MANAGEMENT OF ENDOCRINE DISEASE: Management of Cushing’s syndrome during pregnancy: solved and unsolved questions
Open accessAbstract
With fewer than 200 reported cases, Cushing’s syndrome (CS) in pregnancy remains a diagnostic and therapeutic challenge. In normal pregnancies, misleading signs may be observed such as striae or hypokalemia, while plasma cortisol and urinary free cortisol may rise up to 2- to 3-fold. While the dexamethasone suppression test is difficult to use, reference values for salivary cortisol appear valid. Apart from gestational hypertension, differential diagnosis includes pheochromocytoma and primary aldosteronism. The predominant cause is adrenal adenoma (sometimes without decreased ACTH), rather than Cushing’s disease. There are considerable imaging pitfalls in Cushing’s disease. Aberrant receptors may, in rare cases, lead to increased cortisol production during pregnancy in response to HCG, LHRH, glucagon, vasopressin or after a meal. Adrenocortical carcinoma (ACC) is rare and has poor prognosis. Active CS during pregnancy is associated with a high rate of maternal complications: hypertension or preeclampsia, diabetes, fractures; more rarely, cardiac failure, psychiatric disorders, infection and maternal death. Increased fetal morbidity includes prematurity, intrauterine growth retardation and less prevalently stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism. Therapy is also challenging. Milder cases can be managed conservatively by controlling comorbidities. Pituitary or adrenal surgery should ideally be performed during the second trimester and patients should then be treated for adrenal insufficiency. Experience with anticortisolic drugs is limited. Metyrapone was found to allow control of hypercortisolism, with a risk of worsening hypertension. Cabergoline may be an alternative option. The use of other drugs is not advised because of potential teratogenicity and/or lack of information. Non-hormonal (mechanical) contraception is recommended until sustained biological remission is obtained.
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In the study of Lopes et al, the cutoff values for the diagnosis of Cushing disease were 0.255 μg/dL for the first trimester, 0.260 μg/dL for the second trimester, and 0.285 μg/dL for the third trimester.
“The cutoff values for the diagnosis of Cushing disease in the study were 0.255 µg/dL (7.0 nmol/L) for the first trimester, 0.260 µg/dL (7.2 nmol/L) for the second trimester, and 0.285 µg/dL (7.9 nmol/L) for the third trimester (90, 95).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
Starting in the first trimester, there is an increase in estrogen and CRH produced by the placenta, which can lead to an increase in corticosteroid-binding globulin, a plasma cortisol transport protein.
“Starting in the first trimester, there is an increase in estrogen and CRH produced by the placenta, which can lead to an increase in corticosteroid-binding globulin, a plasma cortisol transport protein.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
In the study of Lopes et al, the reference range for LNSC in each gestational trimester were 0.03 to 0.25 μg/dL in the first trimester, 0.04 to 0.26 μg/dL in the second trimester, and 0.07 to 0.33 μg/dL in the third trimester.
“In the study of Lopes et al (95), the reference range for the LNSC in each gestational trimester were 0.03 to 0.25 µg/dL (0.8-6.9 nmol/L) in the first trimester, 0.04 to 0.26 µg/dL (1.1-7.2 nmol/L) in the second trimester, and 0.07 to 0.33 µg/dL (1.7-9.1 nmol/L) in the third trimester.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
Suppression of serum and plasma cortisol by dexamethasone is blunted during pregnancy, making the DST difficult to interpret.
“Suppression of serum and plasma cortisol by dexamethasone is blunted during pregnancy; therefore, making the DST difficult to interpret in these patients (3, 90, 92).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
The rise in placental CRH and ACTH causes an increase in total plasma cortisol levels.
“This in combination with the rise in placental CRH and ACTH cause an increase in total plasma cortisol levels.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
In contrast to nonpregnant patients, the predominant etiology of CS in pregnant patients is adrenal adenomas, found in 40% to 60% of cases.
“In contrast to nonpregnant patients, the predominant etiology of CS in pregnant patients is adrenal adenomas, found in 40% to 60% of cases (90, 91).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
The biochemical diagnosis of CS during pregnancy can be more challenging because of normal physiologic changes that occur during pregnancy, including activation of the HPA axis.
“The biochemical diagnosis of CS during pregnancy can also be more challenging because of normal physiologic changes that occur during pregnancy, including activation of the HPA axis.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
During the second trimester, UFC increases approximately 1.4-fold, and during the third trimester, approximately 1.6-fold.
“During the second trimester, UFC also increases, leading to an approximately 1.4-fold increase during the second trimester and a 1.6-fold increase during the third trimester.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [90]
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References 45 · Cited by 85
- Authors
- Brue, T., Amodru, V., & Castinetti, F.
- Affiliations
- Inserm (FR)
- 1Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics, Marseille, France
- Corresponding author
- Brue, Thierry
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-06
- Volume
- 178
- Issue
- 6
- Pages
- R259-R266
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2793702269
- Cited by
- 85
- References
- 45
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 5 · 2022: 17 · 2021: 19 · 2020: 16 · 2019: 9 · 2018: 1
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- Cushing's syndrome, pregnancy, hypercortisolism, adrenal adenoma, Cushing's disease, adrenocortical carcinoma, pheochromocytoma, primary aldosteronism, salivary cortisol, dexamethasone suppression test, metyrapone, cabergoline, adrenal insufficiency, hypertension, preeclampsia, fetal growth restriction, teratogenicity, contraception
- MeSH terms
- Adrenal Gland Neoplasms, Contraception, Cushing Syndrome, Diagnosis, Differential, Female, Fetal Growth Retardation, Humans, Hydrocortisone, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Saliva, Hypertension, Pregnancy-Induced, Premature Birth
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