GnRH

[jhov]

Hi bros,

I have a question on GnRH. It is basically a large ''pre-hormone'' which is synthesized in the arcuate nucleus and other nuclei of the hypothalamus. It is then transported via the hypophyseal portal capillaries to the gonadotrophs of the anterior pituitary gland. It is then ''metabolised'' and some subunits are added in specific pulsating actions as to influence the development/formation into into LH or FSH and further modification and physiological action!

It however is also synthesized in the breast and I was wondering if the exact physiological role of it in the breast was clear and if anyone had references for their hypothesis. I have to write a paper on breast cancer and the role the endocrine system plays in the development thereof!

Any and all help is appreciated, thanks!:)
peace
J

[buddha]

J,

Pubmed returns over 700 articles searching for "GnRH breast." It looks like GnRH could be used in preventing tumorous growths.

Curr Med Chem Anti-Canc Agents. 2003 Nov;3(6):399-410. Related Articles, Links

GnRH agonists and antagonists in cancer therapy.

Chengalvala MV, Pelletier JC, Kopf GS.

Women-s Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. chengam@wyeth.com

Gonadotropin releasing hormone (GnRH) is a hypothalamic decapeptide that binds to GnRH receptors on pituitary gonadotrope cells to modulate the synthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins in turn regulate gonadal steroidogenesis and gametogenesis. Chemical characterization and structure-activity analysis of GnRH variants containing systematic amino acid substitutions led to the discovery of GnRH superagonists and antagonists. These peptides are widely used for the treatment of clinical conditions in which modulation of or interference with sex hormone production is beneficial to prevent development or progression of benign conditions (e.g. endometriosis, uterine fibroids) or malignant tumors (e.g. breast, ovarian, endometrial and prostate carcinoma). When compared to native GnRH, GnRH superagonists have increased potency for the short-term release of gonadotropins. However, they show paradoxical action in that chronic treatment with superagonists results in inhibition of gonadotropin production as a result of desensitization of the gonadotropes and down regulation of its receptor. In contrast, GnRH antagonists produce a rapid and dose-dependent suppression of gonadotropin release by competitive blockade of the GnRH receptors without any initial stimulatory effect as seen with superagonists. In recent years, a search for peptidomimetic compounds to replace peptides as therapeutic agents has been undertaken to find compounds with higher affinity for the GnRH receptor but do not have the disadvantages of peptides. Such efforts have resulted in the identification and development of small-molecule non-peptide compounds that are sufficiently stable in vivo and possess favorable pharmacological parameters comparable to peptide antagonists. Some of these compounds are being tested in human volunteers and the preliminary results are very encouraging.

J Med Chem. 2003 Sep 11;46(19):3965-74

Receptor-mediated targeting of a photosensitizer by its conjugation to gonadotropin-releasing hormone analogues.

Rahimipour S, Ben-Aroya N, Ziv K, Chen A, Fridkin M, Koch Y.

Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.

Photodynamic therapy uses a combination of light, oxygen, and a photosensitizer to induce the death of malignant cells. To improve the selectivity of a photosensitizer toward cancerous cells that express gonadotropin-releasing hormone (GnRH) receptors, protoporphyrin IX (PpIX) was conjugated to a GnRH agonist, [d-Lys6]GnRH, or to a GnRH antagonist, [d-pGlu1, d-Phe2, d-Trp3, d-Lys6]GnRH. The condensation of the peptide with PpIX was carried out in a homogeneous solution using benzotriazole-1-yloxytris(pyrrolidinophosphonium) hexafluorophosphate as a coupling reagent. Although these conjugates had lower binding affinity to rat pituitary GnRH receptors than their parent analogues, they fully preserved their agonistic or antagonistic activity in vitro and in vivo. The GnRH agonist conjugate proved to be long-acting in vivo. Thus, 24 h after its administration to rats (2 nmol/rat), serum LH concentrations were significantly higher than in rats treated with the same amount of the parent peptide. The conjugates, notably the agonist, were more phototoxic toward pituitary gonadotrope alphaT3-1 cell line than was unconjugated PpIX. In contrast to PpIX, the phototoxicity of the conjugates toward alphaT3-1 cells or to human breast cancer cells (MCF-7 cells that were transfected with human GnRH receptors) was alleviated by co-incubation with the parent peptide, indicating that phototoxicity is receptor-mediated. The selectivity of the GnRH antagonist conjugate to gonadotrope cells in a primary pituitary culture was approximately 10 times higher than that of the unconjugated PpIX. Thus, GnRH-based conjugates may affect cancer cells not only by acting as classic GnRH analogues to reduce the plasma levels of steroids by desensitization of the pituitary gland but also by selective photodamage of cells that express GnRH receptors.

Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9348-53. Epub 2003 Jul 23. Related Articles, Links

Regulation of gonadotropin gene expression by Mullerian inhibiting substance.

Bedecarrats GY, O'Neill FH, Norwitz ER, Kaiser UB, Teixeira J.

Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

In addition to its role in causing Mullerian duct regression, Mullerian inhibiting substance (MIS) is implicated in the regulation of steroidogenesis, breast and prostate growth, and ovarian follicle recruitment, all of which are processes controlled or influenced by the hypothalamic-pituitary-gonadal axis. Whereas the direct effect of MIS on gonadal, prostate, and breast cells is under investigation, the ability of MIS to modulate pituitary function, thereby affecting those tissues indirectly, has not yet been studied. Using LbetaT2 cells, a murine gonadotrope-derived cell line, we have evaluated the effects of MIS on the expression of the gonadotropin genes. We show that both LbetaT2 cells and adult rat pituitaries express MIS type II receptor (MISRII) mRNA. Within 2 h, follicle-stimulating hormone beta subunit (FSHbeta) mRNA levels are significantly induced by addition of MIS to LbetaT2 cells and remain elevated through 8 h of treatment. Transcriptional activation of both the FSHbeta and luteinizing hormone beta subunit (LHbeta) gene promoters was observed by MIS, which enhances the effect of gonadotropin-releasing hormone (GnRH) agonist on the FSHbeta gene promoter and synergizes with the GnRH agonist to stimulate LHbeta gene promoter activity. Addition of MIS to LbetaT2 cells stimulates the activity of the rat LHbeta gene promoter with as little as 1 microg/ml and in a dose-dependent manner. These studies report both MISRII expression in rat pituitary cells and a gonadotrope-derived cell line and MIS-mediated activation of LHbeta and FSHbeta gene expression, and suggest that MIS may modulate the hypothalamic-pituitary-gonadal axis at more than one level.

[jhov]

Originally posted by buddha
J,

Pubmed returns over 700 articles searching for "GnRH breast." It looks like GnRH could be used in preventing tumorous growths.

Curr Med Chem Anti-Canc Agents. 2003 Nov;3(6):399-410. Related Articles, Links

GnRH agonists and antagonists in cancer therapy.

Chengalvala MV, Pelletier JC, Kopf GS.

Women-s Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. chengam@wyeth.com

Gonadotropin releasing hormone (GnRH) is a hypothalamic decapeptide that binds to GnRH receptors on pituitary gonadotrope cells to modulate the synthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins in turn regulate gonadal steroidogenesis and gametogenesis. Chemical characterization and structure-activity analysis of GnRH variants containing systematic amino acid substitutions led to the discovery of GnRH superagonists and antagonists. These peptides are widely used for the treatment of clinical conditions in which modulation of or interference with sex hormone production is beneficial to prevent development or progression of benign conditions (e.g. endometriosis, uterine fibroids) or malignant tumors (e.g. breast, ovarian, endometrial and prostate carcinoma). When compared to native GnRH, GnRH superagonists have increased potency for the short-term release of gonadotropins. However, they show paradoxical action in that chronic treatment with superagonists results in inhibition of gonadotropin production as a result of desensitization of the gonadotropes and down regulation of its receptor. In contrast, GnRH antagonists produce a rapid and dose-dependent suppression of gonadotropin release by competitive blockade of the GnRH receptors without any initial stimulatory effect as seen with superagonists. In recent years, a search for peptidomimetic compounds to replace peptides as therapeutic agents has been undertaken to find compounds with higher affinity for the GnRH receptor but do not have the disadvantages of peptides. Such efforts have resulted in the identification and development of small-molecule non-peptide compounds that are sufficiently stable in vivo and possess favorable pharmacological parameters comparable to peptide antagonists. Some of these compounds are being tested in human volunteers and the preliminary results are very encouraging.

J Med Chem. 2003 Sep 11;46(19):3965-74

Receptor-mediated targeting of a photosensitizer by its conjugation to gonadotropin-releasing hormone analogues.

Rahimipour S, Ben-Aroya N, Ziv K, Chen A, Fridkin M, Koch Y.

Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.

