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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0003
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3364-3369
Copyright © 2006 by The Endocrine Society

Quality of Life Is Decreased after Treatment for Nonfunctioning Pituitary Macroadenoma

O. M. Dekkers, A. A. van der Klaauw, A. M. Pereira, N. R. Biermasz, P. J. Honkoop, F. Roelfsema, J. W. A. Smit and J. A. Romijn

Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: O. M. Dekkers, Department of Endocrinology and Metabolic Diseases C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: o.m.dekkers{at}lumc.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Although a reduced quality of life (QoL) has been reported after long-term cure of functioning pituitary adenomas, the effect of successful treatment of nonfunctioning pituitary macroadenoma (NFMA) on QoL has not been fully addressed. Therefore, we evaluated a broad spectrum of QoL parameters in patients successfully treated for NFMA in our center.

Design: We conducted a case-control study.

Patients and Methods: We assessed QoL in 99 adult patients (mean age, 61.9 yr; range, 24–86 yr) in remission during long-term follow-up after surgical (n = 99) and additional radiotherapeutic (n = 37) treatment for NFMA by four validated health-related questionnaires (Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index, Nottingham Health Profile, and Short Form-36). Patient outcomes were compared with 125 controls and with age-adjusted reference values derived from the literature.

Results: NFMA patients reported significantly impaired QoL in all questionnaires compared with the 125 controls and the age-adjusted reference values. All subscales of fatigue, assessed using the Multidimensional Fatigue Index (general fatigue, physical fatigue, reduction in activity, reduction in motivation, and mental fatigue) were impaired. The scores in the Nottingham Health Profile pointed toward reduced energy and affected emotional reaction. In several subscales of the Short Form-36 (social functioning, role limitations due to physical problems, role limitations due to emotional problems, and general health perception), NFMA patients reported a reduced QoL.

Conclusion: QoL is considerably reduced in patients after successful treatment of NFMA.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
NONFUNCTIONING PITUITARY macroadenomas (NFMAs) are the most prevalent pituitary macroadenomas (1, 2). The main symptoms are visual field defects and hypopituitarism, which are caused by mass effects of the tumor. Transsphenoidal surgery is considered the treatment of choice, because medical therapy in general is ineffective to reduce tumor size. Visual field defects improve in more than 80% of all patients after surgery (3, 4, 5, 6). In contrast, hypopituitarism does not improve in most patients after surgery for NFMA (5, 7, 8, 9). To prevent tumor recurrence, selected patients may be treated by postoperative radiotherapy (10).

In general, pituitary diseases are associated with impaired quality of life (QoL) (11). This can be explained by several factors. Macroadenomas are associated with different degrees of hypopituitarism, which require hormonal substitution. However, despite optimal endocrine replacement strategies, hypopituitarism is associated with impaired QoL parameters (12, 13). Moreover, GH- and ACTH-producing adenomas may induce irreversible effects, which persist despite long-term cure of the disease (12, 13). Finally, an association between applied radiotherapy and decreased QoL has been reported (12, 14).

Most studies on QoL in pituitary diseases were not focused on NFMA but included heterogeneous groups, consisting of both functioning and nonfunctioning pituitary tumors (11, 15, 16, 17). To our knowledge, no studies on QoL in patients treated for NFMA, compared with healthy controls, have been published. Therefore, in the present study, the aim was to assess QoL in adult NFMA patients treated by transsphenoidal surgery. Patient outcomes of QoL parameters were compared with those of control subjects as well as with age-adjusted reference values derived from the literature. We evaluated physical, psychological, and social aspects of QoL in patients after long-term cure, using four validated, health-related QoL-questionnaires covering a broad spectrum of physical, psychological, and social health: Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Index (MFI-20), Short Form-36 (SF-36), and Nottingham Health Profile (NHP).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Protocol

A total of 128 consecutive patients with NFMA, treated by transsphenoidal surgery in our center between 1985 and 2004, were identified. QoL questionnaires were sent to their homes in prepaid envelopes. After 3 months, nonresponders were contacted by telephone to encourage completion and return of the questionnaires. Each patient was also asked to provide a control person of comparable age and sex with a comparable socioeconomic status derived from the same geographical area. In addition to this control group, we used reference data from healthy subjects of the Dutch and West European population, obtained from studies reporting normal age-adjusted values (18, 19, 20, 21, 22).

