Non-functioning pituitary adenomas (NFPAs) account of 25% of all pituitary adenomas . Most of these tumors represent themselves as macroadenoma and have been delayed in diagnosis until they reached to size enough to produce compressive symptoms like visual affection, headache and/or hypogonadism . The first line of treatment of these tumors is surgical excision . However, due to the nature of growth and extension of these tumor, surgery is usually failed to totally remove all neoplastic tissues, and residual masses is a common postoperative image finding that can re-grow during follow up period in most of patients . Postoperative radiotherapy is still controversial, and is not usually preferred due to its potential side effects that include hypopituitarism, neurocognitive dysfunction and cerebrovascular disease besides the rare occurrence of postradiation secondary intracranial tumor  . However, by immunocytochemistry, most of these tumors are glycoprotein producing, and less commonly are non-functioning somatotroph, lactotroph or corticotroph adenomas. A proportion of NFPA secretes small amounts of FSH and LH and/or their a- and b-subunits either in vitro or in vivo . Different subtypes of dopamine and somatostatin receptors were found in a variable amount in most of NFPA cell membranes. Based on this point, dopamine agonists (DA) and somatostatin analogues (SSA) may have a role in the treatment of NFPA. However, except for some case reports, the results of medical treatment with DA were disappointing . The existence of a functional interaction between dopamine and somatostatin receptors has opened a new perspective of medical treatment for NFPA . Bromocriptine was discovered by scientists at Sandoz in 1965 and was first published in 1968. It was first marketed under the brand name Parlodel . Bromocriptine is a dopamine agonist (DA) and is well established as first line therapy for prolactinomas. This is thought to be due to high levels of dopamine receptors in prolactinoma . Patients with NFPA typically lack serum markers reflecting tumor proliferation, so treatment efficacy is based on tumor size assessment by Magnetic Resonance Imaging (MRI) and Computer Tomography (CT) at regular intervals . The aim of this work is to study the efficacy of bromocriptine (dopamine agonist (DA) drug) in reducing or preventing the re-growth of non-functioning pituitary adenoma NFPA after surgery.
2. Materials and Methods
This is a retrospective study analyzing data from patients records and scans that were carried out at Assiut university hospital for all cases whom were diagnosed by the authors as having non functioning pituitary macroadenoma between 2012-2018. Inclusion criteria include all patients presented with neurological manifestations related to non functioning pituitary macroadenoma who are fit for surgery. Exclusion criteria include functioning pituitary adenoma, pituitary microadenoma and unfit patients. All patients were treated with surgical debulking of the tumor with decompression of optic nerves followed by prescription of Bromocriptine therapy during the postoperative and follow up period as a trial to control the re-growth of the residual mass. Bromocriptine was administered in a dose of 2.5 mg twice daily. The clinical features and neuro-image of our patients were reviewed to confirm the diagnosis of NFPA and the incidence of re growth of the adenoma after surgery. Clinical and radiological outcome were reviewed over a follow up period of six years.
Thirty two patients were included in this study. Twenty one patients (66%) were females and eleven patients (34%) were males. Their ages ranged from 18 to 65 years with a mean age of 37.
All of our patient presented with a variable degree of visual filed and/or acuity affection as a main complaint. All of our patient were operated in the department of neurosurgery, Assiut university. Twenty patients had transsphenoidal approach, and twelve patients (with large suprasellar extension) (Figure 1) had right subfrontal approach and debulking of the mass and the assurance of completion of optic nerves decompression. Postoperative course was smooth in twenty three patients. five patients had CSF leak which stopped by conservative treatment in 1 - 2 week, four patients did not recover well and emergent CT scan was done to all of them and showed frontal contusion in three patients whom been treated conservatively and recovered in 5 - 7 days and hematoma in the operative bed in the fourth patient that required surgical evacuation, and he regain his conscious level after 3 day but with deterioration of his vision. Twenty two patients (69%) their vision improved immediately after surgery, seven patients (22%) remain unchanged, and three patients (9%) had deterioration of their visions. All of our patients had a residual tumor appeared in the immediate post operative images (Figure 2) and all of them received bromocriptine tablets in a dose of 2.5 mg every 12 hours After 6 months of postoperative bromocriptine
Figure 1. Preoperative MRI brain of a 40 years old male patient with sever visual acuity and field affection, rt subfrontal approach was done and decompression of both optic nerves.
