Endocrine outcomes after Endoscopic Transsphenoidal Surgery for Non-Functioning Pituitary Adenomas

Introduction: Non-functioning pituitary adenomas (NFPAs) are common benign tumors that can cause endocrine dysfunction and neurovascular complications. Surgical resection using endoscopic transsphenoidal surgery (ETSS) is a standard treatment for NFPAs


Introduction
Non-functioning pituitary adenomas (NFPAs) are among adulthood's most common benign central nervous system neoplasms, accounting for 15 % of all intracranial tumors, behind meningiomas and gliomas [1].Although NFPAs are hormonally inactive and relatively benign, they have a propensity for growth and expansion and may directly compromise neurovascular structures closely associated with the pituitary gland.In addition, hypopituitarism may also result from direct mechanical compression and ischemia of the pituitary gland or disruption of the adenohypophyseal portal system.Although endocrine deficits are known to be expected in patients with NFPAs

Methods
This study is a retrospective review of records.Adult patients (aged 21 years and above) who underwent ETSS to treat NFPAs in 2011-2018 at National University Hospital, a tertiary neurosurgical institution in Singapore, were included in our study.
All patients with NFPAs presenting at our institution are managed by a multidisciplinary team, which includes a neurosurgeon, endocrinologist, otorhinolaryngologist, and ophthalmologist.
Preoperative magnetic resonance imaging (MRI) of the pituitary gland is routinely performed for all patients for surgical planning; imaging variables collected for this study are orthogonal tumor dimensions, maximum tumor diameter, presence of radiological hemorrhage, optic chiasm compression, and presence of para sellar or sphenoid sinus invasion.
The preoperative anterior pituitary function is assessed by evaluating the cortisol, thyroid, male gonadal, female gonadal, and growth hormone axes.Data on preoperative prolactin levels were also recorded, if available.
Preoperative adrenal insufficiency was defined as low 8 a.m.cortisol; secondary hypothyroidism as low T4 with low or normal TSH; secondary male hypogonadism as low testosterone with normal or low FSH and LH; and secondary female hypogonadism as low oestradiol with normal or low FSH and LH in premenopausal women, or low FSH in postmenopausal women.Insufficiency of the GH axis was defined as low IGF-1.
Patients who were missing laboratory values for pituitary axes were excluded from the analysis of the recovery of those axes, while patients who were lost to follow-up were excluded from our study entirely.
Postoperative endocrine recovery is normalizing biochemical values within 6 months after surgery.
Neuro-ophthalmologic assessment is also routinely performed for all patients with NFPAs at the study institution and includes visual acuity tests and Humphreys visual fields analysis.
The Domain Specific Review Board, Singapore's national medical research ethics board, has approved this study.
Standard statistical methods were used for analysis, such as the chisquared test, Fisher's exact test (for categorical variables), and t-test (for continuous variables).Univariable analysis was first used to identify factors significantly associated with the postoperative recovery of each endocrine axis; identified variables were then included in a multivariable logistic regression model as a further test of significance.Two-tailed significance is set at 5 %, and all data were analyzed with SPSS v22.0.

Results
There were a total of 108 cases of NFPAs treated with ETSS; 9 patients had incomplete clinical and biochemical follow-up data and were thus excluded entirely from the study.99 instances of NFPAs were included in the final analysis.

Preoperative clinical characteristics
Preoperative patient characteristics are shown in Table 1.The mean patient age is 54.3 years (interquartile range 44.9y -62.6y); 57 % of all patients are male.95 % of all patients in the study cohort were symptomatic at presentation, and only 5 % of cases were asymptomatic incidentalomas.Typical clinical symptoms are headache (37.4 %), visual field deficits (73.7 %; bitemporal hemianopsia -45.4 %), and unilateral cranial nerve palsies (9.1 %).
A small proportion of patients presented with pituitary apoplexy (8 %).20 % of all cases were recurrent tumors that had undergone previous surgery, and one-fifth of these cases (4 % of all cases) had undergone previous Gamma Knife surgery.

