FDA Approval for Endogenous Cushing’s Syndrome Drug Recorlev

Posted on January 2, 2022 by MaryO

Ahead of its New Year’s Day decision deadline at the FDA, Xeris Biopharma has snagged an approval for Recorlev, a drug formerly known as levoketoconazole.

Based on results from phase 3 studies called SONICS and LOGICS, the FDA approved the drug for adults with Cushing’s syndrome. Xeris picked up Recorlev earlier this year in its acquisition of rare disease biotech Strongbridge Biopharma. It’s planning to launch in the first quarter of 2022.

Recorlev’s approval covers the treatment of endogenous hypercortisolemia in adults with Cushing’s syndrome who aren’t eligible for surgery or haven’t responded to surgery.

Endogenous Cushing’s disease is caused by a benign tumor in the pituitary gland that prompts the body to produce elevated levels of cortisol, which over time triggers a range of devastating physical and emotional symptoms for patients.

 

In the SONICS study, the drug significantly cut and normalized mean urinary free cortisol concentrations without a dose increase, according to the company. The LOGICS trial confirmed the drug’s efficacy and safety, Xeris says.

Cushion’s is a potentially fatal endocrine disease, and patients often experience years of symptoms before an accurate diagnosis, the company says. After a diagnosis, they’re presented with limited effective treatment options.

Following the approval, the company’s “experienced endocrinology-focused commercial organization can begin rapidly working to help address the needs of Cushing’s syndrome patients in the U.S. who are treated with prescription therapy,” Xeris CEO Paul R. Edick said in a statement.

Aside from its forthcoming Recorlev launch, Xeris markets Gvoke for severe hypoglycemia and Keveyis for primary periodic paralysis.

Back in October, the company partnered up with Merck to help reformulate some of the New Jersey pharma giant’s monoclonal antibody drugs.

From https://www.fiercepharma.com/pharma/xeris-biopharma-scores-fda-approval-for-endogenous-cushing-s-syndrome-drug-recorlev

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , , | 2 Comments »

Curative Treatment on Hyperglycemia in Cushing Syndrome

Posted on December 28, 2021 by MaryO

A retrospective analysis of data from more than 170 patients with Cushing syndrome and hyperglycemia provides insight into the effects of curative treatment on hyperglycemia among these patients.

An analysis of retrospective data from a 20-year period details the impact of curative treatment on hyperglycemia among patients with Cushing syndrome.

Led by a team of investigators from the Mayo Clinic in Rochester, MN, the study examined a cohort of 174 adult patients with Cushing Syndrome and determined 2-in-3 patients with hyperglycemia experienced resolution or improvement of hyperglycemia after a curative procedure.

“This is the first study to analyze the quantitative changes based on the time from the curative surgery, to assess the changes in the intensity of hyperglycemia therapy and identify predictors for hyperglycemia improvement,” wrote investigators.

A team led by Irina Bancos, MD, endocrinologist at the Mayo Clinic Rochester, designed the current study with an interest in examining the impact of curative procedures on hyperglycemia and its management in patients with Cushing syndrome from electronic medical record data of patients treated at a referral center from 2000-2019. The primary purpose of the study was to assess the impact of curative procedures on extent of hyperglycemia and the secondary aim was to investigators how baseline factors might influence improvement of hyperglycemia at follow-up.

For inclusion in the analysis, patients needed to be at least 18 years of age, diagnosed with Cushing syndrome, and have hyperglycemia treated with a curative procedure from January 1, 2000-November 1, 2019. For the purpose of analysis, Cushing syndrome was diagnosed based on clinical evaluation by an endocrinologist and diagnosed according to the most recent guidelines. Hyperglycemia was defined according to American Diabetes Association guidelines.

The primary outcome of interest for the study was the resolution of hyperglycemia following resolution of Cushing syndrome. For the purpose of analysis, resolution was defined as absence of hyperglycemia without the need for antihyperglycemic therapy. Secondary outcomes of interest included changes in HbA1c, and the intensity of hyperglycemia management.

Overall, 174 patients were identified for inclusion in the study. This cohort had a median age of diagnosis of 51 (range, 16-82) years and 73% (n=127) were women. When assessing subtype of Cushing syndrome, the most common form was pituitary Cushing syndrome (60.9%), followed by ectopic (14.4%), and adrenal (24.7%). The median baseline HbA1c was 6.9% (range, 4.9-13.1), 24% of patients were not on any therapy for hyperglycemia, 52% were on oral medications, and 37% were on insulin (mean daily units, 58; range, 10-360).

