Endocrine DOI 10.1007/s12020-013-0127-4
ORIGINAL ARTICLE
Etiology of hypopituitarism in tertiary care institutions in Turkish population: analysis of 773 patients from pituitary study group database F. Tanriverdi • H. S. Dokmetas • N. Kebapcı • F. Kilicli • H. Atmaca • S. Yarman M. E. Ertorer • E. Erturk • F. Bayram • A. Tugrul • C. Culha • M. Cakir • M. Mert • H. Aydin • M. Taskale • N. Ersoz • Z. Canturk • I. Anaforoglu • M. Ozkaya • G. Oruk • Z. Hekimsoy • F. Kelestimur • T. Erbas
•
Received: 23 September 2013 / Accepted: 13 November 2013 Ó Springer Science+Business Media New York 2013
Abstract Hypopituitarism in adult life is commonly acquired and the main causes are known as pituitary tumors and/or their treatments. Since there are new insights into the etiology of hypopituitarism and presence of differences in various populations, more studies regarding causes of hypopituitarism are needed to be done in different ethnic groups with sufficient number of patients. Therefore, we performed a multi-center database study in Turkish population investigating the etiology of hypopituitarism in 773 patients in tertiary care institutions. The study was designed and coordinated by the Pituitary Study Group of SEMT (The Society of Endocrinology and Metabolism of Turkey). Nineteen tertiary reference centers (14 university hospitals and 5 training hospitals) from the different regions of Turkey participated in the study. It is a cross-sectional database
Some part of this study was presented at ENDO Meeting, 2012. F. Tanriverdi (&) F. Bayram F. Kelestimur Department of Endocrinology, Erciyes University Medical School, 38039 Kayseri, Turkey e-mail: [email protected] H. S. Dokmetas F. Kilicli Department of Endocrinology, Cumhuriyet University Medical School, Sivas, Turkey N. Kebapcı Department of Endocrinology, Osmangazi University Medical Faculty, Eskisehir, Turkey H. Atmaca Department of Endocrinology, Karaelmas University, Zonguldak, Turkey S. Yarman Department of Endocrinology, Faculty of Medicine, Istanbul University, Istanbul, Turkey
study, and the data were recorded for 18 months. We mainly classified the causes of hypopituitarism as pituitary tumors (due to direct effects of the pituitary tumors and/or their treatments), extra-pituitary tumors and non-tumoral causes. Mean age of 773 patients (49.8 % male, 50.2 % female) was 43.9 ± 16.1 years (range 16–84 years). The most common etiology of pituitary dysfunction was due to non-tumoral causes (49.2 %) among all patients. However, when we analyze the causes according to gender, the most common etiology in males was pituitary tumors, but the most common etiology in females was non-tumoral causes. According to the subgroup analysis of the causes of hypopituitarism in all patients, the most common four causes of hypopituitarism which have frequencies over 10 % were as follows: nonsecretory pituitary adenomas, Sheehan’s syndrome, lactotroph adenomas and idiopathic. With regard to the type of hormonal deficiencies; FSH/LH deficiency was the most common hormonal deficit (84.9 % of the patients). In 33.8 % of the M. E. Ertorer Division of Endocrinology, Faculty of Medicine, Baskent University, Adana, Turkey E. Erturk Department of Endocrinology, School of Medicine, Uludag University, Bursa, Turkey A. Tugrul Endocrinology Section, Trakya University Medical Faculty, Edirne, Turkey C. Culha Department of Endocrinology, Ankara Research and Training Hospital, Ankara, Turkey M. Cakir Division of Endocrinology, Meram School of Medicine, Selcuk University, Konya, Turkey
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patients, 4 anterior pituitary hormone deficiencies (FSH/LH, ACTH, TSH, and GH) were present. Among all patients, the most frequent cause of hypopituitarism was non-secretory pituitary adenomas. However, in female patients, present study clearly demonstrates that Sheehan’s syndrome is still one of the most important causes of hypopituitarism in Turkish population. Further, population-based prospective studies need to be done to understand the prevalence and incidence of the causes of hypopituitarism in different countries. Keywords Hypopituitarism Pituitary Sheehan’s syndrome Pituitary tumors
Introduction It has been clearly documented by several studies that patients with hypopituitarism, either single or multiple hormone deficiencies, have increased morbidity and mortality [1–4]. Hypopituitarism in adult life is commonly acquired and the main causes are known as pituitary tumors and/or their treatments [5–7]. However, the data regarding the etiology of hypopituitarism were obtained from western countries in limited numbers of patients and to our knowledge there are only two population-based studies which were carried out in Spanish population [8, 9]. Sheehan’s syndrome classically refers to postpartum hypopituitarism due to pituitary necrosis occurring due to severe hypotension or shock secondary to massive bleeding at or just after delivery. Although Sheehan’s syndrome was reported with low frequency in developed countries, it is still a serious health problem in some developing countries and is characterized by varying degrees of anterior pituitary dysfunction [10]. Traumatic brain injury (TBI), which is a worldwide public health problem, has been recently recognized as a cause of neuroendocrine dysfunction. Although it is commonly stated
in textbooks as one of the rare causes of hypopituitarism, recent data have shown that TBI-mediated hypopituitarism could be seen in around 20 % of the patients [11–13]. However, these data were obtained from the selected patients exposed to head trauma, and the frequency of TBI induced hypopituitarism in different populations and outpatient clinics is still unknown. Since there are new insights into the etiology of hypopituitarism and the presence of differences in various populations, more studies regarding causes of hypopituitarism are needed to be done in different ethnic groups with sufficient numbers of patients. Therefore, we performed a multi-center database study in Turkish population investigating the etiology of hypopituitarism in 773 patients in tertiary care institutions.
