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Cushing’s Syndrome during Pregnancy: Personal Experience and Review of the Literature
Abstract
Cushing's syndrome (CS) occurs rarely during pregnancy. We investigated and treated four patients with pituitary-dependent Cushing's syndrome during pregnancy over a 15-yr period at the National Institutes of Health. Except for preservation of menses before conception, our patients presented with typical clinical features, increased urinary free cortisol, and loss of diurnal variation of cortisol. The diagnosis was facilitated, without complications, by the use of CRH testing and inferior petrosal sinus sampling in three women. Transsphenoidal pituitary surgery achieved remission in three women, but there were two fetal/neonatal deaths. This experience and review of 136 previous reports suggest that: 1) urinary free cortisol in CS patients overlaps the normal pregnant range; 2) ACTH levels are not suppressed in adrenal causes of CS, which may be identified by the 8-mg dexamethasone test; 3) inferior petrosal sinus sampling and transsphenoidal pituitary surgery, the optimal diagnostic test and treatment for nonpregnant patients with pituitary-dependent Cushing's syndrome, can safely facilitate the management of pregnant patients; and 4) surgery may achieve remission during pregnancy, but the prognosis for the fetus remains guarded. It is likely that earlier recognition and treatment would improve outcome. There is a need for development of criteria for interpretation of diagnostic tests and increased consideration of CS in pregnancy.
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In the citing paper
“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 [92]
In the citing paper
“Fetal morbidity includes rates of spontaneous abortion, perinatal death, premature birth, and intrauterine growth retardation (see Figure 4).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [92]
In the citing paper
“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 [92]
In the citing paper
“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 [92]
In the citing paper
“Early diagnosis and management of CS during pregnancy are important because of associated fetal and maternal morbidity.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [92]
In the citing paper
“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 [92]
In the citing paper
“Maternal morbidity caused by CS includes hypertension, preeclampsia, wound breakdown, diabetes, fractures, and opportunistic infections (2, 92).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [92]
In the citing paper
“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 [92]
Citations
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“The bars adjacent to the right axis are summary data derived from a recent series (173) to denote the range of serum cortisol observed in CS in pregnancy ( , median and range; n 52); ACTH values for CD (Œ, median and range; n 18) and adrenal CS (‚, median and range; n 17).”
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“Thus, unless levels are more than three times higher than the upper limit of normal values, this cannot be considered a reliable marker of CS after the first trimester.42 However, late night salivary cortisol may be more helpful, especially during the first and the second trimesters.43 The placental secretion of ACTH…”
InfluentialApproach to the Patient: Diagnosis of Cushing Syndrome
Savas, M., Mehta, S., Agrawal, N., van Rossum, E. F. C., & Feelders, R. A. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac492 · Cited by 91
“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).”
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InfluentialAdrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies
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InfluentialLekarev, O., & New, M. I. (2011) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.08.004 · Cited by 77
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“The detection of Cushing disease or Cushing syndrome in pregnant women can be troublesome, but the correct diagnosis is of paramount importance owing to the high rate of maternal and fetal morbidities and mortalities”
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“While surgical treatment has been shown to reduce perinatal mortality rate and maternal morbidity [5], the advantages of medical therapy are evident when surgery is contra-indicated – late gestational age, past history of pre-term delivery, absence of an experienced endocrine surgeon, or patient preference for non-inv…”
BackgroundInfluentialManagement of adrenal tumors in pregnancy.
Eschler, D. C., Kogekar, N., & Pessah-Pollack, R. (2015) · Endocrinology and metabolism clinics of North America (Print) · doi:10.1016/j.ecl.2015.02.006 · Cited by 58
Is urinary free cortisol of value in the diagnosis of Cushingʼs syndrome?
