Pregnancy Doesn’t Boost Cushing Disease Recurrences

Researchers published the study covered in this summary on Research Square as a preprint that has not yet been peer reviewed.

Key Takeaways

  • Among women who underwent pituitary surgery to treat Cushing disease subsequent pregnancy had no apparent effect on Cushing disease recurrence, in a single-center review of 113 women treated over a 30-year period.

Why This Matters

  • No single factor predicts the recurrence of Cushing disease during long-term follow-up of patients who have undergone pituitary surgery.
  • This is the first study to assess the effect of pregnancy on Cushing disease recurrence in a group of reproductive-age women who initially showed post-surgical remission.

Study Design

  • Retrospective study of 355 patients with confirmed Cushing disease who were admitted to a single tertiary hospital in Brazil between 1990 and 2020. All patients had transsphenoidal surgery, with a minimum follow-up of 6 months and median follow-up of 83 months. Remission occurred in 246 of these patients.
  • The current analysis focused on 113 of the patients who achieved remission, were women, were 45 years old or younger at time of surgery (median 32 years old), and had information available on their obstetric history.
  • Ninety-one of these women (81%) did not become pregnant after their surgery, and 22 (19%) became pregnant after surgery.

Key Results

  • Among the 113 women in the main analysis 43 (38%) had a Cushing disease recurrence, a median of 48 months after their pituitary surgery.
  • Following surgery, 11 women in each of the two subgroups (recurrence, no recurrence) became pregnant.
  • Although the subgroup with recurrence had a higher incidence of pregnancy (11/43; 26%) compared with those with no recurrence (11/70; 16%) Kaplan-Meier analysis showed that survival free of Cushing disease recurrence was similar and not significantly different in the women with a postsurgical pregnancy and those who did not become pregnant (P=.531).
  • The review also showed that, of the women who became pregnant, several obstetrical measures were similar between patients who had a recurrence and those who remained in remission, including number of pregnancies per patient, maternal weight gain, type of delivery (normal or cesarean), delivery time (term or premature), neonatal weight, and neonatal size. The review also showed roughly similar rates of maternal and fetal complications in these two subgroups of women who became pregnant.

Limitations

  • The study was retrospective and included a relatively small number of patients.
  • The authors collected information on obstetric history for some patients by telephone or email contacts.

Disclosures

  • The study received no commercial funding.
  • None of the authors had disclosures.

This is a summary of a preprint research study ” Pregnancy After Pituitary Surgery Does Not Influence the Recurrence of Cushing s Disease,  written by researchers at the Sao Paulo (Brazil) University Faculty of Medicine on Research Square provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

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

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.

Figure 2Pituitary 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

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.

Cushing Disease Treated Successfully with Metyrapone During Pregnancy

https://doi.org/10.1016/j.aace.2021.10.004Get rights and content
Under a Creative Commons license
open access

Highlights

Cushing’s Disease (CD) in pregnancy is rare, but poses many risks to the mother and fetus

Although surgery is still considered first line, this CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure

The dose of metyrapone can be titrated to a goal urinary free cortisol of < 150 ug/24 hours given the known rise in cortisol during gestation

Though no fetal adverse events have been reported, metyrapone does cross the placenta and long-term effects are unknown.

ABSTRACT

Background

Cushing Disease (CD) in pregnancy is a rare, but serious, disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience using it to treat a pregnant patient with CD.

Case Report

34-year-old woman with hypertension who was diagnosed with adrenocorticotropic hormone-dependent CD based on a urinary free cortisol (UFC) of 290 μg/24hr (reference 6-42μg/dL) and abnormal dexamethasone suppression test (cortisol 12.4 μg/dL) before becoming pregnant. She conceived naturally 12 weeks post-transsphenoidal surgery, and was subsequently found to have persistent disease with UFC 768μg/dL. Surgery was deemed high risk given the proximity of the tumor to the right carotid artery and high likelihood of residual disease. Instead, she was managed with metyrapone throughout her pregnancy and titrated to goal UFC of <150μg/24hr due to the known physiologic rise in cortisol during gestation. The patient had diet-controlled gestational diabetes, and well-controlled hypertension. She gave birth at 37 weeks gestation to a healthy baby boy, without adrenal insufficiency in the baby or mother.

Discussion

This CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure. While metyrapone is effective, close surveillance is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency. Though no fetal adverse events have been reported, this medication crosses the placenta and long-term effects are unknown.

Conclusion

We describe a CASE of CD during pregnancy that was successfully treated with metyrapone.