Figure 2. Immediate post operative images of the same patients shows large residual mass.
treatment, and with comparing to the immediate post operative images, eleven patients (34%) had mass reduction, (Figure 3) thirteen patients (41%) their residual masses remained unchanged and eight patients (25%) the mass showed slight increase in size but not required re surgery. After two years and throughout the follow up period, seven patients (22%) (all were males) had complete disappearance of the mass, (Figures 4-6) ten patients (31%) had more reduction of the size of the mass (two of them were males) and four patients (13%) the mass remained unchanged (none of them were males) and eleven patients (34%) had increase of the mass and they required re surgery (two of them were males) (Table 1). Tumor control was achieved in 66% of the patient (Figure 7) complete disappearance of the mass was observed in 64% of the males comparing to 0% in females, total tumor control was 82% in males comparing to 57% in females (Figure 8).
Surgery is considered the first option in management of NFPA. however, residual mass is a common postoperative finding in most of those patients due to the fact that the diagnosis is usually delayed and the tumor reached a large size with supra-and para sellar extension  All of our patients had a residual tumor in immediate post operative images. Ferrante et al. , in studying of 295 patients with NFPA underwent surgery, reported total excision of the mass in only
Figure 3. MRI brain of the same patients after 6 months of DA treatment shows reduction of the residual mass.
Figure 4. MRI of the same patient after one year medical treatment shows more shrinkage of the mass.
Figure 5. MRI of the same patients after 2 years medical treatment with complete disappearance of the mass.
Figure 6. MRI brain of the same patients after 6 years follow up shows no recurrence.
Figure 7. Tumor control was achieved in 66% of the patient after 6 years.
Figure 8. Differences between males and females in tumor control.
Table 1. Follow up of the residual mass and differences between males and females.
35.5% of the patients and the rest of the patients had residual mass. Therefore, additional postoperative therapy is still required for those residual NFPA. Radiotherapy is reported to have a role in decreasing the re growth rate of the residual masses . Although Boelaert and Gittoes  reported that pituitary radiotherapy may be less hazardous than was originally though, still this is not without an extra cost of side effects like hypopitutarism, neurocognitive dysfunction and cerebrovascular disease besides the rare occurrence of postradiation secondary intracranial tumor . Prolactinomas have a high level of dopamine 2 receptors and dopamine agonists (DA) are very effective in reducing tumor size and hormone secretion of prolactinoma. NFPAs have varying levels of dopamine receptors . Bromocriptine is a potent agonist at dopamine D2 and at various serotonin receptors . These open the door for finding an additional more safer medical treatment for NFPA. DA was found to have a role in controlling postoperative residual in those tumors. However, no placebo-controlled long-term studies are available to suggest the use of DA in NFPA . 66% of our patients had tumor control after two years treatment with dopamine agonist with 22% of the studied patients had complete disappearance of the mass and 34% of patients failed to respond to bromocriptin. Good response to DA was observed more in males as all our patients (100%) that totally cured and had no residual mass during follow up were males and 20% of patients that had tumor reduction were males. Cooper and Greenman  reported the largest series of NFPT patients who were treated with DA. In one of the groups that they studied, fifty five patients received preventive DA treatment and twenty four patients received treatment after tumor growth. With preventive treatment 87% achieved tumor control. While with secondary treatment, 58% achieved tumor control. Barrow et al.  found that Bromocriptine induced tumor growth stabilization in 75 of 84 patients (89%) with NFPAs as measured on CT scan. Vieira Neto et al.  studied 23 patients with post operative residual tumor. 25% tumor volume reduction was seen on MRI in some of their patients after cabergoline therapy. On the other hand Dekkers et al.  reported that spontaneous reduction of tumor size occurred in 29% of their patients and thus they suggest that just observation of some selected cases of NFPA may be an option for management provided there are no compressive signs as visual affection or hypopituitarism.
Bromocriptine (DA drug) can play a role in reducing the size or preventing the re-growth of non-functioning pituitary adenoma after surgical debulking. Males showed noticeable response comparing to females. Its regular use might limit the need for surgery in this type of tumor. Further studies with large number of patients are highly recommended.
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