Perioperative fluctuation and overall evaluation of adenohypophyseal hormone secretion in patients with nonfunctioning pituitary adenoma

Zhijie PeiDepartment of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China;

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Yi FangDepartment of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China;

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Shuwen MuDepartment of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China;

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Jun LiDepartment of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China;

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Tianshun FengDepartment of Neurosurgery, Oriental Hospital Affiliated to Xiamen University, Fuzhou, Fujian, China; and

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Kunzhe LinDepartment of Neurosurgery, Fuzhou First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China

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Shousen WangDepartment of Neurosurgery, Fuzhou 900th Hospital, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China;

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OBJECTIVE

Perioperative adenohypophyseal hormone assessment can improve therapeutic strategies and be used to evaluate the prognosis of pituitary adenomas. An individual hormone level does not entirely reflect the pituitary gland. Thus, this study aimed to analyze perioperative hormonal changes and propose a normalized method to facilitate overall assessment of the adenohypophysis.

METHODS

The authors retrospectively analyzed 89 male patients with nonfunctioning pituitary adenoma (NFPA) who underwent transsphenoidal surgery. Preoperative clinical data, imaging data, and perioperative hormone levels of the anterior pituitary gland were evaluated. Hormone values were rescaled using minimum-maximum normalization. The sum of the normalized hormone levels was defined as the total hormonal rate (THR).

RESULTS

Preoperative findings indicated correlations among different adenohypophyseal hormones. Luteinizing hormone (p = 0.62) and adrenocorticotropic hormone (p = 0.89) showed no significant changes after surgery, but growth hormone levels increased (p < 0.001). On the contrary, the levels of thyroid-stimulating hormone (p < 0.001), follicle-stimulating hormone (p = 0.02), and prolactin (p < 0.001) decreased. THR indicated a significant postoperative reduction in adenohypophyseal function (p = 0.04). Patients with postoperative hypopituitarism had significantly lower THR than those without (p = 0.003), with an area under the curve of 0.66. For NFPAs that presented with normal preoperative hormone levels, THR was a good clinical predictor of immediate postoperative hypopituitarism, with an area under the curve of 0.74.

CONCLUSIONS

The normalized synthesis index of hormones is a novel and clinically valuable method used to reflect adenohypophyseal secretion. Compared with individual hormones, these results indicated that THR can facilitate the analysis of general hormone levels despite various fluctuations in adenohypophyseal hormones. THR may also contribute to the effective prediction of short-term surgery-induced hypopituitarism.

ABBREVIATIONS

ACTH = adrenocorticotropic hormone; AUC = area under the curve; FSH = follicle-stimulating hormone; GH = growth hormone; GTR = gross-total resection; LH = luteinizing hormone; NFPA = nonfunctioning PA; PA = pituitary adenoma; PRL = prolactin; ROC = receiver operating characteristic; STR = subtotal resection; THR = total hormonal rate; TSH = thyroid-stimulating hormone.

OBJECTIVE

Perioperative adenohypophyseal hormone assessment can improve therapeutic strategies and be used to evaluate the prognosis of pituitary adenomas. An individual hormone level does not entirely reflect the pituitary gland. Thus, this study aimed to analyze perioperative hormonal changes and propose a normalized method to facilitate overall assessment of the adenohypophysis.

METHODS

The authors retrospectively analyzed 89 male patients with nonfunctioning pituitary adenoma (NFPA) who underwent transsphenoidal surgery. Preoperative clinical data, imaging data, and perioperative hormone levels of the anterior pituitary gland were evaluated. Hormone values were rescaled using minimum-maximum normalization. The sum of the normalized hormone levels was defined as the total hormonal rate (THR).

RESULTS

Preoperative findings indicated correlations among different adenohypophyseal hormones. Luteinizing hormone (p = 0.62) and adrenocorticotropic hormone (p = 0.89) showed no significant changes after surgery, but growth hormone levels increased (p < 0.001). On the contrary, the levels of thyroid-stimulating hormone (p < 0.001), follicle-stimulating hormone (p = 0.02), and prolactin (p < 0.001) decreased. THR indicated a significant postoperative reduction in adenohypophyseal function (p = 0.04). Patients with postoperative hypopituitarism had significantly lower THR than those without (p = 0.003), with an area under the curve of 0.66. For NFPAs that presented with normal preoperative hormone levels, THR was a good clinical predictor of immediate postoperative hypopituitarism, with an area under the curve of 0.74.

CONCLUSIONS

The normalized synthesis index of hormones is a novel and clinically valuable method used to reflect adenohypophyseal secretion. Compared with individual hormones, these results indicated that THR can facilitate the analysis of general hormone levels despite various fluctuations in adenohypophyseal hormones. THR may also contribute to the effective prediction of short-term surgery-induced hypopituitarism.

Pituitary adenoma (PA) is a common intracranial benign tumor, with 15% to 30% of cases having nonfunctioning subgroups.1 In general, nonfunctioning pituitary adenomas (NFPAs) are characterized by the absence of clinical symptoms linked to hormone hypersecretion.2 According to the literature, hypopituitarism occurs in a large proportion of patients with NFPAs, ranging from 37% to 85%.35 Hypopituitarism is regarded as an important factor in the prognosis and quality of life of patients.6,7 The development of primary hypopituitarism is due to compression of the portal vessels and pituitary stalk. In addition to enlarged PAs, transsphenoidal surgery, which is the leading therapy for NFPAs, is associated with postoperative hypopituitarism, with an incidence rate of 12.8% to 85.2%.6,8,9 The potential destruction of the normal pituitary gland and compression of filled hemostatic materials may be responsible for short-term hypopituitarism after surgery. Therefore, hormone levels must be monitored and evaluated to adjust therapy strategies in a timely manner and to improve the effectiveness of communication with patients.

