169 results on '"Kaiser, Ursula B"'
Search Results
2. Sex differences in muscle health in simulated micro- and partial-gravity environments in rats
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Rosa-Caldwell, Megan E., Mortreux, Marie, Wadhwa, Anna, Kaiser, Ursula B., Sung, Dong-Min, Bouxsein, Mary L., and Rutkove, Seward B.
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- 2023
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3. OSR1 disruption contributes to uterine factor infertility via impaired Mullerian duct development and endometrial receptivity
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Lofrano-Porto, Adriana, Pereira, Sidney Alcantara, Dauber, Andrew, Bloom, Jordana C.B., Fontes, Audrey N., Asimow, Naomi, de Moraes, Olivia Laquis, Araujo, Petra Ariadne T., Abreu, Ana Paula, Guo, Michael H., De Oliveira, Silviene F., Liu, Han, Lee, Charles, Kuohung, Wendy, Coelho, Michella S., Carroll, Rona S., Jiang, Rulang, and Kaiser, Ursula B.
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Thermo Fisher Scientific Inc. ,Infertility ,Scientific equipment and supplies industry ,Pregnancy ,Embryonic development ,Genes ,Genetic engineering ,Estrogen ,Genetically modified organisms ,Health care industry - Abstract
Three sisters, born from consanguineous parents, manifested a unique Mullerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Mullerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 [Osr1.sup.-/-] embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility., Introduction The Mullerian ducts (MD) are paired embryonic structures that arise from the mesoderm-derived invaginations of the coelomic epithelium into the mesonephros and ultimately develop into segments of the female [...]
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- 2023
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4. Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study
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Canton, Ana P M, Tinano, Flávia R, Guasti, Leonardo, Montenegro, Luciana R, Ryan, Fiona, Shears, Deborah, de Melo, Maria Edna, Gomes, Larissa G, Piana, Mariana P, Brauner, Raja, Espino-Aguilar, Rafael, Escribano-Muñoz, Arancha, Paganoni, Alyssa, Read, Jordan E, Korbonits, Márta, Seraphim, Carlos E, Costa, Silvia S, Krepischi, Ana Cristina, Jorge, Alexander A L, David, Alessia, Kaisinger, Lena R, Ong, Ken K, Perry, John R B, Abreu, Ana Paula, Kaiser, Ursula B, Argente, Jesús, Mendonca, Berenice B, Brito, Vinicius N, Howard, Sasha R, and Latronico, Ana Claudia
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- 2023
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5. Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications
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Argente, Jesús, Dunkel, Leo, Kaiser, Ursula B, Latronico, Ana C, Lomniczi, Alejandro, Soriano-Guillén, Leandro, and Tena-Sempere, Manuel
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- 2023
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6. Quality of life after long-term biochemical control of acromegaly
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Kimball, Allison, Dichtel, Laura E., Yuen, Kevin C. J., Woodmansee, Whitney W., Haines, Melanie S., Nachtigall, Lisa B., Swearingen, Brooke, Jones, Pamela, Tritos, Nicholas A., Sharpless, Julie L., Kaiser, Ursula B., Gerweck, Anu, and Miller, Karen K.
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- 2022
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7. Connecting nutritional deprivation and pubertal inhibition via GRK2-mediated repression of kisspeptin actions in GnRH neurons
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Perdices-Lopez, Cecilia, Avendaño, María S., Barroso, Alexia, Gaytán, Francisco, Ruiz-Pino, Francisco, Vázquez, Maria J., Leon, Silvia, Song, Yong Bhum, Sobrino, Veronica, Heras, Violeta, Romero-Ruiz, Antonio, Roa, Juan, Mayor, Federico, Jr, Murga, Cristina, Pinilla, Leonor, Kaiser, Ursula B., and Tena-Sempere, Manuel
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- 2022
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8. Alcohol intake and risk of pituitary adenoma
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Cote, David J., Smith, Timothy R., Kaiser, Ursula B., Laws, Jr., Edward R., and Stampfer, Meir J.
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- 2022
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9. Consensus on diagnosis and management of Cushing's disease: a guideline update
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Fleseriu, Maria, Auchus, Richard, Bancos, Irina, Ben-Shlomo, Anat, Bertherat, Jerome, Biermasz, Nienke R, Boguszewski, Cesar L, Bronstein, Marcello D, Buchfelder, Michael, Carmichael, John D, Casanueva, Felipe F, Castinetti, Frederic, Chanson, Philippe, Findling, James, Gadelha, Mônica, Geer, Eliza B, Giustina, Andrea, Grossman, Ashley, Gurnell, Mark, Ho, Ken, Ioachimescu, Adriana G, Kaiser, Ursula B, Karavitaki, Niki, Katznelson, Laurence, Kelly, Daniel F, Lacroix, André, McCormack, Ann, Melmed, Shlomo, Molitch, Mark, Mortini, Pietro, Newell-Price, John, Nieman, Lynnette, Pereira, Alberto M, Petersenn, Stephan, Pivonello, Rosario, Raff, Hershel, Reincke, Martin, Salvatori, Roberto, Scaroni, Carla, Shimon, Ilan, Stratakis, Constantine A, Swearingen, Brooke, Tabarin, Antoine, Takahashi, Yutaka, Theodoropoulou, Marily, Tsagarakis, Stylianos, Valassi, Elena, Varlamov, Elena V, Vila, Greisa, Wass, John, Webb, Susan M, Zatelli, Maria C, and Biller, Beverly M K
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- 2021
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10. The effect of experimentally induced sleep fragmentation and estradiol suppression on neurobehavioral performance and subjective sleepiness in premenopausal women.
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Grant, Leilah K, Gonsalvez, Irene, Cohn, Aviva Y, Nathan, Margo D, Harder, Jessica A, Klerman, Elizabeth B, Scheer, Frank A J L, Kaiser, Ursula B, Crawford, Sybil, Luo, Tianyu, Wiley, Aleta, Rahman, Shadab A, and Joffe, Hadine
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- 2024
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11. A refined rodent model of anorexia nervosa: Simulating state‐specific effects of caloric restriction and weight restoration.