When assessing differences between subtypes, results indicated those with pituitary Cushing syndrome were younger at the time of surgery (P=.0009), and included more women (P=.0023), and reported a longer duration of symptoms prior to diagnosis. Investigators noted patients with pituitary Cushing syndrome also had the highest clinical severity score (P <.0001), but patients with ectopic Cushing syndrome had the highest biochemical severity score (P <.0001).

Following Cushing syndrome remission and at the end of follow-up, which occurred at a median of 10.5 months, 21% of patients demonstrated resolution of hyperglycemia, 47% demonstrated improvement, and 32% had no change or worsening hyperglycemia. When assessing secondary end points, results indicate HbA1c decreased by 0.84% (P <.0001) and daily insulin dose decreased by a mean of 30 units (P <.0001). Further analysis indicated hypercortisolism severity score (severe vs moderate/mild: OR, 2.4; 95% CI, 1.1-4.9) and Cushing syndrome subtype (nonadrenal vs adrenal: OR, 2.9; 95% CI, 1.3-6.4) were associated with hyperglycemia improvement, but not type of hyperglycemia (diabetes vs prediabetes: OR, 2,1; 95% CI, 0.9-4.9) at the end of follow-up.

“We demonstrated that almost 70% of patients with CS demonstrate either resolution or improvement in hyperglycemia following CS remission. As a group, patients demonstrate a decrease in HbA1c, and can be treated with less insulin and fewer non-insulin agents. Patients with more severe hyperglycemia, ACTH-dependent CS, and more severe CS are more likely to improve after surgery,” added investigators.

This study, “The impact of curative treatment on hyperglycemia in patients with Cushing syndrome,” was published in The Journal of the Endocrine Society.

From https://www.endocrinologynetwork.com/view/obesity-overweight-responsible-for-1-in-5-future-thyroid-cancers-in-australia

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

Topical Corticosteroid-Induced Iatrogenic Cushing Syndrome in an Infant

Posted on December 16, 2021 by MaryO
https://doi.org/10.1016/j.amsu.2021.102978Get rights and content
Under a Creative Commons license

Highlights

•

Cushing syndrome is an abnormality resulting from high level of blood glucocorticoids.

•

Iatrogenic Cushing syndrome due to the overuse of topical corticosteroids is rarely reported.

•

This report presents a case of topical corticosteroid induced iatrogenic Cushing syndrome in an infant.

Abstract

Introduction

Cushing syndrome (CS) is an endocrinological abnormality that results from a high level of glucocorticoids in the blood. Iatrogenic CS due to the overuse of topical corticosteroids is rarely reported. The current study aims to present a rare case of topical corticosteroid induced iatrogenic CS in an infant.

Case presentation

A 4-month-old female infant presented with an insidious onset of face puffiness that progressed over a 2-month period. The mother reported to have used a cream containing Betamethasone corticosteroid 5–8 times a day for a duration of 3 months to treat diaper dermatitis. Laboratory findings revealed low levels of adrenocorticotrophic hormone (ACTH) and serum. Abdominal ultrasound showed normal adrenal glands. The topical corticosteroid was halted and physiologic topical hydrocortisone doses were administered.

Clinical discussion

Infants are more likely to acquire topical corticosteroid induced iatrogenic CS due to their thin and absorptive skin, higher body surface area, and the high prevalence of conditions that necessitates the use of these medications. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis that are most commonly treated with Clobetasol and Bethamethasone.

Conclusion

Infants are susceptible to develop CS due to topical corticosteroid overuse. Hence, physicians need to consider this in infantile CS cases, and take appropriate measures to avoid their occurrence.

Keywords

Cushing syndrome
Infant
Iatrogenic
Topical corticosteroid

1. Introduction

Cushing syndrome (CS) is a reversible endocrinological abnormality that results from high level of cortisol or other glucocorticoids in the blood [1]. It can be caused by either endogenous factors such as excess steroid production and secretion due to adrenal or pituitary tumors, or exogenously through prolonged use of corticosteroid medications resulting in iatrogenic CS [2]. Iatrogenic CS due to the overuse of oral or parenteral corticosteroids is common, however, while topical corticosteroids are one of the most widely prescribed medications by dermatologists, they are less frequently reported to cause iatrogenic CS [3,4]. Even though CS is very rare in the pediatric population with an annual incidence of only 5 cases per million, children of the pediatric age have a higher risk of developing iatrogenic CS, which is likely due to the high prevalence of conditions that necessitates the use of topical corticosteroids and the thinness of their skin that can more easily absorb the steroid [5,6].

