Accepted Article
Article Type: Original Article
Relationship between pituitary stalk visibility and the severity of hormone deficiencies: Pituitary stalk interruption syndrome revisited
Short title:
Pituitary stalk visibility and hormonal deficiency in PSIS
Weiqing Wang1,2*, Shuwei Wang1*, Yiran Jiang1, Fuhua Yan3, Tingwei Su1, Weiwei Zhou1, Lei Jiang1,Yifei Zhang1, Guang Ning1,2
1. Shanghai Clinical Center for Endocrine and Metabolic Diseases (W.W., S.W., Y.J., T.S., W.Z., L.J., Y.Z., G.N.), Shanghai Institute of Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, P. R. China; 2. Laboratory for Endocrine and Metabolic Diseases of Institute of Health Science (W.W., G.N.), Shanghai Jiaotong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, P. R. China 3. Department of Radiology (F.Y.), Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025, P. R. China; Weiqing Wang and Shuwei Wang contributed equally to this work.
Corresponding author and person to who print request should be addressed: Guang Ning, MD, PhD, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China. Phone: (086) 21-64370045, ext 665340 Fax: (086) 21-64373514 E-mail: [email protected].
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.12788 This article is protected by copyright. All rights reserved.
Accepted Article
Key terms: anterior pituitary hormone deficiency, visibility of pituitary stalk, pituitary stalk interruption syndrome.
Acknowledge: Address all correspondence and requests for reprints to: Guang Ning, MD, PhD, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China. E-mail: [email protected]. And we thank Shenghan Lai, MD, MPH, for his critical revision and statistical analysis. This work was supported by grants from the National Natural Science Foundation of China (81130016), the Science and Technology Commission of Shanghai Municipality (14ZR1425600), and the scientific research project of Shanghai municipal health commission for youth (2012-84)
Disclosure statement: the authors have nothing to disclose
Summary
Context: Pituitary stalk interruption syndrome (PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk (PS) in imaging findings.
Objective: The major objective of the study was to systematically describe the disease including clinical presentations, imaging findings, and to estimate the severity of anterior pituitary hormone deficiency based on the visibility of the PS.
Methods: This was a retrospective study including 74 adult patients with PSIS in Shanghai Clinical Center for Endocrine and Metabolic Diseases between January 2010 and June 2014. Sixty had invisible PS according to the findings on MRI, while the rest had a thin or intersected PS. Basic characteristics and hormonal status were compared.
Results: Of the 74 patients with PSIS, age at diagnosis was 25 (22 to 28) years. Absent pubertal development (97.3%) was the most common presenting symptom, followed by short stature. Insulin
This article is protected by copyright. All rights reserved.
Accepted Article
tolerance test (ITT) and gonadotropin-releasing hormone (GnRH) stimulation test were used to evaluate the function of anterior pituitary. The prevalence of isolated deficiency in growth hormone (GH), gonadotropins，corticotropin and thyrotropin were 100%, 97.2%, 88.2% and 70.3% respectively. Although the ratio of each deficiency did not vary between patients with invisible PS and with visible PS, panhypopituitarism occurred significantly more frequent in patients with invisible PS. Patients with invisible PS had significantly lower levels of luteinizing hormone (LH), follicle-stimulation hormone (FSH) and hormones from targeted glands including morning cortisol, 24-hour urine free cortisol, free triiodothyronine (FT3), free thyroxine (FT4) and testosterone (T) in male than patients with visible PS. Moreover patients with invisible PS had lower peak LH and FSH in GnRH stimulation test, and higher peak cortisol in ITT while peak GH remained unchanged between two groups.
Conclusions: The prevalence of multiple anterior pituitary hormone deficiency was high in adult patients with PSIS. And more importantly, we found the visibility of PS shown on MRI might be an indication of the severity of PSIS.
Introduction: Pituitary stalk interruption syndrome (PSIS) is characterized by a typical triad in pituitary imaging: absent or thin pituitary stalk (PS), ectopic posterior pituitary and anterior pituitary hypoplasia (1-3). The common presentations of the disease generally include short stature, absent or delayed pubertal development and other symptoms associated with anterior pituitary hormone deficiencies. The exact prevalence in normal population is still uncertain due to its rarity. The pathogenesis of the condition has not been fully understood yet. It could be acquired by the aberrant embryonic development of pituitary. This intricate process requires the coordination of complex structural and cellular differentiation, during which neurohypophysis (ventral diencephalon, neural ectodermal) begins to fusion with adenohypopysis (Rathke’s pouch, ectodermal)(4, 5). At first, it was thought that perinatal injury to the PS was the primary cause(6). Later accumulating evidence supported the fact that mutations of certain genes involved in the development of pituitary might be the true cause, which led to increased incidence of adverse events during birth. To date, only 5 gene mutations have been identified in less than 5% of patients with PSIS, including LHX4, OTX2, HESX1, SOX3，GLI2 and PROKR2(7-10). Normally during the formation of mature pituitary, diverticulum descends and gives rise to the posterior lobe right behind the anterior pituitary, in the meanwhile PS comes into shape and brings about the hypothalamic-pituitary vessels with it. When the neural
This article is protected by copyright. All rights reserved.