The adenohypophysis produces six types of hormones: growth hormone (GH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and adrenocorticotropic hormone (ACTH). Most studies focus on pituitary hormone levels individually rather than synthetically because of the different types of units and reference ranges.8,10 Adenohypophyseal hormones have a direct and/or indirect interaction.1113 Moreover, the secretion of the entire pituitary gland is difficult to assess when NFPA exhibits hyperpituitarism or hypopituitarism in different pituitary axes.8 Thus, assessment of a single-hormone axis may not fully reflect the overall pituitary gland. To our knowledge, studies on the overall hormone function of the adenohypophysis are rarely reported. Thus, a concept and method for analysis and overall assessment of adenohypophysis was proposed in a previous work.14 However, the method cannot reflect the secretion of the entire adenohypophysis but rather overall pituitary hormonal changes during the perioperative period.

In this study, we aimed to analyze changes in the aforementioned six hormones and used normal ranges as references to standardize hormone levels. The six hormones were synthesized in the form of the total hormonal rate (THR) to facilitate the perioperative evaluation of the entire function of the adenohypophysis.

Methods

Patient Cohort

This single-center study was conducted retrospectively and included male patients with NFPA who underwent transsphenoidal surgery between 2011 and 2020 at our hospital. The inclusion criteria were as follows: 1) a clinical diagnosis of NFPA without any hyperpituitarism and hormonal symptoms; 2) a complete medical record, including measurement of preoperative and postoperative adenohypophyseal hormone levels (GH, TSH, FSH, LH, PRL, and ACTH) at our hospital; and 3) a diagnosis of PA confirmed with immunohistochemistry. The exclusion criteria were as follows: 1) history of radiotherapy or recurrence; 2) recent use of drugs that alter or affect pituitary hormone levels; and 3) diagnosis of a primary endocrine disorder that affects pituitary hormone levels. A total of 89 patients met the inclusion criteria and comprised the cohort.

All procedures included in the study were approved by the Ethics Committee at Fujian Medical University, China. All patients or their families provided written informed consent for the clinical procedures used and for inclusion in the study.

Radiological Assessment

MRI with and without gadolinium contrast was conducted using the Siemens 3.0-T MAGNETOM Trio Tim MRI system. Data obtained within 1 week prior to surgery and 3 months after surgery were recorded. Data, including tumor diameter, Knosp grade, and extent of resection, were analyzed by two neurosurgeons and one radiologist.

Tumor diameter was defined as the maximum diameter measured using the INFINITT PACS system. PAs were classified as macroadenoma (1–3 cm) and giant adenoma (< 3 cm) on the basis of diameter. We used Knosp grade to classify parasellar extension of NFPAs on coronal MRI (high grade [grades 3–4] vs low grade [grades 0–2]). Tumor removal was assessed on the basis of MRI findings at 3 months postoperatively, and gross-total resection (GTR) and subtotal resection (STR) were distinguished in accordance with the Hoffman classification system.15

Endocrine Assessment

Hormones, including GH, TSH, FSH, LH, PRL, and ACTH, were recorded 7 days prior to surgery and within 7 days postoperatively. All hormone tests were performed by using chemiluminescence detection methods with the Siemens ADVIA Centaur XP machine. Male reference values for each hormone were as follows: < 2 ng/ml GH, 0.35–5.5 mIU/ml TSH, 1.4–18.1 mIU/ml FSH, 1.5–9.3 mIU/ml LH, 2.1–17.7 µg/L PRL, and 4.7–48.8 ng/ml ACTH. Hypopituitarism was diagnosed on the basis of one or more insufficient hormone levels.3

We applied minimum-maximum normalization, which was presented as follows: x(β) = (x − xmin)/(xmax − xmin), where xmin is the minimum value of the normal range and xmax − xmin is the normal range of values.16

After normalization, the normal hormone level ranged from 0 to 1, with < 0 indicating hypopituitarism and > 1 indicating hyperpituitarism. The sum of normalized hormone values was defined as THR to reflect the secretion of the entire adenohypophysis.

A receiver operating characteristic (ROC) curve was constructed to evaluate the predictive values of THR and to distinguish subjects with and without surgery-induced hypopituitarism. The area under the curve (AUC) was also calculated.

The levels of some adenohypophysis hormones differ during female developmental and physiological periods. Accurately matching menstrual history and normal hormone ranges was not feasible because of limited records regarding menstruation and menopause in this retrospective study. Thus, females were not included in our cohort.

Surgical Method

Surgical procedures were performed by a neurosurgeon (S.W.) with over 30 years of experience in transsphenoidal microscopic surgery.

A straight incision was made in the middle of the nasal septum. The sphenoid ostia were located, and the anterior wall of the sphenoid sinus was opened. The sellar floor bone was exposed and removed to reach the sellar floor. The dura mater was opened with an X-shaped incision. Tumors were resected using a circular curette, forceps, and suction instruments. Surgery was performed to remove the tumor. It was difficult to meet the GTR criteria for some PAs with encasement of blood vessels, invasion of surrounding structures, or tough texture. A gelatin sponge was used to fill the tumor cavity after resection. After resection, sellar floor reconstruction was performed. The nasal cavity was packed with Vaseline gauze.

Statistical Analysis

IBM SPSS version 25.0 (IBM Corp.) was applied for data analysis. Data were presented as mean for continuous variables and as percent for categorical variables. The t-test was used to compare continuous variables with a normal distribution, and the Mann-Whitney U-test was used to assess differences in continuous variables without a normal distribution among groups. The chi-square test or Fisher’s exact test was used to assess categorical variables. Spearman and Pearson correlation coefficients were utilized to correlate ordinal grading and continuous variables, respectively. All visualization charts were processed and presented using Prism (version 8, GraphPad Software) and R (version 4.0.2, The R Foundation for Statistical Computing). Values with p < 0.05 were considered statistically different.