The aim of the current study is to present a rare case of topical corticosteroid induced iatrogenic CS in an infant. SCARE guidelines are considered in writing this report [7].

2. Case presentation

2.1. Patient information

A 4-month-old female infant presented with an insidious onset of puffiness of the face; the swelling progressed over a period of 2 months without any other associated symptoms. The infant’s prenatal, developmental, and family history were insignificant, and she was born full term to consanguineous parents via caesarian delivery. After delivery she did not require neonatal intense care unit (NICU) and was discharged in good health. She has been given both bottle and breastfeeding every one to two hrs, and she has received all the required vaccinations at their proper times.

The mother reported to have used a topical corticosteroid cream (Optizol-B cream; a combination of Clotrimazole and Betamethasone) for a period of 3 months with a dose of 5–8 times a day to treat diaper dermatitis of the infant.

2.2. Clinical findings

The infant’s physical examination revealed facial puffiness (Moon face) with no body edema, and cutaneous examination showed the diaper rash without any other cutaneous manifestations. The infant was vitally stable with no dysmorphic features and no skeletal deformities. Her growth parameters were within normal limits, and her systemic examination was unremarkable.

2.3. Diagnostic approach

Laboratory findings revealed low adrenocorticotropic hormone (ACTH) level in the blood measuring 5.9 p.m./l, a serum cortisol level of 24 nmol/l, and normal serum sodium and potassium levels of 144 mEq/l and 4.8 mmol/l, respectively. Abdominal ultrasonography (US) showed normal adrenal glands.

2.4. Therapeutic intervention

The topical corticosteroid cream that contained Bethamethasone was halted and oral hydrocortisone was given (10 mg/m2) tapered over one month. The patient was given a card addressing Cushing syndrome to inform the health care providers in case of emergency situation or unexpected surgical intervention.

2.5. Follow-up and outcome

The infant’s facial puffiness was significantly improved after 7-month follow-up of the patient.

3. Discussion

CS is an endocrinological disorder resulting from high glucocorticoid level in the blood, it is categorized into ACTH dependent (due to pituitary tumors or excess ACTH administration) or ACTH independent CS (due to adrenal neoplasms or excessive glucocorticoid intake) [8,9]. Under normal circumstances, ACTH is secreted by the pituitary gland which in turn stimulates the secretion of cortisol by the adrenal glands [10]. Prolonged exogenous corticosteroid administration can lead to a number of adverse effects based on potency and duration of the treatment, including the suppression of hypothalamic-pituitary-adrenal (HPA) axis and iatrogenic CS, severe infections, and failure to thrive [11]. While iatrogenic CS is frequent with prolonged administration of oral or parenteral corticosteroids, it is occurrence due to topical corticosteroids have rarely been reported [12].

Multiple factors can increase the probability of acquiring the condition, such as corticosteroid potency, amount and frequency of application, age, skin quality, presence of occlusion, and duration of application [4]. In general, infants are more likely to develop topical corticosteroid induced iatrogenic CS, this is due to their thin and absorptive skin, higher body surface area, underdeveloped skin barrier, and the high prevalence of conditions that necessitates the use of these medications [5,6]. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis [8]. This was also the case in this study. This is likely because the diaper area provides occlusion, the perineal skin has intrinsically absorptive properties, the steroid causes local skin atrophy, and percutaneous absorption is even more increased as the result of skin inflammation [13].

The most frequently used corticosteroid for the treatment of diaper dermatitis is reported to be Clobetasol followed by Bethamethasone, with a mean application duration of 2.75 (1–17) months to induce cortisol and ACTH levels suppression [4]. Typical clinical manifestations of CS include facial puffiness (Moon face), generalized body edema and obesity, hirsutism, buffalo hump, hypertension, skin fragility, and purple striae [3,5]. The causative corticosteroid in the current case was Bethamethasone that only resulted in facial puffiness (Moon face) without generalized body edema.