Patients and methods Study design and population The study was designed and coordinated by the Pituitary Study Group of SEMT (The Society of Endocrinology and Metabolism of Turkey). There are 40 tertiary referral endocrine centers dealing with pituitary disorders in Turkey. We invited all of them and 19 centers (47.5 % of all centers; 14 university hospitals and 5 training hospitals) from the different regions of Turkey participated in the study. The present database study is a cross-sectional study and data were recorded for 18 months starting from August 2007. Local Committee on Ethics has approved the study. The following information was obtained from the database: sex, age, date of diagnosis of hypopituitarism, main complaints, etiology of hypopituitarism, types of the deficient pituitary hormones, the tests used for the
M. Mert Department of Endocrinology, Okmeydanı Training and Research Hospital, Istanbul, Turkey
I. Anaforoglu Department of Endocrinology, Trabzon Numune Education and Research Hospital, Trabzon, Turkey
H. Aydin Department of Endocrinology, Yeditepe University Medical School, Istanbul, Turkey
M. Ozkaya Department of Endocrinology, Maras Sutcuimam School of Medicine, Kahramanmaras, Turkey
M. Taskale Department of Endocrinology, Dr Sadi Konuk Research Hospital, Istanbul, Turkey
G. Oruk Department of Endocrinology, Ataturk Training and Research Hospital, Izmir, Turkey
N. Ersoz T. Erbas Department of Endocrinology, Hacettepe University Medical School, Ankara, Turkey
Z. Hekimsoy Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical Faculty, Celal Bayar University, Manisa, Turkey
Z. Canturk Department of Endocrinology, Kocaeli University Medical School, ˙Izmit, Kocaeli, Turkey
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diagnosis of hypopituitarism, type of treatment in pituitary or non-pituitary tumors, and MRI findings. Throughout the study period, all the patients who were admitted to the Outpatient Clinics of each center were included in the database consecutively. The inclusion criteria were as follows: (1) a over 16 years old, (2) having hypopituitarism (previously diagnosed or newly diagnosed during the study period), (3) having at least one anterior pituitary hormone deficiency and/or presence of diabetes insipidus. Based on the above-mentioned criteria, 841 patients were registered to the database. However, 68 patients were excluded due to insufficient or uncertain data. Overall the data of 773 patients with hypopituitarism were analyzed in the present study. Among 773 patients, 29.9 % had diagnosis during study period and 62.4 % of the patients were previously diagnosed (from 1972 to June 2007) as having hypopituitarism. In 7.7 % of the patients, the date of diagnosis was not registered in the database. Expert endocrinologists in each center diagnosed hypopituitarism by using basal hormone levels and/or dynamic tests. All the dynamic tests performed in the centers were as follows: insulin tolerance test (ITT), gonadotrophin releasing hormone (GnRH) stimulation test, thyrotrophin releasing hormone (TRH) stimulation test, adrenocorticotrophic hormone (ACTH) stimulation test, glucagon stimulation test (GST), L-dopa test, GH releasing hormone (GHRH) ? arginine test, GHRH ? GHRP-6 test (GH releasing peptide6), clonidine test, water deprivation test. In 708 patients, GH status was reported and for the diagnosis of GH deficiency, dynamic tests were performed only in 257 of 708 (36.3 %) patients. The distributions of 257 tests were as follows: 192 (74.7 %) ITT, 30 (11.6 %) L-dopa test, 15 (5.8 %) GST, 10 (3.9 %) GHRH ? GHRP-6 test, 6 (2.4 %) clonidine test, and 4 (1.6 %) GHRH ? arginine test. There was not a standard diagnostic protocol for pituitary hormone deficiencies, and all the centers used their own testing protocol and hormone measurement methods. The etiology of hypopituitarism was recorded to the database by the same endocrinologists in each center. Histological, radiological, and/or hormonal profiles of the patients were used for the differential diagnosis of pituitary adenoma subgroups and nonpituitary tumor types. The lymphocytic hypophysitis was diagnosed based on the typical MRI findings. Statistical analysis Statistical analysis was performed using the SPSS 12.0 program. Results were expressed as mean ± standard deviation (SD) and percentages (%). All data were subjected to the Kolmogrov–Smirnov test for normality. Normally distributed values between two variables were compared by unpaired t test. p \ 0.05 was considered significant.
Results Mean age of 773 patients [49.8 % (n = 385) male, 50.2 % (n = 388) female] was 43.9 ± 16.1 years (range; 16–84 years). Mean age of females (47.6 ± 15.8 years) was significantly higher than males (40.4 ± 15.6 years) (p = 0.0001). We classified the causes of hypopituitarism as pituitary tumors (due to direct effects of pituitary tumors and/or their treatments), extra-pituitary tumors and non-tumoral causes. The most common etiology of pituitary dysfunction was due to non-tumoral causes (380 of 773 patients) among all patients (Fig. 1a). However, when we analyzed the causes according to gender, the most common etiology was pituitary tumors in males, but in females the most common etiology was non-tumoral causes (Fig. 1b, c). Data regarding the management of patients with pituitary tumors were available in 322 of 337 patients, and surgery was performed in 219 of 322 (68 %) patients, surgery and radiotherapy were performed in 63 (19.5 %) patients and medical treatment (dopamine agonists or somatostatin analogs) was a treatment option in 40 (12.5 %) patients. In patients with pituitary tumors (n: 337), the time of the onset of hypopituitarism (preoperative or postoperative) was available in 282 patients. One hundred and twenty-four of these 282 (43.9 %) patients had hypopituitarism preoperatively, and 158 of 282 (56.1 %) patients had hypopituitarism postoperatively. In Table 1, the detailed frequencies of the causes of hypopituitarism in all patients were summarized. The most common four causes of hypopituitarism which have frequencies over 10 % were as follows: non-secretory pituitary adenomas, Sheehan’s syndrome, lactotroph adenomas, and idiopathic. When we analyzed the causes according to gender, the most common cause of hypopituitarism is nonsecretory pituitary adenomas (59 of 385 patients; 15.3 %) in males, and the most common cause of hypopituitarism is Sheehan’s syndrome (107 of 388 patients; 27.6 %) in females. Mean age of the females with Sheehan’s syndrome (52.8 ± 12.3 years) is significantly higher than the females without Sheehan’s syndrome (45.6 ± 16.5) (p = 0.0001). Mean age of the diagnosis of hypopituitarism in patients with Sheehan’s syndrome was 48.5 ± 13.6 years. In addition, only 17 % of the females with Sheehan’s syndrome were less than 40 years old. With regard to the type of hormonal deficiencies; 648 of 763 (in 10 patients data unavailable) patients (84.9 %) had FSH/LH deficiency, 534 of 771 (in 2 patients data unavailable) patients (69.3 %) had TSH deficiency, 472 of 752 (in 21 patients data unavailable) patients (62.8 %) had ACTH deficiency, 359 of 708 (in 65 patients data unavailable) patients (50.7 %) had GH deficiency, and 97 of 770 (in 3 patients data unavailable) patients (12.6 %) had ADH deficiency. Therefore, the most common hormonal deficiency in
