The majority of plurihormonal pituitary adenomas produce GH, PRL, and TSH because somatotroph, lactotroph, and thyrotroph cells all arise from the same progenitor [
7]. The expression of pituitary hormones is regulated by several transcription factors: PIT-1 regulates the functional differentiation of GH, PRL, and TSH; STF-1 and GATA-2 regulate the expression of FSH and LH, while ACTH expression is controlled by T-PIT [
7,
8], which might explain the higher association with GH and PRL cosecretion. PHAs constitute a significant proportion of pituitary adenomas, with a prevalence of approximately 31–36% of surgically resected tumors [
9,
10]. The most frequent associations are with GH and PRL or LH and FSH [
11]. GH-producing adenomas with concomitant ACTH production are extremely rare, although they have been reported previously in a few cases [
12‐
20]. Clinically, the majority of PHAs are silent, and diagnosis almost always relies on immunohistochemical analysis of the tumor tissue to demonstrate positivity for unrelated hormones [
8,
9]. Roca
et al. [
20] recently reviewed the literature on PHAs and reported 21 cases with ACTH–GH plurihormonal pituitary adenoma. Of these, 2 cases had Cushing’s disease, 5 had both acromegaly and Cushing’s disease, 11 had signs of acromegaly, and 3 had pituitary apoplexy. Interestingly, they found that six cases had PRL secretion in addition to ACTH and GH. In PHAs, symptoms related to ACTH are uncommon and were observed in only 3.6% of the reported cases; this phenomenon may be due to insufficient autonomous ACTH production or the absence of ACTH production [
21‐
23]. The pathogenesis of plurimorphous plurihormonal tumors is less clearly defined, but it has been suggested that it may result from neoplastic transformation of two separate cell lines or from the transdifferentiation of one single tumor cell line into a different hormone-producing cell line [
8].
In the current study, we present an interesting and rare case of PHA in which the patient had ACTH-producing tumors that clinically manifested as Cushing’s disease and showed GH and PRL positivity by immunohistochemistry, both of which were asymptomatic or silent. In contrast to previously published cases where there was a predominant clinical presentation with acromegaly and symptoms of hyperprolactinemia, our patient presented initially with headaches and visual symptoms, as well as with clinical features of Cushing’s syndrome in the form of uncontrolled blood pressure, diabetes, obesity, and moon face. Postoperative pituitary MRI scans showed a successful reduction in tumor size with some residual tumor remaining in the sella, leading to the resolution of the biochemical and clinical features of cortisol excess. These rare and unusual PHAs tend to be aggressive and associated with a poor outcome [
15]. PHA patients with ACTH cosecretion appear to have a higher rate of tumor recurrence. Careful evaluation of patients with such tumors and strict follow-up regimens are needed owing to the higher morbidity of these patients [
15,
24,
25]. Our case adds a significant body of knowledge to the current literature of such rare tumors. However, further studies are needed to elucidate the features and natural history of these PHAs.