Photodynamic therapy uses a combination of light, oxygen, and a photosensitizer to induce the death of malignant cells. To improve the selectivity of a photosensitizer toward cancerous cells that express gonadotropin-releasing hormone (GnRH) receptors, protoporphyrin IX (PpIX) was conjugated to a GnRH agonist, [d-Lys6]GnRH, or to a GnRH antagonist, [d-pGlu1, d-Phe2, d-Trp3, d-Lys6]GnRH. The condensation of the peptide with PpIX was carried out in a homogeneous solution using benzotriazole-1-yloxytris(pyrrolidinophosphonium) hexafluorophosphate as a coupling reagent. Although these conjugates had lower binding affinity to rat pituitary GnRH receptors than their parent analogues, they fully preserved their agonistic or antagonistic activity in vitro and in vivo. The GnRH agonist conjugate proved to be long-acting in vivo. Thus, 24 h after its administration to rats (2 nmol/rat), serum LH concentrations were significantly higher than in rats treated with the same amount of the parent peptide. The conjugates, notably the agonist, were more phototoxic toward pituitary gonadotrope alphaT3-1 cell line than was unconjugated PpIX. In contrast to PpIX, the phototoxicity of the conjugates toward alphaT3-1 cells or to human breast cancer cells (MCF-7 cells that were transfected with human GnRH receptors) was alleviated by co-incubation with the parent peptide, indicating that phototoxicity is receptor-mediated. The selectivity of the GnRH antagonist conjugate to gonadotrope cells in a primary pituitary culture was approximately 10 times higher than that of the unconjugated PpIX. Thus, GnRH-based conjugates may affect cancer cells not only by acting as classic GnRH analogues to reduce the plasma levels of steroids by desensitization of the pituitary gland but also by selective photodamage of cells that express GnRH receptors.
I read about 50 so far but I saw how many returns it got as well so I wanted to see if anyone did any specific research on it and what they turned up at all. Thank you for this one though, great info and good looking out bro. THANKS!:)
peace
j

[buddha]

A couple more:

Eur J Cancer. 2003 May;39(7):861-9. Related Articles, Links

The use of gonadotrophin-releasing hormone (GnRH) agonists in early and advanced breast cancer in pre- and perimenopausal women.

Robertson JF, Blamey RW.

Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. john.robertson@nottingham.ac.uk

Gonadotrophin-releasing hormone (GnRH) agonists, in particular goserelin ('Zoladex'), are increasingly being used for the treatment of breast cancer in women with functioning ovaries. They act by downregulating pituitary GnRH receptors, thereby suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH), which, in turn, reduce the main source of oestradiol production in the ovaries. GnRH agonists have been shown to be as effective therapeutically as surgical ovarian ablation in pre- and perimenopausal women with advanced breast cancer. The combination of a GnRH agonist such as goserelin with the peripheral oestrogen antagonist, tamoxifen, may be used to produce 'combined oestrogen blockade'. In advanced breast cancer, this regimen prolongs progression-free survival and increases both the response rate and duration relative to the use of a GnRH agonist alone. In patients with early breast cancer, the addition of goserelin to 'standard treatment' (i.e. surgery+/-tamoxifen, chemotherapy or radiotherapy) results in a significant benefit in recurrence-free survival and overall survival. This benefit was most apparent in patients with oestrogen receptor (ER) +ve tumours. Goserelin, when used either alone or in combination with tamoxifen as an adjuvant systemic therapy in women with ER +ve tumours, has been shown in clinical trials to produce recurrence-free survival rates equivalent to cytotoxic chemotherapy such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Evidence suggests that at least part of the effect of adjuvant cytotoxic chemotherapy in premenopausal women is produced by ovarian ablation. Endocrine therapy with goserelin or goserelin plus tamoxifen should now be considered a treatment option in the management of premenopausal women with ER +ve early breast cancer.

Oncol Rep. 2002 Sep-Oct;9(5):1127-32. Related Articles, Links

Gonadotropin releasing hormone receptor expression in primary breast cancer: comparison of immunohistochemical, radioligand and Western blot analyses.

Mangia A, Tommasi S, Reshkin SJ, Simone G, Stea B, Schittulli F, Paradiso A.

Clinical Experimental Oncology Laboratory, University of Bari, Italy.