All patients were seen at least twice yearly by an endocrinologist, with adequate evaluation and treatment of possible deficiencies of pituitary hormones. Evaluation of ACTH deficiency and GH deficiency was performed by insulin tolerance test. Previous studies have demonstrated that patients with multiple pituitary hormone deficiencies, including two or more pituitary hormone deficiencies other than GH deficiency, had a likelihood of approximately 95% of harboring GH deficiency (23, 24, 25). Based on these data, we classified patients in whom GH-stimulation test data were lacking but who were deficient in three other pituitary axes as GH deficient. In addition, the biannual evaluation consisted of measurement of free T4 and testosterone (male patients). If results were below the lower limit of the respective reference ranges, substitution with T4 or testosterone was started. In the case of amenorrhea and low estradiol levels in premenopausal women, estrogen replacement was provided.

The Medical Ethics Committee of the Leiden University Medical Centre approved the study protocol.

Patients and controls (Table 1Go)

A total of 116 of 128 patients (91%) returned the questionnaires, 17 of whom preferred not to participate. Twelve patients did not respond. Thus, 99 completed questionnaires were received (77%). The study population had a mean age of 61.9 yr (range, 24–86 yr). No significant differences in age, gender, and tumor characteristics were found between the study population and the patients who preferred not to participate or who did not return the questionnaires.


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  		TABLE 1. Characteristics of NFMA patients and controls

 
Sixty-six controls were provided by the 99 patients who returned the questionnaires (67%). The control group was extended by controls derived from other studies in our center who had been similarly approached (12, 13). The total control group consisted of 125 controls (66 males, 59 females) with a mean age of 61.5 yr (range, 26–86 yr). Age and gender from the control group were not significantly different from the studied NFMA patients.

Study parameters

Primary study parameters were the results of the four health-related QoL questionnaires. The results were linked to characteristics (age and gender) of the patients, treatment characteristics (surgery, radiotherapy, and multiple surgical procedures), the presence of pituitary deficiencies, and visual field defects.

Questionnaires

HADS. The HADS consists of 14 items pertaining to anxiety and depression. Each item is measured on a four-point scale. Scores for the anxiety and depression subscale range from 0–21 and for the total score from 0–42. A high score points to more severe anxiety and depression (26). A total score of 13 or more was considered increased. Age-related Dutch reference values of the general population were derived from the study of Spinhoven et al. (20).

MFI-20. The MFI-20 contains 20 statements to assess fatigue (27). Five different dimensions of fatigue (four items each) are calculated from these statements: 1) general fatigue, 2) physical fatigue, 3) reduced activity, 4) reduced motivation, and 5) mental fatigue. Every statement is measured on a five-point scale; scores vary from 0–20. Higher scores indicate higher experienced fatigue. Age-related Dutch reference values were derived from Smets et al. (19).

NHP. The NHP is frequently used in patients with pituitary disease to assess general well-being and QoL. The survey consists of 38 yes/no questions, which are subdivided in six scales assessing impairments, i.e. pain (eight items), energy level (three items), sleep (five items), emotional reactions (nine items), social isolation (five items), and disability/functioning, i.e. physical mobility (eight items) (28, 29). Subscale scores are calculated as a weighted mean of the associated items and are expressed as a value between 0 and 100. The total score is the mean of the six subscales. A high score is related to a worse QoL. Age-related West European reference values were derived from the study from Hinz et al. (18).

SF-36. The SF-36 questionnaire comprises 36 items and records general well-being during the previous 30 d (30, 31). The items are formulated as statements or questions to assess eight health concepts: 1) physical functioning, 2) social functioning, 3) limitations in usual role activities because of physical health problems, 4) pain, 5) general mental health (psychological distress and well-being), 6) limitations in usual role activities because of emotional problems, 7) vitality (energy and fatigue), and 8) general health perceptions and change in health. Because the HADS and the MFI-20 are more specific questionnaires for mental health and fatigue, the vitality and general mental health items were left out in this evaluation. Because the scores for the eight items are calculated separately from exclusive item-specific questions (21), the results of the SF-36 items presented in this study are not influenced by the two items we left out in this evaluation. Scores are expressed on a 0–100 scale. Higher scores are associated with better QoL. Age-related West European reference values were derived from the Dutch manual (21, 22).