Key words

Cushing disease
metyrapone
pregnancy
cortisol

INTRODUCTION

Cushing disease (CD) is caused by endogenous overproduction of glucocorticoids due to hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. CD in pregnancy is very rare, and when it occurs, it is considered a high-risk pregnancy with many potential adverse outcomes for both the mother and fetus.1 Infertility is common in CD due to cortisol and androgen excess leading to hypogonadotropic hypogonadism.1 Due to the rarity of CD in pregnancy, there is little guidance in terms of treatment for this patient population. Similar to non-pregnant patients, the first-line treatment is transsphenoidal pituitary adenoma resection, with medical therapy as a second-line treatment option. This report presents a CASE that highlights the use of metyrapone, a steroidogenesis inhibitor, as a sole therapy in cases where surgery is deemed to be high risk and unlikely curative due to location of the tumor.

CASE REPORT

A 34-year-old woman with a past medical history of hypertension and infertility for six years presented to endocrinology for evaluation. Aside from difficulty conceiving, her only complaints were nausea and easy bruising. On exam she did not have clinical features of CD –abdominal violaceous striae, moon facies or a dorsocervical fat pad were absent. Her laboratory results revealed an elevated prolactin level (50-60ng/mL, reference range 1.4-24), an elevated ACTH level (61 pg/mL, reference range 0-46), and low FSH and LH levels (1.7mIU/mL and 1.76mIU/mL, respectively). Further testing demonstrated an elevated urinary free cortisol level (UFC) (290μg/24 hour, reference range 6-42) and her cortisol failed to suppress on a 1mg dexamethasone suppression test (cortisol 12.4μg/dL). Magnetic resonance imaging (MRI) of the pituitary with and without contrast showed a T2 hyperintense, hypoenhancing lesion within the right side of the sella touching the right cavernous internal carotid artery measuring 8x8x9 mm consistent with a pituitary adenoma (Figure 1).

Figure 1. Caption: T1 weighted post gadolinium coronal image of the pituitary gland with a small hypoenhancing lesion within the right side of the sella.

After the presumed diagnosis of CD was made, she was referred to neurosurgery for transsphenoidal resection of the adenoma, which she underwent a few months later. Intra-operatively, a white friable tumor was found, and otherwise the surgery was uneventful. Three months later, however, she was found to have a persistent 8x8x9mm hypoenhancing lesion extending laterally over the right cavernous carotid artery on MRI. The mass approximated but did not contact the right intracranial optic nerve. The pathology from resected tissue was consistent with normal pituitary tissue with staining for growth hormone (80%), ACTH (30%), prolactin (40%), follicle stimulating hormone (5%), luteinizing hormone (40%) and thyroid stimulating hormone (15%), proving the surgery to have been unsuccessful.

Twelve weeks post-operatively, the patient discovered she was pregnant. At 12 weeks gestation, her UFC was 768μg/24h and two midnight salivary cortisol levels were elevated at 0.175 and 0.625μg/dL (reference <0.010-0.090). She was experiencing easy bruising and taking labetalol 400 mg twice daily for hypertension. She had gained 10 pounds by 12 weeks gestation.

A second transsphenoidal surgery during pregnancy was deemed high risk, with a high likelihood of residual disease due to the proximity of the tumor to the right carotid artery. The decision was made to treat the patient medically with metyrapone which was started at 250 mg twice per day at 12 weeks gestation and was eventually uptitrated based on UFC levels every 3-4 weeks (goal of <150μg /24h) to 1000 mg three times per day by the time of delivery with an eventual UFC level of 120μg/24h (Figure 2) . Morning ACTH and serum cortisol levels were monitored for potential adrenal insufficiency.

Figure 2. Caption: This figure depicts the patient’s 24 hour urinary cortisol levels over time as well as the titration of metyrapone dosage in mg/day.

Her hypertension was well controlled throughout pregnancy on labetalol with the addition of nifedipine XL 30mg daily in the second trimester. She remained normokalemic with potassium ranging from 3.8-4.1mEq/L. She was diagnosed with gestational diabetes at 24 weeks by an abnormal two-step oral glucose tolerance test, which was diet-controlled. The patient was induced at 37 weeks gestation due to cervical insufficiency with cerclage in place, and was given stress dose steroids along with metyrapone. She delivered a healthy baby boy vaginally without complications. His Apgar scores were 9 and 9 and he weighed 6 pounds and 5 ounces. At the time of delivery and one week later, the baby’s cortisol levels were normal (6 μg/dL, normal 4-20), without evidence of adrenal insufficiency.