Accepted Article
migration is interrupted in PSIS, the angiogenesis of hypophyseal portal circulation is disturbed as well, leading to the hypoplasia of anterior pituitary and anterior pituitary hormone deficiencies(9). Short stature associated with growth hormone deficiency is the most common presentation in children with PSIS(2, 11-13), and 40-100% of them may at the same time have other anterior pituitary hormone deficiencies(14-16). The function of posterior pituitary is generally intact(2, 12, 14), while there are case reports of patients with PSIS diagnosed with diabetes insipidus(17). The factors concerning the heterogeneity of its presentations have been studied before, breech presentation, hypoglycemia, and micropenis could best discriminate patients with multiple deficiencies from those with isolated GH deficiency(14). Chen et al.(2) stated in his research involving 25 children that patients with invisible PS on MRI tended to have multiple anterior pituitary hormone deficiencies, whereas visibility of the PS was related to isolated GH deficiency. Since the clinical presentations often show in the first decade of life, most of previous studies about PSIS have focused only on children with GH deficiency. There are not sufficient data about adult patients with this condition yet. Our aim of the study is to review the characteristics and clinical features of the disease in a relatively large adult population, and try to evaluate the severity of hormone deficiencies according to the visibility of PS，so as to have a better understanding of this syndrome.
Patients and methods We selected adult patients who were referred to Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine from January 2010 to June 2014 (Figure 1). Inclusion criteria: in conformity with the diagnostic criteria of PSIS, which were the triad of a thin or absent PS, an ectopic posterior pituitary and hypoplasia of anterior pituitary detected by MRI(2, 18, 19). All patients had detailed medical history taken including physical examinations and related hormonal evaluations. Exclusion criteria: lack of hormonal evaluation, without contrast MRI and ambiguous cases. Finally 74 patients were included in our study.
Endocrine evaluation All patients had serum hormones evaluated and most underwent provocative tests if needed. In ITT, both serum GH and cortisol were measured at -30 min, 0 min, 30 min, 45 min, 60 min, 90 min and 120 min after achievement of hypoglycemia. And during GnRH stimulation test, LH and FSH were measured at -15min, 0min, 25min, 45min, 90min, and 180min after GnRH injection. Short
This article is protected by copyright. All rights reserved.
Accepted Article
stature was diagnosed as height below -2 SDs according to 2 national representative cross-sectional surveys, which was
Article Type: Original Article
Relationship between pituitary stalk visibility and the severity of hormone deficiencies: Pituitary stalk interruption syndrome revisited
Short title:
Pituitary stalk visibility and hormonal deficiency in PSIS
Weiqing Wang1,2*, Shuwei Wang1*, Yiran Jiang1, Fuhua Yan3, Tingwei Su1, Weiwei Zhou1, Lei Jiang1,Yifei Zhang1, Guang Ning1,2
1. Shanghai Clinical Center for Endocrine and Metabolic Diseases (W.W., S.W., Y.J., T.S., W.Z., L.J., Y.Z., G.N.), Shanghai Institute of Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, P. R. China; 2. Laboratory for Endocrine and Metabolic Diseases of Institute of Health Science (W.W., G.N.), Shanghai Jiaotong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, P. R. China 3. Department of Radiology (F.Y.), Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025, P. R. China; Weiqing Wang and Shuwei Wang contributed equally to this work.
Corresponding author and person to who print request should be addressed: Guang Ning, MD, PhD, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China. Phone: (086) 21-64370045, ext 665340 Fax: (086) 21-64373514 E-mail: [email protected].
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.12788 This article is protected by copyright. All rights reserved.
Accepted Article
Key terms: anterior pituitary hormone deficiency, visibility of pituitary stalk, pituitary stalk interruption syndrome.
Acknowledge: Address all correspondence and requests for reprints to: Guang Ning, MD, PhD, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital Affiliated to Shanghai Jiao-Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China. E-mail: [email protected]. And we thank Shenghan Lai, MD, MPH, for his critical revision and statistical analysis. This work was supported by grants from the National Natural Science Foundation of China (81130016), the Science and Technology Commission of Shanghai Municipality (14ZR1425600), and the scientific research project of Shanghai municipal health commission for youth (2012-84)
Disclosure statement: the authors have nothing to disclose
Summary
Context: Pituitary stalk interruption syndrome (PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk (PS) in imaging findings.
Objective: The major objective of the study was to systematically describe the disease including clinical presentations, imaging findings, and to estimate the severity of anterior pituitary hormone deficiency based on the visibility of the PS.
Methods: This was a retrospective study including 74 adult patients with PSIS in Shanghai Clinical Center for Endocrine and Metabolic Diseases between January 2010 and June 2014. Sixty had invisible PS according to the findings on MRI, while the rest had a thin or intersected PS. Basic characteristics and hormonal status were compared.
Results: Of the 74 patients with PSIS, age at diagnosis was 25 (22 to 28) years. Absent pubertal development (97.3%) was the most common presenting symptom, followed by short stature. Insulin
This article is protected by copyright. All rights reserved.
