Neuroendocrine and Pituitary
Tumor Clinical Center (NEPTCC) Bulletin
Winter 2017/2018 | Volume 24, Issue 1
Cushing’s Disease in Pregnancy-Melanie Schorr, M.D.
A 28-year-old woman was referred to the Neuroendocrine and Pituitary Tumor Clinical Center for management of Cushing’s disease (CD). Four years prior to referral, she had a full-term uncomplicated pregnancy and delivered a baby girl. Post-partum, she experienced depression, fatigue, hirsutism, and easy bruising, as well as inability to lose weight and secondary amenorrhea. Three years prior to referral, an outside endocrinologist suspected Cushing’s syndrome (CS), and checked 24-hour urine free cortisols (UFC), which were 10x the upper limit of normal (ULN), and late night salivary cortisols (LNSC), which were also elevated. Serum adrenocorticotropic hormone (ACTH) was elevated, suggesting ACTH-dependent CS. A pituitary MRI revealed a 12 x 9 x 6 mm right sellar lesion. The patient then underwent transsphenoidal surgery at an outside hospital, and pathology was consistent with an ACTH-producing pituitary adenoma. Post-operatively, UFC normalized, but she did not become adrenally insufficient, suggesting she was not in remission and was at a high risk of recurrent hypercortisolemia. Post-operative MRI did not show clear residual tumor.
Symptomatically, the patient felt much improved; her mood, fatigue, hirsutism and easy bruising improved, she was able to lose 20 lbs and had resumption of her menstrual periods. However, two years later, symptoms recurred and she gained 100 lbs. She was referred back to her outside endocrinologist, who suspected persistent CD, and checked UFC, which were 1.5x ULN, and LNSC, which were also elevated. Pituitary MRI demonstrated a small area of residual/recurrent disease in the medial wall of the right cavernous sinus. The patient was then referred to the Neuroendocrine and Pituitary Tumor Clinical Center for management of persistent CD. On exam, she did not appear particularly Cushingoid, as she had normal fat distribution, no extremity thinning and no posterior cervical or supraclavicular fat pads. She did have light violaceous striae over her abdomen. It was recommended that more UFC and LNSC be collected to determine the degree of cortisol excess. Plan was also made for referral to an expert pituitary surgeon, but in the interim, the patient called to report that she was pregnant. Cortisol testing, which had been performed when she was at 8 weeks gestation prior to knowledge of the pregnancy, revealed UFC that were approximately 4x ULN and elevated LNSC. This case raised a number of questions, namely (1) How do you interpret UFC and LNSC in pregnancy? (2) Does CS during pregnancy adversely affect maternal and fetal outcomes? (3) Does treatment of CS during pregnancy improve maternal and fetal outcomes? and (4) What are the treatment options for CS during pregnancy?
How do you interpret UFC and LNSC during pregnancy?
Pregnancy is associated with a number of physiologic changes, including activation of the maternal hypothalamic-pituitary-adrenal axis. Placental estradiol increases serum cortisol binding globulin (CBG) levels, which raises total serum cortisol levels, as most cortisol is protein-bound in the circulation. Placental corticotropin-releasing hormone (CRH) stimulates placental and pituitary ACTH, which increases cortisol production from the maternal adrenal glands. Placental progesterone also induces a relative glucocorticoid resistance, which may further increase maternal serum cortisol levels. The fetus is partially protected from this maternal hypercortisolemia because placental 11β-hydroxysteroid dehydrogenase 2 converts 85% of maternal cortisol to biologically inactive cortisone prior to it entering the fetal circulation.
Recent longitudinal studies that have followed healthy women from early pregnancy to post-partum have demonstrated that 24hr UFC levels were elevated 1.7-, 2.4-, and 3.1- fold during the 1st, 2nd, and 3rd trimesters compared to healthy controls. Studies documenting LNSC levels across gestation have reported variable results. One cross-sectional study reported that pregnant women in the 2nd and 3rd trimester had significantly higher LNSC compared to healthy controls, although another longitudinal study reported no significant differences in LNSC across gestation compared to healthy controls. Studies more consistently demonstrate that within 2-3 months post-partum, UFC and LNSC are no longer elevated compared to healthy controls[2,4].
Consistent with these data, the 2008 Endocrine Society Clinical Practice Guideline on the diagnosis of CS recommended that “UFC values in the 2nd or 3rd trimester >3x ULN can be taken to indicate CS,” but that “diagnostic thresholds for LNSC in pregnant patients are not known”. Given that this patient’s UFC was >5x ULN, we were confident that this was consistent with CD, and not physiologic hypercortisolemia of pregnancy.
