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TSH secreting adenoma of the pituitary gland in a female patient with undesired childlessness
Journal of Clinical and Translational Endocrinology: Case Reports 4 (2017) 8e10
Contents lists available at ScienceDirect
Journal of Clinical and Translational Endocrinology: Case Reports journal homepage: www.elsevier.com/locate/jecr
TSH secreting adenoma of the pituitary gland in a female patient with undesired childlessness € lle a, 1, M. Saborowski a, 1, C. Terkamp a, J. Flitsch b, C. Bernreuther c, M.P. Manns a, M. Do H. Leitolf a, S. Zender a, * a b c
Department of Gastroenterology, Hepatology, Endocrinology, Medical School Hannover, Germany Department of Neurosurgery, University Hospital Hamburg Eppendorf, Germany Department of Pathology, University Hospital Hamburg Eppendorf, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 July 2016 Received in revised form 27 March 2017 Accepted 27 March 2017
Context: TSH secreting pituitary adenomas are a very rare cause of hyperthyroidism and related clinical problems like amenorrhea. TSH elevations are often explained by hypothyroidism as in many cases only TSH levels are measured as a global marker for thyroid function. Case description: We report the case of a young woman who saw a general practitioner because of undesired childlessness. Initially misdiagnosed with hypothyroidism the definite diagnosis of a TSH secreting adenoma took five years and finally led to a successful treatment. After adenomectomy was performed the patient presented with normal thyroid function tests and menses in a regular manner. Conclusion: This case emphasizes the need for careful evaluation of rare causes of childlessness. An early MRI scan should be considered when an inadequate increase of TSH in the presence of elevated peripheral hormones is detected. © 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Hyperthyroidism TSH elevation TSH secreting pituitary adenoma TSHoma Amenorrhea Prolactin Prolactinoma Pituitary macroadenoma Childlessness
Introduction TSH secreting adenomas of the pituitary gland (TSHoma) are a very rare cause of hyperthyroidism. Less than 2% of pituitary adenomas seem to be associated with a central inadequate TSH secretion [1]. The incidence of these adenomas has been reported to be very low (at about 0.26 per million per year in a swedish population [2]). Patients usually present with symptoms of hyperthyroidism often with a long history of thyroid dysfunction [1]. In addition, symptoms like goiter, thyroid nodules, visual field defects, headache, menstrual disorders, galactorrhea, and acromegaly are quite common [1,3]. Frequently, a macroadenoma of the pituitary gland is found, but microadenomas are possible as well [1]. An important differential diagnosis are syndromes of resistance to thyroid hormones [1,3,4]. Although usually benign, a few cases of TSH-secreting carcinomas have been described [5]. First line
* Corresponding author. E-mail address: [email protected] (S. Zender). 1 Equal contribution.
therapy of TSH secreting adenomas is surgical resection with improved success rates in micro-compared to macroadenomas [6]. In addition to transsphenoidal resection other therapeutic options like radiosurgery or radiotherapy or medical therapy including somatostatin analogs and dopamine agonists [3] exist. Any therapy should lead to normalization of TSH levels and peripheral hormones. Relapse of hyperthyroidism is possible reinforcing the need of regular biochemical assessment [5,8] after surgery and during medical therapy. Case presentation A 26-year-old obese caucasian female was referred to our endocrine outpatient clinic due to elevated thyroid hormones. The patient reported a history of thyroid malfunction for about five to six years. Initially, suspicious TSH elevations had been detected by a general practitioner that saw the patient because of unfulfilled desire to have children. The patient described menstruation in an irregular manner. No other symptoms suggesting hyperthyroidism were present. The patient had been referred to a nuclear medicine specialist who had repeated the thyroid function tests
http://dx.doi.org/10.1016/j.jecr.2017.03.002 2214-6245/© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
€lle et al. / Journal of Clinical and Translational Endocrinology: Case Reports 4 (2017) 8e10 M. Do
9
Fig. 1. Sagittal MRI post contrast enhancement showing an intrasellar macroadenoma.
