Faculty Profiles - TERASAKA Tomohiro

Androgen suppresses in vivo and in vitro LH pulse secretion and neural Kiss1 and Tac2 gene expression in female mice. Reviewed International journal

Lourdes A Esparza, Tomohiro Terasaka, Mark A Lawson, Alexander S Kauffman

Endocrinology 2020.10

Language：English Publishing type：Research paper (scientific journal)

Androgens can affect the reproductive axis of both sexes. In healthy (non-disease) women, as in men, elevated exogenous androgens decrease gonad function and lower gonadotropin levels; such circumstances occur with anabolic steroid abuse or in transgender men (genetic females identifying as males) taking androgen supplements. The neuroendocrine mechanisms by which endogenous or exogenous androgens regulate gonadotropin release, including aspects of pulsatile LH secretion, remain unknown. Because animal models are valuable for interrogating neural and pituitary mechanisms, we studied neuroendocrine effects of androgens in the normal male physiological range on both in vivo LH secretion parameters in female mice and in vitro LH secretion patterns from isolated female pituitaries. We also assessed androgen effects on hypothalamic and gonadotrope gene expression in females, which may contribute to altered LH secretion profiles. We used a non-aromatizable androgen, DHT, to isolate effects occurring specifically via androgen receptor (AR) signaling. Compared to control females, DHT-treated females exhibited markedly reduced in vivo LH pulsatility, with decreases in pulse frequency, amplitude, pulse peak, and basal LH levels. Correlating with reduced LH pulsatility, DHT-treated females also exhibited suppressed arcuate nucleus Kiss1 and Tac2 expression. Separate from these neural effects, we determined in vitro that the female pituitary is directly inhibited by AR signaling, resulting in lower basal LH levels and reduced LH secretory responses to GnRH pulses, along with lower gonadotropin gene expression. Thus, in normal adult females, male levels of androgen acting via AR can strongly inhibit the reproductive axis at both the neural and pituitary levels.

DOI： 10.1210/endocr/bqaa191

GLUT1-mediated glycolysis supports GnRH-induced secretion of luteinizing hormone from female gonadotropes. Reviewed International journal

Dequina A Nicholas, Vashti S Knight, Karen J Tonsfeldt, Tomohiro Terasaka, Olivia Molinar-Inglis, Shannon B Z Stephens, JoAnn Trejo, Alexander S Kauffman, Pamela L Mellon, Mark A Lawson

Scientific reports 10 ( 1 ) 13063 - 13063 2020.8

Language：English Publishing type：Research paper (scientific journal)

The mechanisms mediating suppression of reproduction in response to decreased nutrient availability remain undefined, with studies suggesting regulation occurs within the hypothalamus, pituitary, or gonads. By manipulating glucose utilization and GLUT1 expression in a pituitary gonadotrope cell model and in primary gonadotropes, we show GLUT1-dependent stimulation of glycolysis, but not mitochondrial respiration, by the reproductive neuropeptide GnRH. GnRH stimulation increases gonadotrope GLUT1 expression and translocation to the extracellular membrane. Maximal secretion of the gonadotropin Luteinizing Hormone is supported by GLUT1 expression and activity, and GnRH-induced glycolysis is recapitulated in primary gonadotropes. GLUT1 expression increases in vivo during the GnRH-induced ovulatory LH surge and correlates with GnRHR. We conclude that the gonadotropes of the anterior pituitary sense glucose availability and integrate this status with input from the hypothalamus via GnRH receptor signaling to regulate reproductive hormone synthesis and secretion.

DOI： 10.1038/s41598-020-69913-z

SRXN1 Is Necessary for Resolution of GnRH-Induced Oxidative Stress and Induction of Gonadotropin Gene Expression. Reviewed

Kim T, Li D, Terasaka T, Nicholas DA, Knight VS, Yang JJ, Lawson MA

Endocrinology 160 ( 11 ) 2543 - 2555 2019.11

The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH. Reviewed

Terasaka T, Kim T, Dave H, Gangapurkar B, Nicholas DA, Muñoz O, Terasaka E, Li D, Lawson MA

Endocrinology 160 ( 8 ) 1999 - 2014 2019.8

Induction of Stress Signaling In Vitro and Suppression of Gonadotropin Secretion by Free Fatty Acids in Female Mouse Gonadotropes. Reviewed