Does CS during pregnancy adversely affect maternal and fetal outcomes?
The first description of CS during pregnancy was a case series of 7 patients published in 1953 by Hunt and McConahey. The fetal or newborn mortality rate in this case series was 43%. More recent reports have confirmed that maternal and fetal complications are common in CS during pregnancy. In a review of 136 cases of treated or untreated CS during pregnancy, the maternal mortality rate was 2% and maternal morbidity included hypertension (68%), diabetes mellitus or impaired glucose tolerance (25%) and preeclampsia (14%). In a review of 128 cases of untreated CS during pregnancy, overall fetal loss was 31%, prematurity was 66%, and low birth weight was 68%.
Does treatment of CS during pregnancy improve maternal and fetal outcomes?
Studies have demonstrated that the treatment of CS during pregnancy reduces fetal mortality. In a review of 213 cases of CS during pregnancy, treatment was associated with a significant reduction in overall fetal loss (from 60.1% with no treatment to 11.3% with medical treatment, 23.9% with surgical treatment and 4.7% with medical and surgical treatment) (Table 1). There was no significant difference in the rate of preterm birth or low birth weight with treatment, although the heterogeneity of the groups in terms of the etiology, diagnosis and treatment of CS may explain the lack of significant difference. In addition to improving fetal mortality, treatment also improves maternal morbidity. In a review of 23 cases of adrenalectomy for adrenocortical adenoma causing CS during pregnancy, there was resolution of symptoms related to CS and/or improved control of diabetes mellitus and/or hypertension in 88% of patients. However, the authors reported that the incidence of preterm delivery and intrauterine growth restriction were not significantly different from those of untreated CS during pregnancy.
Table 1 – Fetal outcome by treatment in women with active Cushing’s syndrome during pregnancy
Reprinted by permission from: Endocrine/Springer Nature, Caimari F, Valassi E, Garbayo P, Steffensen C, Santos A, Corcoy R, Webb SM: CS and pregnancy outcomes: A systematic review of published cases. (2017)
What are the treatment options for CD during pregnancy?
Transsphenoidal surgery for CD during pregnancy is preferred over medical therapy if it is deemed safe for the mother and fetus. Surgery during the 2nd trimester is associated with a lower rate of maternal and fetal complications compared to surgery during the 1st or 3rd trimester. However, in a review of cases of CS during pregnancy, only 20% of women with CD underwent transsphenoidal surgery during pregnancy, perhaps due to a lack of access to expert pituitary surgery teams who feel comfortable operating on pregnant women. Currently, there are no FDA-approved medications to treat CD in pregnancy. For those patients who are not surgical candidates, decline surgery, or need adjunctive therapy, the medication most commonly used off-label for the treatment of CD in pregnancy is metyrapone (pregnancy category C). Metyrapone is an 11β-hydroxylase inhibitor, thereby blocking the conversion of 11-deoxycortisol to cortisol. However, 11β-hydroxylase inhibition also results in the build up of mineralcorticoid precursors, which can cause side effects such as hypertension, hypokalemia, and edema, and therefore blood pressure, serum potassium, and edema must be frequently monitored.
Case presentation (continued)
After a discussion of the benefits and risks of treatment with the patient, pituitary surgeon, and high-risk obstetrics, the decision was made to pursue transsphenoidal surgery in the 2nd trimester. Pathology from this 2nd transsphenoidal surgery was consistent with an ACTH-producing pituitary adenoma. However, the resection was not complete, presumably due to dural and/or cavernous sinus invasion, as post-operative 24hr UFC remained 3-4x ULN, so metyrapone was titrated to achieve a goal UFC 2-3x ULN for the 2nd trimester. Blood pressure and serum potassium were monitored weekly and remained normal. When the patient went into labor, metyrapone was stopped and stress dose glucocorticoids were started for labor and delivery of a full-term, healthy baby boy. Post-partum, glucocorticoids were rapidly tapered off, and UFC and LNSC were repeated 1 month post-partum revealing UFC 1.5-2x ULN and elevated LNSC. Cabergoline was then started to achieve short-term control of hypercortisolemia because dosing was more convenient compared to metyrapone and the patient had chosen to stop breast-feeding. Proton beam radiosurgery was then performed with the goal of achieving long-term control of hypercortisolemia. The patient remains on cabergoline with normalized UFC and LNSC.
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