A specific and definitive diagnostic approach for iatrogenic CS is currently lacking [5]. However, prolonged exogenously administered glucocorticoids can suppress ACTH secretion which results in dismissing the need for proper endogenous production of cortisol [14]. Hence, almost all iatrogenic CS cases are associated with low ACTH and cortisol levels which can aid in the diagnosis of the condition [8]. Same findings were observed in this case. According to multiple studies, exogenous corticosteroid administration can often lead to HPA axis suppression alongside CS [15,16]. However, topical corticosteroid induced iatrogenic CS has been reported without HPA axis suppression [8].

The management of these cases start with the cessation of the causative corticosteroid medication and administration of physiologic topical hydrocortisone [5]. The same approach was followed in this study. In order to prevent the development of this condition in the first-place; clinicians should avoid prescribing high potency corticosteroids in the treatment of infantile dermatological disorders and instead choose low potency topical steroids, and also parents should be advised not to overuse these medications and only apply a thin layer to the affected area [6].

In conclusion, even though iatrogenic CS in infants is rare, overuse of topical corticosteroids can lead to their occurrence. Hence, physicians need to consider extensive steroid use as a causative agent of infantile CS. Appropriate measures need to be taken to avoid their occurrence by prescribing less potent steroids, limiting the use of high potent steroids, and informing parents about adverse effects of steroid overuse in infants.

Source of funding

None is found.

Author statement

Soran Mohammed Ahmed: physician managing the case, follow up the patient, and final approval of the manuscript.

Shaho F. Ahmed, Snur Othman, Berwn A. Abdulla, Shvan M.Hussein, Abdulwahid M.Salih, and Fahmi H. Kakamad: literature review, writing the manuscript, final approval of the manuscript.

Patient consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Guarantor

Fahmi Hussein Kakamad.

Declaration of competing interest

None to be declared.

References

© 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

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

No Synthetic Steroid Version of Korlym at This Time

Posted on December 11, 2021 by MaryO

Teva Pharmaceuticals suffered a fresh legal setback on Tuesday in its effort to market a generic version of the synthetic steroid Korlym to treat Cushing’s syndrome.

The Israeli drugmaker failed to convince the U.S. Court of Appeals for the Federal Circuit that the Patent Trial and Appeal Board improperly denied its bid to cancel a patent held by Corcept Therapeutics covering a method for using Korlym to treat the hormone disorder.

Menlo Park, California-based Corcept last year made over $353 million from sales of Korlym, the company’s only drug, according to a filing with the U.S. Securities and Exchange Commission.

Corcept’s patent relates to using a specific dose of Korlym’s active ingredient mifepristone and another drug to treat Cushing’s syndrome, which creates an excess of the hormone cortisol and causes high blood sugar, among other things.

Corcept sued Teva in New Jersey in 2018, alleging its proposed generic version of Korlym infringed the patent and others, in a case that is still ongoing. Teva asked the Patent Trial and Appeal Board to cancel the patent because earlier publications made it obvious that Corcept’s method would work to treat the disorder.

The board ruled for Corcept last year, and Teva appealed. Teva told the Federal Circuit that the PTAB held it to an improperly high standard for proving that the patent was invalid based on prior art.

Chief U.S. Circuit Judge Kimberly Moore, joined by Circuit Judges Pauline Newman and Jimmie Reyna, rejected Teva’s argument on Tuesday. Moore said the board found that a person of ordinary skill wouldn’t have reasonably expected Corcept’s treatment to be safe and effective before Corcept created it.

Moore also rejected Teva’s argument that the prior art disclosed a range of potential dosages that covered Corcept’s treatment.

Teva, Corcept and lawyers for the two companies didn’t immediately respond to requests for comment.

The case is Teva Pharmaceuticals USA Inc v. Corcept Therapeutics Inc, U.S. Court of Appeals for the Federal Circuit, No. 21-1360.

For Teva: John Rozendaal of Sterne Kessler Goldstein & Fox

For Corcept: Eric Stops of Quinn Emanuel Urquhart & Sullivan

From https://www.reuters.com/legal/transactional/teva-loses-bid-cancel-corcept-drug-patent-federal-circuit-2021-12-07/

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

Desmopressin Stimulation Test in a Pregnant Patient with Cushing’s Disease

Posted on December 5, 2021 by MaryO
https://doi.org/10.1016/j.aace.2021.11.005Get rights and content
Under a Creative Commons license
open access

Highlights

•

Due to the physiologic rise of ACTH during pregnancy, unstimulated ACTH levels may not be an accurate marker to differentiate between adrenal and ACTH-independent Cushing’s syndrome.

•

The desmopressin stimulation test can be done during pregnancy to investigate the etiology of Cushing’s syndrome.

