The possible use of anti-androgens in HPTA restoration
- 08-30-2007, 09:06 AM
The possible use of anti-androgens in HPTA restoration
I posted about this below but got no response...but if someone could just follow this logic and answer this one question for me...
Assuming the following about hypogonadotropic hypogonadism, in cases in which a "jumpstart" is called for:
a) The hypothalamus is the primary source of dysfunction.
b) negative feedback in the hypothalamus is directly related to estrogen and DHT levels.
c) decreasing negative feedback by effectively reducing the influence of estrogen is the mechanism by which SERMS have been effective in the past.
If these three points are in fact correct, could we not conclude that by also attempting to reduce DHT in the brain, we could also achieve an effective jumpstart? Perhaps we could even enhance current jumpstart protocols so as to increase the success rate of HPTA restoration?
- 08-30-2007, 10:05 PM
i think this has a foundation for discussion. if you could decrease the amount of feedback to the hypothalamus there might be the possibility of a jumpstart. or if the amount of receptors in the hypothalamus could be blocked/shutdown. everyone throw in some ideas, we might find something here.
08-31-2007, 04:26 PM
Bearing in mind that I know next to nothing about this stuff, I do remember from some of the hairloss forums that some people stopped taking dutasteride because of brain fog.
My recollection is that dutasteride affected a different type of DHT receptor (?)(type one vs. type 2, I think) in the brain, so for your purposes, dutasteride might be the drug of choice.
That said, I also recollect that dutasteride has a MUCH longer half life than finasteride (weeks vs days).
08-31-2007, 05:23 PM
09-02-2007, 11:19 AM
here are a few articles i have found, while not exactly pertaining to males, it is interesting.
Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat.
Roa J, Vigo E, Castellano JM, Navarro VM, Fernández-Fernández R, Casanueva FF, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M.
Department of Cell Biology, Physiology and Immunology, Faculty of Medicine, University of Córdoba, 14004 Córdoba, Spain.
Kisspeptins, products of the KiSS-1 gene with ability to bind G protein-coupled receptor 54 (GPR54), have been recently identified as major gatekeepers of reproductive function with ability to potently activate the GnRH/LH axis. Yet, despite the diversity of functional states of the female gonadotropic axis, pharmacological characterization of this effect has been mostly conducted in pubertal animals or adult male rodents, whereas similar studies have not been thoroughly conducted in the adult female. In this work, we evaluated maximal LH and FSH secretory responses to kisspeptin-10, as well as changes in sensitivity and hypothalamic expression of KiSS-1 and GPR54 genes, in different physiological and experimental models in the adult female rat. Kisspeptin-10 (1 nmol, intracerebroventricular) was able to elicit robust LH bursts at all phases of the estrous cycle, with maximal responses at estrus; yet, in diestrus LH, responses to kisspeptin were detected at doses as low as 0.1 pmol. In contrast, high doses of kisspeptin only stimulated FSH secretion at diestrus. Removal of ovarian sex steroids did not blunt the ability of kisspeptin to further elicit stimulated LH and FSH secretion, but restoration of maximal responses required replacement with estradiol and progesterone. Finally, despite suppressed basal levels, LH and FSH secretory responses to kisspeptin were preserved in pregnant and lactating females, although the magnitude of LH bursts and the sensitivity to kisspeptin were much higher in pregnant dams. Interestingly, hypothalamic KiSS-1 gene expression significantly increased during pregnancy, whereas GPR54 mRNA levels remained unaltered. In summary, our current data document for the first time the changes in hypothalamic expression of KiSS-1 system and the gonadotropic effects (maximal responses and sensitivity) of kisspeptin in different functional states of the female reproductive axis. The present data may pose interesting implications in light of the potential therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis in the female.
PMID: 16527840 [PubMed - indexed for MEDLINE]
Novel Role of the Anorexigenic Peptide Neuromedin U in the Control of LH Secretion and its Regulation by Gonadal Hormones and Photoperiod.