demonstrating elevated TSH levels in combination with elevated fT3 and fT4 concentrations. Thyroid ultrasound and scintigraphy had been performed showing inhomogeneous echotexture without nodules with homogenous normal uptake at initial presentation in 2010. Although thyroid antibodies were within the normal range a chronic lymphocytic thyroiditis was suggested due to the imaging studies. Because of elevated TSH levels a treatment with levothyroxine (75mg per day) had been started. Continuing blood samples showed rising TSH levels following escalation of thyroid medication. The patient described palpitations and decrease of general well-being which led to termination of levothyroxine medication. Due to suspicious levels of thyroid hormones MRI examination of the pituitary gland was performed. The scan showed a pituitary tumor with dimension of 12 mm 15 mm x 15mm (see Fig. 1). There was no affection of the optical nerve or optic chiasma. The patient reported general dizziness and a decrease of physical performance. In addition, obesity had been a problem for many years. Significant weight reduction was possible in the past for short periods of time followed by repetitive weight gain (current BMI 45,5kg/m2). After MRI was performed the patient initially presented in our endocrine outpatient clinic in 2015. Laboratory tests revealed a significant elevation of TSH, fT3, fT4, TT3, TT4. Thyroxine-binding globulin stayed within the normal range. In addition to these findings, a slight elevation of prolactin (by a factor of 1.3) could be documented. Other pituitary hormones were within the normal range. The patient did not show any symptoms of anterior pituitary malfunction. We repeated an ultrasound
examination of the thyroid gland showing goiter. Additionally, an elevation of red blood cells was found. We excluded syndromes of thyroid hormone resistance by genetic testing of the THRA and THRB genes. With a suspected diagnose of TSH and prolactin cosecreting pituitary adenoma we referred the patient to the department of neurosurgery where a transsphenoidal adenomectomy was performed. Pathological examination with immunohistochemical stainings for expression of ACTH, prolactin, STH, FSH, LH, TSH, KL1, S100, p53, Phospho-Histon 3 and Ki67 was performed and a significant expression of TSH and prolactin (suppl. Table 1 and suppl. Fig. 1) could be demonstrated. In the peri- and postoperative setting hydrocortisone and levothyroxine were administered. The patient returned to our department three weeks after surgery and reported general well-being despite a slight headache. Repeated blood samples showed a normal thyroid functions with TSH, fT3, fT4, TT3, TT4 and TBG within their respected normal range without any thyroid hormone medication (3 and 12 weeks after surgery) (see Table 1). Other pituitary functions were normal, testing of the corticotrope and lactotrope axis showed normal results. Menses started to regularize shortly after surgery. No further medication was required with thyroid hormone levels remaining in the normal range. Post-surgical MRI scan is scheduled. Discussion TSH secreting adenoma of the pituitary gland is a very rare but possible cause of hyperthyroidism. Often mistreated as Graves'
€lle et al. / Journal of Clinical and Translational Endocrinology: Case Reports 4 (2017) 8e10 M. Do
10
Table 1 Thyroid function before and after surgery. Before surgery 2011 (with 37,5mg levothyroxine)
Before surgery 2015 (without medication)
After surgery 2016 (3 After surgery 2016 (11 weeks) Weeks)
TSH [mU/ml] 5.45 (þ)
7.1 (þ)
7.28 (þ)
1.38
2.04
fT4 [ng/dl]
1,67 (þ)
1.66 (þ)
1.96 (þ)
1.04
1.17
fT3 [pmol/ ml] Prolactine [ng/ml]
9,21 (þ)
9,67 (þ)
9.54 (þ)
4.81
5.29
41.0
6.0
7.4
Before surgery 2010 (without medication)
disease despite elevated TSH levels there is a long time span between symptoms, diagnosis and appropriate therapy. In our case, the only symptom that was present was an undesired childlessness. This led to an unsuccessful treatment attempt of suspected hypothyroidism due to elevated TSH levels. The MRI scan that demonstrated a macroadenoma was finally performed five years after initial presentation of the patient to a specialist with elevated levels of thyroid hormones (TSH, fT3, fT4). The scan was performed after years of treatment with levothyroxine without any beneficial effect on the patient's symptoms (besides reducing general performance) and thyroid hormone levels. First line therapy of a TSH secreting adenoma (similar to any hormonally active adenoma except for prolactinoma) is surgical resection. The success rates are dependent of the size of the adenoma with better outcomes in micro-compared to macroadenomas [6]. More recently, Gatto et al. reported a high rate of pituitary insufficiency after transsphenoidal surgery for TSHomas and discussed whether pharmacotherapy may be considered as first line therapy [7]. So far, no further publication has supported their findings. In addition to transsphenoidal resection other therapeutic options like radiosurgery, radiotherapy or medical therapy including somatostatin analogs and dopamine agonists like cabergoline [3] exist, but are not first line therapies. Any therapy should lead to normalization of TSH levels and peripheral hormones. Relapse of hyperthyroidism is possible reinforcing the need of regular biochemical assessment [5,8] after surgery and during any medical therapy. In summary, any combined elevation of TSH and peripheral hormones should lead to diagnostic testing for thyroid hormone resistance or presence of TSHoma. Conclusion In patients with elevated levels of TSH, measurement of peripheral hormones is obligatory to detect any form of hypo- or
