Adrenal Diseases During Pregnancy: Pathophysiology, Diagnosis And Management Strategies

Posted on January 15, 2026 by MaryO

Am J Med Sci. 2014 Jan;347(1):64-73. doi: 10.1097/MAJ.0b013e31828aaeee.

Author information

Abstract

: Adrenal diseases-including disorders such as Cushing’s syndrome, Addison’s disease, pheochromocytoma, primary hyperaldosteronism and congenital adrenal hyperplasia-are relatively rare in pregnancy, but a timely diagnosis and proper treatment are critical because these disorders can cause maternal and fetal morbidity and mortality.

Making the diagnosis of adrenal disorders in pregnancy is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. In addition, pregnancy is marked by several endocrine changes, including activation of the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis.

The aim of this article was to review the pathophysiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

PMID:
23514671
[PubMed – in process]

From http://www.ncbi.nlm.nih.gov/pubmed/23514671

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A Case of Recurrent Cushing’s Disease With Optimised Perinatal Outcomes

Posted on December 21, 2025 by MaryO

Abstract

Summary

This is a case of a patient with a 10-year history of Cushing’s disease (CD) that was previously treated with transsphenoidal pituitary tumour resection. Conception occurred spontaneously, and during early pregnancy recurrent CD became apparent both clinically and biochemically. Repeat transsphenoidal surgery took place during the second trimester, and the high-risk pregnancy resulted in a live neonate. Despite evidence of hypercortisolism and recurrent CD at 6 months postpartum, the patient had a second successful, uncomplicated pregnancy, further adding to the rarity and complexity of this case. Pregnancy in CD is rare because hypercortisolism seen in CD suppresses gonadotropin release, leading to menstrual irregularities and infertility. Diagnosis of CD is particularly challenging because many clinical and biochemical features of normal pregnancy overlap considerably with those seen in CD. Diagnosis and treatment are extremely important to reduce rates of perinatal morbidity and mortality.

Learning points

  • Hypercortisolism suppresses gonadotropin release, leading to menstrual irregularities and infertility. In CD, hypersecretion of both androgens and cortisol further contributes to higher rates of amenorrhoea and infertility.
  • Pregnancy itself is a state of hypercortisolism, with very few studies detailing normal ranges of cortisol in each trimester of pregnancy for midnight salivary cortisol and urinary free cortisol testing.
  • Treatment of CD reduces maternal morbidity and rates of foetal loss, and can be either surgical (preferred) or medical.
  • CD can relapse, often many years after initial surgery.
  • There are a limited number of cases of Cushing’s syndrome in pregnancy, therefore, the best possible treatment is difficult to determine and should be individualised to the patient.

Background

CD is rare in the general population. It is even rarer to present as a clinical conundrum during pregnancy. Diagnosis is challenging due to the overlap of physiological hormonal changes during pregnancy with features of Cushing’s syndrome, and it is further complicated by limited data for cortisol reference ranges in a pregnant state. The prognostic benefits of treatment of CD in pregnancy in reducing perinatal morbidity and mortality must be carefully weighed up against the risks of surgery and/or medical management in pregnancy.

Case presentation

The patient was a 31-year-old female diagnosed with Cushing’s disease at age 20 years. Initial clinical features were oligomenorrhoea, weight gain, hypertension, and impaired glucose tolerance. She had markedly elevated 24 h urinary free cortisol (UFC) of 1,984 nmol/day, which was six times the upper limit of normal (ULN). Results of a 1 mg dexamethasone suppression test (DST) showed failure to suppress cortisol levels, with an elevated morning cortisol of 695 nmol/L (reference range (RR): 100–690). ACTH levels remained inappropriately normal at 7.3 pmol/L (RR: < 12.1), suggesting ACTH-dependent hypercortisolism. A 5 mm by 4.4 mm microadenoma was identified on magnetic resonance imaging (MRI) scan of the pituitary gland, and she underwent initial transsphenoidal pituitary adenectomy. Histopathological examination demonstrated positive staining for adrenocorticotrophic hormone (ACTH). Immediately after surgery, she required hydrocortisone and levothyroxine replacement for several months, which was gradually weaned and eventually ceased. She had routine MRI with gadolinium and biochemical surveillance for 5 years, which showed cortisol levels within the normal ranges and no visible pituitary lesion on imaging, and she was then lost to follow-up. Results of 1 mg DST and 24 h UFC measurements were not available from this time period. Other medical history was significant for mild depression. The patient was a non-smoker and did not drink alcohol.

At age 30 years, the patient experienced weight gain and facial rounding, prompting an endocrinology referral. While awaiting review, she spontaneously achieved conception and was confirmed to be 6 weeks’ gestation at time of the first visit. An early diagnosis of gestational diabetes mellitus was made, and she commenced insulin therapy. Gestational hypertension was also confirmed, treated with methyldopa 500 mg mane and 250 mg midi. Other medications included folic acid 5 mg daily, cholecalciferol, and ferrous sulphate.

The patient was referred to a tertiary hospital high-risk pregnancy service for ongoing care. She was initially reviewed at 8 + 5 weeks’ gestation and was noted to have plethora, round facies, and prominent dorsocervical fat pads. Central adiposity with violaceous striae over the lower abdomen was evident. Visual fields were normal to gross confrontation, and formal visual field assessment was confirmed to be normal. Weight was 70 kg, with BMI 26.7 kg/m2.

As pregnancy progressed, insulin and antihypertensive requirements increased, with an additional methyldopa 250 mg nocte required to keep blood pressure at target.

Investigation

The 24 h UFC was 450 nmol/24 h (1.5× ULN of non-pregnant reference range). Late-night salivary cortisol (LNSC) was 17 nmol/L (non-pregnant reference range <8 nmol/L). Serum pathology results are shown in Table 1. MRI brain performed at 6 weeks’ gestation revealed a possible 6 by 4 mm nodule in the left lateral aspect of the sella (Fig. 1). IV contrast was not used as the patient was within the first trimester.

Table 1Laboratory investigations at initial consultation (8 + 5 weeks gestation). Bold values indicate abnormal results.

Investigation Result Reference range
Fasting glucose, mmol/L 5.2
HbA1c, % 5.4
24 h urinary cortisol, nmol/d 450 54–319
Cortisol (08:22), nmol/L 521 138–650
Midnight salivary cortisol, nmol/L 17 <8
ACTH, pmol/L 10 <12.1
IGF-1, nmol/L 31 12–42
Growth hormone, mIU/L 2.9 0–15
TSH, mIU/L 2.34 0.4–3.2
FT4, pmol/L 11.9 11–17
Figure 1
Figure 1
MRI brain without IV contrast performed in the first trimester of the patient’s first pregnancy, demonstrating a T2 hypointense lesion in the left lateral aspect of the sella, which is most likely consistent with a pituitary adenoma.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 4; 10.1530/EDM-25-0092

At 14 weeks’ gestation, the repeat 24 h UFC was 542 nmol/L and LNSC was 17 nmol. There is a lack of pregnancy-specific reference ranges for 24 h UFC or LNSC measurements, making it difficult to make a definitive biochemical diagnosis. After careful discussion in a multidisciplinary team meeting, she proceeded with bilateral inferior petrosal sinus sampling (IPSS), which demonstrated a central to peripheral gradient with values presented in Table 2.