•

Non-gadolinium enhanced pituitary imaging may not detect pituitary adenoma, which is the most common cause of Cushing’s disease. Contrast-enhanced pituitary magnetic resonance imaging should be considered in pregnant women with ACTH-dependent Cushing’s syndrome.

•

Due to increase maternal and fetal morbidities in active Cushing’s syndrome, prompt diagnosis and appropriate treatment are essential. The treatment of choice is transsphenoidal surgery during the second trimester, preferably at a high-volume pituitary center.

•

There were significantly lower rates of fetal complications in women with active Cushing’s syndrome than a cured disease, including low birth weight.

Abstract

Objective

The hypothalamic-pituitary-adrenal axis stimulation during pregnancy complicates the investigation of Cushing’s syndrome. Our objective is to present a pregnant patient with Cushing syndrome caused by pituitary tumor in which the desmopressin stimulation test helped in the diagnosis and led to appropriate management.

Case report

A 27-year-old woman with 9-week gestation presented with proximal myopathy for 2 months. She had high blood pressure, wide abdominal purplish striae, and proximal myopathy. Her past medical history revealed hypertension and dysglycemia for 1 year. The 8 AM cortisol was 32.4 μg/dL (5-18), late-night salivary cortisol at 11 PM was 0.7 μg/dL (<0.4), and the mean 24-hour urinary free cortisol was 237.6 μg/day (21.0-143.0). The mean ACTH concentrations at 8 AM were 44.0 pg/mL (0-46.0). Non-gadolinium enhanced pituitary magnetic resonance imaging (MRI) reported no obvious lesion. The desmopressin stimulation test showed a 70% increase in ACTH levels from baseline after desmopressin administration. The pituitary MRI with gadolinium showed an 8x8x7-mm pituitary adenoma. Transsphenoidal surgery with tumor removal was done, which showed ACTH-positive tumor cells. After the surgery, the patient carried on the pregnancy uneventfully.

Discussion

During pregnancy, the ACTH level may not be an accurate marker to help in the differential diagnosis of Cushing’s syndrome. Moreover, non-gadolinium pituitary imaging may not detect small pituitary lesions.

Conclusion

In the present Case, the desmopressin stimulation test suggested the diagnosis of Cushing’s disease, which subsequently led to successful treatment. This suggested that the desmopressin test may serve as a useful test to diagnose Cushing’s disease in pregnant individuals.

Keywords

Cushing’s disease
Cushing’s syndrome
desmopressin stimulation test
pregnancy

Introduction

Pregnancy rarely occurs during the course of Cushing’s syndrome (CS).1,2 Given the increase in maternal and fetal morbidities in women with active CS, early diagnosis and treatment of CS are essential.2

The diagnosis of CS using the usual diagnostic tests is challenging due to stimulation of the hypothalamic-pituitary-adrenal axis during pregnancy. The physiologic rise of ACTH from the 7th week of pregnancy also complicates the investigation for the etiology of CS.1 The concern of gadolinium use during pregnancy can affect the sensitivity in detecting small pituitary lesions in ACTH-dependent CS if using non-gadolinium pituitary imaging. Desmopressin is a vasopressin analog selective for V2 receptors. The desmopressin stimulation test has been proposed as a useful procedure for the differential diagnosis of CS.3 Desmopressin stimulates the increase in ACTH and cortisol in patients with CS caused by pituitary tumor or Cushing’s disease (CD) but not in the majority of normal, obese subjects and patients with adrenal CS or ectopic ACTH syndrome.3,4 However, there were limited data on the desmopressin stimulation test during pregnancy.

Here we present the 27-year-old woman with CS in which the desmopressin stimulation test helped in the diagnosis of CD and led to successful treatment.