Vigo E, Roa J, Pineda R, Castellano JM, Navarro VM, Aguilar E, Pinilla L, Tena-Sempere M.
Physiology Section, University of Cordoba, Cordoba, Spain.
Neuromedin U (NMU) is a widely spread neuropeptide, with predominant expression at the gastrointestinal tract and brain, putatively involved in the regulation of a diversity of biological functions, including food intake, energy balance and circadian rhythms; all closely related to reproduction. Yet, the implication of NMU in the control of the gonadotropic axis remains scarcely studied. We report herein analyses on the hypothalamic expression and function of NMU in different physiological and experimental states of rat reproductive system. Expression of NMU mRNA at the hypothalamus was persistently detected along female postnatal development, with maximum levels in adulthood that fluctuated across the cycle and were modulated by ovarian steroids. Acute central administration of NMU evoked increases of serum LH levels in pubertal female rats, while repeated injection of NMU tended to advance vaginal opening. Likewise, central injection of NMU increased serum LH concentrations in cyclic female rats, with peak responses in estrus. In contrast, NMU significantly inhibited pre-elevated LH secretion in gonadectomized and kisspeptin-treated rats. Finally, in acyclic females due to photoperiodic manipulation (constant light), hypothalamic NMU mRNA levels were markedly depressed but relative LH responses to exogenous NMU were significantly augmented. Altogether, our present data support a predominant stimulatory role of NMU in the control of the female gonadotropic axis, which appears under the influence of developmental, hormonal and photoperiodic cues, and might contribute to the joint regulation of energy balance, biological rhythms and reproduction. Key words: Neuromedin U (NMU), Luteinizing hormone (LH), Neuromedin S (NMS), Estrus cycle, Female rat.
PMID: 17726140 [PubMed - as supplied by publisher]
Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats.
Tovar S, Vázquez MJ, Navarro VM, Fernández-Fernández R, Castellano JM, Vigo E, Roa J, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M.
Department of Physiology, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain.
The ability of kisspeptins, ligands of the G protein-coupled receptor 54, to potently elicit LH secretion is now undisputed. Yet, most of the pharmacological characterization of their gonadotropin-releasing effects has been conducted after intracerebral administration. In contrast, the effects of peripheral injection of kisspeptin remains less well defined. In this study, dynamic LH secretory responses to iv administration of kisspeptin-10 in different experimental settings are presented, and compared with those evoked by kisspeptin-52, using a protocol of serial blood sampling in conscious, freely moving male rats. LH responsiveness to peripheral administration of kisspeptin appeared extremely sensitive, as doses as low as 0.3 nmol/kg (0.1 microg/rat) evoked robust LH bursts, the magnitude of which was dose-dependent and apparently maximal in response to 3.0 and 30 nmol/kg kisspeptin-10. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved, whereas basal and depolarization-induced GnRH release ex vivo was significantly enhanced. Finally, iv administration of kisspeptin-52 elicited dynamic LH responses analogous to that of kisspeptin-10; yet, their net magnitude and duration was slightly greater. In summary, we present in this study a series of experiments on the effects of systemic (iv) injection of single or repeated doses of kisspeptin upon dynamic LH secretion in conscious male rats. Aside from potential physiologic relevance, our present data might contribute to setting the basis for the rational therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis.
PMID: 16513831 [PubMed - indexed for MEDLINE]
Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM.