Accepted Article
tolerance test (ITT) and gonadotropin-releasing hormone (GnRH) stimulation test were used to evaluate the function of anterior pituitary. The prevalence of isolated deficiency in growth hormone (GH), gonadotropins，corticotropin and thyrotropin were 100%, 97.2%, 88.2% and 70.3% respectively. Although the ratio of each deficiency did not vary between patients with invisible PS and with visible PS, panhypopituitarism occurred significantly more frequent in patients with invisible PS. Patients with invisible PS had significantly lower levels of luteinizing hormone (LH), follicle-stimulation hormone (FSH) and hormones from targeted glands including morning cortisol, 24-hour urine free cortisol, free triiodothyronine (FT3), free thyroxine (FT4) and testosterone (T) in male than patients with visible PS. Moreover patients with invisible PS had lower peak LH and FSH in GnRH stimulation test, and higher peak cortisol in ITT while peak GH remained unchanged between two groups.
Conclusions: The prevalence of multiple anterior pituitary hormone deficiency was high in adult patients with PSIS. And more importantly, we found the visibility of PS shown on MRI might be an indication of the severity of PSIS.
Introduction: Pituitary stalk interruption syndrome (PSIS) is characterized by a typical triad in pituitary imaging: absent or thin pituitary stalk (PS), ectopic posterior pituitary and anterior pituitary hypoplasia (1-3). The common presentations of the disease generally include short stature, absent or delayed pubertal development and other symptoms associated with anterior pituitary hormone deficiencies. The exact prevalence in normal population is still uncertain due to its rarity. The pathogenesis of the condition has not been fully understood yet. It could be acquired by the aberrant embryonic development of pituitary. This intricate process requires the coordination of complex structural and cellular differentiation, during which neurohypophysis (ventral diencephalon, neural ectodermal) begins to fusion with adenohypopysis (Rathke’s pouch, ectodermal)(4, 5). At first, it was thought that perinatal injury to the PS was the primary cause(6). Later accumulating evidence supported the fact that mutations of certain genes involved in the development of pituitary might be the true cause, which led to increased incidence of adverse events during birth. To date, only 5 gene mutations have been identified in less than 5% of patients with PSIS, including LHX4, OTX2, HESX1, SOX3，GLI2 and PROKR2(7-10). Normally during the formation of mature pituitary, diverticulum descends and gives rise to the posterior lobe right behind the anterior pituitary, in the meanwhile PS comes into shape and brings about the hypothalamic-pituitary vessels with it. When the neural
This article is protected by copyright. All rights reserved.
Accepted Article
migration is interrupted in PSIS, the angiogenesis of hypophyseal portal circulation is disturbed as well, leading to the hypoplasia of anterior pituitary and anterior pituitary hormone deficiencies(9). Short stature associated with growth hormone deficiency is the most common presentation in children with PSIS(2, 11-13), and 40-100% of them may at the same time have other anterior pituitary hormone deficiencies(14-16). The function of posterior pituitary is generally intact(2, 12, 14), while there are case reports of patients with PSIS diagnosed with diabetes insipidus(17). The factors concerning the heterogeneity of its presentations have been studied before, breech presentation, hypoglycemia, and micropenis could best discriminate patients with multiple deficiencies from those with isolated GH deficiency(14). Chen et al.(2) stated in his research involving 25 children that patients with invisible PS on MRI tended to have multiple anterior pituitary hormone deficiencies, whereas visibility of the PS was related to isolated GH deficiency. Since the clinical presentations often show in the first decade of life, most of previous studies about PSIS have focused only on children with GH deficiency. There are not sufficient data about adult patients with this condition yet. Our aim of the study is to review the characteristics and clinical features of the disease in a relatively large adult population, and try to evaluate the severity of hormone deficiencies according to the visibility of PS，so as to have a better understanding of this syndrome.
Patients and methods We selected adult patients who were referred to Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine from January 2010 to June 2014 (Figure 1). Inclusion criteria: in conformity with the diagnostic criteria of PSIS, which were the triad of a thin or absent PS, an ectopic posterior pituitary and hypoplasia of anterior pituitary detected by MRI(2, 18, 19). All patients had detailed medical history taken including physical examinations and related hormonal evaluations. Exclusion criteria: lack of hormonal evaluation, without contrast MRI and ambiguous cases. Finally 74 patients were included in our study.
Endocrine evaluation All patients had serum hormones evaluated and most underwent provocative tests if needed. In ITT, both serum GH and cortisol were measured at -30 min, 0 min, 30 min, 45 min, 60 min, 90 min and 120 min after achievement of hypoglycemia. And during GnRH stimulation test, LH and FSH were measured at -15min, 0min, 25min, 45min, 90min, and 180min after GnRH injection. Short
This article is protected by copyright. All rights reserved.
Accepted Article
stature was diagnosed as height below -2 SDs according to 2 national representative cross-sectional surveys, which was
![[Late-onset pituitary stalk interruption syndrome (PSIS)].](/assets/img/hold.png)