Results

Clinical Data

Eighty-nine male patients with NFPAs were included, with a mean ± SD (range) age of 51.7 ± 12.4 (18–79) years. Tumor size was identified in 75 of 89 cases, and the mean tumor diameter was 29.78 ± 11.49 mm. We classified 57 patients with low Knosp grade (0–2) and 18 patients with high Knosp grade (3–4) on the basis of parasellar extension of NFPAs. When hormone levels were analyzed, preoperative hypopituitarism was detected in 46 patients (corresponding to 30 with LH deficiency, as well as 13 TSH, 12 ACTH, 8 PRL, and 2 FSH deficiency). Based on 3-month postoperative imaging data, GTR and STR were achieved in 71.1% and 28.9% of patients, respectively. After tumor resection, new-onset hypopituitarism occurred in 41 patients, 23 of whom had a history of preoperative hormone deficiency. The patient characteristics and hormone results are detailed in Table 1 and Supplemental Table 1, respectively.

TABLE 1.

Baseline characteristics

CharacteristicValue
Age, yrs51.7 ± 12.4
Time of onset, %
 ≤1 yr42/64
 >1 yr22/64
Diameter, mm29.78 ± 11.49
 Macroadenoma44
 Giant adenoma31
Knosp grade, %
 0–257
 3–418
Primary hypopituitarism46
 TSH13
 FSH2
 LH30
 PRL8
 ACTH12
Resection
 GTR59
 STR24
Secondary hypopituitarism41
 TSH16
 FSH4
 LH14
 PRL11
 ACTH6

Values are shown as number or mean ± SD.

Preoperative Factors

Correlation analysis identified age as a positive factor for THR in our cohort (p = 0.03). Furthermore, FSH (p = 0.08) and PRL (p = 0.06) slightly decreased among older patients (Fig. 1). Patients with symptomatic NFPAs within 1 year had significantly higher levels of PRL than those with a history of symptomatic NFPAs greater than 1 year (p = 0.02).

FIG. 1.
FIG. 1.

Scatter matrix of preoperative factors. The dashed red line represents the 95% confidence interval, the dashed gray line represents the curve of the Loess regression model, and the solid black line is the curve of the linear regression model. A short-dashed wireframe represents a correlation of p < 0.05, and a long-dashed wireframe represents a correlation of p < 0.01.

With regard to tumor diameter, larger NFPAs tended to have lower levels of LH (p = 0.03). No significant correlation was detected between tumor diameter and the other hormones. THR tended to decrease with increase in tumor diameter. THR and tumor diameter did not exhibit any significant correlation (p = 0.61). Furthermore, parasellar extension of NFPAs (Knosp grade) was unrelated to THR (p = 0.25).

Analysis of hormone levels in patients with NFPA revealed complicated correlations among adenohypophyseal hormones. GH secretion levels were negatively correlated with TSH (p < 0.001) and PRL (p = 0.04). In contrast, TSH secretion levels were positively correlated with PRL (p = 0.03). In addition, FSH was positively correlated with LH (p < 0.001) and ACTH (p = 0.01) levels. The assessment of individual hormone levels may have limitations in the preoperative and postoperative evaluations of NFPAs.

Normalized hormone levels may represent the secretion of an individual pituitary axis. Preoperative THR, which is the sum of the secretion statuses of six hormones, was analyzed in our cohort. Positive correlations were found between THR and pituitary hormones, except GH (Fig. 1).

Postoperative Hormone Levels

Adenohypophyseal hormone levels were frequently affected after transsphenoidal surgery in this series. The postoperative GH level increased significantly (p < 0.001). The levels of TSH (p < 0.001), FSH (p = 0.02), and PRL (p < 0.001) were all lower than those measured before surgery. In addition, the levels of LH (p = 0.62) and ACTH (p = 0.89) remained stable throughout the study period (Fig. 2). Synthetic analysis of the function of the entire adenohypophysis is difficult because of different changing tendencies of these hormones.

FIG. 2.
FIG. 2.

Perioperative changes in six pituitary hormones. The perioperative levels of the pituitary hormones showed significantly different changes. Data were analyzed with the t-test. The levels of LH (p = 0.62) and ACTH (p = 0.89) were stable during the perioperative period. The GH level considerably increased (p < 0.001), and the levels of TSH (p < 0.001), FSH (p = 0.02), and PRL (p < 0.001) significantly decreased after surgery. THR, as the sum of the general hormone levels, represents reduction of adenohypophyseal secretory function, with significant differences (p = 0.04). Mean (bars, or middle dashed line for THR) and standard deviation (error bars, or short solid lines for THR) are shown. **p < 0.05; ***p < 0.01.

THR was calculated to comprehensively analyze the secretion of the adenohypophysis. This value immediately and significantly decreased from 1.45 ± 0.68 to 1.19 ± 0.95 after the operation. No differences in the changes of the levels of the six hormones and THR were found between the GTR and STR cases (Supplemental Fig. 1).

Hypopituitarism

Preoperative endocrinology tests revealed adenohypophyseal hormone insufficiency in 46 of 89 NFPAs (51.7%). The incidence of secondary hypopituitarism after transsphenoidal surgery was 41 (46.0%). Of the 43 patients without primary hypopituitarism, 18 (41.9%) experienced new hypopituitarism after surgery. However, no considerable correlation was found between preoperative and new-onset postoperative hypopituitarism (p = 0.44). Of these 89 patients in our cohort, 55 (61.8%) had postoperative hypopituitarism.

Primary hypopituitarism was not significantly related to age (p = 0.63). However, secondary hypopituitarism was slightly associated with age (p = 0.06). Other factors, including onset time, tumor diameter, and parasellar extension, were not significantly associated with primary and secondary hypopituitarism in our cohort. The details are shown in Supplemental Fig. 2.

