involving both animal models and healthy human subjects showed that osilodrostat reduced cortisol levels from a dose of 1 mg/day, while lower doses exerted an anti-aldosterone effect. Since then, several clinical trials and retrospective studies emphasized its efficacy in all etiologies of Cushing’s syndrome.7-9 While the usual recommended starting dose is 2 mg twice a day, precise studies on the short-term effect of osilodrostat on plasma cortisol are lacking. These data could, however, be of interest to tailor the treatment. Moreover, baseline urinary free cortisol (UFC) level is not able to predict response to osilodrostat.10 Taking advantage of serial cortisol measurements performed in inpatient clinics in our center at the time osilodrostat became available, we developed a pharmacokinetic (PK)/pharmacodynamic model of plasma cortisol variation as a function of osilodrostat dose in patients with Adrenocorticotropin-hormone (ACTH)-dependent Cushing’s syndrome.

Patients and methods

Clinical data and hormonal measurements

We retrospectively included patients with ACTH-dependent Cushing’s syndrome, who had serial measurements of plasma cortisol (every 4 hours for 24 hours) before and after the first osilodrostat dose between 2019 and 2024. These measurements were part of our standard of care approach when osilodrostat became available in our tertiary expert center as a thorough evaluation of the efficacy and tolerance of a new drug. The initial dose ranged from 2 to 15 mg/day, depending on the severity of hypercortisolism. Subsequently, osilodrostat dose was gradually adjusted based on the successive cortisol measurements described above. Sex, age at diagnosis, and etiologies were recorded, as well as plasma cortisol measurements 48 hours after the initiation or any change in the osilodrostat dose and time elapsed since change of dose and last administration were recorded. All plasma cortisol measurements were performed with the same Elecsys II Cortisol, Cobas (Roche Diagnostics) assay in the hormonal laboratory of our center; cross-reactivity with 11-deoxycortisol is 4.9%. According to our institutional policy, this retrospective study did not require specific signed informed consent from patients as the data collected were anonymized. It was thus approved by the Ethics Committee of Assistance Publique—Hopitaux de Marseille (RGPD PADS reference RUXXX2). The current study complies with the Declaration of Helsinki.

Pharmacokinetics and statistical analysis

The pharmacodynamic parameters of osilodrostat on cortisol concentrations were analyzed using a kinetic–pharmacodynamic (PD) model in the software Nonlinear Mixed Effects Modeling version 7.4 (NONMEM Icon Development Solutions, Ellicott City, MD, United States). PK analysis from a previously published study6 was used to predict plasma concentration in our patients. The PK parameters were described in the article, and mean concentration values were obtained by digitizing the graph of osilodrostat vs time using the software WebPlotDigitizer version 4.2.11 With these data, a one-compartment population PK model was used to predict osilodrostat concentrations for different dosing regimens. Direct and indirect relationship between osilodrostat-predicted concentration and variation of cortisol concentrations were evaluated to consider a delay. The variation of cortisol concentrations was calculated with reference to a session without treatment. Several functions were tested to describe the relationship such as linear and sigmoidal. Model selection and evaluation were done by the likelihood ratio test (objective function), goodness-of-fit plots (observed vs predicted variation of cortisol concentrations, observed vs individual predictions, normalized prediction distribution errors vs time and variation of cortisol predictions), bootstrap, and visual predictive checks. Graphical analysis was performed with the R software version 4.4.012 using the ggplot2 package.13 Simulations were performed for different doses of osilodrostat to evaluate the variation on cortisol concentrations using the package rxode2.14

Results

Of the patients who were prescribed osilodrostat at least once between 2019 and 2024, 18 were presenting ACTH-dependent Cushing’s syndrome, 12 women (66.6%) and 6 men (33.3%). Mean age was 53.2 ± 15 years. The cause of Cushing’s syndrome was Cushing’s disease in 16 patients (88.9%), ectopic ACTH secretion in 1 patient (5.6%), and ACTH-dependent hypercortisolism of uncertain diagnosis in 1 patient (5.6%). Clinical characteristics are presented in Table 1. It should be noted that none of the patients included were Asian.

 

 

Table 1.

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Clinical characteristics of patients with all included patients and differentiated according to gender.