Table 2Results of bilateral inferior petrosal sinus sampling. ACTH (ng/L) at different timepoints are presented.

0 2 min 5 min 10 min 15 min
Right 258 823 1,040 864 728
Left 73 196 228 263 234
Peripheral 12 41 56 81 86
Right: peripheral 21.50 20.07 18.57 10.67 8.46
Left: peripheral 6.08 4.78 4.07 3.25 2.72

Treatment

The patient underwent transsphenoidal resection of her adenoma at 17+ weeks’ gestation. She recovered uneventfully.

Day 1 postoperative cortisol level remained elevated at 706 nmol/L, falling to 587 nmol/L by Day 3. Postoperative steroid treatment was not required.

Histopathological examination demonstrated a pituitary adenoma with mild nuclear atypia and infrequent positive ACTH staining (Fig. 2). In addition to the tumour and normal pituitary tissue, there was also abundant eosinophilic proteinaceous material present, which may have suggested contents of an associated cyst, although presence of cyst lining was not present to confirm this diagnosis. A small fragment of included bone appeared invaded by the adenoma within the resected tissue.

Figure 2
Figure 2
Positive ACTH staining in pituitary adenoma.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 4; 10.1530/EDM-25-0092

Outcome and follow-up

The patient’s insulin and antihypertensive requirements plateaued postoperatively. Serial ultrasound showed that the fetal size was consistently in the 15th percentile. There were no features of preeclampsia throughout gestation.

At 35 + 5 weeks’ gestation, she had premature rupture of membranes and delivered a healthy live male infant weighing 2,250 g via normal vaginal delivery. Diabetes and hypertension resolved promptly after delivery, with cessation of insulin and antihypertensive medications.

At 5 weeks postpartum morning cortisol was within normal range at 265 nmol/L, with ACTH 6.8 pmol/L. At 10 weeks postpartum, the 24 h UFC was within normal limits at 136 nmol/day, and a 1 mg DST showed a detectable, equivocal cortisol level of 98 nmol/L. Repeat MRI pituitary was performed 2 months postpartum, which did not show any residual pituitary adenoma. No pituitary hormone replacement was required.

By 6 months postpartum, repeat 1 mg DST showed failure to suppress cortisol, with cortisol level at 154 nmol/L (RR without dexamethasone: 138–650 nmol/L), suggesting residual CD. Ambulatory blood pressure monitoring revealed essential hypertension, with average BP 141/101 mmHg across 24 h, requiring treatment with methyldopa. Despite evidence of residual CD, the patient desired a second pregnancy. Reassuringly, her cortisol burden was low, with LNSC 5 nmol/L (RR: < 8) and 24 h UFC 143 nmol/day (non-pregnant RR: 54–319), both within reference range. No definite lesion was identified on MRI brain with intravenous contrast. Extensive discussions between the endocrinologist, maternal–foetal medicine specialist, neurosurgeon, and the patient were held. The pros and cons of pursuing further treatment such as radiotherapy versus proceeding with pregnancy despite suggestion of active Cushing’s disease were explicitly discussed.

The patient confirmed her second pregnancy 11 months after the birth of her first child, and this proceeded without complications. There was no evidence of gestational diabetes on 75 g glucose tolerance tests performed at 16 and 26 weeks’ gestation. Blood pressure was well managed on methyldopa alone. She delivered a healthy male infant via normal vaginal delivery at 38 weeks’ gestation and breastfed successfully. MRI was performed at 16 weeks postpartum and did not show an appreciable sella/suprasellar mass. Repeat 24 h UFC was 275 nmol/day, consistent with ongoing CD. Clinical features of CD returned, included central adiposity, liver function test derangement, and raised HbA1c with fasting hyperinsulinaemia. Pituitary radiation therapy was discussed, including the possibility of more than one dose being required, the strong likelihood of inducing panhypopituitarism, and the unknown duration of time between radiation and remission (1). The alternative option of medical management with osilodrostat was discussed, given its recent availability and government subsidy in Australia. The patient was recently commenced on osilodrostat 1 mg twice daily after ECG attendance to exclude prolonged QTc, and patient education regarding the potential risk of hypoadrenalism and when to seek medical attention.

Discussion

Managing Cushing’s disease (CD) in pregnancy is complex and requires a multidisciplinary approach, as recurrence can occur years after initial remission. Suspected Cushing’s syndrome (CS) requires careful assessment. In cases where active disease poses significant maternal and foetal risks, transsphenoidal pituitary surgery can be safely performed in the second trimester. CD increases the risk of gestational diabetes and hypertension, requiring close monitoring to optimise outcomes. Postpartum, persistent hypercortisolism may indicate recurrence, highlighting the need for long-term endocrine follow-up. Despite mild residual disease, successful pregnancies are possible with appropriate monitoring and management, emphasising the importance of thorough family planning discussions.

UFC values are twice as high in pregnant patients compared to non-pregnant controls (2). In the first trimester of normal pregnancy, UFC values are normal, but by the third trimester, they increase three-fold up to values seen in CS (3). Therefore, CS should only be suspected when UFC values in the second and third trimesters are greater than three times the upper limit of normal (3). LNSC is a useful screening test because in CS, the usual circadian nadir of cortisol secretion is lost. At least 2–3 UFC and/or NSC screening tests are recommended (4). Lopes et al. (5) established reference values for LNSC with suggested normal ranges of 0.8–6.9 nmol/L in the first trimester, 1.1–7.2 nmol/L in the second trimester, and 1.9–9.1 nmol/L in the third trimester (5). The use of a 1 mg DST in pregnancy is not recommended because the hypothalamus–pituitary–adrenal (HPA) axis response to exogenous glucocorticoids is blunted, making it difficult to interpret test results (3).

Adrenal adenomas are responsible for 40–50% of CS cases in pregnancy, while CD causes 33% (3). In non-pregnant patients, ACTH levels are useful to classify the likely cause of CS. Undetectable ACTH levels cannot be relied upon for diagnosis in pregnancy because ACTH levels are elevated in pregnancy (3). Using high-dose dexamethasone suppression testing (HDST) as an initial test in pregnant patients has been recommended (3). A lack of suppression of ACTH with administration of high-dose dexamethasone suggests adrenal aetiology. However, HDST is not always definitive (3). Ultrasound imaging of the adrenal glands is also recommended as an initial investigation because most adrenal lesions can be visualised (3, 5). Pregnancy complicates visualisation of a pituitary mass by MRI imaging because physiologic enlargement of the pituitary gland during pregnancy may mask small tumours (6). Non-contrast MRI has reduced sensitivity for detection of CD. However, gadolinium contrast is not recommended in pregnant women (7).