We also analyzed the hormone levels of patients diagnosed with primary hypopituitarism and found that FSH (p < 0.001), LH (p < 0.001), and ACTH (p < 0.001) levels were significantly lower than normal hormone levels (Table 2, Fig. 3). Lower PRL was slightly correlated with primary hypopituitarism (p = 0.09). Thus, NFPAs with primary hypopituitarism had lower secretion based on THR (p < 0.001). Among patients with secondary hypopituitarism induced by surgery, the levels of FSH (p = 0.01) and LH (p = 0.02) decreased significantly and that of ACTH reduced slightly (p = 0.09). Therefore, THR was significantly higher in patients without secondary hypopituitarism (p < 0.001).

TABLE 2.

Hypopituitarism and adenohypophyseal hormones

CharacteristicPAs w/ Primary HypopituitarismPAs w/o Primary Hypopituitarismp Value
Secondary Hypopituitarismp ValueSecondary Hypopituitarismp Value
YesNoYesNo
Age, yrs48.95 ± 14.9854.13 ± 9.110.0648.11 ± 14.4555.92 ± 8.720.050.84
Diameter, mm27.28 ± 16.0926 ± 12.630.6828.72 ± 18.1724.55 ± 12.010.380.72
GH, μg/L0.25 ± 0.300.22 ± 0.340.670.15 ± 0.120.23 ± 0.390.400.24
TSH, mIU/ml1.34 ± 1.071.35 ± 0.860.981.38 ± 0.641.46 ± 0.620.680.41
FSH, mIU/ml5.41 ± 3.347.43 ± 3.640.016.52 ± 3.419.28 ± 3.540.01<0.001
LH, mIU/ml2.21 ± 1.633.27 ± 2.420.023.03 ± 1.054.61 ± 2.200.01<0.001
PRL, μg/L8.19 ± 5.659.62 ± 3.710.179.92 ± 4.749.76 ± 3.200.900.09
ACTH, ng/L18.15 ± 13.0923.29 ± 15.150.0926.79 ± 12.9228.32 ± 14.710.73<0.001
THR1.23 ± 0.601.65 ± 0.69<0.0011.62 ± 0.402.07 ± 0.610.01<0.001

Values are shown as mean ± SD unless indicated otherwise.

FIG. 3.
FIG. 3.

Relationships between hormone levels and hypopituitarism, as well as performance of ROC curve analysis for predicting surgery-induced hypopituitarism. Group A (with preoperative hypopituitarism) and group B (without preoperative hypopituitarism) are compared. Patients with preoperative hypopituitarism had significantly lower THR levels (p < 0.001) than those without preoperative hypopituitarism, as characterized by considerably lower FSH (p < 0.001), LH (p < 0.001) and ACTH (p < 0.001) levels. THR values were lower in patients with secondary hypopituitarism after surgery than those without surgery-induced hypopituitarism in both groups with or without preoperative hypopituitarism, as characterized by the considerably lower FSH and LH levels. In NFPAs, THR had predictive values for postoperative hypopituitarism, with an AUC of 0.66 (black dotted line). In NFPAs without preoperative hypopituitarism, THR had favorable performance for predicting postoperative hypopituitarism, with an AUC of 0.74 (black solid line). Mean (bars) and standard deviation (error bars) are shown.

Figure 3 also shows the ROC curve for THR, which was used to predict hypopituitarism (AUC 0.66). In patients with NFPA and without primary hypopituitarism prior to surgery, young patients were at high risk for secondary hypopituitarism (p = 0.05). Patients with immediate hypopituitarism after surgery showed lower FSH (p = 0.01) and LH (p = 0.01) levels than those without. Notably, THR performed well for predicting surgery-induced hypopituitarism, with an AUC of 0.74.

Discussion

Interconnections Among Adenohypophyseal Hormones

Pituitary hormones are susceptible to reaction from extrapituitary sources. In addition to feedback loops, local factors, acting within the adenohypophysis, may affect secretory function.11,17,18 In our series, we found that changes in individual hormone levels were often associated with changes in one or more hormones. For example, GH levels were highly correlated with TSH and PRL levels. Apart from GH, TSH had a close correlation with PRL. Moreover, FSH was associated with LH and ACTH levels.

Intracellular connections can regulate the release and action of substances. The secretion of pituitary hormones is under the control of paracrine and extrapituitary organs.19 More than 100 compounds have been identified with connections to paracrine or autocrine actions.20 Gonadotroph is immunoreactive for LH and FSH.2022 In the present study, a positive correlation was found between LH and FSH levels prior to surgery. A local control system between somatotroph and lactotroph has been reported.12 Moreover, signals between gonadotroph and corticotroph have been identified.20 Some clinical studies have demonstrated that FSH deficiency can be secondary to ACTH hypopituitarism.5 Complicated interconnections may be observed among adenohypophyseal cells. However, most relationships remain uncertain. Consequently, the evaluation of the isolated actions of an individual pituitary axis for predicting the prognosis of NFPA had underlying limitations.22 The concept of a total hormone and normalized method could improve the macroscopic evaluation of adenohypophyseal function.

Effects of Transsphenoidal Surgery on NFPAs

Transsphenoidal surgery is the first-line treatment for PAs. However, deterioration and improvement of pituitary function can occur simultaneously in different pituitary axes after NFPA surgery. In a cohort of 49 patients with pituitary macroadenomas, Arafah et al. found that ACTH decreased within hours after adenomectomy, whereas PRL increased in the group without preoperative ACTH deficiency.23 Zhang et al. retrospectively reviewed 164 patients with NFPA and reported an increase in GH levels and decreases in FSH, PRL, and ACTH levels after transsphenoidal surgery.8 In the present study, we included male patients with NFPAs and found that TSH, FSH, and PRL levels were vulnerable to surgery. After the operation, the sellar diaphragm was sunken in most cases, pituitary stalk compression had disappeared, and the pituitary stalk effect was relieved. Therefore, the level of PRL decreased in this cohort. In addition, decreased PRL after surgery represents damage to pituitary endocrine function. In this cohort, the trend of PRL was consistent with that of THR. Meanwhile, serum GH levels increased after surgery. Different endocrine results may be attributed to the perioperative strategies used.