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a
60 50
49.2 43.6
40
%
Fig. 1 a Etiology of hypopituitarism in all patients (n = 773). b Etiology of hypopituitarism in males (n = 385). c Etiology of hypopituitarism in females (n = 388)
30 20 7.2
10 0
Non-tumoral causes (n=380)
b
Pituitary tumors (n=337)
Extra-pituitary tumors (n=56)
60 50.9
50 40.8
%
40 30 20 8.3
10 0
Non-tumoral causes (n=157)
c
Pituitary tumors (n=196)
Extra-pituitary tumors (n=32)
70 60
57.5
50 36.3
%
40 30 20
6.2
10 0
Non-tumoral causes (n=223)
our cohort was gonadotropin deficiency. The percentages of pituitary hormone deficiencies were summarized in Fig. 2. In 710 patients, data regarding all 4 anterior pituitary hormone statuses (FSH/LH, ACTH, TSH, and GH) were available. Based on these data, the distribution of the number of anterior pituitary hormone deficiencies in 710 patients were shown in Fig. 3. In 240 of 710 patients (33.8 %), 4 anterior pituitary hormone deficiencies (FSH/ LH, ACTH, TSH, and GH) were present (Fig. 3). When we performed subgroup analysis in patients with Sheehan’s syndrome, 68 % of them had 4 anterior pituitary hormone deficiencies.
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Pituitary tumors (n=141)
Extra-pituitary tumors (n=24)
Discussion Present study is the first study investigating the etiology of hypopituitarism in Turkish population. We have clearly demonstrated that among all 773 patients the frequency of non-tumoral causes of hypopituitarism was higher than pituitary tumors. Although non-secretory pituitary adenomas are the leading cause of hypopituitarism in male patients, Sheehan’s syndrome is the most common cause of hypopituitarism in females. As far as we know, only two population-based studies were performed assessing the prevalence and incidence of
Endocrine Table 1 Subgroup analysis of the etiologies of hypopituitarism in all 773 patients; [number of patients (% among all patients)] Non-tumoral causes Sheehan’s syndrome: 107 (13.8 %)a Idiopathic: 82 (10.6 %) Idiopathic hypogonadotrophic hypogonadism: 60 (7.8 %) Empty sella: 50 (6.5 %) Congenital: 35 (4.5 %) Head trauma: 17 (2.2 %) Lymphocytic hypophysitis: 12 (1.6 %) Apoplexia: 7 (0.9 %) Subarachnoid hemorrhage: 2 (0.3 %) Aspergilloma: 2 (0.3 %) Histiocytosis: 2 (0.3 %) Meningitis: 1 (0.1 %) Psuedotumor cerebri: 1 (0.1 %) Abscess: 1 (0.1 %) Hemochromatosis: 1 (0.1 %) Pituitary tumors Non-secretory pituitary adenoma: 162 (20.9 %) Lactotroph: 86 (11.1 %) Somatotroph: 69 (8.9 %) Corticotroph: 12 (1.6 %) Gonadotroph: 6 (0.8 %) Thyrotroph: 2 (0.3 %) Extra-pituitary tumors Craniopharyngioma: 40 (5.2 %) Meningioma: 8 (1 %) Glioma: 3 (0.4 %) Undefined: 2 (0.3 %) Astrositoma: 1 (0.1 %) Germ cell tumor: 1 (0.1 %) Clivus tumor: 1 (0.1 %) a
The frequencies over 10 % were presented in bold 90
84.9
80 69.3
70
62.8
%
60
50.7
50 40 30 20
12.6
10 0 FSH/LH
TSH
ACTH
GH
ADH
Fig. 2 Percentages of pituitary hormone deficiencies
hypopituitarism [8, 9]. In the first population-based study carried out by Regal et al. on adult patients in northwestern Spain, the prevalence of 45.5 per 1,00,000 inhabitants and
the incidence of 4.2 new cases per 1,00,000 per year were reported. The most common cause of hypopituitarism was pituitary tumors and/or their treatment accounting for at least 60 % of all cases. Non-tumoral causes were reported as 30 % of all cases and idiopathic group (11 % of all cases) and Sheehan’s syndrome (6 % of all cases) were the first 2 leading etiologies [9]. In the second epidemiological study, which was recently published, the authors investigated the prevalence and causes of hypopituitarism in larger population in the same region of Spain [8]. The prevalence and incidence of hypopituitarism were estimated as 37.5 cases per 1,00,000 inhabitants and 2.07 cases per 1,00,000 per year, respectively. The most common cause of hypopituitarism was pituitary tumors (46.8 %) and Sheehan’s syndrome was not reported [8]. In the present study, we could not define the prevalence/incidence of hypopituitarism because it was not a population-based epidemiological study. However, it reflects the main causes of hypopituitarism in tertiary care institutions in Turkish population. In consistent with these epidemiological studies among all patients, the most common frequent cause of hypopituitarism was non-secretory pituitary adenomas in our study (20.9 % of all patients, Table 1). In the study by Regal et al. the frequency of non-secretory pituitary adenomas was slightly higher (26 %) than our patient group [9]. Most of the non-secretory adenomas are macro-adenomas and the diagnosis is generally delayed; therefore, mass effect of the tumor and extensive pituitary surgery might be the main reasons of high prevalence of hypopituitarism in non-secretory pituitary adenomas. In a previous elegant study, De Marinis et al. [14] have reported that the substantial rate of hypopituitarism may develop (nearly 21 % after 12 months of surgery) in patients who were submitted to neurosurgery for primary benign brain tumors far from the hypothalamic-pituitary region. In the present study, the percentage of the primary brain tumor induced hypopituitarism was very low (\2 %, Table 1), probably due to the lack of referral of these patients to the endocrinology clinics. When we grossly classify the etiologies as tumoral and non-tumoral causes, different from the above-mentioned epidemiological studies, the most common etiology of hypopituitarism was non-tumoral causes in our study, and Sheehan’s syndrome was still the leading cause of hypopituitarism in females in our population. In western populations, Sheehan’s syndrome was reported to be a very rare cause of hypopituitarism due to the advent of modern obstetric care [1, 15, 16]. In a retrospective study from UK, among 172 patients with hypopituitarism 0.5 % of the patients were diagnosed as Sheehan’s syndrome [5]. Furthermore, in KIMS pharmaco-epidemiological database, 1,034 GH deficient patients from western countries were analyzed and Sheehans’s syndrome has been found as the
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33.8
35 30
26.9
24.8
25
%
Fig. 3 Numbers of anterior pituitary hormone deficiencies in 710 patients. (deficiencies of either one or more of the anterior pituitary hormones including; FSH/LH, ACTH, TSH, and GH, were evaluated.)