Case presentation

A 27-year-old woman with 9-week gestation was referred from the orthopedic department to evaluate CS. She presented with proximal myopathy for 2 months. On physical examination, she had Cushingoid appearance, wide purplish striae, bruising, and proximal muscle weakness. Her blood pressure was 160/100 mmHg, and her body mass index was 32.2 kg/m2. Her past medical history revealed that she had hypertension, dyslipidemia, and impaired fasting glucose for 1 year without taking any medication. She also gained 20 kg in the past 2 years. The 8 AM cortisol (chemiluminescent immunometric assay, Immulite/Siemens) was 32.4 μg/dL (normal , 5.0-18.0), late-night salivary cortisol at 11 PM (electrochemiluminescence immunoassay, Roche Cobas) was 0.7 μg/dL (normal, <0.4), and the mean 24-hour urinary free cortisol (UFC) (radioimmunoassay, Immulite/Siemens) was 237.6 μg/day (normal, 21.0-143.0). ACTH concentrations at 8 AM (chemiluminescent immunometric assay, Immulite/Siemens) were 48.4 and 39.6 pg/mL (normal, 0-46.0) (Table 1). At 12 weeks of gestation, non-gadolinium enhanced pituitary magnetic resonance imaging (MRI) reported a mild bulging contour of the right lateral aspect of the pituitary gland without an obvious abnormal lesion (Figure 2A). The desmopressin stimulation test was then carried out at 14 weeks of gestation. Serial blood samples for ACTH and cortisol were obtained basally (at 8 AM) and at 15, 30, 45, and 60 minutes after the intravenous administration of 10 μg of desmopressin. The results were shown in Table 2. Compared with baseline, ACTH levels increased from 34.7 to 58.9 pg/mL (70%) at 15 minutes after desmopressin administration (a ≥35% increase in ACTH levels was considered an indication of CD in non-pregnant individuals)3 (Figure 1). The pituitary MRI with gadolinium revealed an 8x8x7-mm circumscribed lesion with heterogeneous iso- to hyperintensity on T2W in the right inferolateral aspect of the anterior pituitary lobe. The lesion had a delayed enhancement compared to normal pituitary tissue (Figure 2B). Non-contrast MRI adrenal glands showed bilateral normal adrenal glands without mass or nodule. Other abdominal organs were unremarkable. Regarding comorbidities, she had hypertension and gestational diabetes mellitus (GDM). The HbA1c level was 5.7% (39 mmol/mol). Using a two-step strategy, GDM was diagnosed at 12 weeks of gestation. Hypertension and GDM were controlled with 750 mg of methyldopa and 50 units of insulin per day, respectively.

Table 1. Laboratory investigations of the present Case

Variable At 9 weeks of gestation
8 AM cortisol, μg/dL (5.0-18.0) 32.4
Salivary cortisol (11 PM , <0.4 μg/dL) 0.7
UFC (21.0-143.0 μg/day) 183.5 and 291.6
ACTH, pg/mL (8 AM, 0-46.0) 48.4 and 39.6
DHEAS (8 AM, 35.0-430.0 μg/dL) 378.0
PAC (upright position, 8 AM), ng/dL 5.2
PRA (upright position, 8 AM), ng/mL/hr 2.1
Potassium, mmol/L 3.6

UFC, urinary free cortisol; ACTH, adrenocorticotrophic hormone; DHEAS, dehydroepiandrosterone sulphate; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

  1. Download : Download high-res image (130KB)
  2. Download : Download full-size image

Figure 2. Pituitary imaging of the present Case. (A) A non-gadolinium MRI of the pituitary gland at 12 weeks of gestation showing a mild bulging contour of the right lateral aspect of the pituitary gland without an obvious abnormal lesion (B) An MRI of the pituitary gland with gadolinium at 14 weeks of gestation showing an 8x8x7-mm circumscribed lesion with heterogeneous iso- to hyperintensity on T2W in the right inferolateral aspect of the anterior pituitary lobe. The lesion had a delayed enhancement compared to normal pituitary tissue.

Table 2. Desmopressin stimulation test results performing at 14 weeks of gestation

Time 0 min 15 min 30 min 45 min 60 min
ACTH (pg/mL) 34.7 58.9 57.4 49.9 38.2
Cortisol (μg/dL) 30.6 30.2 29.7 29.6 31.0

ACTH, adrenocorticotrophic hormone

  1. Download : Download high-res image (76KB)
  2. Download : Download full-size image

Figure 1. Percentage of ACTH increase after desmopressin administration (time 0 min).