The mechanism of postoperative hypopituitarism remains unclear. Surgical traction and stimulation, compression of filling materials, and disturbance of the adenohypophyseal blood supply are related to hormone deficiency.14,24,25 After surgery, pituitary stalk compression was relieved in most cases, and the pituitary stalk effect disappeared. Consequently, PRL decreases, whereas other hormones will not increase or decrease significantly because of the disappearance of the pituitary stalk effect. Therefore, we hypothesize that hypopituitarism after surgery is primarily due to the removal of the pituitary tumor and mechanical injury of the pituitary. In previous studies, surgery was considered an important factor in the reduction of adenohypophysis function caused by postoperative hypopituitarism.26 Meanwhile, improvement in postoperative hormone levels has been confirmed in clinical practice during long-term follow-up.24,27,28 We observed that the majority of analyses isolated hormonal recovery and deficiency.29,30 If hormone recovery and deficiency are analyzed separately, then distinguishing immediate improvement and deterioration of the entire pituitary gland after surgical therapy is difficult.

Preoperative and Postoperative Hypopituitarism

Hypopituitarism is a common clinical manifestation of NFPAs, with an incidence of 37%–85%.4,5 Hypopituitarism is also a major factor affecting the prognosis and mortality of patients.31 In this study, LH deficiency (30/46 patients) was the most common, followed by TSH (13/46) and ACTH (12/46) deficiency. In previous studies, tumor volume was a factor that influenced hypopituitarism.2 However, we found that tumor diameter did not significantly affect hormone deficiency. In addition, tumor diameter cannot reflect the direction of tumor extension, and it has limitations in the depiction of mass effects. Several studies have also demonstrated that tumor volume is not related to hypopituitarism.24 Notably, superior extension of the PA is an important independent factor of hypopituitarism.2,3,23 Furthermore, primary hypopituitarism may result from compression of the pituitary stalk.

In the current study, hypopituitarism was a common complication of transsphenoidal surgery. Surgery-induced hypopituitarism occurred in 41 of 89 patients. A meta-analysis of 6988 patients with acromegaly reported postoperative hypopituitarism in 12.79% of all cases, of which 2.50% developed panhypopituitarism.9 Ammirati et al. demonstrated that the incidence rates of hypopituitarism after endoscopic and microscopic surgery were 8.51% (95% CI 5.16%–12.59%) and 11.64% (95% CI 5.14% to 20.32%), respectively, in a meta-analysis of 38 transsphenoidal surgical outcomes.32 In previous studies, patients with larger PAs had higher risk of postoperative gland dysfunction.26 However, we found that tumor diameter was not a significant factor in surgery-induced hypopituitarism. We hypothesize that surgery is the main factor for short-term reduction of adenohypophyseal function owing to direct intraoperative damage, continuous intrasellar compression induced by filled hemostatic materials, and blood supply disorders. Selective resection can limit the manipulation of and traction on the normal gland and thereby reduce the incidence of postoperative hypopituitarism. Furthermore, the tumor resection rate did not affect the incidence of postoperative hypopituitarism in our cohort, which is consistent with the results of earlier studies.24,26

Total Hormone Rate

Several intercellular connections among adenohypophyseal cells have been confirmed.20 The function of the adenohypophysis depends on pituitary axis feedback and intracellular regulation. In addition, the levels of certain hormones increase, whereas others decrease, because of enlarged NFPAs or surgery. Thus, the isolated actions of individual hormones cannot effectively and accurately reflect the hormonal tendencies of the entire pituitary gland. Considering that THR was developed with minimum-maximum normalization and calculated with the integration of six types of adenohypophyseal hormones, it can facilitate functional analysis of the entire adenohypophysis. We analyzed the correlation between THR and hormone deficiency, as well as between THR and individual hormone levels. The coefficient was statistically significant; thus, THR could be developed as a composite indicator and used in analysis of pituitary function.

We also analyzed the correlations between THR and clinical indices, such as age, tumor size, and parasellar extension, to determine whether preoperative factors explained the hormonal changes in the pituitary gland. The statistically significant positive correlation between THR and age indicated that NFPAs have less influence on adenohypophysis in older patients. The coefficient supports the increased risk of secondary hypopituitarism in younger patients. Therefore, normal pituitary gland compliance is higher among older NFPA patients as a result of pituitary atrophy.33

THR described perioperative hormones that have an immediate effect on adenohypophysis function. Hypopituitarism of certain hormone axes may improve, whereas those of other hormones decrease after surgery. Isolated analysis of individual hormones, hypopituitarism, and hyperpituitarism may mislead or confuse clinicians assessing prognosis. In the present study, we selected a composite index that can simplify hormonal interregulation and various fluctuation tendencies. THR is an effective indicator for interpretation of adenohypophyseal function during the perioperative period.

Perioperative monitoring of hormone fluctuation is required in NFPAs with normal hormone levels because of the decline in postoperative adenohypophyseal function and hormonal deficiency. Consideration of only 1 hormone axis cannot accurately predict the incidence of hypopituitarism in other hormones. First, we considered the secretion of the entire pituitary gland as the predictive factor for secondary hypopituitarism induced by surgery. We found that THR had AUCs of 0.66 and 0.74 in NFPAs with or without primary hypopituitarism, respectively. Preoperative THR may help clinicians analyze the short-term risk of surgery-induced hypopituitarism. THR combined with individual pituitary axes may facilitate accurate prediction of postoperative hypopituitarism. Further studies are necessary to correlate THR and endocrine outcomes.