All patientsa Women Men
Age at diagnosis 53.2 ± 15 54 ± 17.2 51.5 ± 10.5
Weight 81.7 ± 13.7 79.5 ± 12.7 86.2 ± 15.6
% of CD 88.9 83.3 100
ULN of 24 hour UFC 4.4 ± 8.3 5.5 ± 10.3 2.5 ± 1.8
Osilodrostat starting dose 3.3 ± 2.2 3.7 ± 2.4 2.5 ± 1.4
Cortisol before osilodrostat intake 422.9 ± 159.2 414.7 ± 176.6 439.4 ± 130.7
Cortisol 4 hour after osilodrostat 404 ± 165.6 408.2 ± 200.1 395.5 ± 70.8

 

Abbreviations: CD, Cushing’s disease; ULN, upper limit range; UFC, urinary free cortisol.

aOf note, none of the included patients were Asian.

In their article, Ménard et al.6 showed that the dose–exposure relationship was not strictly proportional. A one-compartment model was enhanced by increasing the relative bioavailability with the dose and was estimated that the dose resulting in a 50% increase in bioavailability was 1.06 mg. The PK parameters derived from Ménard et al.6 were fixed and used to predict osilodrostat concentration in our patients. A direct relationship between the predicted osilodrostat concentrations and variation of cortisol concentrations (%) gave a better fit than an indirect model. The drug effect was modeled with the following sigmoidal function (Eq. 1);

(1)

where Imax is the maximal inhibition and IC50 is the apparent half-maximal inhibitory concentration.

The estimated PD parameters were IC50 and Imax. Their values as well as the relative standard errors (RSE%) and the corresponding bootstrap IC50 are shown in Table 2. Final parameters were used to simulate n = 500 profiles following a single dose of osilodrostat.

 

 

 

Table 2.

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Pharmacodynamic parameters of osilodrostat’s effects on the variation of cortisol concentrations.

Parameters Unit Estimation RSE% Bootstrap
0.025 0.975
KA (fixed)a 1/hour 4.03 — — —
CL/F (fixed)a L/hour 18.3 — — —
V/F (fixed)a L 125 — —
Imax % 44.5 18.7 12.51 90.9
IC50 mg/L 0.011 37.4 0.0001 0.10
Interindividual variability (ω)
 Imax 0.40 30.9 0.003 1.86
 IC50 3.78 41.0 0.003 9.22
Residual unexplained variability (σ)
 Additive % 23.8 12.2 18.2 29.9

 

Abbreviations: CL/F, apparent clearance; IC50, osilodrostat concentration associated with half the maximal inhibition of the cortisol variation; Imax, maximum inhibitory effect of osilodrostat on the variation of cortisol; KA, first-order absorption rate constant; RSE, relative standard error; V/F, apparent volume of distribution.

 

aAdapted from Ménard et al.6

The effects on plasma cortisol variation are depicted in Figure 1. Cortisol concentration declines during the first hour after taking osilodrostat, from 24% for a 1 mg dose to over 42% for a 20 mg dose. Thereafter, from the first hour onward, cortisol increases progressively, with loss of treatment efficacy occurring around the 10th-15th hour for 1 and 2 mg, while for doses above 5 mg, a moderate effect persists over the following hours. Figure 2 shows the variation in cortisol concentration for a 2 mg dose, with median decrease in cortisol variation of 31%, ranging from 0% to 67.5%, with, as mentioned above, a maximum effect 1 hour after osilodrostat intake, and a progressive increase in cortisol levels, mainly during the 12 hours following treatment. The same analysis for 10 mg revealed a median reduction in cortisol of 38%, ranging from 5% to 80%. Figure 3 describes the relationship between osilodrostat concentration and cortisol variation, showing that the maximum effect corresponds to the maximum concentration and that a decrease in osilodrostat concentration results in an increase in cortisol level.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

Figure 1.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

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Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

Figure 2.

Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

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Relation between osilodrostat concentration and cortisol variation.

Figure 3.

Relation between osilodrostat concentration and cortisol variation.

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Discussion

To the best of our knowledge, this is the first study that attempts to define a dose/efficacy relationship between osilodrostat dose and the variation of plasma cortisol. First, our results suggest that the effect of osilodrostat appears immediately after the peak of concentration, 1 hour after treatment intake, which highlights the parallel evolution of osilodrostat and cortisol concentrations. This is unusual, as typically effect peak takes few hours, following concentration peak.15 The relationship between osilodrostat concentration and the effect on cortisol is not linear but sigmoidal with a rapid increase in concentrations producing a rapid significant effect, leading to a maximal effect. Because elimination is a slower process than absorption, the effect’s decline will also be slower: this means that efficiency remains stable during the first 5 hours, with a further progressive increase of cortisol and a loss of efficiency around 10-15 hours after intake. This confirms the need for two intakes per day, with one early in the morning and the other 12 hours later in the evening. In addition, even if our simulation suggests a wide interindividual variability, we were able to determine the impact of different doses of osilodrostat on the percent decrease in plasma cortisol levels. For instance, 20 mg osilodrostat leads to an estimated 42% decrease in cortisol concentration. Interestingly, Ferrari et al.16 recently showed that patients controlled with two doses of osilodrostat for at least 1 month had the same efficacy with a single intake (combing both doses) at 4 or 7 Pm. This is quite surprising and will need to be evaluated in future studies: our preliminary model could give more precise information on this point.