Transsphenoidal surgery with tumor removal was performed at 18 weeks of gestation. Pathological findings showed a 1.3×1.0x0.3 cm of tissue with segments of the pituitary gland and tumor. There were monomorphous round nuclei, stippled chromatin, indistinct nucleoli, and pale eosinophilic cytoplasm cells. These cells were reactive with ACTH and showed loss of reticulin framework, unlike the normal pituitary gland. The next day after the surgery, her 8 AM cortisol was 6.0 μg/dL. Hydrocortisone supplement was started and continued throughout pregnancy. Antihypertensives were discontinued, and the insulin dosages decreased to less than 20 units per day. At 38 weeks of gestation, she gave birth to a 2300-gm male newborn (small for gestational age). Dysglycemia and hypertension resolved after the delivery. One year after the first child’s delivery, the patient had a spontaneous pregnancy without GDM or hypertension. The 8 AM cortisol was 3.9 μg/dL, and hydrocortisone replacement was continued. The patient successfully delivered a term 3300-gm male infant without fetal or maternal complications. Two years after the first transsphenoidal surgery, a 1-μg cosyntropin stimulation test was performed, the basal cortisol was 11.7 μg/dL, and the peak serum cortisol was 23.8 μg/dL. Steroid replacement was withdrawn.

Discussion

Herein we present a 27-year-old woman who was evaluated during her first pregnancy for clinical and laboratory features suggestive of CD. Her morning serum and late-night salivary cortisol concentrations were elevated in addition to non-suppressed ACTH, but a definitive diagnosis was not obtained by a non-gadolinium pituitary MRI. The diagnosis of CD was suggested, however, by the results of a desmopressin stimulation test. The pituitary MRI with gadolinium was proceeded and revealed a pituitary lesion greater than 6 mm.

The prevalence of pregnancy is low due to reduced fertility in CS. To date, there have been less than 300 pregnant patients with CS reported in the literature.2 In pregnancy, the most frequent etiology of CS is adrenal CS (60%), followed by ACTH-producing pituitary adenomas or CD (35%), and very rarely ectopic ACTH (<5%).1 In contrast, CD is the most common cause of CS in non-pregnant people (approximately 70 percent). The clinical diagnosis of CS during pregnancy may be missed due to overlapping features between pregnancy and CS. However, wide purplish cutaneous striae and proximal myopathy are signs with high discrimination index when CS is suspected.5 These signs are not present in normal pregnancy.

In this present Case, CS was diagnosed with apparent clinical features of CS in addition to an elevated UFC and late-night salivary cortisol. The patient denied taking any supplements and her 8 AM cortisol was not suppressed and therefore did not suggest an etiology of exogenous steroid use. Pregnant women without CS may have elevated UFC and late-night salivary cortisol due to increased total and free plasma cortisol from the first trimester until the end of pregnancy.6 This results from an elevated concentration of cortisol transport protein and the increase in placental ACTH and CRH. According to the current guideline, UFC is the recommended test when CS is suspected during pregnancy.5 Since UFC increases during the second trimester, it may not be a reliable marker after the first trimester of pregnancy unless the level is clearly increased (up to 2- to 3-fold the upper limit of normal values).1 Late-night salivary cortisol is also one of the useful tests to diagnose CS during pregnancy because the circadian rhythm of cortisol is preserved in normal pregnancy. Furthermore, it is not influenced by the changes in the binding proteins.7 However, the previous study has shown that late-night salivary cortisol increased progressively throughout pregnancy. When compared with non-pregnant women, median values of late-night salivary cortisol in pregnant women were 1.1, 1.4, and 2.1 times higher in the first, second, and third trimesters respectively. The cutoff values for late-night salivary cortisol on each gestational trimester were: first trimester 0.255 μg/dL, second trimester 0.260 μg/dL, and third trimester 0.285 μg/dL. The respective sensitivities and specificities in each trimester were: first trimester 92 and 100%, second trimester 84 and 98%, and third trimester 80 and 93%.8

Given the non-suppressed ACTH levels after the 7th week of gestation, we were not able to summarize whether the etiology was adrenal CS or ACTH-dependent CS which could be either CD or ectopic ACTH syndrome. In non-pregnant individuals, ACTH suppression usually identifies adrenal CS. However, in pregnancy, ACTH levels were non-suppressed in half of those with adrenal CS due to continued stimulation of maternal hypothalamic-pituitary-adrenal axis by placental CRH.1 Therefore, using the ACTH thresholds in general populations can lead to misdiagnosis when investigating the etiology of CS in pregnant individuals. The hypothalamic-pituitary-adrenal axis response to exogenous glucocorticoids is blunted in pregnant women. Following an overnight dexamethasone administration, pregnant women without CS may have non-suppressed plasma cortisol and UFC.6 In non-pregnant individuals with CS, the high-dose dexamethasone suppression test identify CD with a sensitivity of 82% and a specificity of 50%.4 During pregnancy, the high-dose dexamethasone suppression test failed to identify almost half of the patients with CD.1 Inferior petrosal sinus sampling is usually avoided due to the risk of excessive radiation exposure. Since the non-gadolinium MRI also showed no obvious pituitary lesion in the present Case, in addition to the limitation of the high-dose dexamethasone suppression test and inferior petrosal sinus sampling in pregnancy, we used desmopressin stimulation to help in the investigation of CD since desmopressin can stimulate an ACTH response in a considerable proportion of patients with CD but not in most patients with adrenal CS or ectopic ACTH syndrome.3,4