Preoperative imaging characteristics
The mean maximum tumor diameter is 28.4mm (interquartile range 22.0 -34.0mm) (Table 1).16.2 % of the NFPAs in this study cohort had radiological evidence of hemorrhage.84 % of all tumors were invasive, and 87 % were compressing on the optic chiasm.Factors that are predictive of the presence of preoperative deficits in any anterior pituitary axis, as identified on univariable analysis, are Other factors predictive of endocrine recovery include.
• the absence of preoperative visual loss (p < 0.001) and lack of chiasmal compression (p=0.017) for the thyroid axis, • incidentalomas for the male gonadal axis (p=0.023), • BMI≤29.0 and absence of postoperative panhypopituitarism for the female gonadal axis (p=0.048).
Although these factors are statistically significant, their effect sizes and odds ratios could not be accurately calculated due to zero-cell counts.

New-onset postoperative endocrine deficits
Incidence of new-onset postoperative endocrine deficits by individual axes (Table 4) is 53.7 % for the cortisol axis; 16.7 % for the thyroid axis; 45.0 % for the male gonadal axis; and 6.3 % for the female gonadal axis.Data in this study suggest that the recovery rates for new-onset deficits are poor; only 34.5 % of patients with new-onset, postoperative hypocortisolism were able to achieve recovery of the cortisol axis.Smaller tumors may be associated with the resolution of new-onset deficits of the cortisol axis (maximum tumor diameter < 23mm; OR 12.44, 95 % CI 2.00 -77.60, p=0.007).It was also noted that tumors with preoperative radiological evidence of hemorrhage had a 0 % recovery rate, which approached significance (p=0.068) at the α=5% level.No patients in this study who developed new postoperative deficits in other axes could recover the respective axes.The mean duration of transient diabetes insipidus is 1.9 days (standard deviation 1.0 days; interquartile range 1.0 -2.0 days).
The extent of resection (gross total resection vs. subtotal resection) was not significantly associated with the development of permanent diabetes insipidus.

Predictors of preoperative endocrinopathy
Tumor size has been shown in this study and by other authors [20] as a significant predictor of preoperative hypopituitarism.Elevated body mass index and obesity (21)(22)(23)(24) likely are physical manifestations of hypopituitarism rather than causal factors per se of endocrine deficits.

Rates of postoperative endocrine recovery and Predictive Factors
Within published literature, there is a significant variation in the reported rates of endocrine recovery [14,17,18,25] and an absence of a consensus about the factors most predictive of endocrine recovery.
Such significant variation in rates of endocrine recovery is not adequately explained by current evidence and may, in part, result from wide-ranging physiological differences between individuals Indeed, the results of this study suggest that total tumor size is neither the sole determinant nor the most important predictor of recovery.
The univariable and multivariable analysis did not reveal full tumor size as a statistically significant predictor of recovery of pre-existing, preoperative endocrine deficits in any axis.Instead, the extent of damage sustained by the residual pituitary gland is a more critical determinant of the likelihood of recovery.Incidentolamas, the absence of postoperative panhypopituitarism or diabetes insipidus, or the lack of radiological evidence of hemorrhage, suggest a relatively intact gland that has preserved its capacity for regeneration and recovery.
The hypothesis that endocrine recovery is dependent on the regenerative capacity of the residual pituitary gland is supported by evidence from the few case series published in the literature.Jahangiri found that a rise in TSH after TRH and in LH after GnRH stimulation was of value in predicting possible recovery of pituitary function after surgery.
In particular, the low recovery rates of the thyroid axis suggest that the thyrotropic cells of the anterior pituitary are highly susceptible to injury.An ischaemic mechanism of damage to the thyrotropic cells may be more likely than pure mechanical compression; prolonged ischemia causes cell death that may not be reversed with surgical decompression.As predictive factors of recovery, the absence of visual deficits and chiasmal reduction are surrogate markers of the severity of mass effect and ischemia.Finally, it must be noted that the rates of recovery of the thyrotropic axis reported in the literature are inconsistent across studies and vary considerably.

New onset, postoperative endocrine deficits
Rates of new-onset, postoperative endocrine deficits are broadly consistent with those reported in other case series [14,28].Sample size limitations in this study prevent the accurate estimation of actual recovery rates and identifying factors associated with recovery.
However, these preliminary results broadly suggest that new-onset endocrine deficits in any axis after surgery may be permanent and irreversible.The non-negligible risk of new, permanent postoperative endocrine deficits is an essential factor that should be considered when deciding on surgical treatment of an NFPA.

Extent of resection
Of note is that gross total resection was associated with the recovery of preoperative deficits of the cortisol axis on both univariable and multivariable analysis and was not associated with the development of new obligations or diabetes insipidus after surgery.A study by Webb and co-workers (28) also found that the absence of tumor rests on postoperative pituitary imaging was predictive of endocrine recovery.Thus, it may be reasonable to strive for the complete removal of tumor tissue during surgery; proper surgical technique, and careful identification of the plane between the tumor and normal pituitary tissue, will reduce the risk of iatrogenic injury to the normal pituitary gland.

Surgical management of NFPAsendocrinological considerations
While visual loss and chiasm compression are relatively uncontroversial indications for surgical resection of an NFPA, the endocrinological indications for surgery remain unclear, as the postoperative recovery of pituitary function is not guaranteed.
Surgery may be beneficial in improving endocrine function in patients with pre-existing deficits, but its benefits must be adequately weighed against its risks, such as the development of new obligations, perioperative morbidity, and diabetes insipidus.Further studies are required to assess the burden of care of preoperative endocrinopathy and its impact on the patient's quality of life and to determine if surgery has an unquestionable benefit in alleviating either.In addition, due consideration should also be given to the potential burden of lifelong hormonal replacement for patients who developed permanent, new endocrine deficits after surgery.While the results presented in this study are inconclusive, the authors feel that the benefits of surgical intervention may not necessarily outweigh its risks and wish to caution against excessive zeal to perform surgery for endocrinological indications alone.Furthermore, the necessity of surgery is debatable in clinically asymptomatic individuals with only laboratory or biochemical evidence of pituitary dysfunction.
As not all patients may benefit from surgery, proper patient selection Finally, as recovery is uncertain and there is an indeterminate risk of developing new deficits after surgery, regular postoperative assessment of each significant endocrine axis is necessary.Further studies may help assess the burden of lifelong hormonal replacement and its impact on a patient's quality of life.

Limitations
The authors acknowledge that the retrospective nature of this study is a limitation, and that inherent bias may exist.Several patients were also lost to follow-up and needed complete clinical and biochemical follow-up data; they were excluded from the final analysis.

Conclusion
Pituitary dysfunction alone is not a strong indication for surgery for NFPAs, as preliminary evidence shows that the benefits of surgery may not necessarily outweigh its risks.Proper patient selection is crucialevidence from this and other studies, while inconclusive, suggests that younger patients who have less complicated tumors and less severe preoperative deficits may benefit most from surgery.
Ancillary investigations such as volumetric measurements of residual pituitary gland volume and hormone stimulation tests may also be https://doi.org/10.38207/JNCN/2023/JUN040101appropriate.It is reasonable to strive for complete tumor removal during surgery, as gross total resection increases the chances of endocrine recovery and is not associated with an increased risk of developing new postoperative deficits.Regular postoperative assessment of the significant endocrine axes is essential.

[ 2 ]
, the incidence of hypopituitarism by individual endocrine axes varies significantly, and a wide range of rates of anterior hypopituitarism has been reported by previous studies [3-6].Endoscopic transsphenoidal surgery (ETSS) [7] is a standard surgical procedure performed for the resection of NFPAs [8-10].Visual field deficits and compression of the optic chiasm are relatively uncontroversial indications for surgery; however, it is unclear if surgical treatment is indicated for patients presenting solely with endocrine dysfunction [11], as hormonal recovery is uncertain [12], and there is a significant risk of the development of new endocrine deficits.The rates of postoperative endocrine recovery of patients who underwent ETSS are poorly characterized, and the factors associated with recovery are poorly understood.This study aims to investigate the rates of preoperative endocrine deficits, postoperative endocrine recovery, and new-onset deficits in patients with NFPAs who underwent ETSS to treat NFPAs and to identify factors associated with endocrine recovery.

individual axes (Figure. 1 )
are 45.5 % for the adrenal/cortisol axis; 64.3 % for the male gonadal axis; 25.6 % for the female gonadal axis; 27.3 % for the thyroid axis; and 25.3 % for the somatotropic (growth hormone) axis.The growth hormone axis is only routinely assessed in some patients.Hence available data may underestimate the actual rate of deficits of this axis.Rates of anterior panhypopituitarism (defined as involvement of the three principal axescortisol, male/female gonadal, and thyroid axes) were 17.2 % in this study cohort.The rate of elevated prolactin (from the stalk effect) was found to be 24.2 %; however, prolactin levels were not routinely measured in all patients.

[ 26 ].
The need for definite clarity about predictive factors of endocrine recovery also increases the difficulty of identifying patients likely to achieve healing and who are thus most likely to benefit from surgery.The existing evidence in the literature suggests a weak, inverse relationship between tumor size and the likelihood of endocrine recovery [27].However, this relationship is observed inconsistently across studies [20,28,29], implying that a complex interplay between anatomical and disease factors influences endocrine recovery.
and co-workers [20], by performing volumetric, quantitative measurements of the residual pituitary gland, found that patients who achieved postoperative endocrine normalization had larger preoperative gland volumes.A study by Arafah [27] found that the https://doi.org/10.38207/JNCN/2023/JUN040101patients who had a rise in serum TSH level in response to preoperative thyrotropin-releasing hormone (TRH) stimulation achieved some endocrine improvement postoperatively, suggesting that such a biochemical response was indicative of the presence of remnant viable pituitary tissue.Similarly, Marazuela and co-workers [30] is crucial.Patients most likely to recover pituitary function and thus most likely to benefit from surgery should be carefully identified.It is unclear which factors are definitively associated with recovery.However, based on current evidence, it is likely that multiple anatomical and disease factors influence recovery.Patients with relatively uncomplicated tumorsmore diminutive size, no invasion, no radiological evidence of hemorrhage -may benefit from surgery; other authors have also found that younger patients with less severe preoperative deficits may have better chances of recovery [20].Ancillary investigations such as quantitative, volumetric measurements of the residual pituitary gland [20] and hormone stimulation tests [27,30] to determine regenerative potential may also be appropriate.

Table 1 .
Pre-operative clinical and imaging characteristics of patients in the study cohort (n=99); continuous data is presented as mean (standard deviation) and interquartile range; categorical data, as n and %.

Table 2 .
Predictors of pre-operative anterior hypopituitarism, as identified on univariable and multivariable (logistic regression) analysis.

Table 3 )
are 24.4 % for the cortisol axis, 7.4 % for the thyroid axis, 16.7% for the male gonadal axis, and 63.6% for the female gonadal axis.Prolactin and the growth hormone axis are significant even after adjusting for confounding effects in a logistic regression model.

Table 5 )
. In 16.2 % of these patients, the condition did not resolve.
DiscussionRates of preoperative endocrinopathyThe overall rate of endocrine deficits (in any axis) found in this cohort of patients falls within the range reported in the literature (37 % to 85 %, according to various studies) [5,13,14].Male hypogonadism was this study cohort's most common endocrine deficit, followed by secondary adrenal insufficiency (hypocortisolism).The relative incidence of individual endocrine deficits observed in this study cohort was mainly consistent with that reported in the literature, where GH deficiency, central hypogonadism, and adrenal insufficiency were the most common endocrinopathies found in patients with NFPAs.The lack of routine assessment of the GH axis in all patients at our center prevents an accurate estimation of the actual rate of GH deficits in this study cohort.Rates of central