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Rosa‐Caldwell, Megan E., Breithaupt, Lauren, Kaiser, Ursula B., Garland, Eliza, Pinkham, Sheridyn, Hancock, Madisyn, Jalkut, Sophie L., and Rutkove, Seward B.
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LOW-calorie diet ,ANOREXIA nervosa ,BONE density ,SPRAGUE Dawley rats ,SKELETAL muscle - Abstract
Current rodent models of anorexia nervosa (AN) often have accelerated weight loss that often do not allow for investigation of physiological ramifications of prolonged low weight status characteristic of AN. The purpose of this project was to refine a rodent model of AN to extend the duration of low weight status and allow for investigation of recovery. Eight‐week‐old female Sprague Dawley rats underwent 50%–60% food restriction for 30 days. Rats were group‐housed except during feeding, where AN rats were individually housed and given up to 2 h to consume food. Control (CON) rats were allowed to consume food ad libitum. To simulate recovery, a separate cohort of animals underwent the same food restriction protocol for 30 days, then rats (AN‐R) were allowed to consume food ad libitum to facilitate weight recovery for an additional 30 days. AN‐R rats were compared to age matched controls (CON‐R). AN rats lost ~15% bodyweight and were ~30% lighter than CON. Compared to CON, AN rats had ~35% lower fat content, ~18% lower bone mineral density, ~22% smaller plantaris muscle mass and ~52% smaller ovaries. Upon reintroduction of food, AN‐R rats achieved comparable bodyweights to CON‐R rats after ~10 days. However, after 30 days of recovery, AN‐R rats still had ~14% lower bone mineral density and ~11% smaller plantaris mass and ~21% smaller ovaries. This refinement of rodent AN results in physiological side effects of AN without reaching excessive weight loss requiring euthanasia. Moreover, some physiological consequences of simulated AN are not resolved with weight restoration. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Makorin RING finger protein 3 and central precocious puberty
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Maione, Luigi, Naulé, Lydie, and Kaiser, Ursula B.
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- 2020
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13. MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons
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Abreu, Ana Paula, Toro, Carlos A., Song, Yong Bhum, Navarro, Victor M., Bosch, Martha A., Eren, Aysegul, Liang, Joy N., Carroll, Rona S., Latronico, Ana Claudia, Ronnekleiv, Oline K., Aylwin, Carlos F., Lomniczi, Alejandro, Ojeda, Sergio, and Kaiser, Ursula B.
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Pituitary hormones ,Steroid hormones ,Neurons ,Health care industry - Abstract
The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropin-releasing hormone (GnRH) secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, decreases as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and that MKRN3 repressed promoter activity of human KISS1 and TAC3, 2 key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve an MKRN3-directed ubiquitination-mediated mechanism., Introduction The identification of loss-of-function mutations in MKRN3, encoding makorin ring finger protein 3, in families with central precocious puberty (CPP) linked MKRN3 to the hypothalamic-pituitary-gonadal (HPG) axis for the [...]
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- 2020
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14. Plasma androgens and the presence and course of depression in a large cohort of women
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de Wit, Anouk E., Giltay, Erik J., de Boer, Marrit K., Bosker, Fokko J., Cohn, Aviva Y., Nolen, Willem A., Kaiser, Ursula B., Joffe, Hadine, Penninx, Brenda W.J.H., and Schoevers, Robert A.
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- 2021
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15. S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism
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Masterson, Thomas A., Arora, Himanshu, Kulandavelu, Shathiyah, Carroll, Rona S., Kaiser, Ursula B., Gultekin, Sakir H., Hare, Joshua M., and Ramasamy, Ranjith
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- 2018
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16. Regulation of Gonadotropin Gene Expression by Müllerian Inhibiting Substance
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Bédécarrats, Grégoy Y., O'Neill, Francis H., Norwitz, Errol R., Kaiser, Ursula B., and Teixeira, Jose
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- 2003
17. Pubertal development and regulation
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Abreu, Ana Paula and Kaiser, Ursula B
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- 2016
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18. Pituitary adenoma or neuroendocrine tumour: the need for an integrated prognostic classification.
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Ho, Ken K. Y., Kaiser, Ursula B., Chanson, Phillippe, Gadelha, Monica, Wass, John, Nieman, Lynnette, Little, Andrew, Aghi, Manish K., Raetzman, Lori, Post, Kalmon, Raverot, Gerald, Borowsky, Alexander D., Erickson, Dana, Castaño, Justo P., Laws, Edward R., Zatelli, Maria Chiara, Sisco, Jill, Esserman, Laura, Yuen, Kevin C. J., and Reincke, Martin
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PITUITARY tumors , *NEUROENDOCRINE tumors , *CENTRAL nervous system , *CLASSIFICATION - Abstract
In the 2022 fifth edition of the WHO Classification of Endocrine Tumours and of Central Nervous System Tumours, pituitary adenomas are reclassified as neuroendocrine tumours (NETs). This change confers an oncology label to neoplasms that are overwhelmingly benign. A comprehensive clinical classification schema is required to guide prognosis, therapy and outcomes for all patients with pituitary adenomas. Pituitary adenomas and NETs exhibit some morphological and ultrastructural similarities. However, unlike NETs, pituitary adenomas are highly prevalent, yet indolent and rarely become malignant. This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the merit and clinical implications of the classification change of pituitary adenoma to NET. Many non-histological factors provide mechanistic insight and influence the prognosis and treatment of pituitary adenoma. We recommend the development of a comprehensive classification that integrates clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms. This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the implications of the WHO classification change of pituitary adenoma to neuroendocrine tumours. The authors propose that a comprehensive classification system be developed integrating clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Effects of Sleep Fragmentation and Estradiol Decline on Cortisol in a Human Experimental Model of Menopause.
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Cohn, Aviva Y., Grant, Leilah K., Nathan, Margo D., Wiley, Aleta, Abramson, Mathena, Harder, Jessica A., Crawford, Sybil, Klerman, Elizabeth B., Scheer, Frank A. J. L., Kaiser, Ursula B., Rahman, Shadab A., and Joffe, Hadine
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SLEEP disorders ,ESTRADIOL ,MENOPAUSE - Abstract
Context: Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis. Objective: We examined the effect of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women. Methods: Twenty-two women completed a 5-night inpatient study during the mid-to-late follicular phase (estrogenized). A subset (n = 14) repeated the protocol after gonadotropin-releasing hormone agonist-induced estradiol suppression. Each inpatient study included 2 unfragmented sleep nights followed by 3 experimental sleep fragmentation nights. This study took place with premenopausal women at an academic medical center. Interventions included sleep fragmentation and pharmacological hypoestrogenism, and main outcome measures were serum bedtime cortisol levels and cortisol awakening response (CAR). Results: Bedtime cortisol increased 27% (P = .03) and CAR decreased 57% (P = .01) following sleep fragmentation compared to unfragmented sleep. Polysomnographic-derived wake after sleep-onset (WASO) was positively associated with bedtime cortisol levels (P = .047) and negatively associated with CAR (P < .01). Bedtime cortisol levels were 22% lower in the hypoestrogenized state compared to the estrogenized state (P = .02), while CAR was similar in both estradiol conditions (P = .38). Conclusion: Estradiol suppression and modifiable menopause-related sleep fragmentation both independently perturb HPA axis activity. Sleep fragmentation, commonly seen in menopausal women, may disrupt the HPA axis, which in turn may lead to adverse health effects as women age. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels.
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Montenegro, Luciana, Seraphim, Carlos, Tinano, Flávia, Piovesan, Maiara, Canton, Ana P. M., McElreavey, Ken, Brabant, Severine, Boris, Natalia P., Magnuson, Melissa, Carroll, Rona S., Kaiser, Ursula B., Argente, Jesús, Barrios, Vicente, Brito, Vinicius N., Brauner, Raja, and Latronico, Ana Claudia
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PRECOCIOUS puberty ,GENETIC mutation ,DNA sequencing - Abstract
Background: Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). Objective: We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. Patients and Methods: Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. Results: We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P = .008 and .016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. Conclusions: Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG.
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Pereira, Sidney A, Oliveira, Fernanda C B, Naulé, Lydie, Royer, Carine, Neves, Francisco A R, Abreu, Ana Paula, Carroll, Rona S, Kaiser, Ursula B, Coelho, Michella S, and Lofrano-Porto, Adriana
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GONADOTROPIN ,MESSENGER RNA - Abstract
Studies in humans and mice support a role for Makorin RING finger protein 3 (MKRN3) as an inhibitor of gonadotropin-releasing hormone (GnRH) secretion prepubertally, and its loss of function is the most common genetic cause of central precocious puberty in humans. Studies have shown that the gonads can synthesize neuropeptides and express MKRN3/Mkrn3 mRNA. Therefore, we aimed to investigate the spatiotemporal expression pattern of Mkrn3 in gonads during sexual development, and its potential regulation in the functional testicular compartments by gonadotropins. Mkrn3 mRNA was detected in testes and ovaries of wild-type mice at all ages evaluated, with a sexually dimorphic expression pattern between male and female gonads. Mkrn3 expression was highest peripubertally in the testes, whereas it was lower peripubertally than prepubertally in the ovaries. Mkrn3 is expressed primarily in the interstitial compartment of the testes but was also detected at low levels in the seminiferous tubules. In vitro studies demonstrated that Mkrn3 mRNA levels increased in human chorionic gonadotropin (hCG)–treated Leydig cell primary cultures. Acute administration of a GnRH agonist in adult mice increased Mkrn3 expression in testes, whereas inhibition of the hypothalamic–pituitary–gonadal axis by chronic administration of GnRH agonist had the opposite effect. Finally, we found that hCG increased Mkrn3 mRNA levels in a dose-dependent manner. Taken together, our developmental expression analyses, in vitro and in vivo studies show that Mkrn3 is expressed in the testes, predominantly in the interstitial compartment, and that Mkrn3 expression increases after puberty and is responsive to luteinizing hormone/hCG stimulation. [ABSTRACT FROM AUTHOR]
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- 2023
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22. A 72-Year-Old Woman with Fatigue and Shortness of Breath.
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Hansrivijit, Panupong, Thurber, Emilia G., Malkani, Natasha P., Chen, Wendy Y., Goldsmith, Jeffrey D., Kaiser, Ursula B., and Gupta, Shruti
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PHYSICAL diagnosis ,DIFFERENTIAL diagnosis ,DYSPNEA ,WEIGHT loss ,MEDICAL history taking ,FATIGUE (Physiology) - Abstract
Morning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, and then inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the case of a 72-year-old woman who presented with fatigue, dyspnea on exertion, and a 5-kg unintentional weight loss over the past 3 weeks. Through the history of present illness, physical examination, and relevant testing the differential diagnosis is refined until a final diagnosis is made. [ABSTRACT FROM AUTHOR]
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- 2023
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23. Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination.
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Magnotto, John C., Mancini, Alessandra, Bird, Keisha, Montenegro, Luciana, Tütüncüler, Filiz, Pereira, Sidney A., Simas, Vitoria, Garcia, Leonardo, Roberts, Stephanie A., Macedo, Delanie, Magnuson, Melissa, Gagliardi, Priscila, Mauras, Nelly, Witchel, Selma F., Carroll, Rona S., Latronico, Ana Claudia, Kaiser, Ursula B., and Abreu, Ana Paula
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Context: Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. Objective: This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Methods: Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Results: Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. Conclusion: MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset. [ABSTRACT FROM AUTHOR]
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- 2023
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24. The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty.
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Brito, Vinicius N, Canton, Ana P M, Seraphim, Carlos Eduardo, Abreu, Ana Paula, Macedo, Delanie B, Mendonca, Berenice B, Kaiser, Ursula B, Argente, Jesús, and Latronico, Ana Claudia
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PRECOCIOUS puberty ,ETIOLOGY of diseases ,ENDOCRINE disruptors - Abstract
The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP. [ABSTRACT FROM AUTHOR]
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- 2023
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25. Early Onset GH Excess: Somatotroph Adenoma in a Young Adult.
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Galbiati, Francesca and Kaiser, Ursula B
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ACROMEGALY , *YOUNG adults , *RECEPTOR-interacting proteins , *ADENOMA , *PITUITARY tumors , *GENETIC testing - Abstract
GH-secreting pituitary adenomas can cause gigantism or acromegaly, determined by onset before or after epiphyseal fusion of the distal ends of the radius and ulna. Overlapping phenotypes can occur when the condition presents peripubertally. Gigantism is associated with identifiable hereditary causes and genetic mutations in almost 50% of cases; genetic testing should be considered in patients with gigantism and early-onset acromegaly, especially (but not only) when pituitary tumors have aggressive features and/or are refractory to standard treatments. Here, we present a case of a young adult with a giant somatotroph adenoma resistant to multiple treatment modalities and negative for mutations in AIP , which encodes aryl hydrocarbon receptor-interacting protein. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Long-Term Changes in the Size of Pituitary Microadenomas.
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Hordejuk, Dawid, Cheung, Yee-Ming M., Wang, Wei, Smith, Timothy, Laws, Edward, Kaiser, Ursula B., and Min, Le
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MAGNETIC resonance imaging ,PITUITARY tumors ,BRAIN imaging ,BRAIN damage - Abstract
Pituitary lesions found on brain imaging for other purposes are often called "incidentalomas," and most are microadenomas with diameters less than 10 mm. Little is known about how stable these microadenomas are and how often they should be imaged. This article provides new information about the stability of pituitary microadenomas. Visual Abstract. Size Changes in Pituitary Microadenomas.: Pituitary lesions found on brain imaging for other purposes are often called "incidentalomas," and most are microadenomas with diameters less than 10 mm. Little is known about how stable these microadenomas are and how often they should be imaged. This article provides new information about the stability of pituitary microadenomas. Background: The estimated prevalence of pituitary lesions is 10% to 38.5% in radiologic studies. However, how frequently these incidental lesions should be monitored by serial pituitary magnetic resonance imaging (MRI) remains unclear. Objective: To evaluate changes in pituitary microadenomas over time. Design: Retrospective, longitudinal cohort study. Setting: Mass General Brigham, Boston, Massachusetts. Patients: Evidence of pituitary microadenoma from MRI. Measurements: Dimensions of pituitary microadenomas. Results: During the study period (from 2003 to 2021), 414 patients with pituitary microadenomas were identified. Of the 177 patients who had more than 1 MRI, 78 had no change in the size of the microadenoma over time, 49 had an increase in size, 34 had a decrease in size, and 16 had both an increase and decrease in size. By linear mixed model analysis, the estimated slope was 0.016 mm/y (95% CI, −0.037 to 0.069). In the subgroup analysis, pituitary adenomas with a baseline size of 4 mm or less tended to increase in size. The estimated slope was 0.09 mm/y (CI, 0.020 to 0.161). In contrast, in the subgroup with baseline tumor size greater than 4 mm, the size tended to decrease. The estimated slope was −0.063 mm/y (CI, −0.141 to 0.015). Limitation: Retrospective cohort, some patients were lost to follow-up for unknown reasons, and data were limited to local large institutions. Conclusion: During the study period, approximately two thirds of the microadenomas remained unchanged or decreased in size. The growth, if any, was slow. These findings suggest that less frequent pituitary MRI surveillance for patients with incidental pituitary microadenomas may be safe. Primary Funding Source: None. [ABSTRACT FROM AUTHOR]
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- 2023
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27. Clinical Biology of the Pituitary Adenoma.
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Melmed, Shlomo, Kaiser, Ursula B, Lopes, M Beatriz, Bertherat, Jerome, Syro, Luis V, Raverot, Gerald, Reincke, Martin, Johannsson, Gudmundur, Beckers, Albert, Fleseriu, Maria, Giustina, Andrea, Wass, John A H, and Ho, Ken K Y
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ACROMEGALY ,CUSHING'S syndrome ,PITUITARY tumors - Abstract
All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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28. A High-Throughput Small-Molecule Ligand Screen Targeted to Agonists and Antagonists of the G-Protein-Coupled Receptor GPR54
- Author
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Kuohung, Wendy, Burnett, Maria, Mukhtyar, Deepa, Schuman, Eli, Ni, Jake, Crowley, William F., Glicksman, Marcie A., and Kaiser, Ursula B.
- Published
- 2010
- Full Text
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29. Hypothalamic Overexpression of Makorin Ring Finger Protein 3 Results in Delayed Puberty in Female Mice.
- Author
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Roberts, Stephanie A, Naulé, Lydie, Chouman, Soukayna, Johnson, Tatyana, Johnson, Marciana, Carroll, Rona S, Navarro, Victor M, and Kaiser, Ursula B
- Abstract
Makorin ring finger protein 3 (MKRN3) is an important neuroendocrine player in the control of pubertal timing and upstream inhibitor of gonadotropin-releasing hormone secretion. In mice, expression of Mkrn3 in the hypothalamic arcuate and anteroventral periventricular nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if the persistence of hypothalamic Mkrn3 expression peripubertally would result in delayed puberty. Female mice that received neonatal bilateral intracerebroventricular injections of a recombinant adeno-associated virus expressing Mkrn3 had delayed vaginal opening and first estrus compared with animals injected with control virus. Subsequent estrous cycles and fertility were normal. Interestingly, male mice treated similarly did not exhibit delayed puberty onset. Kiss1 , Tac2 , and Pdyn mRNA levels were increased in the mediobasal hypothalamus in females at postnatal day 28, whereas kisspeptin and neurokinin B protein levels in the arcuate nucleus were decreased, following Mkrn3 overexpression, compared to controls. Cumulatively, these data suggest that Mkrn3 may directly or indirectly target neuropeptides of Kiss1 neurons to degradation pathways. This mouse model suggests that MKRN3 may be a potential contributor to delayed onset of puberty, in addition to its well-established roles in central precocious puberty and the timing of menarche. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
30. Stalking the diagnosis
- Author
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Chamarthi, Bindu, Morris, Charles A., Kaiser, Ursula B., Katz, Joel T., and Loscalzo, Joseph
- Subjects
Breast cancer -- Diagnosis - Abstract
The article discusses the case of a 58-year-old woman with fever and problem swallowing as well as other complications to better understand the complications and challenges associated with diagnosis. The case was an unusual presentation of breast cancer - metastatis to the pituitary gland and showed how difficulties are found in diagnosis.
- Published
- 2010
31. Sleep Fragmentation and Estradiol Suppression Decrease Fat Oxidation in Premenopausal Women.
- Author
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Grant, Leilah K., Coborn, Jamie E., Cohn, Aviva, Nathan, Margo D., Scheer, Frank A. J. L., Klerman, Elizabeth B., Kaiser, Ursula B., Harder, Jessica, Abramson, Mathena, Elguenaoui, Elkhansaa, Russell, Julia A., Wiley, Aleta, Rahman, Shadab A., and Joffe, Hadine
- Subjects
SLEEP-wake cycle ,ESTRADIOL ,PERIMENOPAUSE - Abstract
Context: Body fat gain associated with menopause has been attributed to estradiol (E2) withdrawal. Hypoestrogenism is unlikely to be the only contributing factor, however. Objective: Given the links between sleep and metabolic health, we examined the effects of an experimental menopausal model of sleep fragmentation on energy metabolism. Methods: Twenty premenopausal women (age 21-45 years) underwent a 5-night inpatient study during the mid-to-late follicular phase (estrogenized; n = 20) and the same protocol was repeated in a subset of the participants (n = 9) following leuprolide-induced E2 suppression (hypo-estrogenized). During each 5-night study, there were 2 nights of unfragmented sleep followed by 3 nights of fragmented sleep. Indirect calorimetry was used to assess fasted resting energy expenditure (REE) and substrate oxidation. Results: Sleep fragmentation in the estrogenized state increased the respiratory exchange ratio (RER) and carbohydrate oxidation while decreasing fat oxidation (all P < 0.01). Similarly, in the hypo-estrogenized state without sleep fragmentation, RER and carbohydrate oxidation increased and fat oxidation decreased (all P < 0.01); addition of sleep fragmentation to the hypo-estrogenized state did not produce further effects beyond that observed for either intervention alone (P < 0.05). There were no effects of either sleep fragmentation or E2 state on REE. Conclusion: Sleep fragmentation and hypoestrogenism each independently alter fasting substrate oxidation in a manner that may contribute to body fat gain. These findings are important for understanding mechanisms underlying propensity to body fat gain in women across the menopause transition. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
32. Reproductive Phenotypes in Men With Acquired or Congenital Hypogonadotropic Hypogonadism: A Comparative Study.
- Author
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Maione, Luigi, Sarfati, Julie, Gonfroy-Leymarie, Céline, Salenave, Sylvie, Brailly-Tabard, Sylvie, Chanson, Philippe, Trabado, Séverine, Kaiser, Ursula B., and Young, Jacques
- Subjects
PHENOTYPES ,CONGENITAL hypothyroidism - Abstract
Context: In men with congenital hypogonadotropic hypogonadism (CHH), gonadotropin deficiency and testicular impairment exist since fetal development and persist throughout life. In a few reported cases of acquired HH (AHH), HH onset occurs mainly post pubertally. Objective: This work aimed to compare the natural history and reproductive status in large series of CHH and lesional AHH evaluated in a single expert academic center. Methods: We included 172 controls, 668 male HH patients (CHH: n = 201 [age 16.9 ± 9.0 years], lesional AHH: n = 467 [age 45.6 ± 18.4 years]) caused by hypothalamic and/or pituitary tumors (mainly adenomas and craniopharyngiomas) or infiltrative/traumatic diseases. Results: At diagnosis, CHH were significantly younger, with 52.9% diagnosed before age 18 years, compared to only 9.6% of AHH patients. Cryptorchidism (21.9% vs 0.3%) and micropenis were more prevalent in CHH than AHH patients. Low testicular volume (TV) was present in 97% of patients with CHH (mean TV: 3.4 ± 2.7 mL) but in only 30% of those with AHH (mean TV: 20.8 ± 5.0 mL). Whereas no men with persistent CHH had spontaneous fertility, 70.4% of AHH men fathered at least one child without medical therapy. Total testosterone was lower both in CHH and AHH patients than in controls. Compared to controls, circulating gonadotropins and testicular peptides (insulin-like factor-3 and inhibin B) were decreased both in CHH and AHH, but were significantly higher in patients with AHH. Conclusion: In AHH patients, the HH has later onset and is less severe than in CHH and the phenotype can overlap with that of individuals with normal laboratory values. Our data suggest that age at diagnosis is a predictor of the reproductive phenotype in AHH. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
33. A GPR54-activating mutation in a patient with central precocious puberty
- Author
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Teles, Milena Gurgel, Bianco, Suzy D.C., Brito, Vinicius Nahime, Trabach, Ericka B., Kuohung, Wendy, Shuyun Xu, Seminara, Stephanie B., Mendonca, Berenice B., Kaiser, Ursula B., and Latronico, Ana Claudia
- Subjects
G proteins -- Research ,Mutation (Biology) -- Research ,Precocious puberty -- Genetic aspects ,Precocious puberty -- Research - Abstract
A study to examine the association of gain-of-function mutations of GPR54 receptor leading to the onset of central precocious puberty is conducted. Results show that the mutation leads to prolonged activation of intracellular signaling pathways in response to kisspeptin.
- Published
- 2008
34. GPR54 and KiSS-1: Role in the regulation of puberty and reproduction
- Author
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Kuohung, Wendy and Kaiser, Ursula B.
- Published
- 2006
- Full Text
- View/download PDF
35. Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice
- Author
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Chattopadhyay, Naibedya, Jeong, Kyeong-Hoon, Yano, Shozo, Huang, Su, Pang, Jian L., Ren, Xianghui, Terwilliger, Ernest, Kaiser, Ursula B., Vassilev, Peter M., Pollak, Martin R., and Brown, Edward M.
- Subjects
G proteins -- Research ,Gonadotropin releasing hormone -- Health aspects ,Gonadotropin releasing hormone -- Research ,Chemotaxis -- Analysis ,Mice -- Physiological aspects ,Biological sciences - Abstract
The factors controlling the migration of mammalian gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CAR) promotes migration/chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus derived) and GN11 (olfactory bulb derived). Elevated extracellular [Ca.sup.2+] concentrations promoted chemotaxis of both cell types, with a greater effect in GN11 cells. This effect was CaR mediated, as, in both cell types, over-expression of a dominantnegative CaR attenuated high [Ca.sup.2+]-stimulated chemotaxis. We also demonstrated expression of a [beta]-chemokine, monocyte chemoattractant protein-1 (MCP-1), and its receptor, CC motif receptor-2 (CCR2), in the hypothalamic GnRH neurons as well as in GTI-7 and GN11 cells. Exogenous MCP-1 stimulated chemotaxis of both cell lines in a dose-dependent fashion; the effect was greater in GN11 than in GT1-7 cells, consistent with the higher CCR2 mRNA levels in GN 11 cells. Activating the CaR stimulated MCP-1 secretion in GT1-7 but not in GN11 cells. MCP-1 secreted in response to CaR stimulation is biologically active, as conditioned medium from GT1-7 cells treated with high [Ca.sup.2+] promoted chemotaxis of GN11 cells, and this effect was partially attenuated by a neutralizing antibody to MCP-1. Finally, in the preoptic area of anterior hypothalamus, the number of GnRH neurons was ~27% lower in CaR-null mice than in mice expressing the CaR gene. We conclude that the CaR may be a novel regulator of GnRH neuronal migration likely involving, in part, MCP-1. chemokine; G protein-coupled receptor; gonadotropin-releasing hormone; CC motif receptor-2; monocyte chemoattractant protein-l; calcium-sensing receptor
- Published
- 2007
36. KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty
- Author
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Kaiser, Ursula B. and Kuohung, Wendy
- Published
- 2005
- Full Text
- View/download PDF
37. Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3
- Author
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Abreu, Ana Paula, Dauber, Andrew, Macedo, Delanie B., Noel, Sekoni D., Brito, Vinicius N., Gill, John C., Cukier, Priscilla, Thompson, Iain R., Navarro, Victor M., Gagliardi, Priscila C., Rodrigues, Tânia, Kochi, Cristiane, Longui, Carlos Alberto, Beckers, Dominique, de Zegher, Francis, Montenegro, Luciana R., Mendonca, Berenice B., Carroll, Rona S., Hirschhorn, Joel N., Latronico, Ana Claudia, and Kaiser, Ursula B.
- Published
- 2013
- Full Text
- View/download PDF
38. The GPR54 gene as a regulator of puberty
- Author
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Seminara, Stephanie B., Messager, Sophie, Chatzidaki, Emmanouella E., Thresher, Rosemary R., Acierno, James S., Jr., Shagoury, Jenna K., Bo-Abbas, Yousef, Kuohung, Wendy, Schwinof, Kristine M., Henrick, Alan G., Zahn, Dirk, Dixon, John, Kaiser, Ursula B., Slaugenhaupt, Susan A., Gusella, James F., O'Rahilly, Stephen, Carlton, Mark B.L., Crowley, William F., Jr., Aparicio, Samuel A.J.R., and Colledge, William H.
- Subjects
Puberty -- Genetic aspects - Abstract
A gene for a G protein-coupled receptor called the GPR54 gene appears to be involved in initiating puberty, according to a study in humans and mice. Mutations of this gene were found in a large Saudi Arabian family with a family history of a delayed puberty disorder called idiopathic hypogonadotropic hypogonadism. The receptor produced by this gene may be stimulated by gonadotropin-releasing hormone, the hormone responsible for initiating puberty.
- Published
- 2003
39. Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones.
- Author
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Anderson, Ross C., Hanyroup, Sharika, Song, Yong Bhum, Mohamed-Moosa, Zulfiah, van den Bout, Iman, Schwulst, Alexis C., Kaiser, Ursula B., Millar, Robert P., and Newton, Claire L.
- Subjects
CELL receptors ,G protein coupled receptors ,SMALL molecules ,CELL membranes ,MISSENSE mutation - Abstract
G protein-coupled receptors (GPCRs) facilitate the majority of signal transductions across cell membranes in humans, with numerous diseases attributed to inactivating GPCR mutations. Many of these mutations result in misfolding during nascent receptor synthesis in the endoplasmic reticulum (ER), resulting in intracellular retention and degradation. Pharmacological chaperones (PCs) are cell-permeant small molecules that can interact with misfolded receptors in the ER and stabilise/rescue their folding to promote ER exit and trafficking to the cell membrane. The neurokinin 3 receptor (NK3R) plays a pivotal role in the hypothalamic–pituitary–gonadal reproductive axis. We sought to determine whether NK3R missense mutations result in a loss of cell surface receptor expression and, if so, whether a cell-permeant small molecule NK3R antagonist could be repurposed as a PC to restore function to these mutants. Quantitation of cell surface expression levels of seven mutant NK3Rs identified in hypogonadal patients indicated that five had severely impaired cell surface expression. A small molecule NK3R antagonist, M8, increased cell surface expression in four of these five and resulted in post-translational receptor processing in a manner analogous to the wild type. Importantly, there was a significant improvement in receptor activation in response to neurokinin B (NKB) for all four receptors following their rescue with M8. This demonstrates that M8 may have potential for therapeutic development in the treatment of hypogonadal patients harbouring NK3R mutations. The repurposing of existing small molecule GPCR modulators as PCs represents a novel and therapeutically viable option for the treatment of disorders attributed to mutations in GPCRs that cause intracellular retention. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
40. Oral Contraceptive and Menopausal Hormone Therapy Use and Risk of Pituitary Adenoma: Cohort and Case-Control Analyses.
- Author
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Cote, David J., Kilgallon, John L., Nawabi, Noah L. A., Dawood, Hassan Y., Smith, Timothy R., Kaiser, Ursula B., Laws Jr, Edward R., Manson, JoAnn E., and Stampfer, Meir J.
- Abstract
Context: No prospective epidemiologic studies have examined associations between use of oral contraceptives (OCs) or menopausal hormone therapy (MHT) and risk of pituitary adenoma in women. Objective: Our aim was to determine the association between use of OC and MHT and risk of pituitary adenoma in two separate datasets. Methods: We evaluated the association of OC/MHT with risk of pituitary adenoma in the Nurses’ Health Study and Nurses’ Health Study II by computing multivariable-adjusted hazard ratios (MVHR) of pituitary adenoma by OC/MHT use using Cox proportional hazards models. Simultaneously, we carried out a matched case-control study using an institutional data repository to compute multivariable-adjusted odds ratios (MVOR) of pituitary adenoma by OC/MHT use. Results: In the cohort analysis, during 6 668 019 person-years, 331 participants reported a diagnosis of pituitary adenoma. Compared to never-users, neither past (MVHR = 1.05; 95% CI, 0.80-1.36) nor current OC use (MVHR = 0.72; 95% CI, 0.40-1.32) was associated with risk. For MHT, compared to never-users, both past (MVHR = 2.00; 95% CI, 1.50-2.68) and current use (MVHR = 1.80; 95% CI, 1.27-2.55) were associated with pituitary adenoma risk, as was longer duration (MVHR = 2.06; 95% CI, 1.42-2.99 comparing more than 5 years of use to never, P trend = .002). Results were similar in lagged analyses, when stratified by body mass index, and among those with recent health care use. In the case-control analysis, we included 5469 cases. Risk of pituitary adenoma was increased with ever use of MHT (MVOR = 1.57; 95% CI, 1.35-1.83) and OC (MVOR = 1.27; 95% CI, 1.14-1.42) compared to never. Conclusion: Compared to never use, current and past MHT use and longer duration of MHT use were positively associated with higher risk of pituitary adenoma in 2 independent data sets. OC use was not associated with risk in the prospective cohort analysis and was associated with only mildly increased risk in the case-control analysis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
41. Hyperprolactinemia and infertility: new insights
- Author
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Kaiser, Ursula B.
- Published
- 2012
- Full Text
- View/download PDF
42. A 72-year-old man with persistent fever and hypotension
- Author
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Kaiser, Ursula B. and Hedley-White, E. Tessa
- Subjects
Pituitary gland tumors -- Case studies - Abstract
A 72-year-old man with persistent nausea, vomiting, fever, and low blood pressure was diagnosed with adrenal insufficiency and pituitary gland insufficiency caused by a pituitary gland tumor. The tumor was surgically removed and he was treated with corticosteroids, thyroid hormone and testosterone.
- Published
- 2001
43. Lying Low
- Author
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Vaidya, Anand, Kaiser, Ursula B., Levy, Bruce D., and Loscalzo, Joseph
- Published
- 2011
44. Lying Low
- Author
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Ross, John J., Vaidya, Anand, and Kaiser, Ursula B.
- Published
- 2011
45. Cushingʼs Disease and Idiopathic Intracranial Hypertension: Case Report and Review of Underlying Pathophysiological Mechanisms
- Author
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Zada, Gabriel, Tirosh, Amir, Kaiser, Ursula B., Laws, Edward R., and Woodmansee, Whitney W.
- Published
- 2010
46. Trafficking-defective mutant PROKR2 cycles between endoplasmic reticulum and Golgi to attenuate endoplasmic reticulum stress.
- Author
-
Yong Bhum Song, Seung-Yeol Park, Kunyou Park, Hayoung Hwang, Carroll, Rona S., Hsu, Victor W., and Kaiser, Ursula B.
- Subjects
ENDOPLASMIC reticulum ,G protein coupled receptors ,GENETIC disorders ,QUALITY control ,COMMERCIAL products - Abstract
G protein–coupled receptors (GPCRs) play crucial roles in numerous physiological and pathological processes. Mutations in GPCRs that result in loss of function or alterations in signaling can lead to inherited or acquired diseases. Herein, studying prokineticin receptor 2 (PROKR2), we initially identify distinct interactomes for wild-type (WT) versus a mutant (P290S) PROKR2 that causes hypogonadotropic hypogonadism. We then find that both the WT and mutant PROKR2 are targeted for endoplasmic reticulum (ER)-associated degradation, but the mutant is degraded to a greater extent. Further analysis revealed that both forms can also leave the ER to reach the Golgi. However, whereas most of the WT is further transported to the cell surface, most of the mutant is retrieved to the ER. Thus, the post-ER itinerary plays an important role in distinguishing the ultimate fate of the WT versus the mutant. We have further discovered that this post-ER itinerary reduces ER stress induced by the mutant PROKR2. Moreover, we extend the core findings to another model GPCR. Our findings advance the understanding of disease pathogenesis induced by a mutation at a key residue that is conserved across many GPCRs and thus contributes to a fundamental understanding of the diverse mechanisms used by cellular quality control to accommodate misfolded proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
47. Deletion of Gαq/11 or Gαs Proteins in Gonadotropes Differentially Affects Gonadotropin Production and Secretion in Mice.
- Author
-
Stamatiades, George A, Toufaily, Chirine, Kim, Han Kyeol, Zhou, Xiang, Thompson, Iain R, Carroll, Rona S, Chen, Min, Weinstein, Lee S, Offermanns, Stefan, Boehm, Ulrich, Bernard, Daniel J, and Kaiser, Ursula B
- Abstract
Gonadotropin-releasing hormone (GnRH) regulates gonadal function via its stimulatory effects on gonadotropin production by pituitary gonadotrope cells. GnRH is released from the hypothalamus in pulses and GnRH pulse frequency differentially regulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis and secretion. The GnRH receptor (GnRHR) is a G protein–coupled receptor that canonically activates Gα
q/11 -dependent signaling on ligand binding. However, the receptor can also couple to Gαs and in vitro data suggest that toggling between different G proteins may contribute to GnRH pulse frequency decoding. For example, as we show here, knockdown of Gαs impairs GnRH-stimulated FSH synthesis at low- but not high-pulse frequency in a model gonadotrope-derived cell line. We next used a Cre-lox conditional knockout approach to interrogate the relative roles of Gαq/11 and Gαs proteins in gonadotrope function in mice. Gonadotrope-specific Gαq/11 knockouts exhibit hypogonadotropic hypogonadism and infertility, akin to the phenotypes seen in GnRH- or GnRHR-deficient mice. In contrast, under standard conditions, gonadotrope-specific Gαs knockouts produce gonadotropins at normal levels and are fertile. However, the LH surge amplitude is blunted in Gαs knockout females and postgonadectomy increases in FSH and LH are reduced both in males and females. These data suggest that GnRH may signal principally via Gαq/11 to stimulate gonadotropin production, but that Gαs plays important roles in gonadotrope function in vivo when GnRH secretion is enhanced. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
48. The oestrous cycle and skeletal muscle atrophy: Investigations in rodent models of muscle loss.
- Author
-
Rosa‐Caldwell, Megan E., Mortreux, Marie, Kaiser, Ursula B., Sung, Dong‐Min, Bouxsein, Mary L., Dunlap, Kirsten R., Greene, Nicholas P., and Rutkove, Seward B.
- Subjects
ESTRUS ,MUSCULAR atrophy ,SKELETAL muscle ,MUSCLE physiology ,GRIP strength - Abstract
New Findings: What is the central question of this study?Is the oestrous cycle affected during disuse atrophies and, if so, how are oestrous cycle changes related to musculoskeletal outcomes?What is the main finding and its importance?Rodent oestrous cycles were altered during disuse atrophy, which was correlated with musculoskeletal outcomes. However, the oestrous cycle did not appear to be changed by Lewis lung carcinoma, which resulted in no differences in muscle size in comparison to healthy control animals. These findings suggest a relationship between the oestrous cycle and muscle size during atrophic pathologies. Recent efforts have focused on improving our understanding of female muscle physiology during exposure to muscle atrophic stimuli. A key feature of female rodent physiology is the oestrous cycle. However, it is not known how such stimuli interact with the oestrous cycle to influence muscle health. In this study, we investigated the impact of muscle atrophic stimuli on the oestrous cycle and how these alterations are correlated with musculoskeletal outcomes. A series of experiments were performed in female rodents, including hindlimb unloading (HU), HU followed by 24 h of reloading, HU combined with dexamethasone treatment, and Lewis lung carcinoma. The oestrous cycle phase was assessed throughout each intervention and correlated with musculoskeletal outcomes. Seven or 14 days of HU increased the duration in dioestrus or metoestrus (D/M; low hormones) and was negatively correlated with gastrocnemius mass. Time spent in D/M was also negatively correlated with changes in grip strength and bone density after HU, and with muscle recovery 24 h after the cessation of HU. The addition of dexamethasone strengthened these relationships between time in D/M and reduced musculoskeletal outcomes. However, in animals with Lewis lung carcinoma, oestrous cyclicity did not differ from that of control animals, and time spent in D/M was not correlated with either gastrocnemius mass or tumour burden. In vitro experiments suggested that enhanced protein synthesis induced by estrogen might protect against muscle atrophy. In conclusion, muscle atrophic insults are correlated with changes in the oestrous cycle, which are associated with deterioration in musculoskeletal outcomes. The magnitude of oestrous cycle alterations depends on the atrophic stimuli. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
49. Mutations in the Human Gonadotropin-Releasing Hormone Receptor: Insights into Receptor Biology and Function
- Author
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Bédécarrats, Grégoy Y and Kaiser, Ursula B
- Published
- 2007
50. Central precocious puberty: Recent advances in understanding the aetiology and in the clinical approach.
- Author
-
Maione, Luigi, Bouvattier, Claire, and Kaiser, Ursula B.
- Subjects
PRECOCIOUS puberty ,CENTRAL nervous system ,ETIOLOGY of diseases ,PATHOLOGICAL physiology ,MOLECULAR interactions ,PUBERTY ,GONADOTROPIN releasing hormone ,GENETIC mutation - Abstract
Central precocious puberty (CPP) results from early activation of the hypothalamic‐pituitary‐gonadal (HPG) axis. The current state of knowledge of the complex neural network acting at the level of the hypothalamus and the GnRH neuron to control puberty onset has expanded, particularly in the context of molecular interactions. Along with these advances, the knowledge of pubertal physiology and pathophysiology has also increased. This review focuses on regulatory abnormalities occurring at the hypothalamic level of the HPG axis to cause CPP. The clinical approach to diagnosis of puberty and pubertal disorders is also reviewed, with a particular focus on aetiologies of CPP. The recent identification of mutations in MKRN3 and DLK1 in familial as well sporadic forms of CPP has changed the state of the art of the approach to patients with CPP. Genetic advances have also had important repercussions beyond consideration of puberty alone. Syndromic disorders and central nervous system lesions associated with CPP are also discussed. If untreated, these conditions may lead to adverse physical, psychosocial and medical outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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