Cushing’s syndrome is also characterized by a loss of circadian rhythm leading to increased comorbidities such as diabetes, hypertension, and cardiovascular disease.17,18 This is why 24 hour UFC can only be considered an imperfect marker of glucocorticoid overexposure even though it is an easy-to-use marker, as exemplified by its use in all the clinical trials performed on cortisol-lowering drugs.7,8,10,19 Predicting the efficacy of osilodrostat on plasma cortisol might be helpful to tailor the treatment as a titrating approach. Of note, some studies suggested that there might be an inpatient variability of cortisol secretion in Cushing’s syndrome,20 and this might account for a bias in our results. However, none of our patients had cyclical Cushing’s syndrome. Moreover, 12 patients in our cohort had at least two cortisol cycles (every 4 hours during the day) before starting treatment. A comparison of these two cycles using Student’s t-test showed no significant difference (P = .7), indicating no obvious spontaneous variability. Our preliminary report gives interesting insights into the maximal efficacy expected for a single dose of osilodrostat, thus defining the initial dosage needed to rapidly control hypercortisolism, as opposed to the dose currently recommended by the manufacturer (2 mg twice daily). Thus, our results could help define an optimal dose in the morning, but also in the evening, with the aim of re-establishing a circadian profile. This will, however, have to be confirmed on an interventional study focusing on comorbidities, quality of life and their potential improvements while using this PK model.

The main limitation of this proof-of-concept study is the large CI. This may be due to the relatively low number of patients and the fact that cortisol was measured every 4 hours instead of every hour, but also to the large variability in efficacy between subjects. Due to the number of patients included in the analysis, it was not possible to investigate further if a covariate, such as the gender, may explain these differences between individuals. It is important to highlight that although our model predicts cortisol levels 1 hour post intake as the most reliable predictor of future efficacy, cortisol measurements were taken every 4 hours. Thus, this finding should be confirmed in prospective studies with more frequent cortisol measurements, particularly 1 hour after osilodrostat administration. While the kinetic–pharmacodynamic approach used in this study can present with some inherent limitations, this type of approach is regularly used to define the modalities of use for a medication in a new indication. A nonlinear mixed-effects modeling allows the use of data from the routine clinical follow-up of patients. This method is thus effective and particularly well-suited for sparse data. Finally, a larger study could include closer measurements of cortisol. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is the best method for avoiding cross-reactivity with steroid precursors and could be used for these measurements. However, we used the Elecsys Cortisol II Immunoassay, which shows <5% cross-reactivity with 11-deoxycortisol; thus, our results are credible.

In conclusion, we designed a kinetic–pharmacodynamic model to adapt osilodrostat in patients with ACTH-dependent Cushing’s syndrome. Our model shows that cortisol level 1 hour after treatment is the best indicator of future efficacy. Moreover, depending on the initial cortisol level and the goal to be achieved, different doses should be prescribed. Despite wide inter-patient variability, we believe our model provides insight into the minimal dose necessary to decrease cortisol levels and the maximal efficacy expected for a given dose. Thus, it should help physicians tailor the treatment to reach maximal efficacy in the shortest possible time. The next step will be to analyze whether this percent decrease remains stable on a long-term basis or becomes more important with time, as suggested by some clinical cases showing delayed adrenal insufficiency on stable doses of osilodrostat.21

Authors’ contributions

Cecilia Piazzola (Conceptualization [equal], Formal analysis [equal], Writing—original draft [equal]), Frederic Castinetti (Conceptualization [equal], Formal analysis [equal], Writing—review & editing [equal]), Katharina von Fabeck (Conceptualization [equal], Writing—review & editing [equal]), and Nicolas Simon (Conceptualization [equal], Methodology [equal], Supervision [equal], Validation [equal], Writing—original draft [equal], Writing—review & editing [equal])

Funding

This work received an unrestricted educational grant from Recordati Rare Diseases.