Statistics

SPSS for windows version 12.0 (SPSS Inc., Chicago, IL) was used for data analysis. Data are expressed as mean ± SD, unless otherwise mentioned. We used unpaired t tests to compare patient and control data. Using stepwise linear regression analysis, we assessed independent variables that affect QoL. Results of the linear regression analysis are expressed as the absolute standardized ß of independent predictive factors. One-way ANOVA analysis was performed to compare QoL scores of three different groups: patients without GH deficiency, patients with GH deficiency substituted with recombinant human (rh)GH, and patients with GH deficiency without rhGH substitution. Differences were considered statistically significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient and treatment characteristics (Table 1Go)

Patient characteristics are detailed in Table 1Go. All 99 patients had been treated by transsphenoidal surgery. Twenty-two patients had received prophylactic postoperative radiotherapy. Repeat surgery within 6 months after initial treatment was performed in eight patients for a large residual tumor mass (n = 4), persisting liquor leakage (n = 3), or profuse bleeding (n = 1). The mean follow-up period after initial surgical treatment was 9.9 ± 6.6 yr. In 17 patients, tumor recurrence was observed by magnetic resonance imaging scanning after a mean follow-up duration of 7.1 ± 4.0 yr. Tumor recurrence was treated by radiotherapy (n = 11) or a combination of surgery and radiotherapy (n = 4). In the remaining two patients, an expectant approach was undertaken.

At the time of evaluation, 83% of the patients were GH deficient, 82% were LH/FSH deficient, 63% were ACTH deficient, and 62% were TSH deficient. Hypopituitarism, defined as pituitary deficiency in at least one axis, was present in 93 of 99 patients, panhypopituitarism of the anterior pituitary gland in 48%. Diabetes insipidus was present in 9% of the patients. All patients with ACTH and TSH deficiency received hormonal substitution therapy. Of all GH-deficient patients, 42 (51%) received rhGH substitution at the time of evaluation. Of all GH-deficient patients without substitution at the time of evaluation, rhGH was stopped in eight cases.

Finally, visual field defects were present in 41% of cases.

QoL in NFMA patients compared with controls and age-adjusted reference values (Table 2Go)

NFMA patients reported an impaired QoL compared with the 119 controls and the age-adjusted reference values. The QoL scores were significantly reduced in 19 of 21 subscales compared with own controls and in 10 of 21 subscales compared with age-adjusted reference values.


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  		TABLE 2. QoL parameters (HADS, MFI-20, NHP, and SF-36) in treated NFMA patients compared with controls and age-adjusted reference values

 
Compared with own controls, in patients with NFMA, all subscales of the MFI-20, assessing different aspects of energy/fatigue, were affected. The majority of items assessed by the SF-36 and the NHP, two questionnaires covering multiple aspects of general health and well-being, were affected [with the exception of pain (NHP and SF-36) and health change (SF-36)]. On the three subscales of the HADS, NFMA patients performed worse compared with own controls.

Compared with age-adjusted reference values, the majority of subscales of the MFI-20 were affected, with the exception of general fatigue. According to the SF-36, scores of four of seven subscales were reduced (social functioning and role limitations due to physical problems, emotional problems, and general health perception). Only two subscales of the NHP (energy and emotional reaction) pointed toward a reduced QoL in NFMA patients. There was no significantly affected QoL parameter according to the HADS questionnaire compared with age-adjusted reference values.

The effect of GH deficiency and GH replacement on QoL

A substantial proportion (49%) of the NFMA patients with GH deficiency were not substituted with rhGH. To assess the effect of GH deficiency and rhGH replacement on QoL, we performed ANOVA comparing three groups: patients without GH deficiency (n = 16), patients with GH deficiency substituted with rhGH (n = 42), and patients with GH deficiency but without rhGH substitution (n = 41). The only significant difference between these three groups was in sleep performance (NHP; P < 0.05). Sleep was most affected in patients with a GH deficiency substituted with rhGH.

Linear regression

Stepwise univariate linear regression analysis was performed in a model including gender, age, radiotherapy, multiple operations, ACTH deficiency, TSH deficiency, LH/FSH deficiency, GH deficiency, multiple pituitary deficiencies, and visual defects as independent variables and the questionnaire items as dependent variables.

