Discussion
When women are diagnosed with CS less than 12 months after delivery, they are empirically considered to have had active CS during pregnancy, with a high probability of concomitant hypercortisolism during pregnancy [
3]. Herein, we have reported two patients in whom CS was diagnosed 5 and 8 months after delivery, which is consistent with them having had active CS during pregnancy.
Chronic hypercortisolemia inhibits both the action of gonadotropin-releasing hormone (GnRH) in the gonads and GnRH secretion from the hypothalamus [
1]. Therefore, women with untreated CS rarely become pregnant. In those who do become pregnant, 55% have ACTH-independent CS, whereas ACTH-independent CS accounts for a relatively small proportion in non-pregnant women [
3]. It has been suggested that in CD, there is hypersecretion of cortisol and androgens, which interferes with the gonadal axis, causing amenorrhea in over 70% of patients, whereas adrenal tumors almost exclusively hypersecrete cortisol [
4]. Therefore, the second patient reported herein, in which CD had likely been present during pregnancy, had a relatively rare condition.
The diagnosis of CS in pregnancy is quite difficult for many reasons. First, due to its very low incidence, a high degree of clinical suspicion is required [
1]. Second, the clinical signs of hypercortisolism (weight gain, fatigue, hypertension, and hyperglycemia) overlap with the physiological changes that characterize pregnancy [
2,
5]. Therefore, CS is often not diagnosed until the second trimester [
6]. However, although many of the symptoms overlap, the occurrence of pathological fracture should provoke a CS work-up [
7]. In the present patients, the symptoms reported are common features of pregnancy, meaning that it would have been difficult to diagnose CS earlier.
The diagnosis of CS during pregnancy is also hampered by the changes in the hypothalamic-pituitary-adrenal (HPA) axis that normally occur [
8]. Plasma ACTH and cortisol concentrations and urinary free cortisol (UFC) concentration are high during normal pregnancies, which makes biochemical diagnosis more challenging [
8]. However, a recent study showed that late-night salivary cortisol concentration is higher in patients with CS than in pregnant women [
9]; therefore, the use of a combination of UFC and late-night salivary cortisol is recommended for the diagnosis of CS during pregnancy.
CS during pregnancy is associated with poor maternal and fetal outcomes [
2]. Patients with active CS tend to deliver earlier than those whose CS has been corrected and are more likely to undergo cesarean section. They also more frequently experience complications of pregnancy, including gestational diabetes, hypertension, and preeclampsia. In addition, fetal complications, such as fetal loss, fetal distress, preterm birth, and low birth weight, are more frequent in the presence of active maternal CS [
3]. In both the patients reported here, maternal complications occurred during pregnancy and one neonate was born preterm and both were a low birth weight.
The management of pregnant women with CS is similar to that of non-pregnant patients. For both ACTH-independent and ACTH-dependent CS, surgical treatment should ideally be performed during the second trimester, before the 24th week of gestation. For ACTH-independent CS, which accounts for 55% of the cases of CS during pregnancy, adrenal surgery appears to be more successful than medical therapy. For pregnant women with CD, transsphenoidal surgery or medical therapy (generally using metyrapone) have both been used [
10]. In addition to the specific treatment of CS, any comorbidities should be treated, including diabetes and hypertension [
2]. After the surgical treatment of both of the patients reported herein, their symptoms resolved.
As in the cases reported herein, the diagnosis of CS during pregnancy is difficult because of its low incidence, the overlapping clinical signs, and the changes that occur in the HPA axis during normal pregnancy. However, because CS is associated with higher incidences of maternal and fetal complications, early diagnosis is important. Therefore, when pregnant women present with suspicious symptoms, such as pathological fracture, physicians should consider whether they might be hypercortisolemic.