H Diri and others Sheehan’s syndrome 171:3 311–318 Clinical Study

Extensive investigation of 114 patients with Sheehan’s syndrome: a continuing disorder

1 1 1 2 1 Halit Diri , Fatih Tanriverdi , Zuleyha Karaca , Serkan Senol , Kursad Unluhizarci , Correspondence Ahmet Candan Durak2, Hulusi Atmaca3 and Fahrettin Kelestimur1 should be addressed to F Kelestimur Departments of 1Endocrinology and 2Radiology, Erciyes University Medical School, 38039 Kayseri, Turkey and Email 3Department of Endocrinology, Ondokuz Mayis University Medical School, Samsun, Turkey [email protected]

Abstract

Objective: Sheehan’s syndrome (SS) is a well-known cause of resulting from postpartum pituitary necrosis. Because of its rarity in Western society, its diagnosis is often overlooked. We aimed to investigate the clinical, laboratory, and radiological aspects of SS in a large number of patients. Study design: A retrospective assessment of the medical records of 114 patients with SS was conducted. In addition, sella turcica volumes of 29 healthy women were compared with those of patients by magnetic resonance imaging examinations. Results: The mean period of diagnostic delay was 19.7 years in patients with SS. It was found that 52.6% of patients had nonspecific complaints, 30.7% had complaints related to adrenal insufficiency, and 9.6% had complaints related to hypogonadism when diagnosed. At the time of diagnosis, 55.3% of the patients had panhypopituitarism, while 44.7% had partial hypopituitarism. The number of deficient hormones was found to be increased over the years. None of the patients whose basal was below 4.0 ng/ml had adequate prolactin responses to TRH test, while all patients whose basal prolactin was above 7.8 ng/ml had adequate responses. Mean sella volume was found to be significantly lower in the SS group (340.5G214 mm3) than that in the healthy group (602.5G192 mm3). Conclusions: SS is a common cause of hypopituitarism in underdeveloped and developing countries. The main reasons for diagnostic delay seem to be the high frequency of patients with nonspecific complaints and neglect of SS. In addition, the TRH stimulation test was found to have a high sensitivity and specificity to recognize PRL deficiency. Furthermore,

European Journal of Endocrinology small sella size may have an important contributing role in the etiopathogenesis of SS.

European Journal of Endocrinology (2014) 171, 311–318

Introduction

Sheehan’s syndrome (SS) can be defined as partial or carried out in Turkey has shown that the frequency of SS complete hypopituitarism occurring due to massive was 13.8% among 773 patients with hypopituitarism (4). postpartum uterine hemorrhage that leads to pituitary The main reason for diagnostic delay of SS seems to be infarction (1). It is a common disorder particularly in nonspecific and thus unnoticed symptoms, such as fatigue, underdeveloped and developing regions of the world. weakness, and anorexia. For this reason, there may be a It was estimated by the World Health Organization (WHO) great number of patients with SS who remain undiagnosed in 1996 that SS was taking the lives of 100 000 women and thereby untreated. However, it should be kept in mind a year, and at that time affected more than 3 million that SS may also develop acutely and lead to coma and women in the world (2). In one cohort study, the pre- even death due to severe hypopituitarism (5). Furthermore, valence of SS was estimated to be 3.1% among women clinical and laboratory findings vary according to whether who were older than 20 years in Kashmir, India (3). pituitary deficiency is partial or complete (6, 7, 8). SS is not rare in developing countries; even so, delay The etiopathogenesis of SS is also not clear. Physio- in diagnosis has been a common problem. A recent study logical enlargement of the during