20
14.5 15 10 5 0 one
two
three
four
Numbers of anterior pituitary hormone deficiencies
sixth most common cause (3.1 % of all patients) [17]. These findings suggest that in western countries, although Sheehan’s syndrome is significantly less frequent than our cohort, it is still present and seems to be not a very rare etiology of hypopituitarism as previously considered probably due to migration or less improved obstetric care at rural parts. In a retrospective study from Philippines, data of 143 patients with hypopituitarism at a tertiary care institution were analyzed. Pituitary adenomas were the most common cause of hypopituitarism (40 % of 143 patients). Sheehan’s syndrome was reported as 8 % of all patients which is the third frequent etiology of hypopituitarism suggesting the higher occurrence of Sheehan’s syndrome than western population [18]. In our study, consistent with the abovementioned Philippines data, Sheehan’s syndrome is a common cause of hypopituitarism and 13 % of all patients admitted to tertiary care institution had Sheehan’s syndrome. Only 17 % of our patients with Sheehan’s syndrome were less than 40 years old implying the tendency of decreasing frequency over time probably due to the decrease in home deliveries and the improvement of obstetric care in Turkey. It was previously demonstrated that patients with Sheehan’s syndrome have more severe pituitary hormone deficiencies than hypopituitary patients due to other causes [19–21]. Although we could not compare the clinical consequences due to hypopituitarism in patients with Sheehan’s syndrome versus other etiologies, present findings clearly demonstrated that the patients with Sheehan’s syndrome were significantly older and had higher percentage of panhypopituitarism. In recent years, several studies have demonstrated that non-tumoral causes of hypopituitarism including TBI, chronic repetitive head trauma due to combative sports, subarachnoid hemorrhage (SAH), acute bacterial meningitis, and stroke, may result in high rate of hypopituitarism long term after the event [11, 13, 22–28]. Until now, these non-tumoral etiologies have been known as rare causes of
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hypopituitarism, but large scale population studies in different ethnic groups are still lacking to understand the real percentage of these disorders. In a current meta-analysis including 1,015 TBI patients (52 patients were from Turkey), overall prevalence of hypopituitarism in the chronic phase after head trauma was 27.5 % [11]. Based on these data, the frequency of hypopituitarism is substantially high even in patients with mild TBI [29], and due to the high prevalence of head trauma all over the world, it is hypothesized that causes related to brain damage might outnumber pituitary tumors as an etiological factor for hypopituitarism [30]. In the present study, only 2.2 % of the patients admitted to tertiary care clinics had head trauma as a cause of hypopituitarism and other causes including SAH and meningitis were very rare (Table 1). Our findings imply that the real prevalence of TBI and other non-tumoral causes are underestimated probably due to lack of awareness. Moreover, similar to previous epidemiological studies [8, 9], 10 % of all patients had idiopathic hypopituitarism in our cohort. It is tempting to speculate that some of these patients may have been exposed to head trauma previously. We believe that increasing the public awareness, referral of TBI patients to the endocrinologists by the other disciplines dealing with head, and routine head trauma history in hypopituitary patient management may decrease the misdiagnosis of head trauma induced hypopituitarism [31]. FSH/LH deficiency was the most common pituitary hormone deficiency with nearly 85 % of all the patients. Our findings were in the same line with the previous epidemiological studies [31]. However, it was previously reported that GH deficiency is also one of the most frequent hormonal deficiency in hypopituitary adults [11, 21, 32, 33]. The low frequency of GH deficiency in our cohort could be due to lack of dynamic testing in most of the centers (36 % of the patients had dynamic tests). In the patients without GH deficiency, only 12 % had dynamic testing and they were diagnosed according to IGF-I levels.
Endocrine
However, normal IGF-I levels do not rule out GH deficiency and appropriate dynamic tests need to be done to diagnose GH deficiency in adults [33]. In a case–control study, Benvenga et al. [34] showed that unexplained central hypopituitarism could frequently be caused by TBI. However, in the present database, only 49 of 534 (9 %) patients with central hypothyroidism had TBI and idiopathic etiology, suggesting that the patients presented with central hypothyroidism without any pituitary disorder history such as TBI or idiopathic hypopituitarism might easily be overlooked. One of the most important limitations of the present study was the collection of data from the patients admitted to the tertiary care institutions. Therefore, it is difficult to directly extrapolate the data to Turkish population as an epidemiological finding. The second limitation was the diagnostic procedures for hypopituitarism which were not standardized among the centers. In conclusion, non-tumoral causes are the most common etiological factors of hypopituitarism in Tertiary Care Institutions in Turkish Population. Although non-secretory pituitary adenomas are the leading cause of hypopituitarism in male patients, Sheehan’s syndrome is the most common cause of hypopituitarism in females. Therefore, the present study clearly demonstrates that Sheehan’s syndrome is still one of the most important causes of hypopituitarism in developing countries. Further, population-based prospective studies need to be done to understand the prevalence and incidence of the causes of hypopituitarism in different countries.
