As they are not associated with clinically relevant hormonal hypersecretion, NFPMA remain most often undiagnosed until they present symptoms of tumor mass effect. (1). We confirm in our study that most of these tumors present with headaches and/or visual alterations. NFPMA may also be diagnosed incidentally in about one quarter of cases (1,4). However, autopsy series show that macroadenomas represent less than 1% of pituitary tumors discovered postmortem, thus suggesting that there may be some connection between the presence of an “incidental” macroadenoma and the symptoms leading to brain imaging. In our surgical series, NFPMA were diagnosed “incidentally” in 24% of patients, and even though pituitary incidentalomas by definition are not diagnosed on the basis of tumor-related symptoms, a significant proportion of these patients had headaches, visual deficit at examination and/or pituitary dysfunction that had remained so far undiagnosed .
Hypopituitarism is a common complication of NFPMA at diagnosis. About 60-80% of patients have at least one pituitary hormone deficiency prior to surgery and, depending on the studies, the somatotropic and gonadotropic deficits are the most frequently affected (3,4,11). The prevalence of central hypothyroidism may however be underestimated as the diagnosis of TSH insufficiency remains often difficult given the wide range of normal free thyroxine values in the general population, and the paucity of specific symptoms and signs (21,22). In fact, we found a quite similar prevalence of gonadotropin and TSH deficits in our patients with NFPMA (68% and 62%, respectively), while ACTH deficiency was much less frequent (32%) and diabetes insipidus was very uncommon. Like in many other centers, GH deficiency was not systematically assessed preoperatively. As changes in pituitary function are expected after surgery, preoperative GH testing seems useless as it would need to be repeated after surgery (6). Moreover, our regular practice is to perform GH stimulation testing only in patients who could further benefit from GH therapy. However, when it is done in a systematic way, the majority of patients will be found to be GH-deficient (25).
Preoperative hypopituitarism was associated with tumor size and invasiveness, hyperprolactinemia and the presence of visual disturbances as previously reported by different studies (17,18,26,27,28). Interestingly, we found that tumor width was more closely associated with endocrine dysfunction than tumor height. It is tempting to hypothesize that larger tumors will be more prone to compress the normal gland or the pituitary stalk while taller ones will more frequently induce visual complications, although both dimensions are usually correlated.
Preoperative hyperprolactinemia was observed in nearly half of our patients, as usually observed (28,29,30). It mainly results from pituitary stalk compression (28) and was still present postoperatively in only 16% of patients, indicating that surgery had a significant effect on relieving stalk effect. Previous studies as well as our own data have suggested that in patients with mildly elevated prolactin levels prior to surgery, pituitary function was more likely to recover (17,26,29). These observations suggest the presence of intact pituitary tissue and imply that the mechanism of hypopituitarism may be compression of the portal circulation rather than destruction of the normal pituitary gland (29). A functional inhibitory effect of hyperprolactinaemia on the gonadal function might also be evoked but our data indicate that this is not the main mechanism explaining hypopituitarism in patients with NFPMA.
According to recent guidelines on diagnosis and treatment of NFPMA, surgery is indicated in patients with enlarging tumors or symptomatic tumors with mass effects (1,5,12,13). Surgical management of NFPAs indeed provides successful symptom relief with acceptable morbidity and mortality (16,31). Overall, transsphenoidal surgery – whether microscopic or endoscopic – leads to complete adenoma resection in 20-40% of cases and allows significant debulking in most of them, with an overall complication rate of 5-9% (32,33,34). In contrast, few large studies have extensively evaluated the impact of surgery on pituitary hormonal functions in patients with NFPMA.
While early studies concluded that transsphenoidal surgery carried a significant risk of sacrificing remaining anterior pituitary function, especially in patients with large and compressing tumors (30,35), it is clear from more recent reports that postoperative pituitary function can now be better preserved and even be improved or normalized. We performed a review of several studies published on this issue over the last two decades (Table 6). Large variations are observed between these studies, likely because of differences in patient recruitment and surgical indication, in the definition of pituitary deficits, as well as in surgeon’s experience and procedure. Overall, resolution of one or more hormonal deficits by surgery can be expected in 15-50 of patients, but obviously some studies reported a clear improvement in pituitary function (8,9,17,28,36,37) whereas others could not demonstrate such beneficial effect (15,19,38,39). In the present study, we observed that 50% of all patients with a preoperative hormone deficiency showed improvement of pituitary function after surgery, while a deterioration was seen in less than 20% of all operated patients (whether hormone-deficient or not). Therefore, although Endocrine Society guidelines indicate that hypopituitarism is only a relative surgical indication in patients with NFPA (12), our data suggest that transsphenoidal surgery should not only aim at resolution of visual deficits but also at preservation or improvement of pituitary functions in case of tumor progression (9,33). Furthermore, we also found that permanent DI, which is a common complication of pituitary surgery (5-10%), is more likely to occur when operating a large tumor, which also argues for early surgery.
We also tried to identify factors influencing the outcome of pituitary function after surgery. Few large studies have previously addressed this question (17,18,37). We found that hyperprolactinaemia and a lower tumor diameter were significantly and independently associated with a higher chance of pituitary function recovery. Either tumor width or height predicted endocrine outcome, thus extending results from previous studies (8,18). More precisely in the study of Jahangiri et al, residual size of the normal pituitary gland rather than tumor volume predicted the ability of pituitary axes to improve after transsphenoidal surgery. We did not evaluate this parameter in our study but it is likely that residual normal gland and tumor size (in particular tumor width) are inversely correlated and that endocrine normalization should reflect the amount of functional pituitary tissue which is relieved by decompression. We did not find, however, an association between age and post-operative endocrine outcome, in contrast with a previous report showing that younger age predicted better hormonal recovery (18). .
The main limitations of our study are inherent to its retrospective nature. There were some missing data and each hormone outcome was analyzed in a different (though large) sample size. We also did not perform preoperative testing of GH secretion, which could have led to an underestimation of the degree of pituitary dysfunction. However, isolated GH deficiency is rather rare. On the other hand, our cohort of patients with a confirmed and operated NFPMA was quite large, patients were managed with similar protocols in both centers, surgeries were performed by a limited number of experienced neurosurgeons, and follow-up data at one year were available for 88% of the patients.
In conclusion, in this large cohort of patients operated for a NFPMA, we show that hypopituitarism is present in 80% of the patients before surgery and that, besides GH, the gonadotropin and TSH axes are the more frequently affected. Among patients with preoperative hypopituitarism, nearly half of them will benefit from sustained improvement of pituitary function. Hyperprolactinemia at diagnosis and a lower tumor diameter are independently associated with a favorable endocrine prognosis. As resolution of one or more hormonal deficits can be achieved in a significant number of patients, we suggest that early surgery by experienced pituitary neurosurgeons should be discussed in patients with a growing tumor and hypopituitarism, regardless of visual disturbances.