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“The use of the high-dose dexamethasone suppression test has been suggested by some, with a fall in cortisol of greater than 80% reported to distinguish between adrenal and pituitary source of CS in pregnancy.(6,54) As a result of the limited evidence available and the lack of data from normal pregnancies, the use of t…”
BackgroundMethodInfluentialPhysiological changes in pregnancy and their influence on the endocrine investigation
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“ACTH levels cannot be used to differentiate between pituitary and adrenal causes of CS, as ACTH levels are not suppressed in half of adrenal CS, whereas some pregnant women with pituitary Cushing's disease have been reported to have suppressed ACTH.(45) The aetiology of CS is significantly different in the pregnant co…”
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“However, as previously known from patients with diagnosis de novo during pregnancy, physiologic changes of gestation, specifically the increase in levels of plasma and urine cortisol, complicate the interpretation of clinical and biochemical investigations [1], and postoperative diagnostic work-up in our case led to t…”
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“Eight pregnant subjects have undergone transphenoidal resection of pituitary tumours during pregnancy [24].”
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“Adrenalectomy during pregnancy has been reported in 18 women with phaeochromocytoma, and 31 women with Cushing’s syndrome [3,4,28].”
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Cabergoline treatment for recurrent Cushing’s disease during pregnancy
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Pivonello, R., Martino, M. C. D., Auriemma, R. S., Alviggi, C., Grasso, L. F. S., Cozzolino, A., Leo, M. D., Placido, G. D., Colao, A. A. L., & Lombardi, G. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-013-0019-8 · Cited by 40
“Therefore, the use of ketoconazole can be considered a good option only in pregnant patients with Cushing’s disease requiring an emergency treatment and intolerant to metyrapone [25].”
BackgroundInfluentialPituitary disorders in pregnancy
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BackgroundTuberculum sellae meningioma symptomatic during pregnancy: pathophysiological considerations
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BackgroundInfluentialAACE/ACE Disease State Clinical Review: Medical Management of Cushing Disease
Hamrahian, A. H., Yuen, K. C. J., & Hoffman, A. R. (2014) · Endocrine Practice · doi:10.4158/ep14147.ra · Cited by 27
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“Metyrapone and steroidogenesis inhibitors have been used most often and have had no adverse effects on maternal hepatic function or fetal development in the small number of cases reported.7,8 Ketoconazole has also been successfully used without any major adverse effects.9 Cyproheptadine is not recommended due to the l…”
BackgroundMethodInfluentialMedical Therapy for Cushing’s Syndrome in the Twenty-first Century
Tritos, N. A., & Biller, B. M. K. (2018) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2018.01.006 · Cited by 24
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“reported cases, a specific treatment for hypercortisolism was not introduced [7].”
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“Treatment of choice for ACTH-secreting pituitary adenomas is removal of the pituitary tumor and, in fact, transsphenoidal surgery has been performed in a number of pregnant women with Cushing’s disease [25,27,43].”
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“UFC levels modestly increase in the second and third trimester and, although UFC levels of more than 3 times the upper limit of normal (ULN) are indicative of CS, it can be dif fi cult to distinguish CS from physiological activation of the HPA-axis when UFC levels are mildly elevated (11, 28).”
BackgroundEndogenous Cushing’s syndrome during pregnancy
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“1 3 CS from ACTH-dependent CS in pregnancy [10]; in their series including 122 pregnant women with CS, using the cut-off for serum cortisol suppression at > 80%, they correctly diagnosed all cases of adrenal CS, but missed 3 out of 7 cases of CD [10].”
BackgroundMethodResultInfluentialSurgical indications for pituitary tumors during pregnancy: a literature review
Graillon, T., Cuny, T., Castinetti, F., Courbière, B., Cousin, M., Albarel, F., Morange, I., Bruder, N. J., Brue, T. C., & Dufour, H. (2019) · Pituitary · doi:10.1007/s11102-019-01004-3 · Cited by 27
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Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome
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“Serum-free and salivary cortisol increase during pregnancy [88, 89].”
BackgroundUse of cabergoline for the management of persistent Cushing’s disease in pregnancy
Sek, K., Deepak, D., & Lee, K. (2017) · BMJ Case Reports · doi:10.1136/bcr-2016-217855 · Cited by 21
Advances in the Medical Treatment of Cushing Disease
Tritos, N. A., & Biller, B. M. K. (2020) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2020.05.003 · Cited by 25
Endocrine causes of hypertension in pregnancy
Affinati, A. H., & Auchus, R. J. (2020) · Gland Surgery · doi:10.21037/gs.2019.12.04 · Cited by 26
“For adrenal CS, abdominal ultrasound and adrenal MRI without contrast are the preferred imaging studies (50).”