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pregnancy makes it more vulnerable to ischemic necrosis; Hormonal assessment however, some other factors have also been suggested to Basal levels of hormones and, if indicated, dynamic tests have a contributing role. Thrombosis in the pituitary were carried out to determine hormonal failures in all arteries due to hypercoagulation, arterial vasospasm due patients. During the last 30 years, different methods and to severe hypotension during delivery, pituitary auto- commercial kits have been used to measure hormone immunity, and smaller sella turcica size have been levels. Hence, reference ranges of hormones were taken hypothesized for the etiopathogenesis of the disease according to the values suggested by commercial kits used (9, 10, 11, 12). Herein, we aimed to investigate the initial at that time. clinical and laboratory findings with subsequent course Diagnosis of deficiency was established in patients with SS. In addition, we investigated the by reduced basal estradiol levels with reduced or difference between SS patients and healthy women with inappropriately normal gonadotropin levels. Menstrual regard to sella volumes. irregularities, in particular, in addition to biochemical data were also taken into account for the diag- nosis of gonadotropin deficiency. Thyroid-stimulating hormone (TSH) deficiency was diagnosed by low free Subjects and methods thyroxine levels with normal or decreased TSH levels. Study design Adrenocorticotropic hormone (ACTH) deficiency was determined as low serum cortisol level (%3.0 mg/dl) in The medical records of 114 SS patients who were followed the presence of a low or normal ACTH level. Blood samples up in the Endocrinology Department of Erciyes University were taken at 0800 h for analyzing ACTH and cortisol Medical School between 1985 and 2013 were assessed in levels. The 1 mg ACTH stimulation test was carried out in this retrospective study after obtaining approval from the 49 patients to confirm the diagnosis of secondary adrenal Local Ethics Committee. The diagnosis of SS was based insufficiency. Adrenal failure was defined as peak cortisol on the criteria proposed previously: i) typical obstetrical levels below 18 mg/dl (14).ThebasalPRLleveland history of severe postpartum vaginal bleeding; ii) severe responses to the thyrotropin-releasing hormone (TRH) hypotension or shock for which blood transfusion or stimulation test were evaluated together to detect PRL postpartum fluid replacement is necessary; iii) failure of deficiency. Patients with peak PRL values that did not lactation; iv) failure to resume regular menses after deli- double according to baseline values were accepted as very; v) varying degree of failure, partial European Journal of Endocrinology having PRL deficiency in TRH test (15). Growth hormone or panhypopituitarism; and vi) empty sella discovered on (GH) deficiency was diagnosed by low insulin-like growth computed tomography (CT) scan or magnetic resonance factor 1 level in the presence of greater than or equal to imaging (MRI) (13). three pituitary-deficient hormones or insulin tolerance The demographic data, clinical findings at diagnosis test (ITT). ITT was carried out in 52 patients. A peak GH and during follow-up, obstetric histories, endocrinological level of !3 mg/l after ITT was accepted as GH deficiency investigations, pituitary MRI, and CT findings of the (16). The diagnosis of antidiuretic hormone (ADH) patients were recorded from their hospital files. The initial deficiency was established by measuring serum and urine complaints of patients at diagnosis were classified into osmolalities in patients with (O3 l/day) and four groups: i) nonspecific complaints (fatigue, weakness, confirmed by the response to desmopressin therapy in anorexia, arthralgia, and headache); ii) adrenal insuffi- patients with low urine osmolality. ciency (hypoglycemia, hyponatremia, hypotension, fever, loss of consciousness, nausea, vomiting, and diarrhea); Radiological evaluation iii) (somnolence, edema, cold intolerance, and constipation); and iv) hypogonadism (amenorrhea). Three dimensional volumetric MRI (Philips, Gyroscan In addition, 29 healthy women were enrolled in the Intera 1.5 Tesla; Eindhoven, The Netherlands) was used study as a control group to compare their sella turcica to evaluate pituitary gland and sella turcica volumes at volumes with the patients with SS. The demographic data the Radiology Department of Erciyes University and past medical and obstetric histories of the healthy Medical School. The same MRI scan was performed women were also recorded. The obstetric and reproductive for both the control and the SS groups. Sella turcica histories of all healthy women were normal. volumes (mm3) were measured by using the

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DiChiro formula (0.5!(length!width!depth)) (17). (1.8%) did not have a history of live birth. Twenty-seven Two experienced neuroradiologists evaluated the images (23.7%) patients had a history of stillbirth, 54 (47.4%) had (A C Durak and S Senol). a history of miscarriage, and nine (7.9%) had a history of curettage during their lives. One patient became pregnant through induction of ovulation after the diagnosis of Statistical analysis SS, and had a healthy baby. All statistical analyses were performed with the SPSS 15.0 Obstetric histories of the last delivery revealed that Software. Descriptive data are presented as meanGS.D., 89 (78.1%) patients had delivered at home. Eight (9%) percentages, and occasionally as a range of minimum– out of these 89 patients were subsequently admitted to a maximum. Distribution of data was tested by the hospital and given a blood transfusion because of severe Kolmogorov–Smirnov test before comparison and corre- postpartum hemorrhage. On the other hand, 25 (21.9%) lation tests. The independent samples t-test was used for patients reported that they had delivered at a hospital, normally distributed data. The Spearman’s test was used but two (8%) of them had not been given a blood for correlation analysis, because data were not normally transfusion at hospital in spite of massive hemorrhage. distributed. In addition, the c2 test was used to evaluate Analyses of dates and places of their last deliveries are a relationship between partial hormone deficiency and summarized in Table 1. partially empty sella. Receiver operating characteristic Frequencies of complications at last deliveries were (ROC)-curve analysis was performed in order to find a reported as follows: 20 (17.5%) stillbirths, two (1.8%) cut-off value for prolactin responses to TRH stimulation miscarriages, one (0.9%) uterine rupture, two (1.8%) test. A probability (P) value of !0.05 was considered as retained placentas, and two (1.8%) abdominal trauma- statistically significant. induced stillbirths. Furthermore, five (4.4%) patients had a history of hysterectomy due to massive uterine bleeding or uterine rupture at the last delivery, three (2.6%) patients Results had a C-section, and one (0.9%) patient had a history The mean age of 114 patients previously diagnosed with SS of curettage to end pregnancy. In addition, six (5.3%) between 1985 and 2013 was 63.2G12.5 years, and age at patients reported that they had had twins in their last diagnosis was 52.1G12.7 years. When the past histories pregnancy, but four out of these six pregnancies resulted of patients with SS were analyzed, mean age at the last in stillbirths. delivery was 32.4G6.5 years and thereby the period of Ninety-seven (85.1%) patients reported amenorrhea