Desmopressin has been assigned to pregnancy category B by the US Food and Drug Administration (FDA). In the most recent guideline update on the diagnosis and management of CD, the desmopressin stimulation test can be used to differentiate ectopic CS and CD in patients with normal or high ACTH and have no adenoma or equivocal results of pituitary MRI. However, the guideline did not mention the use of this test in pregnant individuals.9 The literature regarding the use of desmopressin stimulation tests in pregnancy is limited. We were able to identify one study in a pregnant patient with active CS, who was surgically confirmed as CD, in which the desmopressin stimulation test was performed at 10 weeks of gestation and after the delivery. Compared with age-matched healthy non-pregnant women, there were different responses of cortisol and ACTH after desmopressin administration in a pregnant patient with active CS.10 The ACTH peaks after the administration of desmopressin were higher in the pregnant patient. CRH stimulation test was also performed in the pregnant patient with CD. Desmopressin stimulated ACTH values during pregnancy and after the delivery were not significantly different, while the CRH stimulated ACTH values were significantly higher when the test was performed after the delivery. The authors did not mention optimal cutoff values for these diagnostic tests.10 In non-pregnant individuals, the ACTH increase of more than 35% at 15 minutes after the desmopressin administration gave the sensitivity of 84% and the specificity of 43% in the diagnosis of CD.3 Another recent study in ACTH-dependent CS showed that the threshold increase in the ACTH level after desmopressin stimulation of 45% identified CD with a sensitivity of 91% and a specificity of 75%.4 Using the non-pregnant cutoff values for the desmopressin stimulation test, the diagnosis of CD was made in our patient who was later surgically confirmed as CD.

Pituitary microadenomas were the cause of CD in almost 90% of non-pregnant individuals.11 In pregnant women with CD, pituitary microadenomas were also reported to be more common than macroadenomas.1,12 Almost 40% of pituitary microadenomas in CD were invisible or poorly visible in non-contrast MRI, in which contrast-enhanced MRI detected them.13 In the Case series from Lindsay et al., the non-contrast MRI could not correctly identify pituitary adenomas in 38% of pregnant patients with available data.1 The same case series reported a pregnant patient having normal pituitary MRI and was later surgically confirmed as having CD from a 3×3 adenoma with positive staining for ACTH. In the present case, a mild bulging contour of the pituitary gland, although without an obvious abnormal lesion, in addition to desmopressin test results, suggested the need for contrast-enhanced pituitary MRI. Gadolinium contrast is FDA pregnancy category C since it is water-soluble and can cross the placenta into the fetus and amniotic fluid.14 However, since a non-gadolinium MRI may not detect pituitary microadenoma even in patients with normal imaging results,1,15 we suggested physicians consider pituitary MRI with gadolinium as initial imaging in pregnant patients with clinical suspicion of CD.

Prompt diagnosis and treatment of CS are essential due to a higher rate of fetal loss in active CS patients without treatment than those who received either medical or surgical treatment. There are significantly lower rates of various fetal complications, including low birth weight, in women with active CS than in cured CS.2 Although medical and surgical treatment were not compared as prognostic factors for complications, experts recommend transsphenoidal surgery in the second trimester as the treatment of choice for CD in pregnancy.1,15 Medical treatment should be the second choice when surgery cannot be carried out or late diagnosis is made.

Conclusion

In the present Case, the results from the desmopressin stimulation test and the pituitary MRI with gadolinium suggested the diagnosis of CD, which subsequently led to successful treatment. This suggested that the desmopressin test may serve as a useful test to diagnose CD even in the context of pregnancy.

Conflicts of Interest

None of the authors have any potential conflicts of interest associated with this research.

References

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

The authors would like to thank you all the colleagues in the Division of Endocrinology and Metabolism, Department of Medicine, Faculty of medicine, Chulalongkorn University for all the support.

© 2021 Published by Elsevier Inc. on behalf of the AACE. 

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

« Previous Page — Next Page »