BackgroundEndocrine oncology in pregnancy.
Lansdown, A., & Rees, D. (2011) · Best practice & research. Clinical endocrinology & metabolism · doi:10.1016/j.beem.2011.06.011 · Cited by 20
Chronic maternal hypercortisolemia in late gestation alters fetal cardiac function at birth.
Antolic, A. T., Wood, C., & Keller-Wood, M. (2018) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00296.2017 · Cited by 19
“Our data indicate that this biphasic relationship also holds true for the effects of cortisol on the developing heart, with effects that could contribute to the increase in stillbirth rates associated with chronic maternal stress or Cushing’s syndrome in late pregnancy (18, 35, 37, 61, 67).”
BackgroundPituitary Disorders in Pregnancy
Woodmansee, W. W. (2018) · Neurologic Clinics · doi:10.1016/j.ncl.2018.09.009 · Cited by 29
Surgery for Cushing's disease in pregnancy: our experience and a literature review.
Jolly, K., Darr, A., Arlt, W., Ahmed, S., & Karavitaki, N. (2019) · Annals of the Royal College of Surgeons of England · doi:10.1308/rcsann.2018.0175 · Cited by 18
“To date, approximately 200 cases of Cushing’s syndrome in pregnancy have been reported.(3,4) Of these, 40–50% had adrenal adenoma, 30% had Cushing’s disease and 10% had either adrenal carcinoma, adrenocorticotrophic hormone (ACTH)-independent hyperplasia or ectopic ACTH secretion.”
BackgroundAdrenal disorders in pregnancy, labour and postpartum – an overview
Manoharan, M., Sinha, P., & Sibtain, S. (2019) · Journal of Obstetrics and Gynaecology · doi:10.1080/01443615.2019.1648395 · Cited by 17
“(Gicquel et al. 2000; Dackiw et al. 2001; Abiven-Lepage et al. 2010) Previous studies have shown that hypercortisolism is itself associated with frequent maternal morbidity and poor fetal prognosis (Lindsay et al. 2005).”
BackgroundMethodInfluentialPituitary Disease in Pregnancy: Special Aspects of Diagnosis and Treatment?
Petersenn, S., Christ‐Crain, M., Droste, M., Finke, R., Flitsch, J., Kreitschmann‐Andermahr, I., Luger, A., Schopohl, J., & Stalla, G. K. (2019) · Geburtshilfe und Frauenheilkunde · doi:10.1055/a-0794-7587 · Cited by 21
“Surgery during pregnancy may be considered in a few cases, particularly for patients with progressive deterioration of vision and reduced visual field acuity for whom glucocorticoid therapy was ineffective [38].”
InfluentialPatología hipofisaria y gestación
Valassi, E. (2021) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2020.07.007 · Cited by 7
Fahrleitner-Pammer, A., Wagner, D., Krisper, P., Amrein, K., & Dimai, H. (2016) · Osteoporosis International · doi:10.1007/s00198-016-3858-2 · Cited by 16
Antolic, A. T., Feng, X.-D., Wood, C., Richards, E., & Keller-Wood, M. (2015) · Physiological Reports · doi:10.14814/phy2.12548 · Cited by 16
“Higher doses of glucocorticoids administered to the mother have been found to reduce growth (Johnson et al. 1981), as does maternal Cushing’s syndrome (Lindsay et al. 2005).”
BackgroundSíndrome de Cushing: situaciones especiales
Iriarte, M. J. G. (2009) · Endocrinología y Nutrición · doi:10.1016/s1575-0922(09)71408-1 · Cited by 13
Cushing’s syndrome in pregnancy
Nassi, R., Ladu, C., Vezzosi, C., & Mannelli, M. (2015) · Gynecological Endocrinology · doi:10.3109/09513590.2014.984680 · Cited by 16
“To date, only a few cases have been reported in literature [1,2].”