European Journal of Endocrinology diagnostic delay was 19.7G10.2 years. After diagnosis, starting immediately after delivery, while 17 (14.9%) the follow-up time was 7.4G6.9 years. Nine (7.9%) cases patients had regular menses for 32.2G32 (6–120) months had died and 55 (48.2%) were alive. The other 50 (43.9) after the last delivery. In addition, 48 (42.1%) patients patients did not attend follow-up visits in the last 3 years, had postpartum agalactia, and 43 (37.7%) patients reported and therefore it was not known whether they were that they had breastfed normally for 15.1G7 (6–30) still alive. months. Twenty-three (20.2%) patients did not remember The complaints of the patients at presentation were whether they had breastfed, mainly due to stillbirths or nonspecific in 60 patients (52.6%), while complaints miscarriages. related to adrenal insufficiency were noted in 35 patients The results obtained from evaluating histories of (30.7%), complaints related to hypogonadism in 11 postpartum lactation, basal serum PRL levels, and PRL patients (9.6%), and complaints related to hypothyroid- responses to TRH stimulation test (TRH test) together are ism in eight patients (7.0%). Nine (7.9%) patients with SS presented in Table 2. According to these results, in 31 out were initially admitted to hospital due to hypoglycemia, of 71 patients whose basal PRL levels were below and five (4.4%) due to concomitant severe hyponatremia 4.0 ng/ml, a TRH test was performed, but none of them and hypoglycemia. had adequate responses. Thirteen out of those 71 patients The past obstetric history of the patients showed that had a history of normal lactation after their last delivery. the mean number of pregnancies was 5.59G3.2, that of In addition, 11 out of 29 patients whose basal PRL levels deliveries was 4.56G2.4, live births was 4.37G2.4, were higher than 7.8 ng/ml had adequate responses to stillbirths was 1.22G0.4, miscarriages was 1.98G1.5, and TRH test and a history of normal breastfeeding after their curettages to end pregnancy was 1.55G1.0. All patients last delivery. Therefore, diagnosis of PRL deficiency had a past history of pregnancy and delivery, while two in patients who had basal PRL levels between 4.0 and

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Table 1 Distribution of patients (n(%)) with SS according to attending follow-up visits regularly. Recovery of deficient dates and places of last delivery. hormones was not detected in any of the patients. Sixty-seven patients had pituitary MRI performed Total number Last delivery Last delivery in Erciyes University Medical School, 38 patients had Dates of patients at hospital at home MRI performed in other hospitals, and nine patients had 1960–1969 12 (10.5) 1 (8.3) 11 (91.7) pituitary CT reports. According to CT and MRI findings, 1970–1979 39 (34.2) 4 (10.3) 35 (89.7) 1980–1989 37 (32.5) 7 (18.9) 30 (81.1) 86 (75.4%) patients with SS had a completely empty sella, 1990–1999 21 (18.4) 8 (38.1) 13 (61.9) while 28 (24.6%) patients had a partially empty sella. The O 2000 5 (4.4) 5 (100) 0 mean age of the 29 healthy women was 60.4G8.5 years, which was not statistically different from the SS group. Furthermore, no significant difference was found in the 7.8 ng/ml was established according to their TRH stimu- mean number of deliveries of the healthy group (4.28G lation test and/or history of postpartum agalactia. Fourteen 1.9) and the SS group (4.56G2.4). The mean sella volume patients had basal PRL levels between 4.0 and 7.8 ng/ml. of the 67 patients with SS was 340.5G214 mm3 (range, Seven of them did not have adequate PRL responses to 40–1008) and this was significantly lower than that of TRH test, while five patients had adequate responses. The the healthy group (602.5G192 mm3; range, 308–1040; basal PRL levels of six patients with postpartum agalactia P!0.001). The minimum sella size in healthy women was were between 4.0 and 7.8 ng/ml, and four of them had found to be 308 mm3, and 35 out of 67 patients in the blunted responses to TRH test. As TRH tests were not SS group had sella volumes below 308 mm3. performed in the other two patients, they were diagnosed as having PRL deficiency according to postpartum agalac- tia. In addition, when the cut-off value was taken as 10.84 ng/ml in ROC curve analysis to determine adequate Discussion peak PRL response to TRH test, its sensitivity was found as Hypopituitarism due to SS is a rarely encountered disease 97.2% and specificity was 94.1% (Fig. 1). in developed countries due to modern obstetric care. Overall hormonal assessment at the date of diagnosis In previous cohort studies performed in Spain, Japan, and revealed that all of the patients had GH and follicle- the USA, it was found that SS was an uncommon disorder stimulating hormone (FSH)–luteinizing hormone (LH) among women (18, 19, 20). Therefore, SS has become a deficiencies, while 103 (90.4%) patients had TSH defici- neglected and unnoticed syndrome because of its rarity