To see the references and the original article, please go here: https://academic.oup.com/ejendo/article/193/4/K11/8255719?login=false

 

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

Cushing’s: A Comprehensive Guide to Understanding a Devastating Condition

Posted on September 5, 2025 by MaryO

 

This book is perhaps something a little different than most would expect. Firstly, it’s a single-author book on Cushing’s syndrome. It is not, like most textbooks, a compendium of edited submissions from multiple authors where there are often divergent opinions from one chapter to the next. Instead, it’s a treatise reflecting my education and experience. It is not referenced but instead each chapter is followed by suggested readings. It represents my thoughts, understanding and a personal reflection on a career of evaluating a multitude of patients suspected of having the disorder and treating those confirmed to have hypercortisolism due to one cause or another. It reflects my perspectives of the art and science of the field.

In this book you’ll find my personal opinions about all matters from diagnostic testing to approaches to management. I share patient stories that are particularly informative and indicate how I learned from those patients and built on the foundation of my knowledge to take better care of subsequent patients. I relate scientific information, and results of studies, and comment on the utility and practicality of these results. While you are reading, you might learn a thing or two about statistics. I also relate some of the general essentials of the “art of medicine” that I have learned not only from professors I had encountered in my training and education, but also from my patients and colleagues as well as my nursing and administrative colleagues.

I trained in the era of what I like to think of as the modern-day Renaissance of “evidence-based medicine.” This approach dramatically changed the face of medicine, the doctor-patient relationship, and even the influence of third-party payors and government entities. Unfortunately, however, much of the art of medicine has been seemingly deemed less important that data mining and interpretation. I firmly believe that most physicians can acquire the skills and attitudes required to practice medicine with artful expression while incorporating evidenced-based recommendations. Much of this book illustrates an approach to using data and knowledge with experience to formulate action plans for the benefit of patients. I don’t think of the approaches I share as unconventional, but they may be unfamiliar to those who practice with an emphasis on evidenced-based medicine and who have not seen a lot of patients with the set of disorders leading to Cushing syndrome.

I think of the art and science of our craft as the foundation of what we now call “medical decision-making.” So many different factors need to be considered to make the right choices about diagnosis and treatment of diseases. Medical decision-making implies that one looks at all the evidence and facts about a patient, with an understanding of the applicable scientific evidence of medicine, and then utilize one’s experience to make several decisions, including whether a diagnosis is present or absent, the need for further diagnostic studies, and the best approach to treatment.

This approach should treat patients as individuals, according to need based on a multitude of assessments. I have often said, that if you show me 100 patients with Cushing’s disease, all with the same duration of the condition, identical biochemistry, and tumor sizes, you will show me 100 different illnesses. Everybody is different and I relate some examples in this book. Every patient deserves to be treated as an individual. This is where guidelines fail both physicians and patients. They try to fit square pegs into round holes where all patients are treated equally or according to a formulaic approach rather than according to individual needs. I suggest that physicians use their minds to devise an evaluation and management plan rather than defaulting to and following a guideline. If you’re unable to do so, then you probably should refer the patient to an expert.

On Amazon.

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Pregnancy Case: Cushing’s Syndrome with Diabetes Insipidus

Posted on September 3, 2025 by MaryO

Cushing’s Syndrome, a rare but complex endocrine disorder characterized by excessive cortisol production, presents unique challenges and risks during pregnancy. Recent advancements in medical understanding have led to greater awareness of the implications of this syndrome when coupled with conditions like diabetes insipidus, particularly in pregnant patients. The coexistence of these disorders emphasizes the need for a multidisciplinary approach to manage these high-risk pregnancies effectively.

In a groundbreaking case report published in BMC Endocrine Disorders, researchers Hata et al. provide an illuminating examination of a pregnant patient diagnosed with Cushing’s Syndrome along with diabetes insipidus. This syndromic constellation is particularly alarming considering the metabolical and physiological adaptations that occur during pregnancy. The researchers delve deeply into the complexities presented by this rare overlap, offering insight into potential therapeutic pathways and management strategies.

Cushing’s syndrome is often the result of pituitary adenomas or adrenal tumors that result in a hypercortisolemic state. When analyzing its manifestation during pregnancy, clinicians are faced with the delicate balance of managing both maternal and fetal health. In this compelling case, the authors explore the detrimental effects of high cortisol levels and the complications that arise from diabetes insipidus on maternal health.