GnRH biological effect is mediated through specific GnRH membrane receptors (GnRH-receptor, GnRH-R) that have been demonstrated in human breast cancer by molecular and biochemical techniques. The A9E4 monoclonal antibody (moAb) against the epitope 1-29 of N-terminal of human GnRH-R has been proposed, suggesting the possibility to perform retrospective studies for the confirmation of clinical relevance of this receptor. The aim of the present study was to verify the performance of the A9E4 moAb when utilised for immunohistochemical analysis in 71 formalin-fixed paraffin-embedded breast cancer samples; furthermore, a comparison with results obtained with the radioligand biochemical assay (GnRH-Rbca) and with Western blot has been performed. The A9E4 specificity was preliminarily demonstrated by Western blot analysis in both MCF-7 and T47D breast cancer cell lines. In both cell lines, only a protein of 60-64 kDa was demonstrated in the membrane and nuclear compartments. Immuno-reactivity for A9E4 was detected in the cytoplasm of morphologically normal adjacent glandular epithelia and in tumour cells. Cytoplasmic GnRH-R immuno-staining (GnRH-Rica) was shown in 55% of tumours but only 28% of these had a percentage of positive cells higher than >25%. A correlation between the percentage of positive GnRH-Rica cells and femtomoles of the GnRH-Rbca content was shown (c.c.=0.295, p=0.01). The mean content of GnRH-Rbca in the subgroup of tumours with >25% of cell positive at GnRH-Rica was significantly different with respect to that of negative GnRH-Rica tumours (25 fmol vs 11 fmol, respectively; p=0.03 by t-test). The immunohistochemical analysis of GnRH-R by A9E4 moAb in human breast cancer tissues seems to provide information that correlates with the standard biochemical assay. Retrospective clinical studies with GnRH-Rica on archival samples are strongly suggested to verify the prognostic-predictive relevance of this receptor in human breast cancer.

so what do you do for work?

[jhov]

[i]

so what do you do for work? [/B]
Thanks for the studies bro.
I am Biomedical science student specialising in Physiology, biochemistry and two other yet to be determined subject. I think it will be endocrinology and nutrition/metabolism when I have to make my decision on this known next week though. I have been fortunate enough to do a ''free specialisation'' curriculum so I take a little from everything!

Next to this I do medicine and before that I studied physical therapy and was specialising in exercise physiology and massage therapy in that.

Hopefully I will graduate next year and I want to specialise in cardiovascular surgery in medicine in the future!
peace
J

[NO MERCY]

I plan on learning a lot from you two over here in the new forum

[jhov]

Originally posted by NO MERCY
I plan on learning a lot from you two over here in the new forum
Well I am no fool but also no where near the level of some others on this board. So I think we will learn from everyone who posts rational, thought out scientificly backed ''opinion'' ;) on the issues at hand. It is a huge board and I know many members with the knowledge to put some people to shame and I hope everyone posts and takes advantage of this.:)

As for the original post, I am searching for specific info on endogenous GnRH in the breast tissue and it's physiological effect. I know it seems like I can turn up 700 studies on pubmed but I know basically what it does except for endogenous production in the breast. It is also produced in the placenta AND THAT IS ALSO A GREY AREA! I just got spurned on by a comment an assistant professor made in which he said that the GnRh produced in the breast may actually help cause cancer! This shocked the hell out of me to say the least as I thought it aided in cancer therapy. So GnRH specifically synthesised in the breast guys. Thanks :)
peace
J

[John Benz]

Characterization of binding sites for a GnRH-agonist (buserelin) in human breast cancer biopsies and their distribution in relation to tumor parameters.

Baumann KH, Kiesel L, Kaufmann M, Bastert G, Runnebaum B.Department of Gynaecology and Obstetrics, University of Heidelberg, Germany.

Gonadotropin-releasing hormone analogs (GnRH-A) have been added to the armentarium in the therapy of hormone-dependent breast cancer in premenopausal women. The effect of chronic GnRH-A-treatment in premenopausal women is based on the suppression of the hypothalamus-pituitary-ovarian axis and the reduction of sex-steroid serum levels. In addition, a number of experimental and clinical data have been accumulated indicating a direct action of GnRH-A on breast cancer cells and tissue. In this study we analyzed 235 human breast cancer biopsies for specific GnRH-A-binding. We demonstrate high affinity GnRH-A binding sites in human breast cancer tissues. The evaluation of clinical data showed no correlation of the level of GnRH-A-binding with classical tumor parameters.

[jhov]

Originally posted by John Benz
Characterization of binding sites for a GnRH-agonist (buserelin) in human breast cancer biopsies and their distribution in relation to tumor parameters.