European Journal of Endocrinology ency, 82 (71.9%) patients had ACTH deficiency, and 81 in developed countries. However, it seems that SS has (71.1%) patients had PRL deficiency. In addition, five recently become more frequent in Western society, (4.4%) patients had ADH deficiency and were regularly probably due to the influx of migrant populations with using desmopressin replacement therapy. As a result, 63 (55.3%) patients had panhypo- Table 2 Distribution of patients according to TRH tests, basal pituitarism, while 51 (44.7%) patients had partial hypo- PRL values, and history of postpartum agalactia. Data are pituitarism. The rates of deficient hormones at the date of presented as n(%). diagnosis are shown in Table 3. No significant correlation was found between the number of deficient hormones History of postpartum Basal PRL (ng/ml) lactation/response to and sella volumes in 67 patients whose MRIs were TRH test !4.0 4.0–7.8 O7.8 Total available (P: 0.104). Similarly, no significant relationship Agalactia was detected between partial hypopituitarism and parti- Adequate 0 0 0 0 ally empty sella when the 114 patients were considered Blunted 18 (15.8) 4 (3.6) 0 22 (19.3) together (P: 0.079). Not available 24 (21.1) 2 (1.8) 0 26 (22.8) Normal lactation The number of deficient hormones was found to be Adequate 0 1 (0.9) 11 (9.7) 12 (10.5) increased in 10 (19.2%) out of the 51 patients with partial Blunted 5 (4.4) 2 (1.8) 0 7 (6.1) hypopituitarism (Table 4), whereas the hormone profile of Not available 8 (7.0) 0 16 (14.0) 24 (21.0) Not known 19 (36.5%) out of those 51 patients remained the same Adequate 0 4 (3.6) 0 4 (3.6) after a mean 13.1G7.0 years follow-up period. The course Blunted 8 (7.0) 1 (0.9) 0 9 (7.9) of hormonal deficiency was not assessed in the other Not available 8 (7.0) 0 2 (1.8) 10 (8.8) Total 71 (62.3) 14 (12.3) 29 (25.4) 114 (100) 22 patients due to their being diagnosed recently or not

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Roc-curve reasons underlying the delayed diagnosis are insufficient

1.0 medical education in doctors and their subsequent unawareness of the syndrome. Partial hypopituitarism and histories of normal 0.8 lactation and regular menses that continued after the last delivery also seem to be contributing factors to diagnostic delay. A total of 44.7% of patients had partial 0.6 hypopituitarism in this study. Seventeen patients reported that they had continued to menstruate for a mean period Sensitivity of 32.2 months and 43 patients had lactated for a mean 0.4 period of 15.1 months after their last delivery. Diagnostic delay of SS also causes delay in adminis- 0.2 tration of replacement therapies. Although gonadal steroids and GH are not vital replacement therapies as glucocorticoid and thyroid hormone therapies are, they 0.0 have some beneficial effects in SS. Kelestimur et al. (24) 0.0 0.2 0.4 0.6 0.8 1.0 demonstrated that GH therapy had significant beneficial 1–Specificity outcomes in terms of body composition, lipid profile, and quality of life measures in 91 patients with SS. In another Figure 1 study, they also reported that the severity of GH deficiency ROC-curve of the peak PRL responses to TRH test. Full colour in patients with SS was related to the degree of version of this figure available via http://dx.doi.org/10.1530/ hypopituitarism (25). EJE-14-0244. It was detected in this study that the frequency of giving birth at home has decreased over time (Table 1). All five patients who delivered after 2000 had given birth at a poor socioeconomic status and health care problems. Supporting this idea, in 1034 GH-deficient patients, the hospital. Interestingly, these five patients and 25 patients majority of whom were living in developed countries, the overall who delivered at a hospital had massive bleeding frequency of SS was found to be 3.1% (21). In another and were given a blood transfusion except for two