Diabetes insipidus in pregnancy can further complicate the management of Cushing’s syndrome. It is primarily characterized by an inability of the kidneys to concentrate urine due to a deficiency in the antidiuretic hormone (ADH). This disorder can lead to severe dehydration, electrolyte imbalances, and complications such as preterm labor or uterine atony. By detailing the clinical features of the patient, the report underscores the need for vigilant monitoring and timely interventions to prevent adverse outcomes.

Central to the case is the interplay between the hormonal milieu of pregnancy and the pathological processes of Cushing’s syndrome. The physiological increase in cortisol can mask or exacerbate the symptoms of diabetes insipidus. Thus, clinicians must be astute in recognizing the overlays of these conditions to adjust management plans accordingly. This is especially critical in the prenatal period, where traditional approaches might clash with the unique requirements of pregnancy.

Therapeutic management for such patients is multifaceted. Close collaboration among obstetricians, endocrinologists, and neonatologists is essential to ensure that both maternal and fetal welfare are prioritized. This case illustrates the complexity involved in choosing appropriate pharmacotherapy while minimizing risks to the developing fetus. Importantly, the authors suggest that non-invasive monitoring techniques may help in realizing a safer management regime.

The psychological impact on mothers grappling with these intertwined conditions cannot be overstated. The report sheds light on the emotional strain that awaits patients who must anticipate the uncertainties surrounding their pregnancies. Understanding these layers can aid healthcare providers in offering holistic support not just medically, but psychologically as well.

An often-overlooked aspect of such complex cases is the significance of postnatal follow-up. After delivery, the management of Cushing’s Syndrome may need reevaluation as hormonal levels return to baseline. In this case, the potential resolution of diabetes insipidus after childbirth rejuvenates discussions regarding long-term monitoring and treatment adherence, ensuring that mothers receive the care they need as they transition into motherhood.

Women with Cushing’s Syndrome and diabetes insipidus can experience heightened fatigue, which complicates the already demanding experience of pregnancy. The authors advocate for the integration of lifestyle modifications and supportive measures to help manage energy levels, further illustrating the multifaceted management required in such cases. These alterations can significantly contribute to improving the quality of life for these women in an already challenging scenario.

The ethical considerations surrounding the treatment of pregnant patients with rare syndromes add another layer of complexity. The authors emphasize the importance of informed consent, particularly as clinical decisions might involve experimental therapies or interventions that are not standard for pregnant patients. Open dialogues between patients and providers about risks and benefits can lead to better decision-making processes tailored to individual patient needs.

In conclusion, Hata et al.’s illuminating case report on Cushing’s Syndrome with diabetes insipidus in pregnancy serves as a pivotal reference for clinicians navigating the complexities of these coexisting conditions. As medical science continues to evolve, the insights offered in this report will undoubtedly inform best practices for managing intricate cases, further enhancing maternal-fetal medicine. The need for ongoing research and clinical trials remains crucial as we strive to optimize pregnancy outcomes in patients suffering from this rare combination of disorders.

As we look toward the future, the challenges presented by these conditions urge the medical community to prioritize collaborative care models, innovative therapeutic strategies, and comprehensive support systems for affected patients. While this case report sheds light on the clinical intricacies involved, it also heralds a call to action for further exploration into Cushing’s Syndrome and its implications in pregnancy, ensuring that mothers receive the best possible care during one of life’s most critical journeys.

Subject of Research: Cushing’s Syndrome with diabetes insipidus in pregnancy

Article Title: Cushing’s Syndrome with diabetes insipidus in pregnancy: a case report

Article References:

Hata, S., Shinokawa, N., Harada, Y. et al. Cushing’s Syndrome with diabetes insipidus in pregnancy: a case report.
BMC Endocr Disord 25, 197 (2025). https://doi.org/10.1186/s12902-025-01946-9

Image Credits: AI Generated

DOI: 10.1186/s12902-025-01946-9

Keywords: Cushing’s Syndrome, diabetes insipidus, pregnancy, maternal-fetal medicine, endocrine disorders, case report, hypercortisolism, antidiuretic hormone, multidisciplinary approach, healthcare management.