0.3 e4.0 0.78 e1.54 3.5 e6.5 <25
hyperthyroidism. If TSH, fT3 and fT4 are elevated, one should think of rare causes like TSHoma or hormone resistance. After excluding syndromes of resistance to thyroid hormones an early MRI scan should be performed following individualized treatment in case an adenoma is shown. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jecr.2017.03.002. References [1] Beck-Peccoz P, Persani L, Mannavola D, Campi I. TSH-secreting adenomas. Best Pract Res Clin Endocrinol Metab [Internet] 2009;23(5):597e606. http:// dx.doi.org/10.1016/j.beem.2009.05.006. Elsevier Ltd; Available from:. € € m BEN. National inci[2] Onnestam L, Berinder K, Burman P, Dahlqvist P, Engstro dence and prevalence of TSH-secreting pituitary adenomas in Sweden. J Clin Endocrinol Metab 2013;98(2):626e35. [3] Beck-Peccoz P, Lania A, Beckers A, Chatterjee K, Wemeau J-L. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropinsecreting pituitary tumors. Eur Thyroid J [Internet] 2013;2(2):76e82. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821512/? tool¼pmcentrez#sec1_2title. [4] Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid-hormone. Endocr Rev [Internet] 1993;14(3):348e99. Available from::// A1993LF28200006. [5] Brown RL, Muzzafar T, Wollman R, Weiss RE. A pituitary carcinoma secreting TSH and prolactin: a non-secreting adenoma gone awry. Eur J Endocrinol 2006;154(5):639e43. [6] Socin HV, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, et al. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients. Eur J Endocrinol 2003;148(4):433e42. [7] Gatto F, Grasso LF, Nazzari E, Cuny T, Anania P, Di Somma C, et al. Clinical outcome and evidence of high rate post-surgical anterior hypopituitarism in a cohort of TSH-secreting adenoma patients: might somatostatin analogs have a role as first-line therapy? Pituit [Internet] 2014;18(5):583e91. http:// dx.doi.org/10.1007/s11102-014-0611-8. Springer US; Available from:. [8] Losa M, Giovanelli M, Persani L, Mortini P, Faglia G, Beck-Peccoz P. Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab 1996;81(8):3084e90.
Contents lists available at ScienceDirect
Journal of Clinical and Translational Endocrinology: Case Reports journal homepage: www.elsevier.com/locate/jecr
TSH secreting adenoma of the pituitary gland in a female patient with undesired childlessness € lle a, 1, M. Saborowski a, 1, C. Terkamp a, J. Flitsch b, C. Bernreuther c, M.P. Manns a, M. Do H. Leitolf a, S. Zender a, * a b c
Department of Gastroenterology, Hepatology, Endocrinology, Medical School Hannover, Germany Department of Neurosurgery, University Hospital Hamburg Eppendorf, Germany Department of Pathology, University Hospital Hamburg Eppendorf, Germany
a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 July 2016 Received in revised form 27 March 2017 Accepted 27 March 2017
Context: TSH secreting pituitary adenomas are a very rare cause of hyperthyroidism and related clinical problems like amenorrhea. TSH elevations are often explained by hypothyroidism as in many cases only TSH levels are measured as a global marker for thyroid function. Case description: We report the case of a young woman who saw a general practitioner because of undesired childlessness. Initially misdiagnosed with hypothyroidism the definite diagnosis of a TSH secreting adenoma took five years and finally led to a successful treatment. After adenomectomy was performed the patient presented with normal thyroid function tests and menses in a regular manner. Conclusion: This case emphasizes the need for careful evaluation of rare causes of childlessness. An early MRI scan should be considered when an inadequate increase of TSH in the presence of elevated peripheral hormones is detected. © 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Hyperthyroidism TSH elevation TSH secreting pituitary adenoma TSHoma Amenorrhea Prolactin Prolactinoma Pituitary macroadenoma Childlessness
Introduction TSH secreting adenomas of the pituitary gland (TSHoma) are a very rare cause of hyperthyroidism. Less than 2% of pituitary adenomas seem to be associated with a central inadequate TSH secretion [1]. The incidence of these adenomas has been reported to be very low (at about 0.26 per million per year in a swedish population [2]). Patients usually present with symptoms of hyperthyroidism often with a long history of thyroid dysfunction [1]. In addition, symptoms like goiter, thyroid nodules, visual field defects, headache, menstrual disorders, galactorrhea, and acromegaly are quite common [1,3]. Frequently, a macroadenoma of the pituitary gland is found, but microadenomas are possible as well [1]. An important differential diagnosis are syndromes of resistance to thyroid hormones [1,3,4]. Although usually benign, a few cases of TSH-secreting carcinomas have been described [5]. First line
* Corresponding author. E-mail address: [email protected] (S. Zender). 1 Equal contribution.