European Journal of Endocrinology study from Iceland, the prevalence of SS was 5.1/100 000 patients. In addition, eight of the patients who had their women in 2009, which indicates that SS should not be last delivery at home were subsequently admitted to a ignored in Western society either (22). hospital due to massive uterine bleeding. These patients An important issue regarding SS which has been were also given a blood transfusion. However, there were reported in all retrospective studies is delay in diagnosis. no data regarding the amount of bleeding or whether they The mean period of diagnostic delay was found to be were given sufficient blood transfusion. The question of 19.7 years in 114 patients with SS in this study. Other retro- ‘how did SS develop in women who experienced massive spective studies performed in India, France, and Turkey bleeding and received blood or fluid transfusion at a have also found long periods of delay in diagnosis, such as 7, 9, and 27 years respectively (3, 7, 8). We can conclude Table 3 Deficient hormones of anterior pituitary gland in from the evaluation of our results that the main reason patients with SS. for delay in diagnosis is the high frequency of patients Number (%) who have nonspecific complaints: 52.6% of our patients Deficient hormones of patients had nonspecific complaints at the time of diagnosis All hormones 63 (55.3) and they had histories of being admitted to hospitals FSH–LHCGHCACTHCTSH 17 (14.9) with those complaints, but no diagnosis had been FSH–LHCGHCTSHCPRL 12 (10.5) C C established. In a study carried out by Gu¨ven et al. (23), FSH–LH GH TSH 11 (9.6) FSH–LHCGHCPRL 5 (4.4) 126 patients who were admitted to a hospital because of FSH–LHCGH 4 (3.5) severe hypoglycemia were evaluated, and it was found that FSH–LHCGHCACTHCPRL 1 (0.9) C C SS was the second most common cause of hypoglycemia FSH–LH GH ACTH 1 (0.9) Total 114 (100) after diabetic treatments. Presumably the most important

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Table 4 Progression of hormonal deficiency in ten patients deficiency did not improve the subtle abnormalities in with SS. posterior pituitary functions (29). Partial hypopituitarism due to SS has also been Patient Intact hormones at After a Intact hormones reported in other studies (3, 7, 30, 31). In our study, all nos date of diagnosis period of (years) in last clinical visit of the patients had GH and gonadotropin deficiencies, 21 ACTH 18 None while 90.4% of patients had TSH deficiency, 71.9% had 31 ACTHCTSHCPRL 15 ACTHCPRL 35 ACTH 22 None ACTH deficiency, and 71.1% had PRL deficiency at the 60 ACTH 6 None time of diagnosis. The most common intact hormones C 64 ACTH PRL 9 None were ACTH and PRL in this study. PRL deficiency was not 66 PRLCTSH 12 None 81 PRL 22 None found in 28.9% (33 patients). However, there are contra- 90 ACTH 11 None dictory reports about PRL deficiency in SS. Many studies 95 ACTH 10 None have reported that PRL deficiency was sine qua non for 109 ACTHCTSH 8 TSH the diagnosis of SS (7, 30, 32, 33). On the other hand, Ramiandrasoa et al. (8) reported that ten out of 24 (42%) patients with SS did not have lactotroph insufficiency, hospital which contained all modern obstetric facilities?’ defined by a basal PRL level below 3 ng/ml. Similarly, PRL remains to be answered. deficiency was found in 85.2% of females with SS in the The rates of patients who had an obstetric history study performed by Zargar et al. (3). of miscarriage (47.3%) or stillbirth (23.6%) at any time It was revealed in our study that 16 patients with SS in their lives were very high. Furthermore, 20 (17.5%) had adequate PRL responses to TRH (Table 2). In contrast, patients had a history of stillbirth, while two (1.75%) some studies have revealed that PRL was the most patients had a miscarriage in their last pregnancy. In a common and the first hormone to be deficient in patients cohort study involving 7405 women in Turkey, the rate with SS who were tested with TRH stimulation (30, 32, 33). of miscarriage was 25% and the rate of stillbirth was 4% It is noteworthy that the TRH stimulation test was more during their lifetimes (26). High frequencies of stillbirths compatible with histories of postpartum agalactia than and miscarriages in patients with SS may be explained by that with baseline PRL levels to detect lactotroph a disorder such as hypercoagulation (9). deficiency in patients whose basal PRL levels were between As it is well known, the main arteries of the 4.0 and 7.8 ng/ml in this study. This point shows the adenohypophysis are branches of the superior hypo- necessity of the TRH stimulation test to avoid diagnostic

European Journal of Endocrinology physeal artery, and those of the neurohypophysis are errors. None of the 22 patients with postpartum agalactia branches of the inferior hypophyseal artery (10). Anasto- were found to have adequate PRL responses to TRH moses between these two main pituitary artery systems (Table 2). Hence, we can recommend the TRH stimulation are mainly located in the middle-posterior regions of the test as a more sensitive test than basal PRL level to adenohypophysis. It can be speculated that in a case of recognize PRL deficiency. Furthermore, for peak PRL in obliteration in the superior hypophyseal artery, blood TRH tests, a cut-off value of 10.84 ng/ml was found to supply to the adenohypophysis via anastomoses of the have a high sensitivity and specificity in the diagnosis of inferior hypophyseal artery may cause partial hypopitui- . tarism. In a case of a complete and sudden obliteration Patients who had breastfed for a period of time after these anastomoses may not be sufficient. their last delivery may have had PRL deficiency at the time Sheehan & Whitehead (27) previously reported that of diagnosis. Overall, 43 patients had normal breast- the neurohypophysis and hypothalamic nuclei were feeding after their last delivery, but 15 of them had PRL atrophic in over 90% of women with SS at autopsy. deficiency at the time of diagnosis in our study. This Although clinically manifest is uncom- situation might have been due to the progressive course mon in SS, the frequency of partial diabetes insipidus was of SS that is encountered in some patients (3).The found to be 29.6% in SS patients who did not have progressive course is probably due to the antibodies polyuria (28). In that study the osmotic threshold for which develop against pituitary necrotic tissue (11, 34). the onset of thirst in patients with SS was found to be Relatedly, another result obtained from our study was the increased. Thus, it seems that the thirst center is also decrease in number of intact pituitary hormones, parti- affected due to ischemic damage. In addition, GH cularly shown in ten patients (Table 4). However, none of replacement therapy in patients with SS-induced GH the patients followed up regularly in our cohort recovered

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any of the insufficient hormones. Therefore, it seems that physicians about SS is very important, particularly in hypopituitarism is progressive in SS and, if indicated, Western society. In order to eradicate SS, obstetric care replacement therapies should be started early when a should be adequately improved and among young doctors hormonal insufficiency is diagnosed. awareness of the syndrome needs to be increased. The TRH In this study, all the patients had a completely or stimulation test seems to be more useful than baseline partially empty sella. Hence we conclude that a partial or serum PRL levels in the detection of lactotroph deficiency, complete empty sella is sine qua non in the late phase of particularly in patients whose basal PRL levels are between SS; in other words an empty sella on CT or MRI is a 4.0 and 7.8 ng/ml. Lastly, our results also demonstrate characteristic feature of SS. Bakiri et al. (12) found that all that small sella size may have an important contributing 54 patients with SS had an empty sella, while 72% of them role in the etiopathogenesis of SS. had a completely empty sella. Dash et al. (35) reported that the degree of postpartum pituitary necrosis was poorly

correlated with the severity of clinical expression in SS. Declaration of interest Similarly, no significant correlation between the number The authors declare that there is no conflict of interest that could be of deficient hormones and sella volumes, and no relation- perceived as prejudicing the impartiality of the research reported. ship between partial hypopituitarism and partial empty sella, was found in this study. Empty sella is a frequent finding in imaging studies (36, 37), but it should be kept Funding This research did not receive any specific grant from any funding agency in in mind that SS is a rare cause of empty sella. Brismar & the public, commercial or not-for-profit sector. Efendic (38) found that SS was present in only one out of 50 patients with empty sella and Jara-Albarran et al. (39) diagnosed SS in none of the 41 patients with empty sella. References Lymphocytic (LyH) should also be considered in the differential diagnosis of SS. LyH, which 1 Sheehan HL. Postpartum necrosis of the anterior pituitary. Journal of is another pregnancy-related disorder, also generally Pathology and Bacteriology 1937 45 189–214. (doi:10.1002/path. 1700450118) develops at first in the peripartum period and causes 2 Adamson P. The Progress of Nations 1996, Commentary: A failure of hypopituitarism and finally empty sella (40).Some imagination. UNICEF 1996. Available from www.unicef.org/pon96/ findings which differentiate LyH from SS may be hyper- womfail.htm. 3 Zargar AH, Singh B, Laway BA, Masoodi SR, Wani AI & Bashir MI. prolactinemia, diabetes insipidus, increase in thickness of Epidemiologic aspects of postpartum pituitary hypofunction (Sheehan’s European Journal of Endocrinology infundibulum, loss of the neurohypophyseal bright spot syndrome). Fertility and Sterility 2005 84 523–528. (doi:10.1016/ on MRI, and absence of massive uterine hemorrhage; these j.fertnstert.2005.02.022) 4 Tanriverdi F, Dokmetas HS, Kebapci N, Kilicli F, Atmaca H, Yarman S, findings are not so frequently encountered in SS (41). Ertorer ME, Erturk E, Bayram F, Tugrul A et al. Etiology of hypo- A relatively smaller sella turcica volume has been pituitarism in tertiary care institutions in Turkish population: suggested to play an important role in the etiopatho- analysis of 773 patients from pituitary study group database. genesis of SS (12, 42). Smaller sella turcica volume may Endocrine 2014 In press. (doi:10.1007/s12020-013-0127-4) 5 Roberts DM. Sheehan’s syndrome. American Family Physician 1988 37 lead to a larger suprasellar pituitary enlargement, which 223–227. leads to compression of the infundibulum and thereby 6 Sert M, Tetiker T, Kirim S & Kocak M. Clinical report of 28 patients with of the superior hypophyseal artery during pregnancy. The Sheehan’s syndrome. Endocrine Journal 2003 50 297–301. (doi:10.1507/ endocrj.50.297) sella, turcica volume of patients with SS was significantly 7 Dokmetas HS, Kilicli F, Korkmaz S & Yonem O. Characteristic features lower than that of the healthy women in our study, which of 20 patients with Sheehan’s syndrome. Gynecological Endocrinology is similar to previous studies (12, 42). It is noteworthy 2006 22 279–283. (doi:10.1080/09513590600630504) 8 Ramiandrasoa C, Castinetti F, Raingeard I, Fenichel P, Chabre O, Brue T to add that approximately half of our patients, not all of & Courbiere B. Delayed diagnosis of Sheehan’s syndrome in a them, had small sella size. developed country: a retrospective cohort study. European Journal of In conclusion, SS is still a worldwide public health Endocrinology 2013 169 431–438. (doi:10.1530/EJE-13-0279) 9 Gokalp D, Tuzcu A, Bahceci M, Ayyildiz O, Yurt M, Celik Y & Alpagat G. problem. In our study, 52.6% of the patients investigated Analysis of thrombophilic genetic mutations in patients with had nonspecific complaints initially, and SS was first Sheehan’s syndrome: is thrombophilia responsible for the pathogenesis recognized in physical examinations related to hypo- of Sheehan’s syndrome? Pituitary 2011 14 168–173. (doi:10.1007/ gonadism, particularly fine wrinkling around the eyes s11102-010-0276-x) 10 Tessnow AH & Wilson JD. The changing face of Sheehan’s syndrome. and mouth, and as a result of questions about postpartum American Journal of the Medical Sciences 2010 340 402–406. (doi:10.1097/ amenorrhea/agalactia. We therefore believe that training MAJ.0b013e3181f8c6df)