From https://bioengineer.org/pregnancy-case-cushings-syndrome-with-diabetes-insipidus/

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

Paraneoplastic Cushing Syndrome Unmasking Small Cell Lung Cancer: A Rare Presentation

Posted on August 31, 2025 by MaryO

Abstract

We present a case of a middle-aged woman who presented with chest pain and shortness of breath. Laboratory tests revealed persistent hypokalaemia, hyperglycaemia, and metabolic alkalosis despite treatment. Imaging identified a mass near the right hilum suggestive of lung malignancy. Endocrine evaluation showed markedly elevated cortisol and adrenocorticotropic hormone levels, consistent with paraneoplastic Cushing syndrome caused by ectopic hormone production. The analysis of the lung biopsy obtained through bronchoscopy confirmed the diagnosis of small cell lung cancer (SCLC). The patient was treated with metyrapone and spironolactone to stabilise her metabolic abnormalities and was subsequently referred for chemotherapy following a multidisciplinary team review. This case highlights the importance of recognising paraneoplastic syndromes as atypical presentations of malignancy and emphasises the role of a coordinated, multidisciplinary approach in diagnosis and management.

Introduction

Paraneoplastic syndromes, although relatively uncommon, can serve as important early clues to an underlying cancer. One such rare and often overlooked condition is ectopic adrenocorticotropic hormone (ACTH) secretion, a form of paraneoplastic Cushing’s syndrome. This occurs when a non-pituitary tumor, most commonly small cell lung carcinoma (SCLC) or another neuroendocrine tumor, produces ACTH, leading to overstimulation of the adrenal glands and excessive cortisol production.

Unlike the more familiar presentation of Cushing’s syndrome, ectopic ACTH production tends to manifest with severe metabolic disturbances, such as persistent hypokalemia, metabolic alkalosis, hyperglycemia, and muscle weakness, often without the typical physical features like moon facies or central obesity. These atypical and rapidly progressing symptoms can delay diagnosis, especially in patients with aggressive malignancies.

A thorough diagnostic workup, including hormone assays, suppression testing, and imaging, is essential to pinpoint the source of ectopic hormone production. Early identification is critical, as the metabolic derangements associated with this syndrome can lead to significant morbidity if left untreated.

In this report, we present the case of a middle-aged woman whose initial symptoms of chest pain and shortness of breath led to the discovery of SCLC with ectopic ACTH production. Her case highlights the importance of considering paraneoplastic syndromes in the differential diagnosis of unexplained electrolyte abnormalities and metabolic dysfunction.

Case Presentation

We report the case of a 52-year-old Caucasian woman who presented with a one-week history of diffuse chest pain, progressive shortness of breath, and MRC dyspnea grade 1 initially and then progressing to grade 2. She had no prior history of similar symptoms, and her past medical history was unremarkable. On examination, there were no significant findings on systemic review.

Initial laboratory investigations revealed marked hypokalaemia, with a serum potassium level of 2.4 mmol/L, alongside significant hyperglycaemia (blood glucose: 20 mmol/L) and metabolic alkalosis (arterial pH: 7.52, bicarbonate: 32 mmol/L). Notably, the patient had no known history of diabetes mellitus (Table 1).

Parameter Result Reference range Remarks
Serum potassium 2.4 mmol/L 3.5–5.0 mmol/L Marked hypokalaemia
Blood glucose 20 mmol/L 3.9–7.8 mmol/L (fasting) Significant hyperglycaemia; no known diabetes
Arterial pH 7.52 7.35–7.45 Metabolic alkalosis
Serum bicarbonate (HCO₃⁻) 32 mmol/L 22–28 mmol/L Elevated, consistent with metabolic alkalosis
Table 1: Initial laboratory investigations

This table summarizes the patient’s initial biochemical abnormalities, which include marked hypokalaemia, significant hyperglycaemia in the absence of known diabetes mellitus, and evidence of metabolic alkalosis on arterial blood gas analysis.

Despite intravenous and oral potassium supplementation, hypokalaemia persisted (Table 2). Hyperglycaemia also remained uncontrolled initially and was subsequently managed with insulin therapy.

Day Serum potassium (mmol/L) Reference range (mmol/L)
Day 1 2.4 3.5–5.0
Day 2 2.2 3.5–5.0
Day 3 2.8 3.5–5.0
Day 4 3.0 3.5–5.0
Day 5 2.9 3.5–5.0
Day 6 2.6 3.5–5.0
Day 7 2.7 3.5–5.0
Table 2: Daily serum potassium levels (day 1–day 7)

This table presents serum potassium levels measured over a seven-day period, demonstrating persistently low values consistent with hypokalaemia despite Intra-venous and oral pottasium replacement.

The patient presented with chest pain with respiratory symptoms, and an initial chest radiograph was suggestive of lung cancer (Figure 1).