Inferior petrosal sinus sampling (IPSS) is the gold standard for diagnosing CD in the non-pregnant population (4). The most recent guidelines for diagnosis of CS suggest that IPSS is not necessary for diagnosis if MRI clearly shows a tumour >10 mm in the context of dynamic test results and clinical features that also strongly suggest CD (4). Lindsay and colleagues (3) caution the use of IPSS unless prior non-invasive testing remains equivocal due to risks of thromboembolism and exposure to radiation posed by IPSS (3). However, these risks can be mitigated with extra precautions during pregnancy, including use of lead barrier protection, a direct jugular approach, and with the procedure occurring at a specialised centre (3).

Treatment of CS in pregnancy should be individualised depending on the patient presentation and gestational age (4). Active treatment of CS, by either medical or surgical intervention, reduces maternal morbidity and rates of foetal loss (4). Surgery is usually preferred because there are fewer complications at delivery and it has high rates of remission (8). Surgery reduces rates of perinatal and maternal morbidity but does not reduce rates of preterm birth and intrauterine growth restriction (IUGR) (9). Pituitary or adrenal surgery should ideally be done in the second trimester, before week 24 of pregnancy, in a high-volume centre with multidisciplinary team input (8). There is a risk of spontaneous abortion with anaesthesia given in the first trimester and an increased risk of premature labour with anaesthesia given in the third trimester (7).

Unfortunately, CD can recur, and 50% of recurrence occurs within 50 months of pituitary surgery (1, 4). Recurrence is defined as ongoing clinical and biochemical evidence of hypercortisolism after an initial period of remission. Factors that increase the likelihood of postoperative remission included the identification of a tumour on MRI pre-surgery, no invasion of the sinus cavernous by the adenoma, older age (greater than 35 years), low postoperative cortisol and ACTH levels, and long-term hypocortisolism (greater than 1 year) (1). A second pituitary surgery is often the first-line treatment option in recurrence, which has overall lower rates of remission compared to first surgery and increased risk of hypopituitarism due to scar tissue in the pituitary and often the need for more aggressive surgical technique (1). Both fractionated radiotherapy and stereotactic radiosurgery are therapeutic options and achieve high rates of remission (1).

There are no medications that are approved for treatment of CD in pregnancy, although the latest guidelines suggest consideration of metyrapone, ketoconazole, or cabergoline (4, 6). The newer agent, osilodrostat inhibits the enzymes 11-beta-hydroxylase and 18-hydroxylase, reducing production of cortisol and aldosterone respectively, thereby normalising UFC values, reducing systolic and diastolic blood pressure, fasting blood glucose levels, and improving body weight in clinical trials (10). There is no information on osilodrostat use and safety in pregnancy, but it is an effective agent in patients who are unsuitable for surgery and patients with recurrent disease after surgery (10). It is associated with risk of hypoadrenalism, prolongation of the QTc interval, and increased serum testosterone levels, particularly at higher doses (10). Each medication poses its own risk of side effects and therefore treatment must be individualised. Overall, medical treatment should only be used in pregnancy when surgical treatment is contraindicated (6).

Our case demonstrates a rare case of CD in pregnancy with no significant adverse perinatal outcomes for mother or baby, albeit late preterm delivery in the first pregnancy. Ongoing endocrinology surveillance is essential to monitor for recurrent CD.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

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

Patient consent

Written informed consent for publication of their clinical details was obtained from the patient.

Author contribution statement

Several case details and timeline of events were gathered by EW. This is a patient of SG.

References

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A Case of Adrenocorticotropin-dependent Cushing Syndrome with Osilodrostat Exposure in Early Pregnancy

Posted on December 13, 2025 by MaryO

Abstract

Osilodrostat is a novel treatment for adrenocorticotropin-dependent Cushing syndrome; however, its safety during pregnancy has not been reported. This case involves a patient with Cushing disease who became pregnant while on osilodrostat. She was diagnosed at 31 years of age and underwent pituitary tumor removal. After a relapse at 35 years of age, she was initially treated with metyrapone but switched to osilodrostat and hydrocortisone because of nausea, achieving reasonable cortisol control. At 37 years of age, she unknowingly became pregnant despite irregular periods, and the pregnancy was detected at 16 weeks because of ongoing nausea. Osilodrostat was stopped, and she was started on pasireotide and metyrapone. The pregnancy proceeded normally despite elevated urinary free cortisol levels, although she contracted COVID-19 at 25 weeks. At 26 weeks and 1 day, preterm rupture of membranes and breech presentation led to an emergency cesarean section. The newborn had no adrenal insufficiency and developed normally. This case prompts consideration of whether osilodrostat can be used during pregnancy if risks are justified. Pasireotide is rarely used in pregnancy and may have limited effectiveness, but when given, can cause hyperglycemia because of insulin and incretin suppression and should be monitored carefully.

Introduction

Active Cushing syndrome decreases fertility, which explains its rarity in pregnancy. Fewer than 250 cases have been documented [1]. Whether it is ACTH-dependent or ACTH-independent, this disease poses significant risks to both mother and fetus. Its maternal complications include hypertension, preeclampsia, and diabetes [2], whereas the fetal risks include miscarriage, intrauterine growth restriction, and prematurity [3]. Given its rarity, there is no established standard of care for Cushing disease during pregnancy. Surgery offers a potential cure, but it can cause hypopituitarism and may not be feasible in the absence of a visible tumor [4]. Meanwhile, there are also risks associated with radiotherapy and pharmacological treatments [1, 4]. The use of pasireotide, a somatostatin analog, for the treatment of a GH-secreting pituitary macroadenoma without complications has been reported in only 1 case during pregnancy [5]. To the best of our knowledge, this drug has not been used for Cushing disease before. Osilodrostat, like metyrapone, is a newer steroidogenesis inhibitor that blocks 11β-hydroxylase in the adrenal glands. It is effective for both ACTH-dependent and ACTH-independent Cushing syndrome [6]. However, it is contraindicated in pregnancy because of its proven teratogenic effects in animal studies [7]. As a result, data on its use in human pregnancy are lacking. Understanding the normal physiology of the hypothalamic-pituitary-adrenal (HPA) axis in pregnancy is essential. In normal pregnancy, the maternal levels of corticotropin-releasing hormone, ACTH, and cortisol rise both in the serum and urine because of placental production [8, 9]. Although cortisol levels rise, only about 10% crosses the placenta because of 11β-hydroxysteroid dehydrogenase activity [10]. Fetal cortisol production remains minimal until late gestation, as 3β-hydroxysteroid dehydrogenase activity stays low until then [10]. Thus, most fetal cortisol originates from maternal sources [11]. In late pregnancy, fetal adrenal 3β-hydroxysteroid dehydrogenase activity increases, thereby enhancing fetal cortisol synthesis and promoting maturation of the HPA axis [10]. This case report discusses a female patient with recurrent Cushing disease who conceived while taking osilodrostat, which she took until early pregnancy; she was later treated successfully with pasireotide and metyrapone.

Case Presentation

A 30-year-old woman developed moon facies, central obesity, muscle weakness, and amenorrhea. Elevated levels of ACTH and cortisol, along with a roughly 6-mm pituitary adenoma, confirmed a diagnosis of Cushing disease. At 31 years of age, she successfully underwent transsphenoidal surgery, but 4 years later, biochemical relapse occurred with no identifiable residual tumor on imaging (Fig. 1). The patient was initially treated with metyrapone, but because of nausea, this was switched to osilodrostat. A block-and-replace approach was taken with osilodrostat 3 mg/day and hydrocortisone 10 mg/day, after which her cortisol levels normalized, but the menstrual irregularities persisted (Fig. 1).