Conflict of interest
The authors report no conflict of interest.
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ORIGINAL ARTICLE
Etiology of hypopituitarism in tertiary care institutions in Turkish population: analysis of 773 patients from pituitary study group database F. Tanriverdi • H. S. Dokmetas • N. Kebapcı • F. Kilicli • H. Atmaca • S. Yarman M. E. Ertorer • E. Erturk • F. Bayram • A. Tugrul • C. Culha • M. Cakir • M. Mert • H. Aydin • M. Taskale • N. Ersoz • Z. Canturk • I. Anaforoglu • M. Ozkaya • G. Oruk • Z. Hekimsoy • F. Kelestimur • T. Erbas
•
Received: 23 September 2013 / Accepted: 13 November 2013 Ó Springer Science+Business Media New York 2013
Abstract Hypopituitarism in adult life is commonly acquired and the main causes are known as pituitary tumors and/or their treatments. Since there are new insights into the etiology of hypopituitarism and presence of differences in various populations, more studies regarding causes of hypopituitarism are needed to be done in different ethnic groups with sufficient number of patients. Therefore, we performed a multi-center database study in Turkish population investigating the etiology of hypopituitarism in 773 patients in tertiary care institutions. The study was designed and coordinated by the Pituitary Study Group of SEMT (The Society of Endocrinology and Metabolism of Turkey). Nineteen tertiary reference centers (14 university hospitals and 5 training hospitals) from the different regions of Turkey participated in the study. It is a cross-sectional database
Some part of this study was presented at ENDO Meeting, 2012. F. Tanriverdi (&) F. Bayram F. Kelestimur Department of Endocrinology, Erciyes University Medical School, 38039 Kayseri, Turkey e-mail: [email protected] H. S. Dokmetas F. Kilicli Department of Endocrinology, Cumhuriyet University Medical School, Sivas, Turkey N. Kebapcı Department of Endocrinology, Osmangazi University Medical Faculty, Eskisehir, Turkey H. Atmaca Department of Endocrinology, Karaelmas University, Zonguldak, Turkey S. Yarman Department of Endocrinology, Faculty of Medicine, Istanbul University, Istanbul, Turkey
study, and the data were recorded for 18 months. We mainly classified the causes of hypopituitarism as pituitary tumors (due to direct effects of the pituitary tumors and/or their treatments), extra-pituitary tumors and non-tumoral causes. Mean age of 773 patients (49.8 % male, 50.2 % female) was 43.9 ± 16.1 years (range 16–84 years). The most common etiology of pituitary dysfunction was due to non-tumoral causes (49.2 %) among all patients. However, when we analyze the causes according to gender, the most common etiology in males was pituitary tumors, but the most common etiology in females was non-tumoral causes. According to the subgroup analysis of the causes of hypopituitarism in all patients, the most common four causes of hypopituitarism which have frequencies over 10 % were as follows: nonsecretory pituitary adenomas, Sheehan’s syndrome, lactotroph adenomas and idiopathic. With regard to the type of hormonal deficiencies; FSH/LH deficiency was the most common hormonal deficit (84.9 % of the patients). In 33.8 % of the M. E. Ertorer Division of Endocrinology, Faculty of Medicine, Baskent University, Adana, Turkey E. Erturk Department of Endocrinology, School of Medicine, Uludag University, Bursa, Turkey A. Tugrul Endocrinology Section, Trakya University Medical Faculty, Edirne, Turkey C. Culha Department of Endocrinology, Ankara Research and Training Hospital, Ankara, Turkey M. Cakir Division of Endocrinology, Meram School of Medicine, Selcuk University, Konya, Turkey
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patients, 4 anterior pituitary hormone deficiencies (FSH/LH, ACTH, TSH, and GH) were present. Among all patients, the most frequent cause of hypopituitarism was non-secretory pituitary adenomas. However, in female patients, present study clearly demonstrates that Sheehan’s syndrome is still one of the most important causes of hypopituitarism in Turkish population. Further, population-based prospective studies need to be done to understand the prevalence and incidence of the causes of hypopituitarism in different countries. Keywords Hypopituitarism Pituitary Sheehan’s syndrome Pituitary tumors
Introduction It has been clearly documented by several studies that patients with hypopituitarism, either single or multiple hormone deficiencies, have increased morbidity and mortality [1–4]. Hypopituitarism in adult life is commonly acquired and the main causes are known as pituitary tumors and/or their treatments [5–7]. However, the data regarding the etiology of hypopituitarism were obtained from western countries in limited numbers of patients and to our knowledge there are only two population-based studies which were carried out in Spanish population [8, 9]. Sheehan’s syndrome classically refers to postpartum hypopituitarism due to pituitary necrosis occurring due to severe hypotension or shock secondary to massive bleeding at or just after delivery. Although Sheehan’s syndrome was reported with low frequency in developed countries, it is still a serious health problem in some developing countries and is characterized by varying degrees of anterior pituitary dysfunction [10]. Traumatic brain injury (TBI), which is a worldwide public health problem, has been recently recognized as a cause of neuroendocrine dysfunction. Although it is commonly stated
in textbooks as one of the rare causes of hypopituitarism, recent data have shown that TBI-mediated hypopituitarism could be seen in around 20 % of the patients [11–13]. However, these data were obtained from the selected patients exposed to head trauma, and the frequency of TBI induced hypopituitarism in different populations and outpatient clinics is still unknown. Since there are new insights into the etiology of hypopituitarism and the presence of differences in various populations, more studies regarding causes of hypopituitarism are needed to be done in different ethnic groups with sufficient numbers of patients. Therefore, we performed a multi-center database study in Turkish population investigating the etiology of hypopituitarism in 773 patients in tertiary care institutions.