Baumann KH, Kiesel L, Kaufmann M, Bastert G, Runnebaum B.Department of Gynaecology and Obstetrics, University of Heidelberg, Germany.

Gonadotropin-releasing hormone analogs (GnRH-A) have been added to the armentarium in the therapy of hormone-dependent breast cancer in premenopausal women. The effect of chronic GnRH-A-treatment in premenopausal women is based on the suppression of the hypothalamus-pituitary-ovarian axis and the reduction of sex-steroid serum levels. In addition, a number of experimental and clinical data have been accumulated indicating a direct action of GnRH-A on breast cancer cells and tissue. In this study we analyzed 235 human breast cancer biopsies for specific GnRH-A-binding. We demonstrate high affinity GnRH-A binding sites in human breast cancer tissues. The evaluation of clinical data showed no correlation of the level of GnRH-A-binding with classical tumor parameters.
EXELLENT INFO!!! Thank you JohnBenz!:)
peace
J

[x_muscle]

hay guys i revived this thread to ask a question
........i found that some vet pharmacies selling GNRH. and i read some research that GNRH have similar to GH. and sne its way cheaper than gh. what do u think about its application for bodybuilders?


here what i found about it:


Accelerated and Efficacious Results Using Variable Somatotroph Specific and Hypothalamotroph-Specific Poly-Peptide Combinants As An Alternative To Oral Growth Hormone Secretagogues And Recombinant Human Growth Hormone Injections by Rashid A. Buttar,DO, FAAPM, Dean C. Viktora, PhD, Michael E. Quinn, EMT-P.

ABSTRACT

Objective---We conducted a patient outcome based study investigating the possible efficacy of certain natural hypothalamotroph-specific poly-peptide combinants which appear to emulate the action of GHRH resulting in a more efficacious release of endogenous GH.

Background---Although the GH injections and secretatgogues do offer many benefits for the limitations of aging, the need for a safer and more effective modality of therapy has long been warranted.

Methods---35 patients were started on the study with 30 completing the study. The groups were divided into sedentary and athletic groups. A total of 22 subjective criteria were monitored including: sense of well being, overall energy, mental clarity, emotional stability, memory improvement, mood improvement, skin thickness, skin elasticity, wrinkle disappearance, new hair growth, skin texture, healing of old injuries, healing of overall injuries, range of motion, incidence of illness, body contour change, facial contour change, sexual frequency, sexual stamina, libido, quality of erection/ arousal, and change in nocturia. Objective criteria measured were muscle strength, overall energy, exercise endurance and quality of sleep. Changes were recorded by a self-assessment methodology using a scale of -5 to +5 with ) as base line. This accepted modality of evaluation with previous precedent having been set was chosen for this patient outcome based study. Laboratory data consisting of pre- and post-treatment IGF1 levels and base line chemistries were also obtained.

Results---In less than one week, changes experienced were overwhelmingly positive. Improvements were reported of 282.98% in the female subjects and 352.38% in male subjects. Muscle strength increased by 81.0%. Endurance increased by 60%. Quality of sleep improvedby 92.6%. Overall energy increased by 71.4%. Total mean improvement of all 4 objective criteria increased by 76.6%. Interestingly, the 3 week post study IGF-1 levels dropped 20.39% within both athletic and sedentary study groups with a 27.16% drop in IGF-1 levels in the female patients and a 14.61% drop in IGF-1 levels in the male patient population.

Conclusions---Efficacy was far beyond expectation. Objectively measured increases in muscular strength conclusively show this GHRH analog to be clinically superior for resistance training as compared to hGH injections. Simplicity of trans-dermal administration also appears to lead to a greater compliance. Substantial improvements in all criteria are further validation of Trans-D Tropin tm as not only an effective alternative to hGH injections but perhaps a replacement of the more costly, potentially dangerous and less compliant injection treatments. The lack of correlation between clinical improvement and increasing IGF-1 levels also warrants re-evaluation of our currently accepted understanding of IGF-1 levels. The results of this study strongly warrant further clinical research of this GHRH analog

[Big Cat]

I only gave it a cursory glance, so if I missed a passage on gnRH forgive me, but I get the impression you are referring to GHRH, that seems to be what the abstract is about. These are two different hormones.

GnRH or gonadotrophin releasing hormone promotes LH and FSH release from the pituitary.

GHRH or Growth Hormone releasing hormone promotes GH release from the pituitary.