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
To further study the role of GPR54 signaling in the onset of primate puberty, we used the monkey to examine the ability of kisspeptin-10 to elicit the release of gonadotropin-releasing hormone (GnRH) precociously, and we describe the expression of GPR54 and KiSS-1 in the hypothalamus during the peripubertal period. Agonadal juvenile male monkeys were implanted with a lateral cerebroventricular cannula and a jugular vein catheter. The responsiveness of the juvenile pituitary to endogenous GnRH release was heightened with a chronic pulsatile i.v. infusion of synthetic GnRH before kisspeptin-10 (112-121) injection. Intracerebroventricular (30 microg or 100 microg) or i.v. (100 microg) bolus injections of kisspeptin-10 elicited a robust GnRH discharge, as reflected by luteinizing hormone secretion, which was abolished by pretreatment with a GnRH-receptor antagonist. RNA was isolated from the hypothalamus of agonadal males before (juvenile) and after (pubertal) the pubertal resurgence of pulsatile GnRH release and from juvenile, early pubertal, and midpubertal ovary-intact females. KiSS-1 mRNA levels detected by real-time PCR increased with puberty in both male and female monkeys. In intact females, but not in agonadal males, GPR54 mRNA levels in the hypothalamus increased approximately 3-fold from the juvenile to midpubertal stage. Hybridization histochemistry indicated robust KiSS-1 and GPR54 mRNA expression in the region of the arcuate nucleus. These findings are consistent with the hypothesis that GPR54 signaling by its cognate ligand in the primate hypothalamus may be activated at the end of the juvenile phase of development and may contribute to the pubertal resurgence of pulsatile GnRH release, the central drive for puberty.
Pubertal impairment in Nhlh2"null" mice is associated with hypothalamic and pituitary deficiencies.
Cogliati T, Delgado-Romero P, Norwitz ER, Guduric-Fuchs J, Kaiser UB, Wray S, Kirsch IR.
Genetics Branch, Center for Cancer Research, National Cancer Institute (T.C., P.D-R., I.R.K.), and Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (S.W.), National Institutes of Health, Bethesda, Maryland 20889; Departments of Obstetrics, Gynecology, and Reproductive Biology (E.R.N.) and Medicine (U.B.K.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Centre for Vision Science, Queen's University Belfast, School of Biomedical Sciences, Belfast, UK, BT12 6BA (J.G).
Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2(-/-)) are unclear. Here we show that hypothalamic gonadotropin-releasing hormone-1 (GnRH-1) content is reduced in adult Nhlh2(-/-) mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions. This reduction was detected postnatally after normal migration of GnRH-1 neurons within nasal regions had occurred. Phenotype rescue experiments showed that female Nhlh2(-/-) mice were responsive to estrogen treatment. In contrast, puberty could not be primed in female Nhlh2(-/-) mice with a GnRH-1 regimen. The adenohypophysis of Nhlh2(-/-) mice was hypoplastic although it contained a full complement of the five anterior pituitary cell types. GnRH-1 receptors (GnRHRs) were reduced in Nhlh2(-/-) pituitary gonadotropes as compared to wild type. In vitro assays indicated that Nhlh2 expression is regulated in parallel with GnRHR expression. However, direct transcriptional activity of Nhlh2 on the GnRHR promoter was not found. These results indicate that Nhlh2 plays a role in the development and functional maintenance of the hypothalamic-pituitary-gonadal axis at least at two levels: 1) in the hypothalamus by regulating the number and distribution of GnRH-1 neurons and, 2) in the developing and mature adenohypophysis.
PMID: 17717072 [PubMed - as supplied by publisher]
A Role for Androgens in Regulating Circadian Behavior and the Suprachiasmatic Nucleus.
Karatsoreos IN, Wang A, Sasanian J, Silver R.
Dept. of Psychology, Columbia University; Dept. of Psychology Barnard College, New York, NY, 10027; Dept. of Anatomy and Cell Biology, Columbia University, New York, NY, 10032.
The suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock controlling behavioral and physiological rhythms, including rhythmic secretion of gonadal hormones. Gonadectomy (GDX) results in marked alteration of circadian behaviors, including lengthened free-running period, decreased precision of daily onset of running, and elimination of early evening but not late night activity bouts. Androgen replacement restores these responses. These aspects of rhythmicity are thought to be regulated by the brain clock, though the site of androgen action remains unknown. Anatomically, the rodent SCN is composed of a ventrolateral "core" and a dorsomedial "shell", and the present studies show that androgen receptors (AR) are localized to the ventrolateral core SCN. Using a transgenic mouse bearing dual reporter molecules driven by the AR targeted to both membrane and nucleus, we find that projections of AR-containing cells form a dense plexus in the core, with their fibers appearing to exit the SCN dorsally. In a second transgenic strain, in which the retinorecipient gastrin-releasing peptide (GRP) cells express a green-fluorescent protein reporter, we show that GRP cells contain AR. Through immunocytochemistry, we also show that SCN AR cells express FOS following a light pulse. Importantly, GDX reduces the FOS response following a phase shifting light pulse, while androgen replacement restores levels to those in intact animals. Taken together, the results support previous findings of a hypothalamic neuroendocrine feedback loop. As such, the SCN regulates circadian rhythms in gonadal hormone secretion and in turn, androgens act on their receptors within the SCN to alter circadian function.
PMID: 17702841 [PubMed - as supplied by publisher]
Androgen receptor auto-regulates its expression by a negative feedback loop through upregulation of IFI16 protein.
Alimirah F, Chen J, Xin H, Choubey D.
Department of Radiation Oncology, Loyola University Chicago and Edward Hines Jr. VA Hospital, 5th Avenue and Roosevelt Road, Building #1, Mail Code 114B, Hines, IL 60141, USA.
Expression of androgen receptor (AR) in prostate epithelial cells is thought to regulate cell proliferation, differentiation, and survival. However, the molecular mechanisms remain unclear. We report that re-expression of AR in PC-3 human prostate cancer cell line resulted in upregulation of IFI16 protein, a negative regulator of cell growth. We found that the IFI16 protein bound to AR in a ligand-dependent manner and the DNA-binding domain (DBD) of the AR was sufficient to bind IFI16. Furthermore, re-expression of IFI16 protein in LNCaP prostate cancer cells, which do not express IFI16 protein, resulted in downregulation of AR expression and an inhibition of the expression of AR target genes. Our observations identify a role for IFI16 protein in AR-mediated functions.
Androgenic up-regulation of androgen receptor cDNA expression in androgen-independent prostate cancer cells.
Dai JL, Maiorino CA, Gkonos PJ, Burnstein KL.
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, FL 33101, USA.
The expression of the androgen receptor (AR) gene is regulated by androgens. Although androgens down-regulate AR mRNA in most cell lines and tissues, including the prostate, up-regulation occurs in some tissues. Androgen-mediated reduction in AR mRNA is reproduced in COS1 cells and in the androgen-sensitive human prostate cancer cell line LNCaP when each expresses the AR cDNA. We have previously established that the AR cDNA contains the requisite sequences for this down-regulation. Here we shown that androgen promoted up-regulation of AR mRNA in two androgen-independent human prostate cancer cell lines, PC3 and DU145, when each was transfected with a human AR cDNA. This effect was due to the AR cDNA and not to the heterologous promoter driving AR expression. In addition to up-regulation of AR mRNA, androgen induced comparable increases in AR protein levels in PC3 cells stably expressing an AR cDNA (PC3/AR). Up-regulation of AR in PC3/AR cells was accompanied by failure of these cells to undergo desensitization or inactivation of AR following prolonged (96 h) androgen administration, whereas the same conditions resulted in desensitization of AR transactivation in LNCaP cells and in CVl cells that stably express the AR cDNA. Androgen treatment of PC3/AR cells resulted in induction of an androgen-regulated reporter gene (MMTV-CAT) as well as the native prostate-specific antigen gene, which is silent in untransfected PC3 but is androgen up-regulated in LNCaP and in the prostate. These results suggest that ectopic expression of AR in androgen-independent prostate cancer cell lines establishes both typical and atypical androgenic responses in a target gene-specific manner. Androgenic up-regulation of AR cDNA expression may be due to distinct signaling mechanisms that influence androgen action in androgen-independent prostate cancer cells.