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11 Goswami R, Kochupillai N, Crock PA, Jaleel A & Gupta N. Pituitary 26 Demographic T. Health Survey – 2008 (internet): Hacettepe Institute autoimmunity in patients with Sheehan’s syndrome. Journal of Clinical of Population Studies, Ministry of Health, 2008. Available from http:// Endocrinology and Metabolism 2002 87 4137–4141. (doi:10.1210/jc.2001- www.hips.hacettepe.edu.tr/tnsa2008/index.htm. 020242) 27 Sheehan HL & Whitehead R. The neurohypophysis in post-partum 12 Bakiri F, Bendib SE, Maoui R, Bendib A & Benmiloud M. The sella hypopituitarism. Journal of Pathology and Bacteriology 1963 85 145–169. turcica in Sheehan’s syndrome: computerized tomographic study in 54 (doi:10.1002/path.1700850115) patients. Journal of Endocrinological Investigation 1991 14 193–196. 28 Atmaca H, Tanriverdi F, Gokce C, Unluhizarci K & Kelestimur F. (doi:10.1007/BF03346787) Posterior pituitary function in Sheehan’s syndrome. European Journal of 13 Kelestimur F. Sheehan’s syndrome. Pituitary 2003 6 181–188. Endocrinology 2007 156 563–567. (doi:10.1530/EJE-06-0727) (doi:10.1023/B:PITU.0000023425.20854.8e) 29 Karaca Z, Tanriverdi F, Atmaca H, Unluhizarci K & Kelestimur F. 14 Courtney CH, McAllister AS, McCance DR, Bell PM, Hadden DR, Posterior pituitary functions are not altered after growth hormone replacement therapy in hypopituitarism due to Sheehan’s syndrome. Leslie H, Sheridan B & Atkinson AB. Comparison of one week 0900 h Growth Hormone & IGF Research 2012 22 146–149. (doi:10.1016/j.ghir. serum cortisol, low and standard dose synacthen tests with a 4 to 6 2012.04.008) week insulin hypoglycaemia test after pituitary surgery in assessing 30 Ozbey N, Inanc S, Aral F, Azezli A, Orhan Y, Sencer E & Molvalilar S. HPA axis. Clinical Endocrinology 2000 53 431–436. (doi:10.1046/j.1365- Clinical and laboratory evaluation of 40 patients with Sheehan’s 2265.2000.01106.x) syndrome. Israel Journal of Medical Sciences 1994 30 826–829. 15 Barbieri RL, Cooper DS, Daniels GH, Nathan D, Klibanski A & 31 Haddock L, Vega LA, Aguilo F & Rodriguez O. Adrenocortical, thyroidal Ridgway EC. Prolactin response to thyrotropin-releasing hormone and human growth hormone reserve in Sheehan’s syndrome. Fertility and (TRH) in patients with hypothalamic–. Johns Hopkins Medical Journal 1972 131 80–99. Sterility 1985 43 66–73. 32 Shahmanesh M, Ali Z, Pourmand M & Nourmand I. Pituitary function 16 Gasco V, Corneli G, Rovere S, Croce C, Beccuti G, Mainolfi A, Grottoli S, tests in Sheehan’s syndrome. Clinical Endocrinology 1980 12 303–311. Aimaretti G & Ghigo E. Diagnosis of adult GH deficiency. Pituitary 2008 (doi:10.1111/j.1365-2265.1980.tb02714.x) 11 121–128. (doi:10.1007/s11102-008-0110-x) 33 Jialal I, Naidoo C, Norman RJ, Rajput MC, Omar MA & Joubert SM. 17 Di Chiro G & Nelson KB. The volume of the sella turcica. American Pituitary function in Sheehan’s syndrome. Obstetrics and Gynecology Journal of Roentgenology, Radium Therapy, and Nuclear Medicine 1962 87 1984 63 15–19. 989–1008. 34 De Bellis A, Kelestimur F, Sinisi AA, Ruocco G, Tirelli G, Battaglia M, 18 Regal M, Paramo C, Sierra SM & Garcia-Mayor RV. Prevalence and Bellastella G, Conzo G, Tanriverdi F, Unluhizarci K et al. incidence of hypopituitarism in an adult Caucasian population in Anti-hypothalamus and anti-pituitary antibodies may contribute to northwestern Spain. Clinical Endocrinology 2001 55 735–740. perpetuate the hypopituitarism in patients with Sheehan’s syndrome. (doi:10.1046/j.1365-2265.2001.01406.x) European Journal of Endocrinology 2008 158 147–152. (doi:10.1530/ 19 Asaoka K. A study on the incidence of post-partum hypopituitarism EJE-07-0647) (Sheehan’s syndrome). Nihon Naibunpi Gakkai Zasshi 1977 53 895–909. 35 Dash RJ, Gupta V & Suri S. Sheehan’s syndrome: clinical profile, 20 Feinberg EC, Molitch ME, Endres LK & Peaceman AM. The incidence of pituitary hormone responses and computed sellar tomography. Sheehan’s syndrome after obstetric hemorrhage. Fertility and Sterility Australian and New Zealand Journal of Medicine 1993 23 26–31. 2005 84 975–979. (doi:10.1016/j.fertnstert.2005.04.034) (doi:10.1111/j.1445-5994.1993.tb00533.x) 21 Abs R, Bengtsson BA, Hernberg-Stahl E, Monson JP, Tauber JP, Wilton P 36 De Marinis L, Bonadonna S, Bianchi A, Maira G & Giustina A. Primary & Wuster C. GH replacement in 1034 growth hormone deficient empty sella. Journal of Clinical Endocrinology and Metabolism 2005 90 5471–5477. (doi:10.1210/jc.2005-0288)