Initial-chest-X-ray-
Figure 1: Initial chest X-ray

Posteroanterior chest radiograph showing a spiculated opacity in the right mid-zone (black arrow), suggestive of a pulmonary mass. The lesion projects over the right hilum and may represent a primary bronchogenic carcinoma. No gross pleural effusion or pneumothorax is identified.

Further evaluation with contrast-enhanced CT of the thorax revealed a right hilar mass suspicious for a bronchogenic malignancy (Figure 2).

Computed-tomography-(CT)-thorax-
Figure 2: Computed tomography (CT) thorax

Contrast-enhanced axial CT of the thorax demonstrating a spiculated right hilar mass (black arrow) measuring approximately 4 cm in greatest diameter. The mass is abutting the right main bronchus and associated with enlargement of adjacent mediastinal lymph nodes. No evidence of pleural effusion, chest wall invasion, or direct mediastinal involvement is seen on this image.

Given the persistent hypokalaemia, hyperglycaemia, and metabolic alkalosis, the possibility of a paraneoplastic endocrine syndrome was considered.

Endocrine workup showed markedly elevated serum cortisol levels (>2000 nmol/L), which failed to suppress following both low- and high-dose dexamethasone suppression tests. Plasma ACTH levels were also significantly elevated at 615 ng/L, consistent with ectopic ACTH secretion (Table 3).

Test Result Reference range Interpretation
Serum cortisol >2000 nmol/L Morning: 140–690 nmol/L Markedly elevated
Low-dose dexamethasone suppression test No suppression observed Cortisol suppressed to <50 nmol/L Abnormal; cortisol not suppressed
High-dose dexamethasone suppression test No suppression observed Cortisol suppressed by >50% Abnormal; cortisol not suppressed
Plasma ACTH 615 ng/L 10–60 ng/L Significantly elevated; ectopic ACTH secretion
Table 3: Endocrine workup results demonstrating elevated cortisol and adrenocorticotropic hormone (ACTH) levels with lack of suppression on dexamethasone testing

Serum cortisol  levels during low- and high-dose dexamethasone suppression tests. Despite administration of both low- and high-dose dexamethasone, serum cortisol levels remained markedly elevated. Plasma ACTH was also significantly elevated at 615 ng/L, consistent with ectopic ACTH secretion. Reference ranges are included for comparison.

Flexible bronchoscopy was performed, and biopsy of the right endobronchial tumour confirmed the diagnosis of SCLC (Figures 3, 4).

Bronchoscopic-view-of-the-right-hilar-mass-
Figure 3: Bronchoscopic view of the right hilar mass

Bronchoscopic view of the right bronchial tree demonstrating an irregular, lobulated endobronchial mass (black arrow). The lesion appears friable and hypervascular, partially obstructing the bronchial lumen, suggestive of a malignant endobronchial tumor.

Histological-section-of-small-cell-lung-cancer-(SCLC)
Figure 4: Histological section of small cell lung cancer (SCLC)

The arrow indicates a dense cluster of small, hyperchromatic tumour cells characteristic for SCLC.

The combination of persistent metabolic derangements, imaging findings, and histological confirmation supported the diagnosis of paraneoplastic Cushing’s syndrome secondary to ectopic ACTH production by SCLC. This rare clinical entity results from autonomous ACTH secretion by the tumour, leading to adrenal hyperplasia and excessive cortisol production.

Further staging workup was performed to assess the extent of the disease. Contrast-enhanced CT of the abdomen and MRI of the brain showed no evidence of distant metastasis. The disease was therefore classified as limited-stage SCLC.

The patient was commenced on metyrapone and spironolactone following a comprehensive discussion with the endocrinology team. This intervention resulted in the stabilisation of her potassium levels (Figure 5). Furthermore, in the context of her diagnosis of SCLC, a multidisciplinary team (MDT) was convened to discuss her case. Following this collaborative discourse, it was determined that a referral to the oncology department was warranted for the initiation of chemotherapy.

-Serum-potassium-trend-showing-initial-treatment-resistance-and-subsequent-stabilization-after-initiation-of-metyrapone-and-spironolactone
Figure 5: Serum potassium trend showing initial treatment resistance and subsequent stabilization after initiation of metyrapone and spironolactone

The graph demonstrates persistently low serum potassium levels despite aggressive intravenous and oral supplementation. Notable stabilization and eventual normalization of potassium values are observed following the initiation of metyrapone and spironolactone, indicated toward the end of the monitoring period. The shaded green area represents the normal reference range for serum potassium (3.5–5.5 mmol/L).