 

Changes in urinary free cortisol (UFC) and pituitary magnetic resonance imaging (MRI) findings over time. The MRI scans at diagnosis, after surgery, at recurrence, and before pregnancy are shown alongside ACTH, cortisol, and UFC levels. The blood tests indicated recurrence, but no tumor was seen on MRI. Cortisol levels improved after osilodrostat treatment.

Figure 1.

Changes in urinary free cortisol (UFC) and pituitary magnetic resonance imaging (MRI) findings over time. The MRI scans at diagnosis, after surgery, at recurrence, and before pregnancy are shown alongside ACTH, cortisol, and UFC levels. The blood tests indicated recurrence, but no tumor was seen on MRI. Cortisol levels improved after osilodrostat treatment.

Diagnostic Assessment

At 38 years of age, the patient presented with nausea. The patient was followed up with an upper gastrointestinal endoscopy revealing no abnormalities. After a prolonged period of nausea, a pregnancy test revealed that she was 16 weeks pregnant.

Treatment

At this point, she had been on osilodrostat, which was immediately stopped and replaced with pasireotide 10 mg every 4 weeks because of pregnancy. Later, 24-hour urinary free cortisol (UFC) levels increased, leading to an early increase in pasireotide dose to 20 mg after 3 weeks before the recommended 4-week period elapsed; the same dose was administered every 4 weeks thereafter. And the same time, the initiation of up to 1000 mg metyrapone daily (Fig. 2). The patient also had hyperglycemia, which prompted insulin initiation, and subcutaneous heparin was also added because of the risk of thrombosis. At 25 weeks of pregnancy, she developed pharyngeal pain and a cough, which quickly resolved. At 26 weeks and 1 day, she experienced preterm premature rupture of membranes with the fetus in breech position, necessitating an emergency cesarean section. During this time, she tested positive for severe acute respiratory syndrome coronavirus 2 via polymerase chain reaction; however, she remained asymptomatic. Hydrocortisone was given before delivery as a steroid cover. Postpartum, osilodrostat was resumed, and pasireotide/metyrapone was discontinued. Two months after delivery, her disease remained stable, with UFC at 62.0 μg/day (171 nmol/day), within the normal reference range of 26.0 to 187.0 μg/day (72-516 nmol/day).

 

Urinary free cortisol (UFC) levels and medications during pregnancy. The UFC levels during pregnancy are shown. The UFC levels increased after stopping osilodrostat, and these remained high even after starting pasireotide. Adding metyrapone led to a decrease in the UFC.

Figure 2.

Urinary free cortisol (UFC) levels and medications during pregnancy. The UFC levels during pregnancy are shown. The UFC levels increased after stopping osilodrostat, and these remained high even after starting pasireotide. Adding metyrapone led to a decrease in the UFC.

Outcome and Follow-up

A live baby girl was born with extremely low birth weight, weighing 871 g. She was admitted to the neonatal intensive care unit with Apgar scores of 2 and 10 at 1 and 5 minutes, respectively, and was temporarily placed on a ventilator because of respiratory distress syndrome. During her stay, no signs of adrenal insufficiency appeared, and blood samples taken at noon showed ACTH levels of 23.3 pg/mL (5.1 pmol/L) and cortisol levels of 2.7 µg/dL (74.5 nmol/L). The normal reference ranges in adults are 7.2 to 63.3 pg/mL (1.6-13.9 pmol/L) for ACTH and 4.5 to 21.1 µg/dL (124.2-582.1 pmol/L) for cortisol. She was discharged at 40 weeks’ corrected gestational age, with subsequent normal growth and development.

Discussion

It remains challenging to manage Cushing disease during pregnancy because of limited treatment options and fetal safety concerns. An important aspect of managing hypercortisolemia in pregnancy is understanding the physiological regulation of the maternal-fetal HPA axis. In infants with very low birth weight, cortisol levels measured within an hour after birth typically range from 3.6 to 10.8 µg/dL (99-298 nmol/L) [12]. Although the neonate in this case had lower cortisol levels (2.7 µg/dL, 74.5 nmol/L), the blood sample was taken around noon, a time when levels are usually lower. Nevertheless, no signs of adrenal insufficiency were observed. Because newborns develop a stable cortisol rhythm within the first month [13], these findings suggest adequate adrenal function. Better obstetric outcomes can be expected when maternal hypercortisolism is successfully managed, such as reduced rates of prematurity and low birth weight [14]. A previous case report noted successful delivery after treatment with metyrapone, targeting UFC levels below 150 µg/day (414 nmol/day) [15]. Metyrapone was necessary in this patient because the cortisol levels were rising despite pasireotide monotherapy. This was gradually titrated to control UFC levels, which achieved some success. We introduced pasireotide during pregnancy based on previous reports of its use in acromegaly without adverse fetal outcomes [5]. However, pasireotide carries significant risk of hyperglycemia because of its inhibitory effects on insulin and incretin secretion [16]; this was seen in our patient, who required insulin therapy. Although rarely used in pregnancy—with only 1 reported case to our knowledge—it may be considered a viable option if other treatments are unsuccessful or unsuitable. Osilodrostat is contraindicated during pregnancy because it has shown teratogenic effects in animal studies, leading to limited human data [6]. In this case, the patient was unknowingly exposed during early pregnancy. However, no fetal malformations were observed, and this could be attributed to the underdeveloped fetal adrenal cortex during early gestation, which mainly relies on maternal hormone supply [10]. Osilodrostat was resumed after delivery, achieving effective disease control and clinical stability. It is also essential to consider that the preterm birth in this case may have resulted from suboptimal cortisol control, maternal COVID-19 infection, and the use of osilodrostat and pasireotide—drugs with minimal clinical data for use during pregnancy. These factors cannot be excluded entirely. However, based on our expertise, the contraindication of osilodrostat in pregnancy may warrant reevaluation.

Learning Points

  • Osilodrostat should not be used during pregnancy. Although preterm birth in this case may have resulted from various factors—including limited clinical data on osilodrostat and pasireotide—that the neonate showed no congenital abnormalities or adrenal problems indicates that the current caution against using osilodrostat in pregnancy might need to be reconsidered.
  • In early pregnancy, the fetal adrenal glands are immature and dependent on maternal hormones, so the effects of drugs that inhibit adrenal steroid synthesis may be relatively minor.
  • Pasireotide is rarely used during pregnancy. If administered, close monitoring is necessary, as insulin and incretin suppression may induce hyperglycemia.

