To date, there is no single factor to predict the recurrence of CD in the long-term follow-up of patients. Previous studies showed that several factors, such as PS serum cortisol, PS ACTH, recovery of the HPA axis/return of the circadian rhythm of cortisol secretion, the extent of glucocorticoid replacement, early responses of ACTH and/or serum cortisol to secretagogues, among others [6, 7], can contribute to a recurrence. This fact can be explained by the rarity of the disease, the heterogeneity of studies, studies with a small number of patients and/or short time of follow-up and lack of consensus for recurrence criteria diagnosis. However, even patients with “rigid” criteria of remission and “low risk” can present a recurrence in the long-term follow-up with a non-negligible frequency.
This study is the first to evaluate the influence of pregnancy on the recurrence rate in a group of reproductive-age female CD patients that initially show post-surgical remission (n = 113). This group recurred at a rate of 38%, with a median of 48 months (range 8-240) after pituitary surgery, similar to a recurrence rate of overall patients, 30.9% (76/246). This relative higher recurrence rate in comparison to mean of literature may be explained by the great long-term surveillance, 30 years, in our study.
Even though the patients having pregnancy after pituitary surgery presented a higher recurrence rate of 50%, there was no significant difference in relation to other subgroup (NP/PP) according to the survival-free recurrence curve. This higher recurrence rate in the PA could be due to the subgroup being younger and having had longer follow-up time than the other.
Other parameters at diagnosis and PS periods for predicting recurrence were analyzed in this study. Recurrence patients showed a higher sinus cavernous invasion. Additionally, the lower survival-free recurrence was related to higher PS plasma ACTH more than 68.2 pg/mL at 5th PS Day and normal pituitary at pathological analyses.
We decided to study the influence of pregnancy on the recurrence rate of post-surgical CD patients because in our clinic experience, we occasionally observe early recurrence in patients some months after pregnancy, even in patients considered “low risk”. We suggest that hormonal changes that occur during the pregnancy may stimulate putative tumor cell remnants. There is no similar study in the literature. However, one interesting study analyzed the impact of pregnancy on progression of corticotropic tumor after bilateral adrenalectomy in 11 patients with 20 pregnancies, and it concluded that pregnancy does not accelerate corticotropic tumor growth and ACTH increase in Nelson’s syndrome [13].
A healthy pregnancy is considered a transient physiologic state of ‘hypercortisolism’ [14]. There is a state of increased HPA axis function, leading to increased circulating cortisol and ACTH levels, reaching values in the range seen in Cushing’s syndrome (CS). These changes may lead to a misdiagnosis of CS during this period, with clinical features mimicking those seen in patients with CS. However, these changes lack the specific clinical manifestations of CS [9].
The mechanisms of ACTH increase during normal pregnancy are not fully elucidated, but they may include placental synthesis and the release of biologically active corticotropin-releasing hormone (CRH) and ACTH, pituitary desensitization to cortisol feedback, or enhanced pituitary responses to corticotropin-releasing factors, such as vasopressin and CRH [9, 10]. conditions that could stimulate the remnants of corticotropic tumor cells and cause CD recurrence.
On the other hand, the CRH-binding protein is elevated during the first two trimesters of pregnancy, but it decreases considerably in the final trimester, and bioavailable plasmatic CRH is consequently elevated [10, 15, 16].
CD in pregnancy is a rare phenomenon with few cases reported in the literature, and most of them are ACTH-independent [10]. CD is associated with fetal morbidity and mortality. When untreated, fetal mortality is nearly 20%, and treatment reduces but does not abolish this adverse outcome. Maternal morbidity includes hypertension, hyperglycemia, and eclampsia [17].
This study had some limitations that could influence the results. This study was retrospective and had a relatively small number of patients in each subgroup. Obstetric history was collected through telephone or email contacts in a portion of patients. However, we believe that the final number of included patients and quality of data were appropriate to perform this study.
We conclude that in our cohort, there was no difference in the recurrence rate in female patients according to pregnancy history. However, other studies with higher numbers of patients are necessary to confirm these data.