Discussion

This case illustrates a rare but clinically significant presentation of paraneoplastic Cushing’s syndrome secondary to ectopic ACTH secretion from SCLC. The patient’s initial symptoms of chest pain and breathlessness were non-specific, but persistent metabolic derangements, including hypokalaemia, hyperglycaemia, and metabolic alkalosis, proved refractory to standard treatment. These findings raised suspicion for an underlying endocrine disorder, leading to targeted hormonal evaluation [1,2].

Diagnostic workup revealed markedly elevated cortisol and ACTH levels, with failure to suppress during low- and high-dose dexamethasone suppression tests. Imaging and histological analysis subsequently identified a right hilar mass consistent with SCLC as the source of ectopic ACTH production. Although rare, ectopic ACTH syndrome is a well-recognised paraneoplastic manifestation of SCLC, reported in approximately 1-5% of cases [3]. It can lead to severe metabolic derangements that complicate management and worsen prognosis if unrecognised [4].

Management of ectopic Cushing’s syndrome requires prompt biochemical stabilisation to mitigate life-threatening complications such as hypokalaemia and hypertension. In this case, metyrapone, an 11β-hydroxylase inhibitor, effectively reduced cortisol synthesis, while spironolactone antagonised mineralocorticoid receptors to correct hypokalaemia. Other agents such as ketoconazole, mitotane, or intravenous etomidate may be considered in similar cases, especially when rapid cortisol control is needed or oral therapy is contraindicated [1,5]. However, these therapies carry risks of hepatotoxicity, adrenal insufficiency, or sedation, underscoring the importance of careful monitoring.

Definitive treatment of the underlying malignancy remains the cornerstone of care, as sustained control of ectopic ACTH production depends on tumour response. Early initiation of chemotherapy in SCLC can lead to a reduction in tumour burden and, in some cases, resolution of the paraneoplastic syndrome [4]. However, the metabolic instability associated with hypercortisolism often complicates oncologic management, highlighting the need for coordinated multidisciplinary care.

This case underscores the diagnostic challenge posed by ectopic Cushing’s syndrome and the importance of recognising paraneoplastic endocrine presentations in patients with unexplained metabolic derangements.

Conclusions

This case underscores the importance of considering paraneoplastic syndromes in patients with persistent, unexplained metabolic derangements such as hypokalaemia, hyperglycaemia, and metabolic alkalosis. In this patient, early recognition of ectopic ACTH secretion prompted targeted investigations, leading to the timely diagnosis of SCLC. This facilitated the initiation of appropriate endocrine therapy with metyrapone and spironolactone to stabilise the biochemical abnormalities and allowed safe progression to oncological management.

The case also highlights the complexities of managing ectopic Cushing’s syndrome, where severe metabolic disturbances can delay definitive cancer treatment. A coordinated, multidisciplinary approach involving endocrinology, oncology, and respiratory teams was crucial in optimising patient care and improving the likelihood of a favourable outcome.

For clinicians, this case reinforces the need to maintain a high index of suspicion for paraneoplastic endocrine disorders in patients with unexplained electrolyte and metabolic abnormalities, particularly when accompanied by respiratory symptoms or imaging suggestive of a pulmonary lesion. Early identification and intervention in such cases are critical for minimising morbidity and enabling timely cancer-directed therapy.

References

  1. Jeong C, Lee J, Ryu S, et al.: A case of ectopic adrenocorticotropic hormone syndrome in small cell lung cancer. Tuberc Respir Dis (Seoul). 2015, 78:436-9. 10.4046/trd.2015.78.4.436
  2. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90:4955-62. 10.1210/jc.2004-2527
  3. Coe SG, Tan WW, Fox TP: Cushing’s syndrome due to ectopic adrenocorticotropic hormone production secondary to hepatic carcinoid: diagnosis, treatment, and improved quality of life. J Gen Intern Med. 2008, 23:875-8. 10.1007/s11606-008-0587-z
  4. Perakakis N, Laubner K, Keck T, et al.: Ectopic ACTH-syndrome due to a neuroendocrine tumour of the appendix. Exp Clin Endocrinol Diabetes. 2011, 119:525-9. 10.1055/s-0031-1284368
  5. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125

https://www.endocrine.org/journals/jcem-case-reports/unilateral-adrenalectomy-for-pediatric-cyclical-cushing-syndrome

 

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