From https://academic.oup.com/jcemcr/article/3/12/luaf269/8327956?login=false

 

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Adrenal Cushing’s Syndrome in Pregnancy Complicated by Fetal Growth Restriction Following Retroperitoneoscopic Adrenalectomy

Posted on December 7, 2025 by MaryO

Abstract

A 29-year-old Japanese pregnant woman, G5P3A1, conceived spontaneously and was referred to our hospital because of uncontrolled hypertension at 24 weeks of gestation. On admission, she presented with physical findings characteristic of Cushing’s syndrome (CS), such as moon face, buffalo hump, and reddish-purple striae. Laboratory examination revealed hyperglycemia and hypercortisolism with suppressed adrenocorticotropic hormone levels. Imaging studies revealed a right adrenocortical adenoma, and the patient was clinically diagnosed with adrenal CS. At 28 weeks, she underwent retroperitoneoscopic adrenalectomy, which normalized maternal cortisol levels and improved metabolic abnormalities. Despite these improvements, she was diagnosed with fetal growth restriction accompanied by superimposed preeclampsia at approximately 33 weeks. The maternal serum soluble fms-like kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio was markedly elevated. At 36 weeks, an emergency cesarean section was performed for fetal compromise, resulting in the delivery of a small-for-gestational-age infant. Histopathological examination of the placenta revealed ischemic changes consistent with placental insufficiency. Both the mother and infant were discharged in stable conditions. The present case shows that although adrenalectomy during pregnancy can correct endocrine abnormalities, it does not necessarily prevent subsequent fetal growth restriction.

Introduction

Cushing’s syndrome (CS) is an endocrine disorder caused by chronic hypercortisolism. Because cortisol can disrupt ovulation, leading to menstrual irregularities and infertility [1,2], pregnancy in women with CS is exceedingly rare. Moreover, diagnosis during pregnancy is particularly challenging as many hallmark features of hypercortisolism – fatigue, weight gain, acne, and mood instability – are common in normal pregnancies.

Untreated CS during gestation is associated with substantially increased maternal and perinatal morbidity and mortality. Aggressive management during gestation, including cortisol synthesis inhibitors or surgical resection of pituitary adenomas or adrenal tumors, has been shown to improve maternal and fetal outcomes [3-5]. However, intensive treatment may not fully reduce the risks of fetal growth restriction and preterm delivery [5,6], and the underlying reason for this remains unclear.

Herein, we report a case of adrenal CS in a pregnant woman who underwent retroperitoneoscopic adrenalectomy at 28 weeks of gestation. Despite achieving biochemical remission of hypercortisolism after surgery, she developed fetal growth restriction and required preterm cesarean delivery due to fetal compromise.

This article was previously presented as a meeting abstract at (1) the 97th Annual Congress of the JES on June 7, 2024; (2) the 60th Annual Congress of JSPNM on July 15, 2024; and (3) the 47th Annual Meeting of JSGOS on November 24, 2024.

Case Presentation

A 29-year-old Japanese woman with a G5P3A1 conceived spontaneously. She had no medical history other than asthma and no particular familial history. She began receiving antenatal care at a nearby facility during the first trimester. She did not undergo screening tests for predicting the development of preeclampsia (PE), such as the first-trimester ultrasound at 11-14 weeks or pregnancy-associated plasma protein A assessment. Her casual blood glucose level was 87 mg/dL at 10+6 weeks of gestation. Initially, she was normotensive, but her blood pressure gradually increased to 144/100 mmHg at 18 weeks of gestation, and diagnosed as having chronic hypertension. Thereafter, her hypertension worsened, reaching 177/100 mmHg at 21 weeks of gestation, and she was diagnosed with superimposed PE. Around the same time, her body weight increased by 11.5 kg from the pre-pregnancy weight (from 58.5 kg to 70 kg), and generalized edema developed. As a result, she was admitted to the referring hospital and started taking antihypertensive treatment with oral methyldopa 750 mg/day, which lowered her blood pressure to a range of 130-150/80-100 mmHg, decreased her body weight to 66.5 kg, and improved the generalized edema. Although she was discharged from the hospital, her blood pressure increased again; thus, she was transferred to our institution, a tertiary referral perinatal medical center, at 24+6 weeks of gestation for subsequent perinatal management.

At her initial visit, her height and body weight were 153 cm and 66.2 kg, respectively. Her vital signs were as follows: body temperature 36.0℃, blood pressure 159/115 mmHg with the use of antihypertensive medication, and heart rate 80/min. She had an obvious full-moon face, acne vulgaris (Figure 1A), a buffalo hump, and reddish-purple striae on her abdomen and thighs (Figures 1B, 1C). She also had bilateral pitting edema in her lower legs and thin skin on the backs of her hands. No anemic palpebral conjunctiva, cervical lymphadenopathy, or thyroid enlargement was observed.

Macroscopic-findings-characteristic-of-Cushing’s-syndrome
Figure 1: Macroscopic findings characteristic of Cushing’s syndrome

(A) Moon face, (B) reddish-purple striae

on abdomen, and (C) reddish-purple striae on thighs.

An increased neutrophil count and decreased eosinophil count were observed, although the white blood cell count was within the normal range (Table 1). Biochemical analysis showed that the serum potassium level was decreased (2.3 mEq/L). The serum total protein, albumin, blood urea nitrogen, and cholinesterase levels were mildly decreased. Renal function, hepatic function, and lipid profiles were within normal limits, except for elevated triglyceride levels. A spot urine test indicated an elevated urine protein-to-creatinine ratio (0.436 g/gCr) (Table 2). Regarding diabetes-related tests, fasting plasma glucose (91 mg/dL), glycated hemoglobin (HbA1c) (5.4%), and glycated albumin (GA) (12.9%) were all within their normal ranges. The serum C-peptide level was elevated. A 75 g oral glucose tolerance test (OGTT) conducted at 25+4 weeks of gestation showed serum glucose levels of 191 mg/dL at one hour and 212 mg/dL at two hours (Table 2), indicating postprandial hyperglycemia. Endocrinological evaluation revealed elevated morning serum cortisol levels with loss of diurnal variation. This hypercortisolism is accompanied by suppressed plasma adrenocorticotropic hormone (ACTH) levels (Table 3). The 24-hour urinary free cortisol (UFC) level was markedly elevated (1,380 μg/day). In contrast, dehydroepiandrosterone sulfate (DHEA-S) levels decreased. Serum thyroid-stimulating hormone (TSH) was markedly decreased (0.091 IU/mL), accompanied by mild reductions in free T3 (1.65 pg/mL) and free T4 (0.65 ng/dL), which indicated central hypothyroidism. Abdominal ultrasonography revealed a nodule in the right adrenal gland with a maximum diameter of approximately 30 mm (28 × 27 × 25 mm) (Figure 2A). Abdominal magnetic resonance imaging (MRI) detected a 27-mm well-defined nodular lesion at the same location, which demonstrated a signal drop on opposed-phase images (Figure 2B). Obstetric ultrasonography revealed an estimated fetal body weight of 742 g (adequate for gestational age) (Figures 3A–3C), an amniotic fluid index of 16.4 cm (Figure 3D), and no major structural anomalies of the fetus. From the day of referral, oral nifedipine (40 mg/day) was initiated as antihypertensive therapy. Potassium chloride (KCl) was administered orally.