Li S, Mbong EF, John DT, Terasaka T, Li D, Lawson MA

Endocrinology 159 ( 2 ) 1074 - 1087 2018.2

Reactive Oxygen Species Link Gonadotropin-Releasing Hormone Receptor Signaling Cascades in the Gonadotrope Reviewed

Tomohiro Terasaka, Mary E. Adakama, Song Li, Taeshin Kim, Eri Terasaka, Danmei Li, Mark A. Lawson

FRONTIERS IN ENDOCRINOLOGY 8 286 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS MEDIA SA

Biological rhythms lie at the center of regulatory schemes that control many aspects of living systems. At the cellular level, meaningful responses to external stimuli depend on propagation and quenching of a signal to maintain vigilance for subsequent stimulation or changes that serve to shape and modulate the response. The hypothalamus-pituitary-gonad endocrine axis that controls reproductive development and function relies on control through rhythmic stimulation. Central to this axis is the pulsatile stimulation of the gonadotropes by hypothalamic neurons through episodic release of the neuropeptide gonadotropin-releasing hormone. Alterations in pulsatile stimulation of the gonadotropes result in differential synthesis and secretion of the gonadotropins LH and FSH and changes in the expression of their respective hormone subunit genes. The requirement to amplify signals arising from activation of the gonadotropin-releasing hormone (GnRH) receptor and to rapidly quench the resultant signal to preserve an adaptive response suggests the need for rapid activation and feedback control operating at the level of intracellular signaling. Emerging data suggest that reactive oxygen species (ROS) can fulfill this role in the GnRH receptor signaling through activation of MAP kinase signaling cascades, control of negative feedback, and participation in the secretory process. Results obtained in gonadotrope cell lines or other cell models indicate that ROS can participate in each of these regulatory cascades. We discuss the potential advantage of reactive oxygen signaling for modulating the gonadotrope response to GnRH stimulation and the potential mechanisms for this action. These observations suggest further targets of study for regulation in the gonadotrope.

DOI： 10.3389/fendo.2017.00286

Combined Effects of Androgen and Growth Hormone on Osteoblast Marker Expression in Mouse C2C12 and MC3T3-E1 Cells Induced by Bone Morphogenetic Protein Reviewed

Kosuke Kimura, Tomohiro Terasaka, Nahoko Iwata, Takayuki Katsuyama, Motoshi Komatsubara, Ryota Nagao, Kenichi Inagaki, Fumio Otsuka

JOURNAL OF CLINICAL MEDICINE 6 ( 1 ) 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling.

DOI： 10.3390/jcm6010006

The Clinical and Hormonal Characteristics of Primary Adrenal Lymphomas: The Necessity of Early Detection of Adrenal Insufficiency Reviewed

Ko Harada, Kosuke Kimura, Masaya Iwamuro, Tomohiro Terasaka, Yoshihisa Hanayama, Eisei Kondo, Eiko Hayashi, Tadashi Yoshino, Fumio Otsuka

INTERNAL MEDICINE 56 ( 17 ) 2261 - 2269 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

Objective To analyze the clinical and endocrine characteristics of patients with primary adrenal lymphoma.
Patients We retrospectively reviewed the cases of five patients with primary adrenal lymphoma who were treated in our hospital between April 2004 and March 2015. We investigated the characteristics of the clinical and pathological findings, treatment, prognosis and complications of adrenal insufficiency.
Results Adrenal insufficiency, which was confirmed by the laboratory data at the initial presentation, was observed in two cases. One case was complicated by relative adrenal insufficiency during a course of chemotherapy. The plasma adrenaline and urinary adrenaline levels were decreased in four cases and three cases, respectively. Diffusion MRI was radiologically diagnostic. In all of the cases, the patients were pathologically diagnosed with diffuse large-B cell lymphoma and were treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy. Two patients received central nervous system prophylaxis with high-dose methotrexate. Four of the patients survived and one patient died during the follow-up period.
Conclusion The early detection of adrenal insufficiency and the administration of an appropriate dose of hydrocortisone are necessary during the course of chemotherapy as well as at the initial manifestation. The exclusion of adrenal dysfunction prior to invasive diagnostic procedures, such as CT-guided needle biopsy, is also critical.