European Journal of Endocrinology hypopituitary adults: demographic and clinical characteristics, dosing 37 Guitelman M, Garcia Basavilbaso N, Vitale M, Chervin A, Katz D, and safety. Clinical Endocrinology 1999 50 703–713. (doi:10.1046/ Miragaya K, Herrera J, Cornalo D, Servidio M, Boero L et al. Primary j.1365-2265.1999.00695.x) empty sella (PES): a review of 175 cases. Pituitary 2013 16 270–274. 22 Kristjansdottir HL, Bodvarsdottir SP & Sigurjonsdottir HA. Sheehan’s (doi:10.1007/s11102-012-0416-6) syndrome in modern times: a nationwide retrospective study in 38 Brismar K & Efendic S. Pituitary function in the . Iceland. European Journal of Endocrinology 2011 164 349–354. Neuroendocrinology 1981 32 70–77. (doi:10.1159/000123133) (doi:10.1530/EJE-10-1004) 39 Jara-Albarran A, Bayort J, De Juan M & Benito C. Spontaneous partial 23 Gu¨ven M, Bayram F, Gu¨ven K & Kelestimur F. Evaluation of patients empty sella. A study of 41 cases. Experimental and Clinical Endocrinology admitted with hypoglycaemia to a teaching hospital in Central 1984 83 63–72. (doi:10.1055/s-0029-1210313) Postgraduate Medical Journal Anatolia. 2000 76 150–152. (doi:10.1136/ 40 Unluhizarci K, Bayram F, Colak R, Ozturk F, Selcuklu A, Durak AC & pmj.76.893.150) Kelestimur F. Distinct radiological and clinical appearance of lympho- 24 Kelestimur F, Jonsson P, Molvalilar S, Gomez JM, Auernhammer CJ, cytic hypophysitis. Journal of Clinical Endocrinology and Metabolism 2001 Colak R, Koltowska-Haggstrom M & Goth MI. Sheehan’s syndrome: 86 1861–1864. (doi:10.1210/jcem.86.5.7440) baseline characteristics and effect of 2 years of growth hormone 41 Karaca Z, Tanriverdi F, Unluhizarci K & Kelestimur F. Pregnancy and replacement therapy in 91 patients in KIMS–Pfizer International pituitary disorders. European Journal of Endocrinology 2010 162 453–475. Metabolic Database. European Journal of Endocrinology 2005 152 (doi:10.1530/EJE-09-0923) 581–587. (doi:10.1530/eje.1.01881) 42 Sherif IH, Vanderley CM, Beshyah S & Bosairi S. Sella size and contents 25 Kelestimur F. GH deficiency and the degree of hypopituitarism. Clinical in Sheehan’s syndrome. Clinical Endocrinology 1989 30 613–618. Endocrinology 1995 42443–444. (doi:10.1111/j.1365-2265.1995.tb02658.x) (doi:10.1111/j.1365-2265.1989.tb00265.x)

Received 26 March 2014 Revised version received 22 May 2014 Accepted 10 June 2014

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