Parameter Test value Reference range
CBC
WBC 8.1×109/L 3.3-8.6 ×109/L
Neut 83.5% 38.5-80.5%
Lymph 10.5% 16.5-49.5%
Mono 5.8% 2.0-10%
Eosino 0.1% 0.0-8.5%
RBC 3.17×1012/L 3.86-4.92 ×1012/L
Hb 11.5 g/dL 11.4-16.8 g/dL
Plt 190×109/L 158-348 ×109/L
Serum Biochemistry
TP 5.7 g/dL 6.6-8.1 g/dL
Alb 3.3 g/dL 4.1-5.1 g/dL
T-Bil 1 mg/dL 0.4-1.5 mg/dL
AST 15 U/L 13-30 U/L
ALT 27 U/L 7-23 U/L
LDH 326 U/L 124-222 U/L
ALP 55 U/L 38-113 U/L
γ-GTP 29 U/L 9-32 U/L
Na 146 mEq/L 138-145 mEq/L
K 2.3 mEq/L 3.6-4.8 mEq/L
Cl 107 mEq/L 101-108 mEq/L
Ca 8.5 mg/dL 8.8-10.1 mg/dL
P 2.1 mg/dL 2.7-4.6 mg/dL
BUN 6 mg/dL 8-20 mg/dL
UA 3.4 mg/dL 2.6-5.5 mg/dL
Cr 0.45 mg/dL 0.46-0.79 mg/dL
CRP 0.1 mg/dL 0-0.14 mg/dL
HDL-C 66 mg/dL 48-103 mg/dL
LDL-C 134 mg/dL 65-163 mg/dL
TG 211 mg/dL 30-117 mg/dL
FPG 91 mg/dL 73-109 mg/dL
HbA1c 5.4% 4.9-6.0%
GA 12.9% 12.3-16.5%
C-peptide 3.7 ng/mL 0.6-1.8 ng/mL
Endocrinology
Adrenaline <0.01 ng/mL <0.17 ng/mL
Noradrenaline 0.09 ng/mL 0.15-0.57 ng/mL
Dopamine <0.02 ng/mL <0.03 ng/mL
Cortisol 24.7 μg/dL 3.7-19.4 μg/dL
Aldosterone <4.0 pg/mL 4.0-82.1 pg/mL
Renin activity 0.7 ng/mL/hr 0.2-3.9 ng/mL/hr
DHEA-S 43 μg/dL 92-399 μg/dL
TSH 0.091 IU/mL 0.350-4.940 IU/mL
FT3 1.65 pg/mL 1.68-3.67 pg/mL
FT4 0.65 ng/dL 0.70-1.48 ng/dL
Table 1: Laboratory data of CBC, serum biochemistry, and endocrinology

CBC: complete blood count, WBC: white blood cell count, Neut: neutrophil, Lymph: lymphocyte, Mono: monocyte, Eosino: eosinophil, RBC: red blood cell count, Hb: hemoglobin, Plt: platelet count, TP: total protein, Alb: albumin, T-Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyl transpeptidase, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphorus, BUN: blood urea nitrogen, UA: uric acid, Cr: creatinine, CRP: C-reactive protein, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, TG: triglyceride, FPG: fasting plasma glucose, HbA1c: hemoglobin A1c, GA: glycated albumin, C-peptide: connecting peptide, DHEA-S: dehydroepiandrosterone sulfate, TSH: thyroid-stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine

Parameter Test value
75-g OGTT
PG
0 min 91 mg/dL
30 min 153 mg/dL
60 min 191 mg/dL
90 min 204 mg/dL
120 min 225 mg/dL
IRI
0 min 10.8 μU/mL
30 min 29.3 μU/mL
60 min 48.7 μU/mL
90 min 64.6 μU/mL
120 min 91.2 μU/mL
Urinalysis
U-Cr 39 mg/dL
U-TP 17 mg/dL
U-TP/Cr 0.436 g/gCr
Table 2: Laboratory data of 75-g OGTT and urinalysis

OGTT: oral glucose tolerance test, PG: plasma glucose, IRI: immunoreactive insulin, U-Cr: urinary creatinine, U-TP: urinary total protein

Parameter Test value Reference range
ACTH/F diurnal rhythm
ACTH
6:00 AM 2.1 pg/mL 7.2-63.3 pg/mL
4:00 PM 2.0 pg/mL 7.2-63.3 pg/mL
11:00 PM 2.3 pg/mL 7.2-63.3 pg/mL
F
6:00 AM 24.7 μg/dL 3.7-19.4 μg/dL
4:00 PM 25 μg/dL 3.7-19.4 μg/dL
11:00 PM 25.8 μg/dL 3.7-19.4 μg/dL
Table 3: Laboratory data of ACTH/F diurnal rhythm

ACTH: adrenocorticotropic hormone, F: cortisol

Radiological-findings-of-the-right-adrenal-tumor-(white-arrow)
Figure 2: Radiological findings of the right adrenal tumor (white arrow)

(A) Trans-abdominal ultrasonography image and (B) coronal section of the trunk on MRI.

Obstetric-ultrasonography
Figure 3: Obstetric ultrasonography

(A) The plane used for biparietal diameter measurement, (B) the plane used for abdominal circumference measurement, (C) the plane used for femoral length measurement, and (D) the plane used for amniotic fluid index measurement.

Physical examination revealed typical signs of CS, such as a moon face, buffalo hump, and reddish-purple striae. In addition, laboratory findings showed elevated UFC, increased nocturnal serum cortisol levels (>5.0 μg/dL), and suppressed ACTH levels (<5.0 pg/mL). On the basis of these findings, the patient was diagnosed with ACTH-independent CS. Furthermore, imaging studies identified a right adrenal mass, leading to a final diagnosis of CS caused by a right adrenal tumor. Both central hypothyroidism and impaired glucose tolerance were considered secondary complications, primarily caused by hypercortisolemia due to CS. The serum potassium level was maintained at approximately 3.0 mEq/L after the administration of oral KCl. An increase in the nifedipine dose from 20 mg/day to 40 mg/day stabilized the blood pressure at approximately 140/90 mmHg (Figure 4A). Intensive insulin therapy with insulin lispro was initiated on hospital day 4 (Figure 4B), and the insulin dosage was gradually increased for postprandial hyperglycemia. The maximum insulin dose was 41 units/day on day 23 of hospitalization. Throughout this period, the UFC levels remained persistently elevated (Figure 4C).

Clinical-course-between-hospitalization-and-cesarean-delivery
Figure 4: Clinical course between hospitalization and cesarean delivery

(A) Blood pressure trend, (B) total dose of insulin, and (C) urinary free cortisol trend.

A clinical team of obstetricians, urologists, and endocrinologists discussed the treatment plans for CS and perinatal management. Pharmacological treatment had two problems: radicality and risk of fetal adrenal insufficiency due to placental passage of medication; therefore, we decided to perform adrenalectomy during pregnancy. At 28+3 weeks of gestation, a retroperitoneoscopic adrenalectomy was performed by urologists. After the induction of general anesthesia, the patient lay on the bed in a complete left lateral position (Figures 5A, 5B). Consequently, the endoscope and instrument ports were placed in the same configuration as those used in the conventional retroperitoneal approach for nonpregnant patients. Port placements were planned guided by abdominal ultrasonography to identify the uterine position, and the assistant port was positioned at a location that minimized potential interference with the uterus. The surgery was completed without complications. The operative time was 83 minutes, and bleeding was minimal. Histopathological examination indicated that the tumor was an adrenocortical adenoma (Figures 6A–6C).

