The debate over the optimal treatment strategy for patients with PA has evolved significantly since the initial view by many that acute neurosurgical intervention was almost always needed [59]. Numerous retrospective and a few prospective studies have tried to establish a more pragmatic approach to treatment [4, 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61] in which non-surgical treatment plays an increasingly important role. Currently, there is a consensus that surgical decompression of the PA mass, most commonly via the transsphenoidal route, should be considered for any patient presenting with severe symptoms, which include severe visual field deficits and/or impaired consciousness [4, 62, 63]. However, whether surgery offers a superior long-term therapeutic benefit to conservative management remains unclear [4, 15,16,17, 62, 64]. Sibal et al. retrospectively reviewed 45 cases of PA and found that most patients experienced complete or near complete resolution of ophthalmologic deficits with no reported deaths following conservative management or surgery [16]. These findings were further supported in a recent multicenter, prospective study reported by Mamelak et al., in which investigators found no significant difference in outcomes in patients who underwent surgery compared to conservative management [4]. Many studies have documented little difference in hormonal outcomes between surgical and non-surgical patients, with only about 10% of patients recovering hormonal defects in either group (Table 3) [2, 4, 18, 19]. The resolution of cranial nerve palsies is comparable and often more favorable in conservatively managed patients at three to six-month follow-up [61].

In the largest observational study performed to date, symptoms, co-morbidities, demographics, and hormonal defects were almost identical between surgical and medical management cohorts, except that surgical patients had slightly larger tumors, but this difference was not significant [4]. The only statistically significant difference between these groups was the rate of bitemporal hemianopsia. Hospital stays were similar, though surgical patients had more complications. Patients with severe visual field defects and greater optic nerve compression were more likely to undergo surgery. At 3 to 6 months post-apoplexy, visual field, hormonal, oculomotor, and quality of life metrics were similar in both groups. The study did not show that surgery led to better visual outcomes, only that these criteria were commonly used to recommend surgery. This lack of outcome difference does not necessarily mean surgery is preferred for visual field defects, just that it was more often chosen.

An important but often overlooked aspect of PA is that the resulting mass effect is largely due to blood and edematous, necrotic tissue, which regress over time. Prior reports have noted regression in 70–95% of patients 3 months post apoplexy (see Fig. 1) [4, 19, 61]. Thus, symptom resolution due to diminished mass effect may be noted in most patients with PA, regardless of whether they undergo surgery. Whether these studies, often performed at centers with expert pituitary teams, represent general outcomes remains to be seen, particularly since growing evidence suggests that the degree of an institution’s experience in pituitary surgery is associated with overall outcomes [4, 65,66,67]. Despite the uncertainty in current literature, immediate decompression is generally safe and commonly used as the primary treatment modality in cases of severe visual deficits [68].

Change in Volume of Apoplectic Tissue in Medically Managed Patients by 2 to 3 Months After Symptom Onset. Volumes were measured using the (A × B × C)/2 approximation method. Each line represents one patient (n = 24). There was a significant 61% median reduction in volume over time (P = .0002), with only one patient showing volume enlargement. Reproduced with permission from: Mamelak, A. et al. (2023). A Prospective, Multicenter, Observational Study of Surgical vs. Nonsurgical Management for Pituitary Apoplexy. Journal of Clinical Endocrinology & Metabolism, 109(2), e711–e725. https://doi.org/10.1210/clinem/dgad541

The optimal timing of surgical intervention when indicated is also not well defined. Patients presenting with severe cognitive impairment and visual deficits such as blindness should be promptly identified as urgent surgical candidates and likely undergo rapid decompression. However, such cases are relatively infrequent. Jho et al. found that patients with PA associated with more severe symptoms were more likely to undergo earlier surgery, similar to other reported studies [18, 62]. Establishing guidelines for intervention becomes more nuanced when addressing patients whose symptoms are stable or are showing signs of improvement. The challenge stems from the lack of evidence-based criteria guiding clinical decision-making in these scenarios.

The existing literature offers varied conclusions on the influence of early surgical intervention, and a consistent definition of “early surgery” is lacking. Woo et al. found that patients who underwent transsphenoidal surgery within three days of symptom onset experienced complete recovery of visual acuity, compared to 83% who had surgery later [69]. Furthermore, this study indicated that 66% of patients who underwent early surgery showed complete or partial recovery, compared to only 40% who received later interventions. These findings parallel those of Rutkowski et al., who ultimately found no differences in the rate of neurological and endocrine deficits following either early, defined as resection within three days of symptom onset, or delayed surgery. The authors also observed that earlier surgery was associated with greater gross total resection rates than delayed treatment (100% versus 44%, p = .003) despite similar size at the initial presentation [17]. Ultimately, no differences were found in the rates of neurological and endocrine deficits following either early or delayed surgery. Similarly, Bill et al. reported that patients who had surgery within seven days of symptom onset achieved complete recovery of visual functions [70]. Meanwhile, Randeva et al. reported that all patients who underwent surgery within eight days of symptom onset experienced complete recoveries [15].

A more comprehensive multi-center analysis compared outcomes by defining early surgery as either two, three, or four days post-symptom onset [4]. Investigators also considered 3-, 4-, and 5 days post-admission to the center where surgery was performed to exclude care delays. Their analysis indicated no advantage to any time-point cut-off for early surgery, with identical outcomes in the visual field, hormonal recovery, and oculomotor palsy regardless of the timing of surgical intervention. While patients who underwent surgery within these time frames exhibited more adverse visual field defects initially, their overall outcomes were comparable to those of patients who had surgery at 7 to 30 days post PA onset as well as those managed medically at the three-month evaluation mark.

In the acute clinical setting, once a presumptive diagnosis of PA has been made, pituitary axis hormones should be measured, and corticosteroids should be initiated immediately, even if lab results are unavailable, as this can always be discontinued if no longer indicated. Meticulous monitoring of vital signs and neurological status is crucial to detect any signs of clinical deterioration. Laboratory evaluations should include assessments of all pituitary axis hormones, electrolytes, renal function, liver function, coagulation parameters, and sodium levels. Monitoring urinary output and fluid balance is essential for detecting hyper or hyponatremia, which should be corrected rapidly. Depending on the institution’s protocols, adrenal insufficiency may be initially managed with a hydrocortisone bolus of 100 mg or equivalent, followed by a maintenance dose ranging from 10 to 40 mg in twice-daily doses. Thyroid-related deficiencies can be replaced slowly, and acute replacement of gonadotroph or somatotroph hormones is rarely indicated. If a patient is found to have a hormonally active prolactinoma, prompt initiation of medical therapy with dopamine agonists is likely indicated.

Once stabilized, an initial decision regarding acute neurosurgical intervention is appropriate. Patients with altered consciousness after corticosteroid replacement and correction of hyponatremia or with severe visual acuity diminishment should undergo surgery promptly, preferably within 48–72 h. Other patients can be observed for several days to monitor visual field stability or improvement, with surgery indicated only if deterioration occurs. This approach allows for transferring patients to specialized centers, improving outcomes. This approach also allows the transfer of patients to centers with greater expertise in pituitary surgery if needed, thereby reducing sup-optimal surgical outcomes. Discussion between the surgery team, endocrinologists, and the patient or family will determine the preferred treatment choice, with many patients opting for surgery, especially as this can often relieve headaches. In stable patients, the timing of surgery does not seem to impact outcomes greatly and can be done in an elective fashion within 2 to 10 days after onset. For patients with surgical risks, observation, and medical management may result in similar outcomes at 3 months due to regression of the apoplectic tissue and blood.

Regardless of the management approach, all patients with PA require subsequent monitoring. MRI of the pituitary is important to evaluate for residual tumors, as these tumors can continue to grow. This is especially important in patients treated with medical management alone, as residual tumors have been reported to grow in 11–12% [20, 71]. Some of these patients may eventually undergo elective surgery to remove residual tumors even after the apoplectic event is resolved. Imaging studies should be conducted approximately three to six months after the apoplexy incident. Subsequently, annual MRI scans are recommended for a minimum of five years.

Hormone levels should be evaluated approximately four to eight weeks after an apoplexy event. Approximately 10 to 20% of patients achieve partial or complete recovery of pituitary function; however, about 80% will require ongoing hormonal supplementation or replacement therapy [2, 4, 18, 19]. GH deficiency is the most commonly observed endocrine deficiency in these patients, though it is infrequently replaced due to various factors, including clinical guidelines and patient-specific considerations. Long-term follow-up with endocrinology is recommended in most cases, especially if hormone supplementation or suppression (for functioning adenomas) is required. This protocol ensures comprehensive monitoring and management, maintaining appropriate neuroendocrine functions and quality of life.