DOI： 10.2169/internalmedicine.8216-16

The possible involvement of intestine-derived IgA(1): a case of IgA nephropathy associated with Crohn's disease Reviewed

Tomohiro Terasaka, Haruhito A. Uchida, Ryoko Umebayashi, Keiko Tsukamoto, Keiko Tanaka, Masashi Kitagawa, Hitoshi Sugiyama, Hiroaki Tanioka, Jun Wada

BMC NEPHROLOGY 17 ( 1 ) 122 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: A link between IgA nephropathy and Crohn's disease has recently been reported. Other researchers hypothesize that intestine-derived IgA complexes deposit in glomerular mesangial cells, eliciting IgA nephropathy. Intestinal mucosal plasma cells mainly secrete IgA(2). Nevertheless, IgA(1) deposition is strongly implicated as being the primary cause of IgA nephropathy.
Case presentation: A 46-year-old Japanese man developed IgA nephropathy 29 years ago, following tonsillectomy. As a result, a normal urinalysis was obtained. The patient previously suffered Crohn's disease followed by urinary occult blood and proteinuria six years ago. Exacerbation of IgA nephropathy was highly suspected. Therefore a renal biopsy was performed. A diagnosis of exacerbation of IgA nephropathy with mesangial cell proliferation and fibrotic cellular crescent was based upon the pathological findings. The patient exhibited a positive clinical course and eventually achieved a remission with immunosuppressive therapy including prednisolone treatment. Immunostaining for the detection of IgA subtypes was performed on both of his kidney and excised ileum. The results revealed IgA(1) and IgA(2) deposition by submucosal cells in intestine. Furthermore, IgA(1) deposition of mesangial areas in the patient's kidney, indicated an association of IgA(1) with the exacerbation of IgA nephropathy.
Conclusion: This case represents the possibility that the intestine-derived IgA(1) can be the origin of galactose-deficient IgA which is known to cause IgA nephropathy exacerbation.

DOI： 10.1186/s12882-016-0344-1

A case of an adrenocorticotropic hormone-producing pituitary adenoma removed via electromagnetic-guided neuroendoscopy Reviewed

Yusuke Tomita, Kazuhiko Kurozumi, Tomohiro Terasaka, Kenichi Inagaki, Fumio Otsuka, Isao Date

Neurological Surgery 44 ( 6 ) 473 - 479 2016.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Igaku-Shoin Ltd

The use of navigation systems is safe and reliable for neurological surgery. We performed endoscopic transsphenoidal surgery to totally resect an adrenocorticotropic hormone (ACTH) -producing pituitary adenoma associated with oculomotor nerve palsy. A 70-year-old woman developed right ptosis 4 months before admission. She developed anisocoria 2 months later and was referred to the department of neurology from clinic. Brain magnetic resonance imaging (MR1) showed an intrasellar tumor that partially invaded the right cavernous sinus, and she was then referred to our department. She exhibited a round face ("moon face") and central obesity. Laboratory test results showed a high urinary Cortisol level and high serum ACTH level, and neither the serum Cortisol nor ACTH level was suppressed by a low-dose dexamethasone test. We performed transsphenoidal surgery using high-dimensional endoscopy under electromagnetic navigation. The tumor invading the cavernous sinus was visualized via endoscopy and confirmed on navigation using a flexible needle probe. Postoperative MRI showed total removal of the tumor, and the serum ACTH level recovered to the normal range. The patient's right oculomotor palsy resolved within 1 week postoperatively. In summary, electromagnetic navigation was useful for total resection of a pituitary tumor invading the cavernous sinus, contributing to normalization of the ACTH level and improvement in neurological symptoms.

DOI： 10.11477/mf.1436203313

Scopus

BMP-6 modulates somatostatin effects on luteinizing hormone production by gonadrotrope cells Reviewed

Kishio Toma, Fumio Otsuka, Kohei Oguni, Tomohiro Terasaka, Motoshi Komatsubara, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Hirofumi Makino

PEPTIDES 76 96 - 101 2016.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

The effects of somatostatin analogs and roles of BMP-6 in the regulation of luteinizing hormone (LH) secretion were investigated using mouse gonadotrope L beta T2 cells. LH mRNA expression and LH secretion induced by GnRH were suppressed by treatments with somatostatin analogs, including octreotide and pasireotide, in L beta T2 cells. Of note, the inhibitory effects of somatostatin analogs on LH secretion were enhanced by the action of BMP-6. BMP-6 increased the expression levels of somatostatin receptor (SSTR)5, suggesting that BMP-6 upregulates SSTR activity that leads to reduction of GnRH-induced LH secretion. In addition, GnRH-induced phosphorylation of MAPKs including ERK, but not P38 or SAPK, was suppressed by pasireotide in the presence of BMP-6. Given that each inhibitor of ERK, JNK or P38 signaling suppressed GnRH-induced LH transcription, MAPKs are individually involved in the induction of LH production by L beta T2 cells. Somatostatin analogs also impaired BMP-6-induced Smad1/5/8 phosphorylation by suppressing BMPRs and augmenting Smad6/7 expression. Collectively, the results indicate that somatostatin analogs have dual effects on the modulation of GnRH-induced MAPK signaling and BMP activity. The pituitary BMP system may play a regulatory role in GnRH-induced LH secretion by tuning the responsiveness to somatostatin analogs in gonadotrope cells. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.peptides.2016.01.011