Photograph-showing-the-patient-in-the-left-lateral-decubitus-position-after-general-anethesia
Figure 5: Photograph showing the patient in the left lateral decubitus position after general anethesia

(A) Abdominal area and (B) dorsal area.

Histopathological-findings-of-the-right-adrenal-gland-(A,-B,-C)-and-placenta-(D)
Figure 6: Histopathological findings of the right adrenal gland (A, B, C) and placenta (D)

(A) Macroscopic view of the right adrenal gland showing the normal adrenal tissue (black asterisk) and the adrenal tumor (white asterisk). (B, C) Microscopic findings of the right adrenal gland and tumor (H&E staining).

(B) Normal adrenal gland (black asterisk) and adrenal tumor (white asterisk) separated by a thin fibrous capsule (black arrow).

(C) Tumor cells with abundant eosinophilic to clear cytoplasm arranged in a trabecular to microacinar growth pattern.

(D) Microscopic findings of the placenta (H&E staining) showing fibrin deposition within villous vessels (black arrow) and chorionic villi with loss of nuclear detail and crowding (black asterisk).

After surgery, the maternal glucose tolerance rapidly improved, and intensive insulin therapy with insulin lispro became unnecessary (Figure 4B). To avoid postoperative adrenal insufficiency, replacement therapy with hydrocortisone was initiated at 200 mg/day immediately after surgery, and the dosage was gradually tapered to 25 mg/day before delivery (Figure 4C). Maternal thyroid function normalized two weeks after surgery. At 29 weeks of gestation, oral nifedipine (40 mg/day) was stopped and blood pressure was monitored; however, high blood pressure was sustained. Therefore, oral nifedipine was resumed at 20 mg/day at 31 weeks of gestation. At approximately 33 weeks of gestation, the fetus exhibited slow growth, leading to a diagnosis of fetal growth restriction. The levels of serum soluble fms-like kinase 1 (sFlt-1)/placental growth factor (PlGF) were 173 (7990/46.1) at 33+0, 299 (11600/38.9) at 34+1, and 316 (15200/48.1) at 35+5 weeks. Trends in the estimated fetal body weight and standard deviation are shown in Figure 7. At 36+1 weeks of gestation, cardiotocography revealed severely prolonged deceleration regardless of the absence of uterine contraction, and an emergency cesarean section was performed. A male infant weighing 1,726 g and 41 cm in height, diagnosed as small for gestational age, was born with Apgar scores of 8 at one minute and 9 at five minutes. The umbilical arterial pH was 7.36. The size and weight of the placenta were 14.7 × 12.8 × 3.0 cm and 315 g, respectively, and histopathological examination revealed findings consistent with ischemic infarction (Figure 6D). Antihypertensive drugs administered to the mother were discontinued on day 8. The mother and neonate were discharged on POD 20. The child achieved normal development at the age of two years.

Trends-in-estimated-fetal-body-weight-(EFBW)-and-standard-deviation-(SD)
Figure 7: Trends in estimated fetal body weight (EFBW) and standard deviation (SD)

Discussion

This case illustrates adrenal CS in pregnancy, complicated by the subsequent development of fetal growth restriction, despite retroperitoneoscopic adrenalectomy at 28 weeks of gestation. Notably, a markedly increased maternal serum sFlt-1/PlGF ratio was detected at the time of diagnosis of fetal growth restriction. To the best of our knowledge, this is the first case in which angiogenic markers were evaluated in a pregnant woman with adrenal CS.

The coexistence of CS and pregnancy is extremely rare [4]. The primary reason for this rarity is infertility, often caused by the hypercortisolism characteristic of CS. Specifically, hypercortisolism suppresses the hypothalamic-pituitary-gonadal axis, leading to impaired follicular development and anovulation by disrupting the secretion of gonadotropin-releasing hormone (GnRH) [1,7]. Pregnancy poses significant challenges in patients with ACTH-dependent CS, in whom excessive ACTH production is accompanied by androgen overproduction. As a result, adrenal etiologies of CS are more common than pituitary-dependent etiologies during pregnancy [3]. Several factors make it difficult to diagnose CS during pregnancy. First, the characteristic physical findings of CS closely mimic physiological changes in normal pregnancy. For example, weight gain, abdominal striae, and edema are common symptoms of both conditions. Therefore, this overlap can cause delayed diagnosis or misdiagnosis of CS during pregnancy [3]. It has been reported that 21.5% of pregnant women with CS are diagnosed only after delivery [3]. Second, physiological hormonal changes during pregnancy complicate the diagnostic process. During gestation, the placenta produces corticotropin-releasing hormone (CRH) and ACTH [8]. Additionally, elevated estrogen levels increase the synthesis of corticosteroid-binding globulin, resulting in a state of physiological hypercortisolism in pregnant women [9,10]. Consequently, the dexamethasone suppression test, which is key to the diagnosis of CS, is often unreliable in pregnant women because of the high incidence of false-positive results [4].

Despite these diagnostic hurdles, certain findings are highly valuable in identifying CS during pregnancy. First, careful examination of physical signs specific to CS, such as skin thinning and the presence of wide, reddish-purple striae, is crucial. Second, the evaluation of diurnal cortisol rhythms was informative. While this rhythm is preserved in normal pregnancy, it is characteristically absent in CS. Therefore, measuring late-night serum cortisol levels is useful for differentiating between these two states [11]. Third, a 24-hour UFC level exceeding three times the upper limit of normal for non-pregnant individuals is strongly suggestive of CS [4,7,9]. In the present case, these key features were decisive for the diagnosis. We found wide, reddish-purple striae, a loss of diurnal cortisol rhythm, and a markedly elevated 24-hour UFC level. Based on these findings, we definitively diagnosed the patient with CS complicating pregnancy.

According to a systematic review of 263 pregnancies complicated by CS, untreated pregnant women were significantly more likely to develop PE than those treated beforehand (26.5% vs. 2.3%) [3]. PE is characterized by defective placentation and impaired spiral artery remodeling, leading to placental ischemia during early pregnancy. Placental ischemia produces sFlt-1, a splice variant of Flt-1 that binds to vascular endothelial growth factor and PlGF and serves as a biochemical marker of endothelial dysfunction that inhibits angiogenesis [12]. Systemic endothelial dysfunction leads to maternal hypertension, proteinuria, and damage to other organs, including the placenta. In this case, placental histopathology indicated ischemic changes without retroplacental hematoma. In addition, a marked elevation of the sFlt-1/PlGF ratio – resulting from both increased sFlt-1 and decreased PlGF – was detected, supporting the presence of placental ischemia due to impaired placentation in early pregnancy.

In this case, several factors may have contributed to the placental ischemia. First, poor control of maternal hyperglycemia or hypertension may have played a role. As hyperglycemia is known to induce oxidative stress [13], it is possible that hyperglycemia in early pregnancy causes placental ischemia indirectly via oxidative stress. Recent studies suggest that hypertension in early pregnancy may contribute to impaired placentation, thereby increasing the risk of subsequent superimposed PE [14,15]. Therefore, chronic hypertension associated with CS may also be related to placental ischemia, although the maternal outpatient blood pressure was within the normal range during early pregnancy in the present case. Second, chronic hypercortisolemia can directly contribute to abnormal placentation. Previous animal experiments have shown that elevated maternal serum cortisol levels enhance uterine arterial contractions [16], which may induce placental ischemia. Furthermore, chronic hypercortisolism may exceed the protective capacity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which shields the fetus from excessive cortisol, thereby directly affecting the fetus [17]. Based on these findings, it is presumed that irreversible placental damage had already occurred at the time of the surgical resection in this case. Preconceptional or at least early diagnosis and treatment of CS are crucial for preventing fetal growth restriction associated with superimposed PE after surgery.

The second trimester is generally considered the optimal period for adrenalectomy in pregnant patients with adrenal CS [18]; however, successful procedures have been reported even during the third trimester [6,19]. Endoscopic adrenalectomy is favored over open approaches owing to its reduced morbidity, although direct comparisons between the transperitoneal and retroperitoneal approaches in pregnancy are lacking. In non-pregnant patients, both approaches yield similar operative times, blood loss, and hospital stays [20]. In this case, the retroperitoneal approach was used. This technique offers several advantages during pregnancy as follows: it allows surgery in the lateral position, minimizes inferior vena cava compression by the gravid uterus, avoids entry into the peritoneal cavity, thereby preventing interference from the enlarged uterus, and reduces the risk of intra-abdominal inflammatory spread to the uterus and adjacent organs. Based on our experience and considering the potential advantages of the retroperitoneoscopic approach, we propose that retroperitoneoscopic adrenalectomy should be considered even in the early third trimester, as it may safely prolong gestation and reduce the need for preterm delivery.

Conclusions

This case highlights the challenges of managing adrenal CS during pregnancy. Uncontrolled CS may impair placental development during early pregnancy; therefore, preconceptional or at least early recognition and appropriate management are crucial to minimize the risk of subsequent fetal growth restriction. Further research is needed to clarify the pathophysiological relationship between hypercortisolism and impaired placentation in early pregnancy and to refine strategies for managing this rare but high-risk condition.

References

  1. Castinetti F, Brue T: Impact of Cushing’s syndrome on fertility and pregnancy. Ann Endocrinol (Paris). 2022, 83:188-90. 10.1016/j.ando.2022.04.001
  2. Eschler DC, Kogekar N, Pessah-Pollack R: Management of adrenal tumors in pregnancy. Endocrinol Metab Clin North Am. 2015, 44:381-97. 10.1016/j.ecl.2015.02.006
  3. Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, Webb SM: Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine. 2017, 55:555-63. 10.1007/s12020-016-1117-0
  4. Hamblin R, Coulden A, Fountas A, Karavitaki N: The diagnosis and management of Cushing’s syndrome in pregnancy. J Neuroendocrinol. 2022, 34:e13118. 10.1111/jne.13118
  5. Sammour RN, Saiegh L, Matter I, et al.: Adrenalectomy for adrenocortical adenoma causing Cushing’s syndrome in pregnancy: a case report and review of literature. Eur J Obstet Gynecol Reprod Biol. 2012, 165:1-7. 10.1016/j.ejogrb.2012.05.030
  6. Martínez García R, Martínez Pérez A, Domingo del Pozo C, Sospedra Ferrer R: Cushing’s syndrome in pregnancy. Laparoscopic adrenalectomy during pregnancy: the mainstay treatment. J Endocrinol Invest. 2016, 39:273-6. 10.1007/s40618-015-0345-0
  7. Younes N, St-Jean M, Bourdeau I, Lacroix A: Endogenous Cushing’s syndrome during pregnancy. Rev Endocr Metab Disord. 2023, 24:23-38. 10.1007/s11154-022-09731-y
  8. Sasaki A, Shinkawa O, Margioris AN, et al.: Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery. J Clin Endocrinol Metab. 1987, 64:224-9. 10.1210/jcem-64-2-224
  9. Jung C, Ho JT, Torpy DJ, et al.: A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J Clin Endocrinol Metab. 2011, 96:1533-40. 10.1210/jc.2010-2395
  10. Petraglia F, Sawchenko PE, Rivier J, Vale W: Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature. 1987, 328:717-19. 10.1038/328717a0
  11. Savas M, Mehta S, Agrawal N, van Rossum EF, Feelders RA: Approach to the patient: diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2022, 107:3162-74. 10.1210/clinem/dgac492
  12. Jung E, Romero R, Yeo L, et al.: The etiology of preeclampsia. Am J Obstet Gynecol. 2022, 226:S844-66. 10.1016/j.ajog.2021.11.1356
  13. González P, Lozano P, Ros G, Solano F: Hyperglycemia and oxidative stress: an integral, updated and critical overview of their metabolic interconnections. Int J Mol Sci. 2023, 24:9352. 10.3390/ijms24119352
  14. Ueda A, Hasegawa M, Matsumura N, et al.: Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study. Hypertens Res. 2022, 45:135-45. 10.1038/s41440-021-00763-6
  15. Burton GJ, Jauniaux E: Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. 2018, 218:S745-61. 10.1016/j.ajog.2017.11.577
  16. Xiao D, Huang X, Bae S, Ducsay CA, Zhang L: Cortisol-mediated potentiation of uterine artery contractility: effect of pregnancy. Am J Physiol Heart Circ Physiol. 2002, 283:H238-46. 10.1152/ajpheart.00842.2001
  17. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS: Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 1994, 105:11-17. 10.1016/0303-7207(94)90176-7
  18. Wang Y, An Y, Hou X, et al.: Cushing’s syndrome in pregnancy secondary to adrenocortical adenoma: a case series and review. Endocrinol Diabetes Metab. 2024, 7:e00474. 10.1002/edm2.474
  19. Shaw JA, Pearson DW, Krukowski ZH, Fisher PM, Bevan JS: Cushing’s syndrome during pregnancy: curative adrenalectomy at 31 weeks gestation. Eur J Obstet Gynecol Reprod Biol. 2002, 105:189-91. 10.1016/s0301-2115(02)00148-3
  20. Nigri G, Rosman AS, Petrucciani N, et al.: Meta-analysis of trials comparing laparoscopic transperitoneal and retroperitoneal adrenalectomy. Surgery. 2013, 153:111-19. 10.1016/j.surg.2012.05.042

From https://www.cureus.com/articles/425273-adrenal-cushings-syndrome-in-pregnancy-complicated-by-fetal-growth-restriction-following-retroperitoneoscopic-adrenalectomy#!/

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Pregnancy Case: Cushing’s Syndrome with Diabetes Insipidus

Posted on September 3, 2025 by MaryO

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article References:

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

Image Credits: AI Generated

DOI: 10.1186/s12902-025-01946-9

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

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

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