therapy of TSH secreting adenomas is surgical resection with improved success rates in micro-compared to macroadenomas [6]. In addition to transsphenoidal resection other therapeutic options like radiosurgery or radiotherapy or medical therapy including somatostatin analogs and dopamine agonists [3] exist. Any therapy should lead to normalization of TSH levels and peripheral hormones. Relapse of hyperthyroidism is possible reinforcing the need of regular biochemical assessment [5,8] after surgery and during medical therapy. Case presentation A 26-year-old obese caucasian female was referred to our endocrine outpatient clinic due to elevated thyroid hormones. The patient reported a history of thyroid malfunction for about five to six years. Initially, suspicious TSH elevations had been detected by a general practitioner that saw the patient because of unfulfilled desire to have children. The patient described menstruation in an irregular manner. No other symptoms suggesting hyperthyroidism were present. The patient had been referred to a nuclear medicine specialist who had repeated the thyroid function tests
http://dx.doi.org/10.1016/j.jecr.2017.03.002 2214-6245/© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
€lle et al. / Journal of Clinical and Translational Endocrinology: Case Reports 4 (2017) 8e10 M. Do
9
Fig. 1. Sagittal MRI post contrast enhancement showing an intrasellar macroadenoma.
demonstrating elevated TSH levels in combination with elevated fT3 and fT4 concentrations. Thyroid ultrasound and scintigraphy had been performed showing inhomogeneous echotexture without nodules with homogenous normal uptake at initial presentation in 2010. Although thyroid antibodies were within the normal range a chronic lymphocytic thyroiditis was suggested due to the imaging studies. Because of elevated TSH levels a treatment with levothyroxine (75mg per day) had been started. Continuing blood samples showed rising TSH levels following escalation of thyroid medication. The patient described palpitations and decrease of general well-being which led to termination of levothyroxine medication. Due to suspicious levels of thyroid hormones MRI examination of the pituitary gland was performed. The scan showed a pituitary tumor with dimension of 12 mm 15 mm x 15mm (see Fig. 1). There was no affection of the optical nerve or optic chiasma. The patient reported general dizziness and a decrease of physical performance. In addition, obesity had been a problem for many years. Significant weight reduction was possible in the past for short periods of time followed by repetitive weight gain (current BMI 45,5kg/m2). After MRI was performed the patient initially presented in our endocrine outpatient clinic in 2015. Laboratory tests revealed a significant elevation of TSH, fT3, fT4, TT3, TT4. Thyroxine-binding globulin stayed within the normal range. In addition to these findings, a slight elevation of prolactin (by a factor of 1.3) could be documented. Other pituitary hormones were within the normal range. The patient did not show any symptoms of anterior pituitary malfunction. We repeated an ultrasound
examination of the thyroid gland showing goiter. Additionally, an elevation of red blood cells was found. We excluded syndromes of thyroid hormone resistance by genetic testing of the THRA and THRB genes. With a suspected diagnose of TSH and prolactin cosecreting pituitary adenoma we referred the patient to the department of neurosurgery where a transsphenoidal adenomectomy was performed. Pathological examination with immunohistochemical stainings for expression of ACTH, prolactin, STH, FSH, LH, TSH, KL1, S100, p53, Phospho-Histon 3 and Ki67 was performed and a significant expression of TSH and prolactin (suppl. Table 1 and suppl. Fig. 1) could be demonstrated. In the peri- and postoperative setting hydrocortisone and levothyroxine were administered. The patient returned to our department three weeks after surgery and reported general well-being despite a slight headache. Repeated blood samples showed a normal thyroid functions with TSH, fT3, fT4, TT3, TT4 and TBG within their respected normal range without any thyroid hormone medication (3 and 12 weeks after surgery) (see Table 1). Other pituitary functions were normal, testing of the corticotrope and lactotrope axis showed normal results. Menses started to regularize shortly after surgery. No further medication was required with thyroid hormone levels remaining in the normal range. Post-surgical MRI scan is scheduled. Discussion TSH secreting adenoma of the pituitary gland is a very rare but possible cause of hyperthyroidism. Often mistreated as Graves'