Invasive Intrasellar Plasmacytoma Mimicking Pituitary Adenoma Reviewed

Tomohiro Terasaka, Kenichi Inagaki, Fumio Otsuka

INTERNAL MEDICINE 55 ( 11 ) 1501 - 1502 2016

White Feces Caused by the Administration of a Somatostatin Analogue Reviewed

Masaya Iwamuro, Tomohiro Terasaka, Fumio Otsuka, Hiroyuki Okada

INTERNAL MEDICINE 55 ( 13 ) 1817 - 1817 2016

Pheochromocytoma Manifesting Persistent Right Shoulder Pain and Hypochondralgia

Hideharu Hagiya, Eri Nakamura, Tomohiro Terasaka, Kou Hasegawa, Kikuko Asano, Takahiro Nada, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Fumio Otsuka

JOURNAL OF GENERAL AND FAMILY MEDICINE 16 ( 4 ) 292 - 296 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

We report a 42-year-old female who initially complained of sub-acute onset of right upper quadrant abdominal pain with right shoulder pain. A CT scan incidentally revealed an adrenal tumor, and a final diagnosis of pheochromocytoma was made on the basis of endocrinological examinations. Symptomatically, the pheochromocytoma in our patient mimicked a hepato-biliary disease by presenting abdominal pain accompanying right shoulder pain that was assumed to be referred pain via the right phrenic nerve. Physicians may need to consider the possibility of pheochromocytoma in patients with abdominal symptoms.

DOI： 10.14442/jgfm.16.4_292

Regulatory effects of fibroblast growth factor-8 and tumor necrosis factor-alpha on osteoblast marker expression induced by bone morphogenetic protein-2 Reviewed

Takayuki Katsuyama, Fumio Otsuka, Tomohiro Terasaka, Kenichi Inagaki, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Hirofumi Makino

PEPTIDES 73 88 - 94 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

BMP induces osteoblast differentiation, whereas a key proinflammatory cytokine, TNF-ce., causes inflammatory bone damage shown in rheumatoid arthritis. FGF molecules are known to be involved in bone homeostasis. However, the effects of FGF-8 on osteoblast differentiation and the interaction between FGF-8, BMPs and TNF-alpha have yet to be clarified. Here we investigated the effects of FGF-8 in relation to TNF-ci actions on BMP-2-induced osteoblast marker expression using myoblast cell line C2C12, osteoblast precursor cell line MC3T3-E1 and rat calvarial osteoblasts. It was revealed that FGF-8 inhibited BMP-2-induced expression of osteoblast differentiation markers, including Runx2, osteocalcin, alkaline phosphatase, type-1 collagen and osterix, in a concentration-dependent manner. The inhibitory effects of FGF-8 on BMP-induced osteoblast differentiation and Smad1/5/8 activation were enhanced in the presence of TNF-alpha. action. FGF-8 also inhibited BMP-2-induced expression of Wnt5a, which activates a non-canonical Wnt signaling pathway. FGF-8 had no significant influence on the expression levels of TNF receptors, while FGF-8 suppressed the expression of inhibitory Smad6 and Smad7, suggesting a possible feedback activity through FGF to BMP receptor (BMPR) signaling. Of note, inhibition of ERK activity and FGF receptor (FGFR)-dependent protein kinase, but not JNK or NF kappa B pathway, suppressed the FGF-8 actions on BMP-induced osteoblast differentiation. FGF-8 was revealed to suppress BMP-induced osteoblast differentiation through the ERK pathway and the effects were enhanced by TNF-alpha. Given the finding that FGF-8 expression was increased in synovial tissues of rheumatoid arthritis, the functional interaction between FGFR and BMPR signaling may be involved in the development process of inflammatory bone damage. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.peptides.2015.09.007