Patients and methods Study design and population The study was designed and coordinated by the Pituitary Study Group of SEMT (The Society of Endocrinology and Metabolism of Turkey). There are 40 tertiary referral endocrine centers dealing with pituitary disorders in Turkey. We invited all of them and 19 centers (47.5 % of all centers; 14 university hospitals and 5 training hospitals) from the different regions of Turkey participated in the study. The present database study is a cross-sectional study and data were recorded for 18 months starting from August 2007. Local Committee on Ethics has approved the study. The following information was obtained from the database: sex, age, date of diagnosis of hypopituitarism, main complaints, etiology of hypopituitarism, types of the deficient pituitary hormones, the tests used for the
M. Mert Department of Endocrinology, Okmeydanı Training and Research Hospital, Istanbul, Turkey
I. Anaforoglu Department of Endocrinology, Trabzon Numune Education and Research Hospital, Trabzon, Turkey
H. Aydin Department of Endocrinology, Yeditepe University Medical School, Istanbul, Turkey
M. Ozkaya Department of Endocrinology, Maras Sutcuimam School of Medicine, Kahramanmaras, Turkey
M. Taskale Department of Endocrinology, Dr Sadi Konuk Research Hospital, Istanbul, Turkey
G. Oruk Department of Endocrinology, Ataturk Training and Research Hospital, Izmir, Turkey
N. Ersoz T. Erbas Department of Endocrinology, Hacettepe University Medical School, Ankara, Turkey
Z. Hekimsoy Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical Faculty, Celal Bayar University, Manisa, Turkey
Z. Canturk Department of Endocrinology, Kocaeli University Medical School, ˙Izmit, Kocaeli, Turkey
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diagnosis of hypopituitarism, type of treatment in pituitary or non-pituitary tumors, and MRI findings. Throughout the study period, all the patients who were admitted to the Outpatient Clinics of each center were included in the database consecutively. The inclusion criteria were as follows: (1) a over 16 years old, (2) having hypopituitarism (previously diagnosed or newly diagnosed during the study period), (3) having at least one anterior pituitary hormone deficiency and/or presence of diabetes insipidus. Based on the above-mentioned criteria, 841 patients were registered to the database. However, 68 patients were excluded due to insufficient or uncertain data. Overall the data of 773 patients with hypopituitarism were analyzed in the present study. Among 773 patients, 29.9 % had diagnosis during study period and 62.4 % of the patients were previously diagnosed (from 1972 to June 2007) as having hypopituitarism. In 7.7 % of the patients, the date of diagnosis was not registered in the database. Expert endocrinologists in each center diagnosed hypopituitarism by using basal hormone levels and/or dynamic tests. All the dynamic tests performed in the centers were as follows: insulin tolerance test (ITT), gonadotrophin releasing hormone (GnRH) stimulation test, thyrotrophin releasing hormone (TRH) stimulation test, adrenocorticotrophic hormone (ACTH) stimulation test, glucagon stimulation test (GST), L-dopa test, GH releasing hormone (GHRH) ? arginine test, GHRH ? GHRP-6 test (GH releasing peptide6), clonidine test, water deprivation test. In 708 patients, GH status was reported and for the diagnosis of GH deficiency, dynamic tests were performed only in 257 of 708 (36.3 %) patients. The distributions of 257 tests were as follows: 192 (74.7 %) ITT, 30 (11.6 %) L-dopa test, 15 (5.8 %) GST, 10 (3.9 %) GHRH ? GHRP-6 test, 6 (2.4 %) clonidine test, and 4 (1.6 %) GHRH ? arginine test. There was not a standard diagnostic protocol for pituitary hormone deficiencies, and all the centers used their own testing protocol and hormone measurement methods. The etiology of hypopituitarism was recorded to the database by the same endocrinologists in each center. Histological, radiological, and/or hormonal profiles of the patients were used for the differential diagnosis of pituitary adenoma subgroups and nonpituitary tumor types. The lymphocytic hypophysitis was diagnosed based on the typical MRI findings. Statistical analysis Statistical analysis was performed using the SPSS 12.0 program. Results were expressed as mean ± standard deviation (SD) and percentages (%). All data were subjected to the Kolmogrov–Smirnov test for normality. Normally distributed values between two variables were compared by unpaired t test. p \ 0.05 was considered significant.
Results Mean age of 773 patients [49.8 % (n = 385) male, 50.2 % (n = 388) female] was 43.9 ± 16.1 years (range; 16–84 years). Mean age of females (47.6 ± 15.8 years) was significantly higher than males (40.4 ± 15.6 years) (p = 0.0001). We classified the causes of hypopituitarism as pituitary tumors (due to direct effects of pituitary tumors and/or their treatments), extra-pituitary tumors and non-tumoral causes. The most common etiology of pituitary dysfunction was due to non-tumoral causes (380 of 773 patients) among all patients (Fig. 1a). However, when we analyzed the causes according to gender, the most common etiology was pituitary tumors in males, but in females the most common etiology was non-tumoral causes (Fig. 1b, c). Data regarding the management of patients with pituitary tumors were available in 322 of 337 patients, and surgery was performed in 219 of 322 (68 %) patients, surgery and radiotherapy were performed in 63 (19.5 %) patients and medical treatment (dopamine agonists or somatostatin analogs) was a treatment option in 40 (12.5 %) patients. In patients with pituitary tumors (n: 337), the time of the onset of hypopituitarism (preoperative or postoperative) was available in 282 patients. One hundred and twenty-four of these 282 (43.9 %) patients had hypopituitarism preoperatively, and 158 of 282 (56.1 %) patients had hypopituitarism postoperatively. In Table 1, the detailed frequencies of the causes of hypopituitarism in all patients were summarized. The most common four causes of hypopituitarism which have frequencies over 10 % were as follows: non-secretory pituitary adenomas, Sheehan’s syndrome, lactotroph adenomas, and idiopathic. When we analyzed the causes according to gender, the most common cause of hypopituitarism is nonsecretory pituitary adenomas (59 of 385 patients; 15.3 %) in males, and the most common cause of hypopituitarism is Sheehan’s syndrome (107 of 388 patients; 27.6 %) in females. Mean age of the females with Sheehan’s syndrome (52.8 ± 12.3 years) is significantly higher than the females without Sheehan’s syndrome (45.6 ± 16.5) (p = 0.0001). Mean age of the diagnosis of hypopituitarism in patients with Sheehan’s syndrome was 48.5 ± 13.6 years. In addition, only 17 % of the females with Sheehan’s syndrome were less than 40 years old. With regard to the type of hormonal deficiencies; 648 of 763 (in 10 patients data unavailable) patients (84.9 %) had FSH/LH deficiency, 534 of 771 (in 2 patients data unavailable) patients (69.3 %) had TSH deficiency, 472 of 752 (in 21 patients data unavailable) patients (62.8 %) had ACTH deficiency, 359 of 708 (in 65 patients data unavailable) patients (50.7 %) had GH deficiency, and 97 of 770 (in 3 patients data unavailable) patients (12.6 %) had ADH deficiency. Therefore, the most common hormonal deficiency in
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a
60 50
49.2 43.6
40
%
Fig. 1 a Etiology of hypopituitarism in all patients (n = 773). b Etiology of hypopituitarism in males (n = 385). c Etiology of hypopituitarism in females (n = 388)
30 20 7.2
10 0
Non-tumoral causes (n=380)
b
Pituitary tumors (n=337)
Extra-pituitary tumors (n=56)
60 50.9
50 40.8
%
40 30 20 8.3
10 0
Non-tumoral causes (n=157)
c
Pituitary tumors (n=196)
Extra-pituitary tumors (n=32)
70 60
57.5
50 36.3
%
40 30 20
6.2
10 0
Non-tumoral causes (n=223)
our cohort was gonadotropin deficiency. The percentages of pituitary hormone deficiencies were summarized in Fig. 2. In 710 patients, data regarding all 4 anterior pituitary hormone statuses (FSH/LH, ACTH, TSH, and GH) were available. Based on these data, the distribution of the number of anterior pituitary hormone deficiencies in 710 patients were shown in Fig. 3. In 240 of 710 patients (33.8 %), 4 anterior pituitary hormone deficiencies (FSH/ LH, ACTH, TSH, and GH) were present (Fig. 3). When we performed subgroup analysis in patients with Sheehan’s syndrome, 68 % of them had 4 anterior pituitary hormone deficiencies.
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Pituitary tumors (n=141)
Extra-pituitary tumors (n=24)
Discussion Present study is the first study investigating the etiology of hypopituitarism in Turkish population. We have clearly demonstrated that among all 773 patients the frequency of non-tumoral causes of hypopituitarism was higher than pituitary tumors. Although non-secretory pituitary adenomas are the leading cause of hypopituitarism in male patients, Sheehan’s syndrome is the most common cause of hypopituitarism in females. As far as we know, only two population-based studies were performed assessing the prevalence and incidence of
Endocrine Table 1 Subgroup analysis of the etiologies of hypopituitarism in all 773 patients; [number of patients (% among all patients)] Non-tumoral causes Sheehan’s syndrome: 107 (13.8 %)a Idiopathic: 82 (10.6 %) Idiopathic hypogonadotrophic hypogonadism: 60 (7.8 %) Empty sella: 50 (6.5 %) Congenital: 35 (4.5 %) Head trauma: 17 (2.2 %) Lymphocytic hypophysitis: 12 (1.6 %) Apoplexia: 7 (0.9 %) Subarachnoid hemorrhage: 2 (0.3 %) Aspergilloma: 2 (0.3 %) Histiocytosis: 2 (0.3 %) Meningitis: 1 (0.1 %) Psuedotumor cerebri: 1 (0.1 %) Abscess: 1 (0.1 %) Hemochromatosis: 1 (0.1 %) Pituitary tumors Non-secretory pituitary adenoma: 162 (20.9 %) Lactotroph: 86 (11.1 %) Somatotroph: 69 (8.9 %) Corticotroph: 12 (1.6 %) Gonadotroph: 6 (0.8 %) Thyrotroph: 2 (0.3 %) Extra-pituitary tumors Craniopharyngioma: 40 (5.2 %) Meningioma: 8 (1 %) Glioma: 3 (0.4 %) Undefined: 2 (0.3 %) Astrositoma: 1 (0.1 %) Germ cell tumor: 1 (0.1 %) Clivus tumor: 1 (0.1 %) a
The frequencies over 10 % were presented in bold 90
84.9
80 69.3
70
62.8
%
60
50.7
50 40 30 20
12.6
10 0 FSH/LH
TSH
ACTH
GH
ADH
Fig. 2 Percentages of pituitary hormone deficiencies
hypopituitarism [8, 9]. In the first population-based study carried out by Regal et al. on adult patients in northwestern Spain, the prevalence of 45.5 per 1,00,000 inhabitants and
the incidence of 4.2 new cases per 1,00,000 per year were reported. The most common cause of hypopituitarism was pituitary tumors and/or their treatment accounting for at least 60 % of all cases. Non-tumoral causes were reported as 30 % of all cases and idiopathic group (11 % of all cases) and Sheehan’s syndrome (6 % of all cases) were the first 2 leading etiologies [9]. In the second epidemiological study, which was recently published, the authors investigated the prevalence and causes of hypopituitarism in larger population in the same region of Spain [8]. The prevalence and incidence of hypopituitarism were estimated as 37.5 cases per 1,00,000 inhabitants and 2.07 cases per 1,00,000 per year, respectively. The most common cause of hypopituitarism was pituitary tumors (46.8 %) and Sheehan’s syndrome was not reported [8]. In the present study, we could not define the prevalence/incidence of hypopituitarism because it was not a population-based epidemiological study. However, it reflects the main causes of hypopituitarism in tertiary care institutions in Turkish population. In consistent with these epidemiological studies among all patients, the most common frequent cause of hypopituitarism was non-secretory pituitary adenomas in our study (20.9 % of all patients, Table 1). In the study by Regal et al. the frequency of non-secretory pituitary adenomas was slightly higher (26 %) than our patient group [9]. Most of the non-secretory adenomas are macro-adenomas and the diagnosis is generally delayed; therefore, mass effect of the tumor and extensive pituitary surgery might be the main reasons of high prevalence of hypopituitarism in non-secretory pituitary adenomas. In a previous elegant study, De Marinis et al. [14] have reported that the substantial rate of hypopituitarism may develop (nearly 21 % after 12 months of surgery) in patients who were submitted to neurosurgery for primary benign brain tumors far from the hypothalamic-pituitary region. In the present study, the percentage of the primary brain tumor induced hypopituitarism was very low (\2 %, Table 1), probably due to the lack of referral of these patients to the endocrinology clinics. When we grossly classify the etiologies as tumoral and non-tumoral causes, different from the above-mentioned epidemiological studies, the most common etiology of hypopituitarism was non-tumoral causes in our study, and Sheehan’s syndrome was still the leading cause of hypopituitarism in females in our population. In western populations, Sheehan’s syndrome was reported to be a very rare cause of hypopituitarism due to the advent of modern obstetric care [1, 15, 16]. In a retrospective study from UK, among 172 patients with hypopituitarism 0.5 % of the patients were diagnosed as Sheehan’s syndrome [5]. Furthermore, in KIMS pharmaco-epidemiological database, 1,034 GH deficient patients from western countries were analyzed and Sheehans’s syndrome has been found as the
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33.8
35 30
26.9
24.8
25
%
Fig. 3 Numbers of anterior pituitary hormone deficiencies in 710 patients. (deficiencies of either one or more of the anterior pituitary hormones including; FSH/LH, ACTH, TSH, and GH, were evaluated.)
20
14.5 15 10 5 0 one
two
three
four
Numbers of anterior pituitary hormone deficiencies
sixth most common cause (3.1 % of all patients) [17]. These findings suggest that in western countries, although Sheehan’s syndrome is significantly less frequent than our cohort, it is still present and seems to be not a very rare etiology of hypopituitarism as previously considered probably due to migration or less improved obstetric care at rural parts. In a retrospective study from Philippines, data of 143 patients with hypopituitarism at a tertiary care institution were analyzed. Pituitary adenomas were the most common cause of hypopituitarism (40 % of 143 patients). Sheehan’s syndrome was reported as 8 % of all patients which is the third frequent etiology of hypopituitarism suggesting the higher occurrence of Sheehan’s syndrome than western population [18]. In our study, consistent with the abovementioned Philippines data, Sheehan’s syndrome is a common cause of hypopituitarism and 13 % of all patients admitted to tertiary care institution had Sheehan’s syndrome. Only 17 % of our patients with Sheehan’s syndrome were less than 40 years old implying the tendency of decreasing frequency over time probably due to the decrease in home deliveries and the improvement of obstetric care in Turkey. It was previously demonstrated that patients with Sheehan’s syndrome have more severe pituitary hormone deficiencies than hypopituitary patients due to other causes [19–21]. Although we could not compare the clinical consequences due to hypopituitarism in patients with Sheehan’s syndrome versus other etiologies, present findings clearly demonstrated that the patients with Sheehan’s syndrome were significantly older and had higher percentage of panhypopituitarism. In recent years, several studies have demonstrated that non-tumoral causes of hypopituitarism including TBI, chronic repetitive head trauma due to combative sports, subarachnoid hemorrhage (SAH), acute bacterial meningitis, and stroke, may result in high rate of hypopituitarism long term after the event [11, 13, 22–28]. Until now, these non-tumoral etiologies have been known as rare causes of
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hypopituitarism, but large scale population studies in different ethnic groups are still lacking to understand the real percentage of these disorders. In a current meta-analysis including 1,015 TBI patients (52 patients were from Turkey), overall prevalence of hypopituitarism in the chronic phase after head trauma was 27.5 % [11]. Based on these data, the frequency of hypopituitarism is substantially high even in patients with mild TBI [29], and due to the high prevalence of head trauma all over the world, it is hypothesized that causes related to brain damage might outnumber pituitary tumors as an etiological factor for hypopituitarism [30]. In the present study, only 2.2 % of the patients admitted to tertiary care clinics had head trauma as a cause of hypopituitarism and other causes including SAH and meningitis were very rare (Table 1). Our findings imply that the real prevalence of TBI and other non-tumoral causes are underestimated probably due to lack of awareness. Moreover, similar to previous epidemiological studies [8, 9], 10 % of all patients had idiopathic hypopituitarism in our cohort. It is tempting to speculate that some of these patients may have been exposed to head trauma previously. We believe that increasing the public awareness, referral of TBI patients to the endocrinologists by the other disciplines dealing with head, and routine head trauma history in hypopituitary patient management may decrease the misdiagnosis of head trauma induced hypopituitarism [31]. FSH/LH deficiency was the most common pituitary hormone deficiency with nearly 85 % of all the patients. Our findings were in the same line with the previous epidemiological studies [31]. However, it was previously reported that GH deficiency is also one of the most frequent hormonal deficiency in hypopituitary adults [11, 21, 32, 33]. The low frequency of GH deficiency in our cohort could be due to lack of dynamic testing in most of the centers (36 % of the patients had dynamic tests). In the patients without GH deficiency, only 12 % had dynamic testing and they were diagnosed according to IGF-I levels.
Endocrine
However, normal IGF-I levels do not rule out GH deficiency and appropriate dynamic tests need to be done to diagnose GH deficiency in adults [33]. In a case–control study, Benvenga et al. [34] showed that unexplained central hypopituitarism could frequently be caused by TBI. However, in the present database, only 49 of 534 (9 %) patients with central hypothyroidism had TBI and idiopathic etiology, suggesting that the patients presented with central hypothyroidism without any pituitary disorder history such as TBI or idiopathic hypopituitarism might easily be overlooked. One of the most important limitations of the present study was the collection of data from the patients admitted to the tertiary care institutions. Therefore, it is difficult to directly extrapolate the data to Turkish population as an epidemiological finding. The second limitation was the diagnostic procedures for hypopituitarism which were not standardized among the centers. In conclusion, non-tumoral causes are the most common etiological factors of hypopituitarism in Tertiary Care Institutions in Turkish Population. Although non-secretory pituitary adenomas are the leading cause of hypopituitarism in male patients, Sheehan’s syndrome is the most common cause of hypopituitarism in females. Therefore, the present study clearly demonstrates that Sheehan’s syndrome is still one of the most important causes of hypopituitarism in developing countries. Further, population-based prospective studies need to be done to understand the prevalence and incidence of the causes of hypopituitarism in different countries.
Conflict of interest
The authors report no conflict of interest.
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