The patient’s metyrapone dose was reduced to 500mg three times a day after pregnancy and her 2 month postpartum 24 hour UFC was 42μg/24hr. The patient stopped the metyrapone on her own four months later and her UFC was found to be elevated at 272ug/24hr (normal 6-42μg/24hr). An MRI one year postpartum revealed a 10x10x9 mm adenoma in the right sella with some suprasellar extension without compression of the optic chiasm, but with abutment of the right carotid artery. Due to the persistently elevated cortisol, large size of the tumor, and potential for cure, especially if followed by radiation therapy, a second transsphenoidal surgery was recommended. However, due to the COVID-19 pandemic the patient underwent a delayed surgery 1.5 years postpartum. The pathology was consistent with a pituitary adenoma that stained strongly and diffusely for ACTH and synaptophysin, only. Her postoperative day 2 cortisol was 1.1μg/dL (reference range 6.7-22.6) and hydrocortisone 20mg in the morning and 10mg in the afternoon was started. She remains on hydrocortisone replacement and went on to conceive again, one month after her second surgery.

DISCUSSION

We describe a patient with pre-existing CD who became pregnant and was managed successfully with metyrapone throughout her pregnancy.

Although CD is rare in pregnancy, it can occur, and poses risks to both the mother and fetus.1,2 Potential maternal complications include hypertension, preeclampsia, diabetes, fractures and more uncommonly, cardiac failure, psychiatric disorders, infection and maternal death.1,2 There is also increased fetal morbidity including prematurity, intrauterine growth retardation and less commonly CD can lead to stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism.1,2

It is, therefore, imperative that these patients receive prompt care to control cortisol levels. The treatment of CD in pregnancy is challenging as there are no large research trials studying the efficacy and safety of medications in CD during pregnancy. Pituitary surgery is first-line recommendation and should be done late in the first trimester or in the second trimester to prevent spontaneous pregnancy loss.3 In this CASE, however, it was felt that a second surgery would be high-risk given the proximity of the tumor to the right carotid artery and possibly not curative, and thus surgery was not a feasible option. She was therefore successfully managed with medical therapy with metyrapone alone throughout her pregnancy.

Metyrapone use in pregnancy has been previously reported in the literature and has been shown to be effective in reducing cortisol levels.4,5,6 Although not approved for use in pregnancy, this steroidogenesis inhibitor is the most commonly used medication to treat Cushing’s syndrome in pregnant women.3,5 Due to metyrapone’s inhibition of 11-beta-hydroxylase, there is a buildup of steroidogenesis precursors such as 11-deoxycorticosterone, which can worsen hypertension, increase frequency of preeclampsia, and cause hypokalemia.3 Metyrapone also leads to elevation of adrenal androgens, which in conjunction with accumulation of 11-deoxycorticosterone, can cause hirsutism and virilization. 8

Though the use of Cabergoline has been reported in cases with Cushing disease during pregnancy, no long term safety data is available regarding it effects on pregnancy as well as the fetus. Moreover, studies assessing the effect of cabergoline in persistent or recurrent CD show a response rate of 20-30% only in cases with mild hypercortisolism. 9

There is no consensus on how to medically treat patients with CD during pregnancy. We chose a goal UFC of <150μg/24 hours because of the physiological rise of cortisol to two to three times the upper limit of normal during pregnancy.3,7 During pregnancy, there is an increase in corticotropin-releasing hormone from the placenta, which is identical in structure to the hypothalamic form.7 This leads to increased levels of ACTH which stimulates the maternal adrenal glands to become slightly hypertrophic and accounts for the rise in serum cortisol levels in pregnancy.7 Corticosteroid-binding globulin also increases in pregnancy, along with serum free cortisol, leading to urinary free cortisol increasing to 3-fold the normal range.7 We therefore aimed to keep our patient’s urinary free cortisol approximately 3 times the upper limit of normal on our assay, to maintain normal cortisol levels for pregnancy.

Close surveillance of patients is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency.3 Although no fetal adverse events from metyrapone have been reported, the medication does cross the placenta, leading to the potential for fetal adrenal insufficiency, and long-term effects are unknown.3

CONCLUSION

This CASE demonstrates the successful use of metyrapone alone to treat CD throughout pregnancy resulting in the birth of a healthy baby without adrenal insufficiency. These cases are particularly challenging given the lack of FDA-approved therapies and the lack of consensus on directing titration of medications and the duration of therapy.

Uncited reference

4.6..

REFERENCES:

Clinical Relevance: Cushing’s Disease (CD) in pregnancy is a rare, but serious, disease that has potential adverse effects on maternal and fetal health. Surgery is considered first line therapy, and there is little consensus on medical treatment of CD in pregnancy. This CASE demonstrates the successful use and titration of metyrapone throughout pregnancy.

From https://www.sciencedirect.com/science/article/pii/S2376060521001164

Estrogen receptor α plays an important role in Cushing’s syndrome during pregnancy

Abstract

Cushing’s syndrome (CS) during pregnancy is very rare with a few cases reported in the literature.

Of great interest, some cases of CS during pregnancy spontaneously resolve after delivery. Most studies suggest that aberrant luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR) seems to play a critical role in the pathogenesis of CS during pregnancy.

However, not all women during pregnancy are observed cortisol hypersecretion. Moreover, some cases of adrenal tumors or macronodular hyperplasia with LHCGR expressed, have no response to hCG or LH.

Therefore, alternative pathogenic mechanisms are indicated. It has been recently reported that estrogen binding to estrogen receptor α (ERα) could enhance the adrenocortical adenocarcinoma (ACC) cell proliferation.

Herein, we hypothesize that ERα is probably involved in CS development during pregnancy.

Better understanding of the possible mechanism of ERα on cortisol production and adrenocortical tumorigenesis will contribute to the diagnosis and treatment of CS during pregnancy.

Read the entire article here: https://www.sciencedirect.com/science/article/pii/S0306987720303893?via%3Dihub

Pregnancy Could Be Linked to Onset of Cushing’s Symptoms

More than 25 percent of women with Cushing’s disease experienced their first symptoms within one year of giving birth, a small study by the Pacific Neuroscience Institute found.

The findings suggest a possible causal relationship between the biological stress of pregnancy and Cushing’s disease (CD), with more than a two-fold risk of women developing the disease within one year of pregnancy.

The study, “Pregnancy-associated Cushing’s disease? An exploratory retrospective study,” was published in the journal Pituitary.

Eighty percent of Cushing’s disease cases are women, and most are of reproductive age.

Levels of the body’s main stress hormone, cortisol, normally increase during pregnancy. In the last weeks before birth, cortisol levels are two to three times higher than normal, similar to Cushing’s disease.

Because cortisol levels gradually increase during pregnancy, a diagnosis of Cushing’s disease within the gestation period is problematic.

Circumstantial “evidence suggests a higher incidence of CD immediately following pregnancy, in the peripartum period [a few weeks after childbirth],” the study’s authors wrote.

To shed additional light on the matter, researchers retrospectively investigated the frequency of Cushing’s disease onset related to pregnancy.

A total of 64 women with biochemically-diagnosed Cushing’s disease and treated at Providence Saint John’s Health Center in Santa Monica, California, from July 2007 to December 2017 were included in this study.

For the analysis, patients were divided into three groups:

  1. Women with pregnancy-associated CD: “defined as symptom-onset within 1 year of pregnancy that was explicitly linked to the pregnancy by the patient’s own recollection of her pregnancy and subsequent symptoms related to CD”;
  2. Women of reproductive age: “defined as age 15–45 years, in whom CD onset was not associated temporally with pregnancy within the past year”;
  3. Women not of reproductive age at the time of CD onset.

Results showed that 64 percent of the patients were of childbearing age at the time of diagnosis. Of these, 27 percent (11 women) had pregnancy-associated Cushing’s disease. This might be due to small, slow-growing or dormant corticotroph pituitary adenomas that were stimulated by pregnancy-related hormonal changes; however, this hypothesis was not confirmed by the researchers.

On average, patients in group 1 had two pregnancies prior to Cushing’s disease onset, compared to zero for 30 other women with disease onset during reproductive age. This suggests that undergoing the biological stress of pregnancy more than once could play a role in Cushing’s development.

“Another possible explanation of the association between CD and pregnancy is simply that patients are more likely to remember the onset of their CD symptoms in relation to a landmark life event such as pregnancy and childbirth, which leads to long-term physical changes in most women, irrespective of Cushing’s status,” the researchers noted.

In contrast, 19 of the 30 patients at reproductive age without pregnancy-associated disease had no pregnancies before being diagnosed, which weakens the association between pregnancy and Cushing’s and draws attention to various other factors that may also be involved in disease onset, apart from gestation-related hormonal changes.

The time from the onset of symptoms to diagnosis for women with pregnancy-related disease varied from two to six years.

“It was in fact weight gain or failure to lose weight post-pregnancy, which was the most frequent complaint and presentation in our patients with pregnancy-associated CD, and which often lead to an eventual diagnosis of CD,” the researchers stated.

“As such, appropriate biochemical testing may be indicated in women who 6–18 months after pregnancy, are still unable to lose the weight of pregnancy, continue to gain weight, have new, persistent or more [treatment-resistant] hypertension and diabetes mellitus, and/or other classical stigmata of CD,” they suggested.

All patients with biochemically-confirmed Cushing’s disease underwent surgery to remove pituitary adenoma. Sustained surgical remission rates for groups 1, 2, and 3 were 91%, 80%, and 83%, respectively.

“This possible association suggests a heightened degree of clinical suspicion and biochemical testing for CD may be warranted after childbirth. Further study of this possible link between pregnancy and CD is warranted,” the team concluded.

From https://cushingsdiseasenews.com/2018/09/21/cushings-disease-symptoms-onset-pregnancy-could-be-linked-study-suggests/

%d bloggers like this: