A Case Report of Cushing’s Disease Presenting With Psychosis and Muscle Weakness Postpartum

Posted on October 31, 2023 by MaryO

Abstract

Cushing’s syndrome is a condition leading to overproducing of cortisol by the adrenal glands. If the pituitary gland overproduces cortisol, it is called Cushing’s disease. Cushing’s syndrome and even Cushing’s disease during and after pregnancy are rare events. There is not enough literature and guidance for managing and treating these patients. The diagnosis of Cushing’s syndrome in pregnancy is often delayed because the symptoms overlap. We presented a thin 31-year-old woman, admitted 2 months after a normal-term delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course. She had no clinical discriminatory features of Cushing’s syndrome. Given that the patient only presented with psychosis and proximal myopathy and had an uncomplicated pregnancy, our case was considered unusual. The patients also had hyperpigmentation and severe muscle weakness which are among the less common presentations of Cushing’s syndrome. Our findings suggest that an early diagnosis of Cushing’s disease is important in pregnancy period for its prevalent fetal and maternal complications, and it should be treated early to optimize fetal and maternal outcomes as there is an increasing trend toward live births in treated participants.

Introduction

Cushing’s syndrome is a condition that originates from excessive production of glucocorticoids. The condition is most common in women of childbearing age and is characterized by altered distribution of the adipose tissue to the central and upper regions of the trunk (central obesity and buffalo hump), face (moon face), capillary wall integrity (easy bruising), hyperglycemia, hypertension, mental status changes and psychiatric symptoms, muscle weakness, signs associated with hyperandrogenism (acne and hirsutism), and violaceous striae among other signs. Hypercortisolism and hyperandrogenism suppress the production of the pituitary gonadotropins, which in turn leads to menstrual irregularities and infertility.1–3 Moreover, the main common cause of developing Cushing’s syndrome is the use of exogenic steroid.3
Cushing’s disease is a form of Cushing’s syndrome with overproduction of adrenocorticotropic hormone (ACTH) due to pituitary adenoma. The diagnosis is made using clinical features and paraclinical tests including urinary free cortisol (UFC), serum ACTH, dexamethasone suppression tests (DSTs), pituitary magnetic resonance imaging (MRI), and sometimes by inferior petrosal sinus sampling (IPSS).4 Although women with Cushing’s disease are less likely to become pregnant, timely diagnosis and appropriate management are especially important during possible pregnancy, preventing neonatal and maternal complications and death. The diagnosis is challenging due to the overlap of the disease symptoms with the changes associated with a normal pregnancy. Moreover, the hormonal milieu during pregnancy has recently been proposed as a potential trigger for Cushing’s disease in some cases; hence, the term “pregnancy-associated Cushing’s disease” has been used for the disease in the recent literature. In this study, we presented a thin 31-year-old woman who was referred to our clinic 2 months after a normal delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course.

Case Presentation

Our patient was a 31-year-old woman who presented 2 months after the delivery of her second child. She had a history of type 2 diabetes mellitus and hypertension in the past 2 years prior to her presentation. She had been admitted to another center following an episode of falling and muscle weakness. Two weeks later, she was admitted to our center with an impression of pulmonary thromboembolism due to tachypnea, tachycardia, and dyspnea. During follow-up, she was found to have leukocytosis, hyperglycemia (random blood sugar: 415 mg/d; normal level: up to 180 mg/dL) and hypokalemic metabolic alkalosis (PH: 7.5, HCO3 [bicarbonate]: 44.7 mEq/L, paO2 [partial pressure of oxygen]: 73 mm Hg, pCO2: 51.7 mm Hg, potassium: 2.7 mEq/L [normal range: 3.5-5.1 mEq/L]), which was refractory to the treatment; therefore, an endocrinology consultation was first requested. On physical examination, the patient was agitated, confused, and psychotic. Her vital signs were: blood pressure 155/100 mm Hg, heart rate: 130 bpm, and respiratory rate: 22 bpm, temperature: 39°C. As it has shown in Figure 1A, her face is not typical for moon face of Cushing’s syndrome, but facial hirsutism (Figure 1A) and generalized hyperpigmentation is obvious (Figure 1A-C). She was a thin lady and had a normal weight and distribution of adiposity (Body Mass Index [BMI] = 16.4 kg/m2; weight: 40 kg, and height: 156 cm). Aside from thinness of skin, she did not have the cutaneous features of Cushing’s syndrome (e.g. purpura, acne, and violaceous striae) and did not have supraclavicular and dorsocervical fat pad (buffalo hump), or plethora. In other words, she had no clinical discriminatory features of Cushing’s syndrome despite the high levels of cortisol, as confirmed by severely elevated UFC (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). In addition, as will be mentioned later, the patient had axonal neuropathy which is a very rare finding in Cushing’s syndrome.
Figure 1. Clinical finding of our case with Cushing’s disease. (A) Hirsutism, (B) muscle atrophy seen in proximal portion of lower limbs, and (C) hyperpigmentation specially on the skin of the abdominal region.

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She had a markedly diminished proximal muscle force of 1 out of 5 across all extremities; the rest of the physical examinations revealed no significant abnormalities (Figure 1B). On the contrary, based on her muscle weakness, hirsutism, psychosis and hyperpigmentation and refractory hypokalemic alkalosis, hyperglycemia, and hypertension, Cushing’s syndrome was suspected; therefore, 24-hour UFC level was checked that the results showed a severely elevated urinary cortisol (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). Serum ACTH level was also inappropriately elevated (45 pg/mL; normal range: 10-60 pg/mL). High-dose dexamethasone failed to suppress plasma cortisol level and 24-hour urine cortisol level. A subsequent pituitary MRI showed an 8-mm pituitary mass, making a diagnosis of Cushing’s disease more probable. Meanwhile, the patient was suffering from severe muscle weakness that did not improve after the correction of hypokalemia. Then, a neurology consultation was requested. The neurology team evaluated laboratory data as well as EMG (Electromyography) and NCV (Nerve Conduction Velocity) of the patient, and based on their findings, “axonal neuropathy” was diagnosed for her weakness; so they ruled out the other neuromuscular diseases. A 5-day course of intravenous immunoglobulin (IVIG) was started for her neuropathy; however, the treatment did not improve her symptoms and the patient developed fungal sepsis and septic shock. Therefore, she was processed with broad-spectrum antibiotics and antifungal agents and recovered from the infection.
Mitotane was started for the patient before definitive surgical treatment to suppress hormonal production due to her poor general condition. Despite the 8-mm size of the pituitary mass which is likely to be a source of ACTH, our patient was underweight and showed the atypical clinical presentation of Cushing’s disease, making us suspect an ectopic source for the ACTH. Therefore, a Gallium dotatate scan was performed to find any probable ectopic sources; however, the results were unremarkable. The patient underwent Trans-Sphenoidal Surgery (TSS) to resect the pituitary adenoma because it was not possible to perform IPSS in our center. Finally, the patient’s condition including electrolyte imbalance, muscle weakness, blood pressure, and hyperglycemia started to improve significantly. The pathologist confirmed the diagnosis of a corticotropic adenoma. Nevertheless, the patient suddenly died while having her meal a week after her surgery; most likely due to a thromboembolic event causing a cardiac accident.

Discussion

Our patient was significantly different from other patients with Cushing’s disease because of her atypical phenotype. She was unexpectedly thin and had psychosis, hyperpigmentation, proximal myopathy, axonal neuropathy and no clinical discriminatory features of Cushing’s syndrome such as central adiposity, dorsocervical or supraclavicular fat pad, plethora or striae. She had also a history of type 2 diabetes and hypertension 2 years before her admission. The patient was diagnosed with Cushing’s later. From what was presented, the patient did not know she had Cushing’s until after her delivery and despite the highly elevated UFC, and she completed a normal-term delivery. Given that she only presented with psychosis and proximal myopathy, her pregnancy was considered unusual. Her clinical features such as hyperpigmentation and severe muscle weakness are among less common presentations.5
11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) is an enzyme responsible for converting cortisone (inactive glucocorticoid) into cortisol (active). It is speculated that this enzyme has a role in obesity (Figure 2).6,7
Figure 2. The enzymatic actions of 11β-hydroxysteroid dehydrogenase on its substrate interconverting inactive and active glucocorticoid.

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In a case reported by Tomlinson, a 20-year-old female was diagnosed with Cushing’s disease despite not having the classical features of the disease. It has been suggested that the mechanism is a partial defect in 11β-HSD1 activity and concomitant increase in cortisol clearance rate. Thus, the patient did not have a classic phenotype; the defect in the conversion of cortisone to cortisol rises cortisol clearance and protects the patient from the effects of cortisol excess. This observation may help explain individual susceptibility to the side effects of glucocorticoids.6
Further studies of Tomlinson et al showed that a deficit in the function of (and not a mutation related to) 11β-HSD2 might have been responsible for the absence of typical Cushing’s symptoms. 11-HSD2 keeps safe the mineralocorticoid receptor from excess cortisol. Mutation in the HSD11B2 gene explains an inherited form of hypertension, apparent mineralocorticoid excess syndrome, in which Cushing’s disease results in cortisol-mediated mineralocorticoid excess affecting the kidney and leads to both hypokalemia and hypertension.8
It is frequent in Cushing’s syndrome that the patients usually have no mineralocorticoid hypertension; however, it is still proposed that a defect in 11β-HSD1 can be responsible for the presence of mineralocorticoid hypertension in a subgroup of patients. In fact, 11β-HSD1 is expressed in several tissues like the liver, kidneys, placenta, fatty tissues and gonads,9 meaning that this enzyme may potentially affect the results of cortisol excess in Cushing’s syndrome/disease. Abnormality in the function of this enzyme could explain the absence of the symptoms like central obesity, easy bruising, and typical striae during Cushing’s disease. Several factors affect the action of glucocorticoids. In this regard, the impact of the different types and levels of impairment in glucocorticoid receptors have been highlighted in some studies, as it can lead to different levels of response to glucocorticoids10 as well as a variety in the symptoms observed in Cushing’s disease.
The predominant reaction of the NADP(H)-dependent enzyme 11-Tukey’s honestly significant difference (HSD)1 happens through the catalysis of the conversion of inactive cortisol into receptor-active cortisol. The reverse reaction is mediated through the unidirectional NAD-dependent 11-HSD type 2 (Figure 2).11
In another case reported by Ved V. Gossein, a 41-year-old female was evaluated for hirsutism and irregular menstrual cycles. Her BMI was 22.6 kg/m2. The patient had no signs or symptoms of overnight recurrent Cushing’s syndrome, the 48-hour DST failed to suppress cortisol levels, and 24-hour urinary cortisol levels were persistently elevated on multiple occasions. Adrenocorticotropic hormone levels were unreasonably normal, suggesting ACTH-dependent hypercortisolism. Despite these disorders, she had 2 children. Magnetic resonance imaging (MRI) of the pituitary did not show any abnormalities. Moreover, abdominal MRI did not show adrenal mass or enlargement. Genetic testing to determine glucocorticoid resistance syndrome showed no mutation.12
Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized or partial insensitivity of target tissues to glucocorticoids.13–17 There is a compensatory increase in hypothalamic-pituitary activity due to decreased sensitivity of peripheral tissues to glucocorticoids systems.13–17 Excessive ACTH secretion leads to high secretion of cortisol and mineralocorticoids and/or androgens. However, the clinical features of Cushing’s syndrome do not develop after resistance to the effects of cortisol. Generalized glucocorticoid resistance is a rare condition characterized by high cortisol levels but no scarring of Cushing’s syndrome.18
An important aspect of our case was her pregnancy. Our patient had a history of hypertension and diabetes type 2, 2 years before her presentation to our center that could be because of an undiagnosed Cushing’s disease. The patient’s pregnancy terminated 2 months prior the admission and she had a normal vaginal delivery. So, we suspect that she become pregnant while involved with the disease. Aside from focusing on how this can happen in a patient with such high levels of glucocorticoids, more attention should be paid to occurring pregnancy in the background of Cushing’s disease. In fact, up to 250 patients were reported, of which less than 100 were actively treated.19–22
Cushing’s disease is associated with serious complications in up to 70% of the cases coinciding with pregnancy.21 The most frequent maternal complications reported in the literature are hypertension and impaired glucose tolerance, followed by preeclampsia, osteoporosis, severe psychiatric complications, and maternal death (in about 2% of the cases). Prematurity and intrauterine growth retardation account for the most prevalent fetal complications. Stillbirth, intrauterine deaths, intrauterine hemorrhage, and hypoadrenalism have also been reported.23 Early diagnosis is especially challenging during pregnancy because of many clinical and biochemical shared features of the 2 conditions.23,24 These features include an increase in ACTH production, corticosteroid-binding globulin (CBG) 1 level, level of cortisol (urinary, plasma and free), hyperglycemia, weight gain, and an increased chance for occurrence of bruising, hypertension (mistaken with preeclampsia), gestational diabetes mellitus, weight gain, and mood swings.3 There are some suggestions proposed in the studies that help in screening and differentiation of Cushing’s from the normal and abnormal effects of pregnancy and Cushing’s disease from Cushing’s syndrome in suspected pregnant patients. Contrary to Cushing’s syndrome, the nocturnal minimum level of cortisol is preserved in pregnancy.23,25 There is not yet a diagnostic cut-off determined on mentioned level; however, a few studies elucidate the evaluation of hypercortisolemia in a pregnant patient.26–28
Urinary free cortisol, a measure that reflects the amount of free cortisol in circulation, normally increases during pregnancy, and it can increase up to 8 times the normal level with Cushing’s disease during the second and the third trimesters,23,29 which is a useful tool to evaluate cortisol levels in a suspected pregnant woman. Because the suppression of both UFC and plasma cortisol is decreased in pregnancy,23,30 a low-dose DST is not very helpful for screening Cushing’s disease in pregnant patients. However, a high-dose DST with a <80% cortisol suppression might only indicate Cushing’s disease.3,31 Thus, it helps differentiating between ectopic ACTH syndrome and Cushing’s disease.32 The use of high-dose DST can distinguish between adrenal and pituitary sources of CS in pregnancy. Owing to the limited evidence available and the lack of data on normal pregnancies, the use of corticotropin-releasing hormone (CRH), desmopressin, and high-dose DST in pregnancy is not recommended yet.33 More timely diagnosis as well as timely intervention may have saved the life of our patient.
To differentiate between ectopic ACTH syndrome and Cushing’s disease, adrenal imaging should be considered. For higher plasma levels, combined employment of CRH stimulation test and an 8-mg DST can be helpful.3 Bilateral inferior petrosal sinus sampling (B-IPSS) might be needed when the findings are not in accordance with other results, but it is recommended to perform B-IPSS only if the noninvasive studies are inconclusive and only if there is enough expertise, experience, and technique for its performance.3
Although axonal neuropathy has been reported as a rare syndrome associated with paraneoplastic ectopic Cushing’s syndrome and exogenous Cushing’s syndrome, its association with Cushing’s disease has not been reported.5,32 Our patient had severe muscle weakness that we initially attributed it to myopathy and hypokalemia associated with Cushing’s syndrome. In our study, the diagnosis of axonal neuropathy was made based on electrophysiological studies by a neurology consultant and then IVIG was administered; however, the patient’s weakness did not improve after this treatment. The co-occurrence of Guillain-Barré syndrome which may also be classified as axonal neuropathy has also been reported in a pregnant woman with ectopic Cushing’s syndrome.34,35 Whether this finding is coincidental or the result of complex immune reactions driven by Cushing’s disease, or the direct effect of steroids, these results cannot be deduced from current data.36 Some data suggest that the fluctuations and inferior petrosal sinus sampling may trigger the flare of autoimmune processes, specifically when the cortisol levels start to decline during the course of Cushing’s syndrome.35,8 Also, due to COVID-19 pandemic affecting vital organs like kidney, paying attention to COVID-19 is suggested.37–40

Conclusions

We presented a thin young female with psychosis, proximal myopathy, and axonal neuropathy with Cushing’s disease who had a recent pregnancy that was terminated without any fetal or maternal complications despite the repeated elevated serum cortisol and 24-hour UFC; therefore, we suggest that she might have glucocorticoid resistance. Glucocorticoid resistance is a rare disease in which the majority, but not all, of patients have a genetic mutation in the hGR-NR3C1 gene. As we did not perform genetic testing for our patient, the data are lacking.
Another clue to the absence of the classic Cushing’s disease phenotype in our case is the role of isoenzymes of 11-HSD1 and 11-HSD2. Other mechanisms, such as the defect somewhere in the glucocorticoid pathway of action such as a decreased number of receptors, a reduction in ligand affinity, or a postreceptor defect, play an important role in nonclassical clinical manifestations of Cushing’s syndrome.

Acknowledgments

The authors thank the patient for allowing us to publish this case report. The authors show their gratitude to the of the staff of the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) specially Mrs. Farahnaz Nikkhah for its technical and editorial assists.

Ethics Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Informed Consent

Written informed consent was obtained from the patient and for her anonymized information to be published in this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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12. Gossain VV, El-Rifai M, Krishnan P, Bhavsar B. Cushing’s syndrome with no clinical stigmata—a variant of glucocorticoid resistance syndrome. Clin Diabetes Endocrinol. 2018;4:23-25.
13. Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab. 2008;93(5):1563-1572.
14. Cidlowski JA, Malchoff CD, Malchoff DM. Glucocorticoid receptors, their mechanism of action, and glucocorticoid resistance. In: Jameson JL, De Groot LJ, eds. Endocrinology: Adult and Pediatric. Saunders; 2016:1717-1726.
15. Charmandari E, Kino T. Chrousos syndrome: a seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signaling changes. Eur J Clin Investig. 2010;40: 932-942.
16. Nicolaides NC, Charmandari E. Chrousos syndrome: from molecular pathogenesis to therapeutic management. Eur J Clin Invest. 2015;45(5):504-514.
17. Nicolaides N, Lamprokostopoulou A, Sertedaki A, Charmandari E. Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance. Hormones. 2016;15(1): 23-34.
18. Huizenga NATM De Lange P, Koper JW, et al. Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene. J Clin Endocrinol Metab. 2000;85:2076-2081.
19. Luger A, Broersen LHA, Biermasz NR, et al. ESE clinical practice guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021;185: G1-G33.
20. Sridharan K, Sahoo J, Palui R, et al. Diagnosis and treatment outcomes of Cushing’s disease during pregnancy. Pituitary. 2021;24(5):670-680.
21. Caimari F, Valassi E, Garbayo P, et al. Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine. 2017;55(2):555-563.
22. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab. 2005;90(5):3077-3083.
23. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev. 2005;26(6):775-799.
24. Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstetr Gynecol. 1992;79:130-137.
25. Carr BR, Parker CR Jr, Madden JD, et al. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstetr Gynecol. 1981;139:416-422.
26. Mellor A, Harvey RD, Pobereskin LH, Sneyd JR. Cushing’s disease treated by trans-sphenoidal selective adenomectomy in mid-pregnancy. Br J Anaesth. 1998;80(6):850-852.
27. Doshi S, Bhat A, Lim K. Cushing’s syndrome in pregnancy. J Obstetr Gynaecol. 2003;23:568-569.
28. Wood PJ, Barth JH, Freedman DB, Perry L, Sheridan B. Evidence for the low dose dexamethasone suppression test to screen for Cushing’s syndrome—recommendations for a protocol for biochemistry laboratories. Ann Clin Biochem. 1997;34(pt 3):222-229.
29. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab. 2005;90(5): 3077-3083.
30. Wallace C, Toth EL, Lewanczuk RZ, Siminoski K. Pregnancy-induced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab. 1996;81(1):15-21.
31. Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F. Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J Clin Endocrinol Metab. 1999;84(2):440-448.
32. Vilar L, Naves LA, Freitas MdC, et al. Endogenous Cushing’s syndrome: clinical and laboratorial features in 73 cases. Arq Bras Endocrinol Metabol. 2007;51(4):566-574.
33. Hamblin R, Coulden A, Fountas A, Karavitaki N. The diagnosis and management of Cushing’s syndrome in pregnancy. J Neuroendocrinol. 2022;34(8):e13118.
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35. Moeindarbary S, Abbasi dalooei M, Ghahremani S, et al. Guillain-Barré syndrome following Cushing’s syndrome in a pregnant woman: a case report. Int J Pediatr. 2019;7:10651-10657.
36. Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The immune system in Cushing’s syndrome. Trends Endocrinol Metab. 2020;31(9):655-669.
37. Besharat S, Alamda NM, Dadashzadeh N, et al. Clinical and demographic characteristics of patients with COVID-19 who died in Modarres Hospital. Open Access Maced J Med Sci. 2020;8:144-149.
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Cushing’s Syndrome in Pregnancy in Which Laparoscopic Adrenalectomy was Safely Performed by a Retroperitoneal Approach

Posted on October 2, 2023 by MaryO

Abstract

Introduction

Laparoscopic adrenalectomy is the standard treatment for adrenal tumors caused by Cushing’s syndrome. However, few pregnant women have undergone adrenalectomy because of the risk of general anesthesia and surgery.

Case presentation

A 28-year-old woman presented with gradually worsening Cushing’s signs at around 12 weeks of pregnancy. Magnetic resonance imaging displayed a 38-mm left adrenal tumor, which was the cause of the adrenal Cushing’s syndrome. Metyrapone was started, which increased androgen levels. Since the management of Cushing’s syndrome by medication alone is challenging, unilateral laparoscopic adrenalectomy by a retroperitoneal approach was performed at 23 weeks of the pregnancy. No perioperative complications were noted.

Conclusion

Adrenalectomy is considered safe in pregnant women with Cushing’s syndrome. Laparoscopic adrenalectomy by retroperitoneal approach should be chosen and performed between 14 and 30 weeks of pregnancy to prevent mother and fetal complications.

Abbreviations & Acronyms

  • CS
  • Cushing’s syndrome
  • MRI
  • magnetic resonance imaging

Keynote message

We report a rare case of adrenalectomy performed via a retroperitoneal approach for Cushing’s syndrome in a pregnant woman. Cushing’s syndrome may affect the fetus, and surgery can be considered in addition to medical management. Adrenalectomy should be performed in the second trimester of pregnancy. Pneumoperitoneal pressure, position, and surgical approaches must receive careful attention.

Introduction

CS is characterized by excessive cortisol secretion and characteristic symptoms such as full moon-like facial features and central obesity. Premenopausal women with CS rarely become pregnant because excessive glucocorticoid secretion inhibits the synthesis of gonadotropins, leading to impaired ovarian and endometrial function, and causing amenorrhea or oligomenorrhea.1 Furthermore, even when women with CS become pregnant, the incidence of severe complications is high. CS can cause maternal hypertension, diabetes/glucose intolerance, osteopenia/osteoporosis, preeclampsia, pulmonary edema, heart failure, opportunistic infections, and even death. Additionally, CS can potentially cause stillbirth, prematurity, and intrauterine fetal growth restriction.1–6 Therefore, CS must be detected at an early stage in pregnancy; however, CS may go undetected because of the overlapping signs of preeclampsia and/or gestational diabetes.

A cortisol-secreting adrenal tumor is the underlying cause of CS, and laparoscopic adrenalectomy is the standard treatment to it. Medical treatment of CS can include medications that inhibit 11β-hydroxylase, such as metyrapone and osilodrostat, but surgical treatment is considered if the disease is difficult to control with medical treatment. Nonobstetric surgery during pregnancy is performed in 1%–2% of pregnant women.7 Although general anesthesia is relatively safe during pregnancy, the indication for the surgery must be carefully considered because of potential risks such as neurodevelopmental delay, sudden death, etc.

Herein, we present a case of a pregnant woman diagnosed with CS who underwent unilateral laparoscopic adrenalectomy by a retroperitoneal approach without any problems.

Case presentation

The patient was a 28-year-old primiparous woman. Since around 12 weeks of pregnancy, she has experienced facial and lower limb edema; gained 6-kg weight in 1 month; increased facial acne; and experienced subcutaneous bleeding on the forearms, red abdominal dermatitis, proximal muscle weakness, palpitations, insomnia, and decreased vision in eyes. Her symptoms gradually worsened from 14 weeks, and she was referred to our hospital to clarify the cause at 18 weeks of pregnancy.

Adrenal CS was suspected on the basis of her Cushing’s signs, cortisol 25 μg/dL, and adrenocorticotropic hormone <1.5 pg/mL. She had hypokalemia, hypogammaglobulinemia, and liver dysfunction, and her condition was rapidly worsening. Given her pregnant state, she was admitted for intensive testing for the case of CS from 19 weeks of pregnancy. MRI revealed a well-defined 38-mm left adrenal tumor, which was the cause of the adrenal CS (Fig. 1). She was started on metyrapone with 250 mg per day, which increased androgens (0.53–0.69 ng/mL in 1 week). We considered that the management of CS by medication alone would be challenging and performed adrenalectomy during her pregnancy. The dose of metyrapone was increased to 1000 mg per day eventually.

Details are in the caption following the image

Magnetic resonance imaging on admission shows a left adrenal tumor with a long axis of 38 mm (arrowhead). Signal reduction was partially observed on opposed-phase images, leading to diagnosis of cortical adenoma.

She was admitted to the hospital at 23 weeks and 2 days of gestation, and laparoscopic left adrenalectomy was performed via a retroperitoneal approach in the right lateral and jackknife position on the following day (Fig. S1). During the surgery, blood pressure was carefully controlled by an anesthesiologist and the patient’s position and fetal heart rate were monitored by an obstetrician. The operation time, insufflation time, and general anesthesia time were 68, 59, and 123 min, respectively, and the blood loss volume was 75 mL, without any complications. Pathological findings revealed an adrenocortical adenoma. The specimen was positive for one of the nine Weiss criteria (Fig. 2).

Details are in the caption following the image

(a) Intraoperative findings of the retroperitoneal approach. Arrowheads indicate the tumor. (b) Gross appearance of the resected adrenal tumor; a brownish-toned, substantial mass, 60 × 34 × 15 mm in size. (c, d) Hematoxylin–eosin staining showed that nodular lesion with a fibrous capsule, with foci of homogeneous cells with eosinophilic or pale, foamy sporangia and small round nuclei.

Postoperatively, metyrapone was discontinued and both lower leg edema, facial acne, fatigue, and muscle weakness improved. Metyrapone was discontinued after surgery. Hydrocortisone, which had been administered at 150 mg/day during the perioperative period, was reduced every few weeks and was taken at 30 mg/day at delivery. She delivered by cesarean section at 38 weeks and 2 days of gestation, with good outcomes for the mother and her infant. Hydrocortisone was discontinued 15 weeks after delivery.

We showed the changes in cortisol and ACTH from the first visit to postpartum (Fig. 3).

Details are in the caption following the image

The transition of Cortisol and ACTH. Cortisol decreases rapidly after surgery and rises again before delivery. As cortisol improved, ACTH also increased.

Discussion

CS seldom occurs during pregnancy. Symptoms such as weight gain, skin striae, fatigue, and a round face can also occur in normal pregnancies. The dexamethasone suppression test can result in false positives because of ACTH produced by placenta in normal pregnancy. During pregnancy, there is a physiological state of high cortisol levels. The disappearance of diurnal rhythm is a useful indicator for diagnosis of CS in pregnancy because circadian rhythm is maintained in normal pregnancy. Useful diagnostic criteria include urine cortisol levels greater than three times the upper limit of normal, loss of diurnal cortisol rhythm, and presence of adrenal tumors on MRI.

The pharmacologic treatment of endogenous cortisol is complex, and hormonal management is challenging. While the management of the cortisol levels is important, metyrapone is a risk factor for gestational hypertension and may inhibit fetal cortisol production by crossing the placenta.1–6, 8–12

In this case, because androgens were also elevated and drug management was expected to be challenging, the surgery was aggressively considered. Despite the reports of successful adrenalectomy is after 28 weeks of gestation,6, 13, 14 The surgery should be performed by an experienced team between 14 and 30 weeks of pregnancy, that is, after organogenesis phase and before the fetus grows too large.1, 13, 15

A few pregnant women with adrenal CS undergo adrenalectomy. However, the laparoscopic approach is safe, and maternal and fetal complications were higher in women who did not undergo surgery.16 Less postoperative pain, faster wound healing, and faster postoperative recovery are the main advantages of laparoscopic surgery.17

In pregnant women, pneumoperitoneal pressure should be kept <12 mmHg because increased intraabdominal pressure decreases placental blood flow and can cause fetal acidosis due to the absorption of carbon dioxide used for insufflation.

Laparoscopic adrenalectomy can be safely performed through both transperitoneal and retroperitoneal approaches.18 However, in pregnant women, performing the surgery by the retroperitoneal approach in the lateral position is preferable to prevent putting pressure on the fetus during the surgery. The retroperitoneal approach is advantageous, as less pressure is placed on the uterus and adhesions are prevented. After taking the lateral position, the obstetrician is advised to check the position and confirm that the abdomen is not compressed and that the fetal heart rate is normal.

Conclusions

We present a case of a pregnant woman diagnosed with adrenal CS who underwent a unilateral laparoscopic adrenalectomy by a retroperitoneal approach without any problems. Adrenalectomy is a useful treatment when CS is difficult to control despite metyrapone and other medical support.

Author contributions

Nobuyoshi Takeuchi: Conceptualization; methodology; project administration; writing – original draft. Yusuke Imamura: Conceptualization; methodology; supervision; writing – review and editing. Kazuki Ishiwata: Data curation; supervision. Manato Kanesaka: Data curation; supervision. Yusuke Goto: Data curation; supervision. Tomokazu Sazuka: Data curation; supervision. Sawako Suzuki: Data curation; supervision. Hisashi Koide: Data curation; supervision. Shinichi Sakamoto: Data curation; supervision. Tomohiko Ichikawa: Data curation; supervision.

Conflict of interest

The authors declare no conflicts of interest.

Approval of the research protocol by an Institutional Reviewer Board

Not applicable.

Informed consent

Informed consent for the release of the case report and accompanying images has been obtained from the patient.

Registry and the Registration No. of the study/trial

Not applicable.

From https://onlinelibrary.wiley.com/doi/10.1002/iju5.12637

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Persistent vs Recurrent Cushing’s Disease Diagnosed Four Weeks Postpartum

Posted on September 9, 2022 by MaryO

Abstract

Background. Cushing’s disease (CD) recurrence in pregnancy is thought to be associated with estradiol fluctuations during gestation. CD recurrence in the immediate postpartum period in a patient with a documented dormant disease during pregnancy has never been reported. Case Report. A 30-year-old woman with CD had improvement of her symptoms after transsphenoidal resection (TSA) of her pituitary lesion. She conceived unexpectedly 3 months postsurgery and had no symptoms or biochemical evidence of recurrence during pregnancy. After delivering a healthy boy, she developed CD 4 weeks postpartum and underwent a repeat TSA. Despite repeat TSA, she continued to have elevated cortisol levels that were not well controlled with medical management. She eventually had a bilateral adrenalectomy. Discussion. CD recurrence may be higher in the peripartum period, but the link between pregnancy and CD recurrence and/or persistence is not well studied. Potential mechanisms of CD recurrence in the postpartum period are discussed below. Conclusion. We describe the first report of recurrent CD that was quiescent during pregnancy and diagnosed in the immediate postpartum period. Understanding the risk and mechanisms of CD recurrence in pregnancy allows us to counsel these otherwise healthy, reproductive-age women in the context of additional family planning.

1. Introduction

Despite a relatively high prevalence of Cushing’s syndrome (CS) in women of reproductive age, it is rare for pregnancy to occur in patients with active disease [1]. Hypercortisolism leads to infertility through impairment of the hypothalamic gonadal axis. Additionally, while Cushing’s disease (CD) is the leading etiology of CS in nonpregnant adults, it is less common in pregnancy, accounting for only 30–40% of the CS cases in pregnant women [2]. It has been suggested that in CD there is hypersecretion of both cortisol and androgens, impairing fertility to a greater extent, while in CS of an adrenal origin, hypersecretion is almost exclusively of cortisol with minimal androgen production [3]. Regardless of the cause, active CS in pregnancy is associated with a higher maternal and fetal morbidity, hence, prompt diagnosis and treatment are essential.

Pregnancy is considered a physiological state of hypercortisolism, and the peripartum period is a common time for women to develop CD [3, 4]. A recent study reported that 27% of reproductive-age women with CD had onset associated with pregnancy [4]. The high rate of pregnancy-associated CD suggests that the stress of pregnancy and peripartum pituitary corticotroph hyperstimulation may promote or accelerate pituitary tumorigenesis [4–6]. During pregnancy, the circulating levels of corticotropin-releasing hormone (CRH) in the plasma increase exponentially as a result of CRH production by the placenta, decidua, and fetal membranes rather than by the hypothalamus. Unbound circulating placental CRH stimulates pituitary ACTH secretion and causes maternal plasma ACTH levels to rise [4]. A review of the literature reveals many studies of CD onset during the peripartum period, but CD recurrence in the peripartum period has only been reported a handful of times [7–10]. Of these, most cases recurred during pregnancy. CD recurrence in the immediate postpartum period has only been reported once [7]. Below, we report for the first time a case of CD recurrence that occurred 4 weeks postpartum, with a documented dormant disease throughout pregnancy.

2. Case Presentation

A 30-year-old woman initially presented with prediabetes, weight gain, dorsal hump, abdominal striae, depression, lower extremity weakness, and oligomenorrhea with a recent miscarriage 10 months ago. Diagnostic tests were consistent with CD. Results included the following: three elevated midnight salivary cortisols: 0.33, 1.38, and 1.10 μg/dL (<0.010–0.090); 1 mg dexamethasone suppression test (DST) with cortisol 14 μg/dL (<1.8); elevated 24 hr urine cortisol (UFC) measuring 825 μg/24 hr (6–42); ACTH 35 pg/mL (7.2–63.3). MRI of the pituitary gland revealed a left 4 mm focal lesion (Figure 1(a)). After transsphenoidal resection (TSA), day 1, 2, and 3 morning cortisol values were 18, 5, and 2 μg/dL, respectively. Pathology did not show a definitive pituitary neoplasm. She was rapidly titrated off hydrocortisone (HC) by six weeks postresection. Her symptoms steadily improved, including improved energy levels, improved mood, and resolution of striae. She resumed normal menses and conceived unexpectedly around 3 months post-TSA. Hormonal evaluation completed a few weeks prior to her pregnancy indicated no recurrence: morning ACTH level, 27.8 pg/mL; UFC, 5 μg/24 hr; midnight salivary cortisol, 0.085 and 0.014 μg/dL. Her postop MRI at that time did not show a definitive adenoma (Figure 1(b)). During pregnancy, she had a normal oral glucose tolerance test at 20 weeks and no other sequela of CD. Every 8 weeks, she had 24-hour urine cortisol measurements. Of these, the highest was 93 μg/24 hr at 17 weeks and none were in the range of CD (Table 1). Towards the end of her 2nd trimester, she started to complain of severe fatigue. Given her low 24 hr urine cortisol level of 15 μg/24 hr at 36 weeks gestation, she was started on HC. She underwent a cesarean section at 40 weeks gestation for oligohydramnios and she subsequently delivered a healthy baby boy weighing 7.6 pounds with APGAR scores at 1 and 5 minutes being 9 and 9. HC was discontinued immediately after delivery. Around four weeks postpartum she developed symptoms suggestive for CD. Diagnostic tests showed an elevated midnight salivary cortisol of 0.206 and 0.723 μg/dL, and 24-hour urine cortisol of 400 μg/24 hr. MRI pituitary illustrated a 3 mm adenoma in the left posterior region of the gland, which was thought to represent a recurrent tumor (Figure 1(c)). A discrete lesion was found and resected during repeat TSA. Pathology confirmed corticotroph adenoma with MIB-1 < 3%. On postoperative days 1, 2, and 3, the cortisol levels were 26, 10, and 2.8 μg/dL, respectively. She was tapered off HC within one month. Her symptoms improved only slightly and she continued to report weight gain, muscle weakness, and fatigue. Three months after repeat TSA, biochemical data showed 1 out of 2 midnight salivary cortisols elevated at 0.124 μg/dL and elevated urine cortisol of 76 μg/24 hr. MRI pituitary demonstrated a 3 × 5 mm left enhancement, concerning for residual or enlarged persistent tumor. Subsequent lab work continued to show a biochemical excess of cortisol, and the patient was started on metyrapone but reported no significant improvement of her symptoms and only mild improvement of excess cortisol. After a multidisciplinary discussion, the patient made the decision to pursue bilateral adrenalectomy, as she refused further medical management and opted against radiation given the risk of hypogonadism.

(a)
(a)
(b)
(b)
(c)
(c)
(a)
(a)(b)
(b)(c)
(c)
Figure 1 
(a) Initial: MRI pituitary with and without contrast showing a coronal T1 postcontrast image immediately prior to our patient’s pituitary surgery. The red arrow points to a 3 × 3 × 5 mm hypoenhancing focus representing a pituitary microadenoma. (b) Postsurgical: MRI pituitary with and without contrast showing a coronal T1 postcontrast image obtained three months after transsphenoidal pituitary surgery. The red arrow shows that a hypoenhancing focus is no longer seen and has been resected. (c) Postpartum: MRI pituitary with and without contrast showing a coronal T1 postcontrast image obtained four weeks postpartum. The red arrow points to a 3 mm relatively hypoenhancing lesion representing a recurrent pituitary adenoma.
Table 1 
24-hour urine-free cortisol measurements collected approximately every 8 weeks throughout our patient’s pregnancy.

3. Discussion

The symptoms and signs of Cushing’s syndrome overlap with those seen in normal pregnancy, making diagnosis of Cushing’s disease during pregnancy challenging [1]. Potential mechanisms of gestational hypercortisolemia include increased systemic cortisol resistance during pregnancy, decreased sensitivity of plasma ACTH to negative feedback causing an altered pituitary ACTH setpoint, and noncircadian secretion of placental CRH during pregnancy causing stimulation of the maternal HPA axis [5]. Consequently, both urinary excretion of cortisol and late-night salivary cortisol undergo a gradual increase during normal pregnancy, beginning at the 11th week of gestation [2]. Cushing’s disease is suggested by 24-hour urinary-free cortisol levels greater than 3-fold of the upper limit of normal [2]. It has also been suggested that nocturnal salivary cortisol be used to diagnose Cushing’s disease by using the following specific trimester thresholds: first trimester, 0.25 μg/dL; second trimester, 0.26 μg/dL; third trimester 0.33, μg/dL [11]. By these criteria, our patient had no signs or biochemical evidence of CD during pregnancy but developed CD 4 weeks postpartum.

A recent study by Tang et al. proposed that there may be a higher risk of developing CD in the peripartum period, but did not test for CD during pregnancy, and therefore was not able to definitively say exactly when CD onset occurred in relation to pregnancy [4]. Previous literature suggests that there may be a higher risk of ACTH-secreting pituitary adenomas following pregnancy as there is a significant surge of ACTH and cortisol hormones at the time of labor. This increased stimulation of the pituitary corticotrophs in the immediate postpartum period may promote tumorigenesis [6]. It has also been suggested that the hormonal milieu during pregnancy may cause accelerated growth of otherwise dormant or small slow-growing pituitary corticotroph adenomas [4, 5]. However, the underlying mechanisms of CD development in the postpartum period have yet to be clarified. We highlight the need for more research to investigate not only the development, but also the risk of CD recurrence in the postpartum period. Such research would be helpful for family planning.

4. Conclusion

Hypothalamic-pituitary-adrenal axis activation during pregnancy and the immediate postpartum period may result in higher rates of CD recurrence in the postpartum period, as seen in our patient. In general, more testing for CS in all reproductive-age females with symptoms suggesting CS, especially during and after childbirth, is necessary. Such testing can also help us determine when CD occurred in relation to pregnancy, so that we can further understand the link between pregnancy and CD occurrence, recurrence, and/or persistence. Learning about the potential mechanisms of CD development and recurrence in pregnancy will help us to counsel these reproductive-age women who desire pregnancy.

Abbreviations

CD: Cushing’s disease
TSA: Transsphenoidal resection
DST: Dexamethasone suppression test
ACTH: Adrenocorticotropic hormone
MRI: Magnetic-resonance imaging
HC: Hydrocortisone
CTH: Corticotroph-releasing hormone
HPA: Hypothalamic-pituitary-adrenal.

Data Availability

The data used to support the findings of this study are included within the article.

Additional Points

Note. Peripartum refers to the period immediately before, during, or after pregnancy and postpartum refers to any period after pregnancy up until 1 year postdelivery.

Disclosure

This case report is a follow up to an abstract that was presented in ENDO 2020 Abstracts. https://doi.org/10.1210/jendso/bvaa046.2128.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank Dr. Puneet Pawha for his help in reviewing MRI images and his suggestions.

References

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Copyright © 2022 Leena Shah et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

From https://www.hindawi.com/journals/crie/2022/9236711/

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

Pregnancy Doesn’t Boost Cushing Disease Recurrences

Posted on March 25, 2022 by MaryO

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.

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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.

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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

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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. 

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