Limitations

Apart from the retrospective design, this study had several limitations. This study was limited to male patients with NFPAs, and further clinical examination is necessary to confirm the clinical value of THR for female patients with other pituitary tumors. We collected data on only six hormones to reflect adenohypophyseal function and ignored other relevant hormones, such as insulin-like growth factor–1. This study was also limited to perioperative hormone evaluation, and its results do not represent long-term prognosis. Whether THR is also suitable for adenohypophysis assessment with long-term follow-up needs further studies. Furthermore, the composite index—namely, THR—was not calculated by multiplying the standardized indicator value by the weight of the indicator because of uncertain differences in the relative weights of these hormones. Hence, these six hormones were tentatively considered to have equal weight in pituitary secretion in our cohort. Moreover, this study was a single-center study with a limited amount of data. Therefore, multicenter data are required to test the generalization of the THR index.

Conclusions

We found correlations among adenohypophyseal hormones, indicating that hormone secretion was not limited to individual pituitary axes. Standardized methods can be used to comprehensively evaluate the function of the adenohypophysis and to help clinicians analyze the whole adenohypophysis on the basis of the sum of normalized hormone levels. Postoperative hormone levels may present different changes that are not conducive to analysis of the prognosis of the entire adenohypophysis. Based on the THR data, patients with adenohypophysis may have an immediate reduction in secretion as a result of surgery. Use of THR can simplify the different fluctuations of hormone levels and facilitate analysis of prognosis. Moreover, we found that THR contributes to the effective prediction of postoperative hypopituitarism in NFPAs. Therefore, use of THR with individual hormone levels must be considered to improve the prediction of immediate surgery-induced hypopituitarism.

Acknowledgments

We thank the Neurosurgery Department of Fuzong Clinical Medical College of Fujian Medical University. The present study was funded by the Fujian Provincial Key Project of Science and Technology Plan (grant no. 2019Y9045) and the Fujian Medical University Sailing Fund Project (grant no. 2019QH2043).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Pei, Fang. Acquisition of data: Pei, Fang, Mu, Li, Feng, Lin. Analysis and interpretation of data: Wang, Pei, Fang, Mu, Li, Feng, Lin. Drafting the article: Pei, Fang. Critically revising the article: Pei. Approved the final version of the manuscript on behalf of all authors: Wang. Statistical analysis: Pei, Mu. Study supervision: Wang, Lin.

Supplemental Information

Online-Only Content

Supplemental material is available online.

References

  • 1

    Delgado-López P, Pi-Barrio J, Dueñas-Polo M, Pascual-Llorente M, Gordón-Bolaños M. Recurrent non-functioning pituitary adenomas: a review on the new pathological classification, management guidelines and treatment options. Clin Transl Oncol. 2018;20(10):12331245.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Margaritopoulos D, Vassiliadi DA, Markou M, Evangelatou E, Tzanela M, Tsagarakis S. Suprasellar extension independently predicts preoperative pituitary hormone deficiencies in patients with nonfunctioning pituitary macroadenomas: a single-center experience. Hormones (Athens). 2020;19(2):245251.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Higham CE, Johannsson G, Shalet SM. Hypopituitarism. Lancet. 2016;388(10058):24032415.

  • 4

    Fleseriu M, Bodach ME, Tumialan LM, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline for pretreatment endocrine evaluation of patients with nonfunctioning pituitary adenomas. Neurosurgery. 2016;79(4):E527E529.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Esposito D, Olsson DS, Ragnarsson O, Buchfelder M, Skoglund T, Johannsson G. Non-functioning pituitary adenomas: indications for pituitary surgery and post-surgical management. Pituitary. 2019;22(4):422434.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Tampourlou M, Fountas A, Ntali G, Karavitaki N. Mortality in patients with non-functioning pituitary adenoma. Pituitary. 2018;21(2):203207.

  • 7

    Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516524.

  • 8

    Zhang R, Wang Z, Gao L, et al. Clinical characteristics and postoperative recovery of hypopituitarism in patients with nonfunctional pituitary adenoma. World Neurosurg. 2019;126(7):e1183e1189.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Carvalho P, Lau E, Carvalho D. Surgery induced hypopituitarism in acromegalic patients: a systematic review and meta-analysis of the results. Pituitary. 2015;18(6):844860.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    O’Reilly MW, Reulen RC, Gupta S, et al. ACTH and gonadotropin deficiencies predict mortality in patients treated for nonfunctioning pituitary adenoma: long-term follow-up of 519 patients in two large European centres. Clin Endocrinol (Oxf). 2016;85(5):748756.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Schwartz J, Van de Pavert S, Clarke I, Rao A, Ray D, Vrana K. Paracrine interactions within the pituitary gland. Ann N Y Acad Sci. 1998;839(3):239243.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Harvey S, Martínez-Moreno CG, Luna M, Arámburo C. Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview. Gen Comp Endocrinol. 2015;220(5):103111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Vankelecom H, Denef C. Paracrine communication in the anterior pituitary as studied in reaggregate cell cultures. Microsc Res Tech. 1997;39(2):150156.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Wang S, Li B, Ding C, Xiao D, Wei L. A novel "total pituitary hormone index" as an indicator of postoperative pituitary function in patients undergoing resection of pituitary adenomas. Oncotarget. 2017;8(45):7911179125.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Hoffman HJ. Craniopharyngiomas. The role for resection. Neurosurg Clin N Am. 1990;1(1):173180.

  • 16

    Go DS, Kim YE, Yoon SJ. Development of the Korean community health determinants index (K-CHDI). PLoS One. 2020;15(10):e0240304.

  • 17

    Vázquez-Borrego MC, Gahete MD, Martínez-Fuentes AJ, et al. Multiple signaling pathways convey central and peripheral signals to regulate pituitary function: lessons from human and non-human primate models. Mol Cell Endocrinol. 2018;463:422.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    van der Spoel E, Roelfsema F, Akintola AA, et al. Interrelationships between pituitary hormones as assessed from 24-hour serum concentrations in healthy older subjects. J Clin Endocrinol Metab. 2020;105(4):12011214.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Jones TH, Brown BL, Dobson PR. Paracrine control of anterior pituitary hormone secretion. J Endocrinol. 1990;127(1):513.

  • 20

    Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk. J Neuroendocrinol. 2008;20(1):170.

  • 21

    Todd JF, Small CJ, Akinsanya KO, Stanley SA, Smith DM, Bloom SR. Galanin is a paracrine inhibitor of gonadotroph function in the female rat. Endocrinology. 1998;139(10):42224229.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Thackray VG, Mellon PL, Coss D. Hormones in synergy: regulation of the pituitary gonadotropin genes. Mol Cell Endocrinol. 2010;314(2):192203.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Arafah BM, Kailani SH, Nekl KE, Gold RS, Selman WR. Immediate recovery of pituitary function after transsphenoidal resection of pituitary macroadenomas. J Clin Endocrinol Metab. 1994;79(2):348354.

    • Search Google Scholar
    • Export Citation
  • 24

    Song C, Zhang N, Yu H, Zhou P, Yin S, Jiang S. Functional protection during operations of pituitary adenoma. J Clin Neurosurg. 2019;16(2):115118.

    • Search Google Scholar
    • Export Citation
  • 25

    Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab. 2000;85(5):17891793.

    • Search Google Scholar
    • Export Citation
  • 26

    Little AS, Gardner PA, Fernandez-Miranda JC, et al. Pituitary gland recovery following fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenoma: results of a prospective multicenter study. J Neurosurg. 2020;133(6):17321738.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Galloway L, Ali M, Lansdown A, et al. The impact of endoscopic transsphenoidal pituitary adenoma surgery on endocrine function: a single-centre study. Acta Neurochir (Wien). 2021;163(2):391398.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Jahangiri A, Wagner JR, Han SW, et al. Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis. J Neurosurg. 2016;124(3):589595.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Baldia M, Rajaratnam S, Rajshekhar V. Postoperative hormonal outcomes in patients with large and giant non-functioning pituitary adenomas. Neurol India. 2020;68(3 suppl):S106S112.

    • Search Google Scholar
    • Export Citation
  • 30

    Zhan R, Ma Z, Wang D, Li X. Pure endoscopic endonasal transsphenoidal approach for nonfunctioning pituitary adenomas in the elderly: surgical outcomes and complications in 158 patients. World Neurosurg. 2015;84(6):15721578.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Olsson DS, Trimpou P, Hallén T, et al. Life expectancy in patients with pituitary adenoma receiving growth hormone replacement. Eur J Endocrinol. 2017;176(1):6775.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84(8):843849.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Cui B, Chen N, Wang X, Zhuo Y, Chen L. KC L. High-resolution MRI study of pituitary glands in healthy adult of the Han nationality. Zhonghua Fang She Xue Za Zhi. 2010;44(6):579584.

    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand
  • View in gallery
    FIG. 1.

    Scatter matrix of preoperative factors. The dashed red line represents the 95% confidence interval, the dashed gray line represents the curve of the Loess regression model, and the solid black line is the curve of the linear regression model. A short-dashed wireframe represents a correlation of p < 0.05, and a long-dashed wireframe represents a correlation of p < 0.01.

  • View in gallery
    FIG. 2.

    Perioperative changes in six pituitary hormones. The perioperative levels of the pituitary hormones showed significantly different changes. Data were analyzed with the t-test. The levels of LH (p = 0.62) and ACTH (p = 0.89) were stable during the perioperative period. The GH level considerably increased (p < 0.001), and the levels of TSH (p < 0.001), FSH (p = 0.02), and PRL (p < 0.001) significantly decreased after surgery. THR, as the sum of the general hormone levels, represents reduction of adenohypophyseal secretory function, with significant differences (p = 0.04). Mean (bars, or middle dashed line for THR) and standard deviation (error bars, or short solid lines for THR) are shown. **p < 0.05; ***p < 0.01.

  • View in gallery
    FIG. 3.

    Relationships between hormone levels and hypopituitarism, as well as performance of ROC curve analysis for predicting surgery-induced hypopituitarism. Group A (with preoperative hypopituitarism) and group B (without preoperative hypopituitarism) are compared. Patients with preoperative hypopituitarism had significantly lower THR levels (p < 0.001) than those without preoperative hypopituitarism, as characterized by considerably lower FSH (p < 0.001), LH (p < 0.001) and ACTH (p < 0.001) levels. THR values were lower in patients with secondary hypopituitarism after surgery than those without surgery-induced hypopituitarism in both groups with or without preoperative hypopituitarism, as characterized by the considerably lower FSH and LH levels. In NFPAs, THR had predictive values for postoperative hypopituitarism, with an AUC of 0.66 (black dotted line). In NFPAs without preoperative hypopituitarism, THR had favorable performance for predicting postoperative hypopituitarism, with an AUC of 0.74 (black solid line). Mean (bars) and standard deviation (error bars) are shown.

  • 1

    Delgado-López P, Pi-Barrio J, Dueñas-Polo M, Pascual-Llorente M, Gordón-Bolaños M. Recurrent non-functioning pituitary adenomas: a review on the new pathological classification, management guidelines and treatment options. Clin Transl Oncol. 2018;20(10):12331245.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Margaritopoulos D, Vassiliadi DA, Markou M, Evangelatou E, Tzanela M, Tsagarakis S. Suprasellar extension independently predicts preoperative pituitary hormone deficiencies in patients with nonfunctioning pituitary macroadenomas: a single-center experience. Hormones (Athens). 2020;19(2):245251.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Higham CE, Johannsson G, Shalet SM. Hypopituitarism. Lancet. 2016;388(10058):24032415.