Age was an independent predictor for reduced physical ability (NHP; standardized ß = 0.48; P < 0.01) and reduced physical function (SF-36; standardized ß = 0.48; P < 0.01). The presence of multiple hormonal deficiencies was an independent predictor for role limitations due to physical problems (SF-36; standardized ß = 0.28; P < 0.05), impaired social functioning (SF-36; standardized ß = 0.29; P < 0.05), sleep (NHP; standardized ß = 0.25; P < 0.05), and increased general fatigue (MFI-20; standardized ß = 0.24; P < 0.05). LH/FSH deficiency was an independent predictor for reduced activity (MFI-20; standardized ß = 0.28; P < 0.05) and increased physical fatigue (MFI-20; standardized ß = 0.25; P < 0.05). Female gender was an independent predictor for increased anxiety (HADS; standardized ß = 0.35; P < 0.05). Radiotherapy, visual field defects, and GH deficiency were not found to be independent predictors for reduced QoL in any of the questionnaires.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The data in this study indicate that QoL is reduced in patients successfully treated for NFMA. According to the parameters tested by the HADS, MFI-20, NHP, and SF-36 questionnaires, patients reported a decreased QoL in 10 of 21 subscales, compared with both age-adjusted reference values and controls. Almost all subscales of the MFI-20, assessing energy/fatigue, showed a significantly decreased QoL. Linear regression analysis revealed the presence of multiple pituitary deficiencies and, to a lesser extent, age as the predominant predictors of a decreased QoL.

In the present study, NFMA patients were compared with own controls and age-adjusted reference values derived from the literature. The advantage of using own controls is that they are from the same geographic area and socioeconomic class as the patients (32). However, these controls might be subject to a selection bias, because patients might have chosen controls with a supposed good health status (33). To overcome this potential bias, we also compared the NFMA patients to age-adjusted reference values from the literature. Moreover, the use of two different control groups might lead to more credible results if the results are consistent (32). The scores of the NFMA patients showed an impaired QoL in more subscales of the four questionnaires compared with own controls than compared with the age-adjusted reference values, confirming the possible difference in health status between the two groups. Nonetheless, even compared with the reference data obtained from the literature, our NFMA patients scored worse, supporting our conclusions with respect to the negative effect of NFMA on QoL. Although the response rate in our series of patients with NFMA was 91%, and completed questionnaires were received from 77% of the patients, it seems unlikely that the nonresponders have influenced the outcome of our study because there were no differences in patient characteristics between responders and nonresponders/decliners.

Literature on QoL in patients with NFMA is scarce. To our knowledge, only two studies evaluated QoL in NFMA patients (11, 14). Johnson et al. (11) reported a reduced QoL in NFMA patients, before treatment, using the SF-36 questionnaire, compared with scores from the normal population. Other reports on QoL in NFMA, consisting of heterogeneous groups of patients with both functioning and nonfunctioning tumors, showed a reduced QoL in patients with pituitary tumors in general (15, 34, 35). However, it was not possible to perform subgroup analysis to estimate QoL specifically in NFMA because of the small number of patients (15, 34). Moreover, the effects of pituitary diseases on QoL cannot simply be generalized for all pituitary diseases. NFMA patients differ from patients with functioning pituitary adenomas in several aspects. NFMA is more prevalent in older and male patients compared with functioning pituitary adenomas (36). Nonfunctioning adenomas are treated only when tumor size indicates a macroadenoma, whereas treatment indication in functioning adenomas is focused at hormone overproduction in addition to tumor size. Therefore, pituitary tumors in treated NFMA tend to be larger than tumors in patients treated for functioning pituitary adenomas. In accordance, in NFMA patients, there is a higher degree of pituitary deficiencies, whereas patients cured from functioning pituitary tumors also suffer from irreversible effects of previous hormone overproduction, as is the case in functioning adenomas such as Cushing’s disease or acromegaly (12, 13). Compared with NFMA, QoL in acromegaly patients is clearly decreased (17). QoL assessment in heterogeneous groups, consisting of both functioning and nonfunctioning adenomas, may therefore not be an appropriate strategy to assess QoL in patients treated for NFMA.

The study from Page et al. (14) did not reveal a reduced QoL in surgically treated NFMA patients compared with patients after mastoid surgery. The results of the SF-36 questionnaire from these patients after mastoid surgery are summarized in Table 3Go. These results do not show concordant differences compared with our NFMA patients, pointing toward a general role for medical illness in impaired QoL. However, this also underscores the notion that the SF-36 questionnaire is not disease specific, i.e. not specific for the assessment of QoL in patients with pituitary diseases (31).


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  		TABLE 3. Summary of SF-36 results in patients treated for NFMA and in patients after mastoid surgery

 
Our results point toward a reduced QoL in physical and psychological as well as social items. Treated NFMA patients report increased fatigue, both mental and physical, reduced energy, and role limitations due to physical problems as well as reduced activity and reduced motivation. Interestingly, physical functioning seemed not to be affected compared with age-adjusted reference values. NFMA patients also report affected emotional reactions and role limitations due to emotional problems as well as affected social functioning. Nonetheless, the HADS questionnaire did not reveal any significant difference between NFMA patients and age-adjusted reference values. This finding is in accordance with the report of Korali et al. (37) in which no elevated rates of mental disorders could be found after treatment for NFMA, even in the case of multiple pituitary deficiencies.

We could not properly assess the effect of hypopituitarism per se on QoL, because hypopituitarism was present in 93% of all NFMA patients. Although the number of patients with hypopituitarism seems rather high, it is comparable to the percentage (94%) of patients with hypopituitarism presented in a series of consecutive patients treated for NFMA in our hospital (38). The patient population in the present series seems therefore not skewed toward those patients with more severe disease. Hypopituitarism was found to be an independent predictor of reduced QoL in patients treated for Cushing’s disease, affecting both physical and psychosocial items (13). In the present study, the presence of multiple pituitary deficiencies was the most predominant predictor for decreased QoL, pointing toward an important role of pituitary function for optimal QoL. Hormonal substitution therapy does not reproduce the normal plasma hormone profiles of healthy individuals. Moreover, the effects of hormones in general are difficult to quantify at the tissue level. Consequently, titration of endocrine replacement therapy is possible only within certain physiological limits. These intrinsic imperfections in endocrine replacement therapy may result in subtle physiological derangements. Most importantly, this imperfection in endocrine substitution may result in a decreased QoL. In this study, LH/FSH deficiency was an independent predictor for reduced activity and increased physical fatigue. This may reflect the lack of sensitive signs and symptoms for monitoring adequacy of testosterone and estrogen substitution (39). We did not measure routinely levels of dehydroepiandrostenedione. However, we recently documented in a randomized placebo-controlled trial that dehydroepiandrostenedione substitution superimposed on GH substitution did not substantially improve QoL in patients with secondary adrenal failure (40). In this study, female gender was an independent predictor for anxiety. The predisposition for female gender as an independent risk factor for a decreased QoL is unclear and has been previously described in patients with primary brain tumors (41). However, it does not seem to be a disease-specific phenomenon given the fact that QoL studies in nonpituitary diseases (malignancies, coronary heart disease, and inflammatory bowel disease) also report decreased QoL in female patients compared with male patients (41, 42, 43, 44, 45).

GH deficiency was not found to be an independent predictor for any of the subscales of the four questionnaires. In our study, only 51% of all GH-deficient patients received rhGH substitution. We could not detect a beneficial effect of rhGH substitution on QoL scores. However, this study was, in a strict sense, not designed to assess the effect of rhGH substitution on QoL. A recent meta-analysis on the effect of rhGH substitution on QoL suggested that rhGH substitution does not improve QoL compared with placebo (46). Because this meta-analysis estimated the overall effect of various QoL questionnaires, it is still possible that rhGH substitution may have a beneficial effect on QoL subscales. Moreover, several studies report an improved QoL and well-being (47, 48, 49, 50), suggesting that in selected patients, rhGH substitution may have a beneficial effect on QoL (51).

The four health-related questionnaires used in this study were not disease specific, i.e. they were not developed to assess QoL in NFMA, although the NHP is frequently used in patients with pituitary disease. However, we found a reduced QoL in the majority of subscales of the MFI-20, the SF-36, and the NHP. This seems to point toward a strong overall effect of the pituitary diseases on general health and well-being of both the physical and the psychosocial aspects.

In conclusion, QoL is reduced in patients after successful treatment of NFMA. According to the MFI-20, NHP, and SF-36, patients reported a decreased QoL in almost all subscales compared with age-adjusted reference values and controls. The presence of multiple pituitary deficiencies was the predominant predictor for a reduced QoL.


   Footnotes
 
Disclosure statement: All the authors (O.M.D., A.A.v.d.K., A.M.P., N.R.B., P.J.H., F.R., J.W.A.S., and J.A.R.) have nothing to declare.

First Published Online June 20, 2006

Abbreviations: HADS, Hospital Anxiety and Depression Scale; MFI, Multidimensional Fatigue Index; NFMA, nonfunctioning pituitary macroadenoma; NHP, Nottingham Health Profile; QoL, quality of life; rh, recombinant human; SF-36, Short Form-36.

Received January 3, 2006.

Accepted June 12, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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