€lle et al. / Journal of Clinical and Translational Endocrinology: Case Reports 4 (2017) 8e10 M. Do
10
Table 1 Thyroid function before and after surgery. Before surgery 2011 (with 37,5mg levothyroxine)
Before surgery 2015 (without medication)
After surgery 2016 (3 After surgery 2016 (11 weeks) Weeks)
TSH [mU/ml] 5.45 (þ)
7.1 (þ)
7.28 (þ)
1.38
2.04
fT4 [ng/dl]
1,67 (þ)
1.66 (þ)
1.96 (þ)
1.04
1.17
fT3 [pmol/ ml] Prolactine [ng/ml]
9,21 (þ)
9,67 (þ)
9.54 (þ)
4.81
5.29
41.0
6.0
7.4
Before surgery 2010 (without medication)
disease despite elevated TSH levels there is a long time span between symptoms, diagnosis and appropriate therapy. In our case, the only symptom that was present was an undesired childlessness. This led to an unsuccessful treatment attempt of suspected hypothyroidism due to elevated TSH levels. The MRI scan that demonstrated a macroadenoma was finally performed five years after initial presentation of the patient to a specialist with elevated levels of thyroid hormones (TSH, fT3, fT4). The scan was performed after years of treatment with levothyroxine without any beneficial effect on the patient's symptoms (besides reducing general performance) and thyroid hormone levels. First line therapy of a TSH secreting adenoma (similar to any hormonally active adenoma except for prolactinoma) is surgical resection. The success rates are dependent of the size of the adenoma with better outcomes in micro-compared to macroadenomas [6]. More recently, Gatto et al. reported a high rate of pituitary insufficiency after transsphenoidal surgery for TSHomas and discussed whether pharmacotherapy may be considered as first line therapy [7]. So far, no further publication has supported their findings. In addition to transsphenoidal resection other therapeutic options like radiosurgery, radiotherapy or medical therapy including somatostatin analogs and dopamine agonists like cabergoline [3] exist, but are not first line therapies. Any therapy should lead to normalization of TSH levels and peripheral hormones. Relapse of hyperthyroidism is possible reinforcing the need of regular biochemical assessment [5,8] after surgery and during any medical therapy. In summary, any combined elevation of TSH and peripheral hormones should lead to diagnostic testing for thyroid hormone resistance or presence of TSHoma. Conclusion In patients with elevated levels of TSH, measurement of peripheral hormones is obligatory to detect any form of hypo- or
0.3 e4.0 0.78 e1.54 3.5 e6.5 <25
hyperthyroidism. If TSH, fT3 and fT4 are elevated, one should think of rare causes like TSHoma or hormone resistance. After excluding syndromes of resistance to thyroid hormones an early MRI scan should be performed following individualized treatment in case an adenoma is shown. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jecr.2017.03.002. References [1] Beck-Peccoz P, Persani L, Mannavola D, Campi I. TSH-secreting adenomas. Best Pract Res Clin Endocrinol Metab [Internet] 2009;23(5):597e606. http:// dx.doi.org/10.1016/j.beem.2009.05.006. Elsevier Ltd; Available from:. € € m BEN. National inci[2] Onnestam L, Berinder K, Burman P, Dahlqvist P, Engstro dence and prevalence of TSH-secreting pituitary adenomas in Sweden. J Clin Endocrinol Metab 2013;98(2):626e35. [3] Beck-Peccoz P, Lania A, Beckers A, Chatterjee K, Wemeau J-L. 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropinsecreting pituitary tumors. Eur Thyroid J [Internet] 2013;2(2):76e82. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821512/? tool¼pmcentrez#sec1_2title. [4] Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid-hormone. Endocr Rev [Internet] 1993;14(3):348e99. Available from: