Pulsatile Hormonal Signaling to Extracellular Signal-Regulated Kinase: Exploring System Sensitivity to Gonadotropin-Releasing Hormone Pulse Frequency and Width

Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses that stimulate synthesis and secretion of pituitary gonadotropin hormones and thereby mediate control of reproduction. It acts via G-protein-coupled receptors to stimulate effectors, including ERK. Information could be encoded in GnRH pulse frequency, width, amplitude, or other features of pulse shape, but the relative importance of these features is unknown. Here we examine this using automated fluorescence microscopy and mathematical modeling, focusing on ERK signaling. The simplest scenario is one in which the system is linear, and response dynamics are relatively fast (compared with the signal dynamics). In this case integrated system output (ERK activation or ERK-driven transcription) will be roughly proportional to integrated input, but we find that this is not the case. Notably, we find that relatively slow response kinetics lead to ERK activity beyond the GnRH pulse, and this reduces sensitivity to pulse width. More generally, we show that the slowing of response kinetics through the signaling cascade creates a system that is robust to pulse width. We, therefore, show how various levels of response kinetics synergize to dictate system sensitivity to different features of pulsatile hormone input. We reveal the mathematical and biochemical basis of a dynamic GnRH signaling system that is robust to changes in pulse amplitude and width but is sensitive to changes in receptor occupancy and frequency, precisely the features that are tightly regulated and exploited to exert physiological control in vivo

Enzyme Replacement in Gaucher Disease

The development of enzyme replacement therapy for Gaucher disease was a triumph of translational medicine. What were the key steps in its development? What are the controversies surrounding its use

Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 0.5–1% of all colorectal cancer cases. It is caused by germline mutations in the gene encoding the adenomatous polyposis coli ( APC ) tumor suppressor. Somatic APC inactivation due to mutation or loss of heterozygosity (LOH) promotes the development of adenomatous polyps by stabilizing the transcriptional coactivator β‐catenin. Although colorectal cancer is by far the most common malignancy seen in FAP patients, the widespread use of prophylactic colectomy in these patients has increased the clinical importance of extracolonic tumors that are part of the neoplastic spectrum in FAP. Many of these tumors exhibit LOH or somatic APC mutation, strongly supporting a causative role of APC inactivation in their pathogenesis. Here we describe a 47‐year‐old female FAP patient with clinical manifestations of virilization who was found to have an ovarian steroid cell tumor, a rare neoplasm not known to be associated with FAP. Immunohistochemical analysis of the ovarian tumor demonstrated strong nuclear β‐catenin staining consistent with somatic APC inactivation, and molecular analysis confirmed biallelic APC inactivation in the tumor. Our findings provide the first evidence that ovarian steroid cell tumors may be an extracolonic manifestation of FAP and implicate β‐catenin activation as an oncogenic mechanism in ovarian steroid cell tumorigenesis. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90384/1/20953_ftp.pd

Antibodies against gonadotropin-releasing hormone (GnRH) and destruction of enteric neurons in 3 patients suffering from gastrointestinal dysfunction

Background: Antibodies against gonadotropin-releasing hormone (GnRH) and gastrointestinal dysmotility have been found after treatment with GnRH analogues. The aim of this study was to examine the presence of such antibodies in patients with dysmotility not subjected to GnRH treatment and study the anti-GnRH antibody effect on enteric neurons viability in vitro. Methods: Plasma and sera from 3 patients suffering from either enteric dysmotility, irritable bowel syndrome (IBS) or gastroparesis were analysed for C-reactive protein (CRP), and for GnRH antibodies and soluble CD40 by ELISA methods. Primary cultures of small intestinal myenteric neurons were prepared from rats. Neuronal survival was determined after the addition of sera either from the patients with dysmotility, from healthy blood donors, antiserum raised against GnRH or the GnRH analogue buserelin. Only for case 1 a full-thickness bowel wall biopsy was available for immunohistochemical analysis. Results: All 3 patients expressed antibodies against GnRH. The antibody titer correlated to the levels of CD40 (r(s) = 1.000, p < 0.01), but not to CRP. Serum from case 3 with highest anti-GnRH antibody titer, and serum concentrations of sCD40 and CRP, when added to cultured rat myenteric neurons caused remarkable cell death. In contrast, serum from cases 1 and 2 having lower anti-GnRH antibody titer and lower sCD40 levels had no significant effect. Importantly, commercial antibodies against GnRH showed no effect on neuron viability whereas buserelin exerted a protective effect. The full-thickness biopsy from the bowel wall of case 1 showed ganglioneuritis and decrease of GnRH and GnRH receptor. Conclusion: Autoantibodies against GnRH can be detected independently on treatment of GnRH analogue. Whether the generation of the antibody is directly linked to neuron degeneration and chronic gastrointestinal symptoms in patients with intestinal dysmotility, remains to be answered

Suboptimal management of severe menopausal symptoms by Nigerian Gynaecologists: a call for mandatory continuing medical education for physicians

<p>Abstract</p> <p>Background</p> <p>Effective management of menopause is an important way to improve the quality of life of the increasing number of older women. The study sought to find out if Nigerian Gynaecologists offer effective treatment for severe menopausal symptoms.</p> <p>Methods</p> <p>126 Nigerian Gynaecologists representing the six health zones of Nigeria were interviewed to determine the menopausal symptoms they had ever encountered in their practices, frequency of the symptoms, treatments ever offered for severe symptoms including their attitude to, and practice of hormone replacement therapy.</p> <p>Results</p> <p>A Nigerian Gynaecologist encountered an average of one patient with menopausal symptoms every three months (range: 0-3 patients per month). The commoner symptoms they encountered were hot flushes (88%), insomnia (75.4%), depression (58.0%), irritability (56.3%), night sweats (55.6%) and muscle pains (54.8%) while urinary symptoms (16.7%) and fracture (1.6%) were less common. Treatments ever offered for severe symptoms were reassurance (90.5%), anxiolytics (68.3%), analgesics (14.3), HRT (7.9%), Vitamins (4%), Beta-blockers (3.2%) and Danazol (2.4%). These treatments were offered as a matter of institutional traditions rather than being based on any evidence of their efficacy.</p> <p>Conclusion</p> <p>The result revealed that most Nigerian Gynaecologists prefer reassurance and anxiolytics for managing severe menopausal symptoms instead of evidence-based effective therapies. A policy of mandatory continuing medical education for Nigerian physicians is recommended to ensure evidence-based management of gynaecological problems, including menopause.</p

Influence of a Sustained Release Deslorelin Acetate Implant on Reproductive Physiology and Associated Traits in Laying Hens

The aim of this study was to develop an animal model with non-laying hens which would allow for investigation of the relationship between egg production and common diseases in hens. A total of 40 Lohmann Selected Leghorn hens were kept for 20 weeks in a floor housing system in two groups: group “Adult” (21 weeks of age) and group “Juvenile” (14 weeks of age). In each group, 10 hens were administered a 4.7 mg sustained release deslorelin acetate implant subcutaneously; in group “Adult” after, in group “Juvenile” before the onset of lay. In both groups, the remaining hens served as control hens. An examination of each hen was performed weekly, including ultrasonography to check for ovarian follicles, analysis of estradiol-17ß plasma concentration, and assessment of comb size. Digital radiographs of the keel bone were taken in experimental weeks 7 and 15. No follicles were detected on the ovary of treated hens for a certain time period which varied between individuals (between 8 weeks and until the end of the experiment). Estradiol-17ß concentrations were significantly higher in control hens. The comb was significantly smaller in treated hens. A lower prevalence of keel bone damage (group “Adult”) and foot pad dermatitis (FPD) (both groups) was found in treated compared to control hens. These results show that a model with laying and non-laying hens can be achieved by administering a deslorelin acetate implant. Furthermore, they indicate a relationship between egg production and keel bone damage as well as FPD

Generation of Immortal Cell Lines from the Adult Pituitary: Role of cAMP on Differentiation of SOX2-Expressing Progenitor Cells to Mature Gonadotropes

The pituitary is a complex endocrine tissue composed of a number of unique cell types distinguished by the expression and secretion of specific hormones, which in turn control critical components of overall physiology. The basic function of these cells is understood; however, the molecular events involved in their hormonal regulation are not yet fully defined. While previously established cell lines have provided much insight into these regulatory mechanisms, the availability of representative cell lines from each cell lineage is limited, and currently none are derived from adult pituitary. We have therefore used retroviral transfer of SV40 T-antigen to mass immortalize primary pituitary cell culture from an adult mouse. We have generated 19 mixed cell cultures that contain cells from pituitary cell lineages, as determined by RT-PCR analysis and immunocytochemistry for specific hormones. Some lines expressed markers associated with multipotent adult progenitor cells or transit-amplifying cells, including SOX2, nestin, S100, and SOX9. The progenitor lines were exposed to an adenylate cyclase activator, forskolin, over 7 days and were induced to differentiate to a more mature gonadotrope cell, expressing significant levels of α-subunit, LHβ, and FSHβ mRNAs. Additionally, clonal populations of differentiated gonadotropes were exposed to 30 nM gonadotropin-releasing hormone and responded appropriately with a significant increase in α-subunit and LHβ transcription. Further, exposure of the lines to a pulse paradigm of GnRH, in combination with 17β-estradiol and dexamethasone, significantly increased GnRH receptor mRNA levels. This array of adult-derived pituitary cell models will be valuable for both studies of progenitor cell characteristics and modulation, and the molecular analysis of individual pituitary cell lineages

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future