  • 4

    Fleseriu M, Bodach ME, Tumialan LM, et al. Congress of Neurological Surgeons systematic review and evidence-based guideline for pretreatment endocrine evaluation of patients with nonfunctioning pituitary adenomas. Neurosurgery. 2016;79(4):E527E529.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Esposito D, Olsson DS, Ragnarsson O, Buchfelder M, Skoglund T, Johannsson G. Non-functioning pituitary adenomas: indications for pituitary surgery and post-surgical management. Pituitary. 2019;22(4):422434.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Tampourlou M, Fountas A, Ntali G, Karavitaki N. Mortality in patients with non-functioning pituitary adenoma. Pituitary. 2018;21(2):203207.

  • 7

    Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516524.

  • 8

    Zhang R, Wang Z, Gao L, et al. Clinical characteristics and postoperative recovery of hypopituitarism in patients with nonfunctional pituitary adenoma. World Neurosurg. 2019;126(7):e1183e1189.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Carvalho P, Lau E, Carvalho D. Surgery induced hypopituitarism in acromegalic patients: a systematic review and meta-analysis of the results. Pituitary. 2015;18(6):844860.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    O’Reilly MW, Reulen RC, Gupta S, et al. ACTH and gonadotropin deficiencies predict mortality in patients treated for nonfunctioning pituitary adenoma: long-term follow-up of 519 patients in two large European centres. Clin Endocrinol (Oxf). 2016;85(5):748756.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Schwartz J, Van de Pavert S, Clarke I, Rao A, Ray D, Vrana K. Paracrine interactions within the pituitary gland. Ann N Y Acad Sci. 1998;839(3):239243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Harvey S, Martínez-Moreno CG, Luna M, Arámburo C. Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview. Gen Comp Endocrinol. 2015;220(5):103111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Vankelecom H, Denef C. Paracrine communication in the anterior pituitary as studied in reaggregate cell cultures. Microsc Res Tech. 1997;39(2):150156.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Wang S, Li B, Ding C, Xiao D, Wei L. A novel "total pituitary hormone index" as an indicator of postoperative pituitary function in patients undergoing resection of pituitary adenomas. Oncotarget. 2017;8(45):7911179125.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Hoffman HJ. Craniopharyngiomas. The role for resection. Neurosurg Clin N Am. 1990;1(1):173180.

  • 16

    Go DS, Kim YE, Yoon SJ. Development of the Korean community health determinants index (K-CHDI). PLoS One. 2020;15(10):e0240304.

  • 17

    Vázquez-Borrego MC, Gahete MD, Martínez-Fuentes AJ, et al. Multiple signaling pathways convey central and peripheral signals to regulate pituitary function: lessons from human and non-human primate models. Mol Cell Endocrinol. 2018;463:422.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    van der Spoel E, Roelfsema F, Akintola AA, et al. Interrelationships between pituitary hormones as assessed from 24-hour serum concentrations in healthy older subjects. J Clin Endocrinol Metab. 2020;105(4):12011214.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Jones TH, Brown BL, Dobson PR. Paracrine control of anterior pituitary hormone secretion. J Endocrinol. 1990;127(1):513.

  • 20

    Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk. J Neuroendocrinol. 2008;20(1):170.

  • 21

    Todd JF, Small CJ, Akinsanya KO, Stanley SA, Smith DM, Bloom SR. Galanin is a paracrine inhibitor of gonadotroph function in the female rat. Endocrinology. 1998;139(10):42224229.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Thackray VG, Mellon PL, Coss D. Hormones in synergy: regulation of the pituitary gonadotropin genes. Mol Cell Endocrinol. 2010;314(2):192203.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Arafah BM, Kailani SH, Nekl KE, Gold RS, Selman WR. Immediate recovery of pituitary function after transsphenoidal resection of pituitary macroadenomas. J Clin Endocrinol Metab. 1994;79(2):348354.

    • Search Google Scholar
    • Export Citation
  • 24

    Song C, Zhang N, Yu H, Zhou P, Yin S, Jiang S. Functional protection during operations of pituitary adenoma. J Clin Neurosurg. 2019;16(2):115118.

    • Search Google Scholar
    • Export Citation
  • 25

    Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab. 2000;85(5):17891793.

    • Search Google Scholar
    • Export Citation
  • 26

    Little AS, Gardner PA, Fernandez-Miranda JC, et al. Pituitary gland recovery following fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenoma: results of a prospective multicenter study. J Neurosurg. 2020;133(6):17321738.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Galloway L, Ali M, Lansdown A, et al. The impact of endoscopic transsphenoidal pituitary adenoma surgery on endocrine function: a single-centre study. Acta Neurochir (Wien). 2021;163(2):391398.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Jahangiri A, Wagner JR, Han SW, et al. Improved versus worsened endocrine function after transsphenoidal surgery for nonfunctional pituitary adenomas: rate, time course, and radiological analysis. J Neurosurg. 2016;124(3):589595.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Baldia M, Rajaratnam S, Rajshekhar V. Postoperative hormonal outcomes in patients with large and giant non-functioning pituitary adenomas. Neurol India. 2020;68(3 suppl):S106S112.

    • Search Google Scholar
    • Export Citation
  • 30

    Zhan R, Ma Z, Wang D, Li X. Pure endoscopic endonasal transsphenoidal approach for nonfunctioning pituitary adenomas in the elderly: surgical outcomes and complications in 158 patients. World Neurosurg. 2015;84(6):15721578.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Olsson DS, Trimpou P, Hallén T, et al. Life expectancy in patients with pituitary adenoma receiving growth hormone replacement. Eur J Endocrinol. 2017;176(1):6775.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32

    Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84(8):843849.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Cui B, Chen N, Wang X, Zhuo Y, Chen L. KC L. High-resolution MRI study of pituitary glands in healthy adult of the Han nationality. Zhonghua Fang She Xue Za Zhi. 2010;44(6):579584.

    • Search Google Scholar
    • Export Citation

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