Fertility issues in aggressive pituitary tumors
Marques, J. V. O., & Boguszewski, C. L. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09530-y · Cited by 18
“Tumor enlargement is less important as cause of gonadal dysfunction in Cushing’s disease, as most patients harbor mic roadenomas and , consequen t l y, agg r e s s i ve corticotropinomas is rarely seen associated with pregnancy [18, 43, 44].”
BackgroundWang, W., Yuan, F., & Xu, D. (2015) · Frontiers of Medicine · doi:10.1007/s11684-015-0407-x · Cited by 15
A successful case of Cushing's disease pregnancy treated with ketoconazole
Costenaro, F., Rodrigues, T., de Lima, P. B., Ruszczyk, J., Rollin, G. A. F., & Czepielewski, M. (2015) · Gynecological Endocrinology · doi:10.3109/09513590.2014.995615 · Cited by 15
“For the fetus, maternal CS increases the rates of spontaneous abortion, intrauterine growth restriction, perinatal death and premature birth [2,4].”
BackgroundInfluentialEarly severe pre-eclamptic findings in a patient with Cushing's syndrome
Delibaşı, T., Ustun, I., Aydin, Y., Berker, D., Erol, H., Gul, K., Unal, M., & Guler, S. (2006) · Gynecological Endocrinology · doi:10.1080/09513590601069447 · Cited by 15
“Plasma cortisol, cortisol-binding protein and urinary free cortisol all increase during the second and third trimesters of normal pregnancy [2,3].”
BackgroundInfluentialAdrenal Cushing Syndrome Diagnosed During Pregnancy: Successful Medical Management With Metyrapone
Azzola, A., Eastabrook, G. D. M., Matsui, D. M., Berberich, A. J., Tirona, R. G., Gray, D., Gallego, P., & Uum, S. H. M. V. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa167 · Cited by 23
“Cushing syndrome (CS) during pregnancy is rare, with only about 200 cases reported in the literature [1].”
BackgroundTang, K., Lü, L., Feng, M., Zhang, H., Chen, K., Sun, X., Zhu, H., Wang, R., & Lu, Z. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00305 · Cited by 17
Diagnosis and treatment outcomes of Cushing’s disease during pregnancy
Sridharan, K., Sahoo, J., Palui, R., Patil, M., Kamalanathan, S., Ramesh, A., & Kubera, N. S. (2021) · Pituitary · doi:10.1007/s11102-021-01142-7 · Cited by 17
Pregnancy during the course of Cushing’s syndrome: a case report and literature review
Ildefonso-Najarro, S. P., Dueñas, E. A. P., Moya, C. J. B., Carrion-Rojas, J., & Concepción‐Zavaleta, M. J. (2020) · Endocrinology Diabetes and Metabolism Case Reports · doi:10.1530/edm-20-0022 · Cited by 15
Evaluation and Management of Endocrine Hypertension During Pregnancy.
Corsello, S., & Paragliola, R. (2019) · Endocrinology and metabolism clinics of North America (Print) · doi:10.1016/j.ecl.2019.08.011 · Cited by 13
Zhang, X., Liao, H., Zhu, X., Shi, D., & Chen, X. (2019) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-019-2262-2 · Cited by 16
Metadata
- Authors
- Lindsay, J. R., Jonklaas, J., Oldfield, E. H., & Nieman, L. K.
- Affiliations
- National Institutes of Health (US)
- Georgetown University Medical Center (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- Corresponding author
- Nieman, Lynnette K.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2005-05
- Volume
- 90
- Issue
- 5
- Pages
- 3077-3083
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2142121727
- Cited by
- 343
- References
- 0
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 13 · 2023: 11 · 2022: 16 · 2021: 17 · 2020: 16 · 2019: 15 · 2018: 18 · 2017: 68 · 2016: 11 · 2015: 26 · 2014: 15 · 2013: 10 · 2012: 18
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- National Institutes of Health
- 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, pituitary-dependent Cushing's syndrome, transsphenoidal microsurgery, inferior petrosal sinus sampling, CRH stimulation test, urinary free cortisol, diurnal cortisol rhythm, ACTH, dexamethasone suppression test, fetal outcomes, adrenal Cushing's syndrome
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Cushing Syndrome, Diagnosis, Differential, Female, Humans, Hydrocortisone, Pregnancy, Pregnancy Complications
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