PMID: 8883219 [PubMed - indexed for MEDLINE]
09-03-2007, 06:45 PM
Ideal way to correct andropause
www.ultimatemedicalresearch.com read the several articles in this section on testosterone and Estrogen. Also go to the audio section to listen to the recorded conferences with doctors on these subjects. Then go to UMR in the media for articles published in Planet muscle. last take the wellness survey to find out what you are deficient in according the work of Theirry Hertoghe, Nick Delgado and Ron Rothenberg MD.
09-03-2007, 10:02 PM
Last Thursday I went to Quest and had a blood draw.
I will have results in couple weeks.
I woke up, drank glass of water and went strait to the lab.
It was a day when I do my T&hcg shots and I also take LiquiDex (Arimidex) at the same time, all E3D schedule.
I did all that after I came back from lab.
If you have a time please put the ideal numbers next to all (or as many as you wish) tests I had.
I did tested following:
C-reactive protein CRP
Lipoprotein (A) Lp(A)
Estradiol, Free, LC/MS/MS (36169X)
Estradiol, Free (Males (Adult): < or = 0.45 pg/mL )
Estradiol (Males (Adult): < or = 29 pg/mL)
Estrogens, Fractionated, LC/MS/MS (36742X)
968-2**Estradiol, Ultrasensitive, LC/MS/MS
Estrogen, Total, Serum (439X)
Testosterone, Free, Bio/Total (LC/MS/MS)
Testosterone Total (included in T panel)
Testosterone Free(included in T panel)
Testosterone Bioavailable(included in T panel)
SHBG(included in T panel)
Albumin, serum(included in T panel)
Dihydrotestosterone, Free, Serum (36168X)
Dihydrotestosterone ng/dL (ADULT MALES: 25-75 )
DIHYDROTESTOSTERONE, FREE (DHT, Free pg/mL ADULT MALES: 1.00-6.20 )
I will do my 2, 16 & 4 at different lab latter.
09-04-2007, 11:11 AM
I posted my blood labs a few days ago and this is essentially what I have found. (note that I am not TRT)
Bloodwork Results Are In! Help!
TEST, TOTAL.....342.....(400 - 1080 ng/dL) LOW
ESTRADIOL.....35.....(0 - 52 pg/mL)
DHT.....565.6.....(155 - 553 pg/mL) HIGH
So if I understand your theory correctly, you believe that by reducing estrogen to somewhere between 10 - 30 pg/mL (via anastrozole/AI), you would expect total testosterone to increase and DHT to decrease?
What makes this all the more interesting to me is the fact that in some of the hair loss forums, a number of people have said that arimidex helped their hairloss. I wonder if the mechanism is via lowering DHT the same intended effect as finasteride.
09-04-2007, 11:55 AM
I think in your considerations you are missing large part of his statement:
"We men need DHT. The solution is to decrease the estrones (especially the 16aOHE) and estadiol bring to mid range say under 30, not above 40. and not below 10. "
Most/many of us, including me, are missing this test.
Genova Diagnostics EstroEssence
Thas is 11 (eleven numbers that we usually know nothing about)
Knowledge gain by that test could guide dosing of
to name some.
09-04-2007, 05:38 PM
www.ultimatemedicalresearch.com ) that is to not say that AI will help or hurt, i just know that the enzyme pathways must be corrected with the diet, the supplements with the right concentrations (DIM IC3 etc), balancing of hormones etc. The problem when you present the numbers for lab, without also answering clinical symptoms to match up, it is like shooting in the dark. that is why we also encourage you to take the free wellness survey at the site mentioned as well to tie it all in. In a prior book we published all the expected ideallys for lab, yet each lab has different ranges and nomenclature. So please dont ask me to go line by line for your lab values for these reasons. I believe some of the early copies of my books can still be obtained on ebay as we are long ago all sold out. Early titles with this info would be #1 way to Fitness, Grow Young and Slim, and Healthy Aging Breakthrough by Nick Delgado PhD
We still have in stock "How to look great and Feel Sexy" listed under weight Loss section of products-$30 and "Mastering the Powers of your Inner Health"- by phone request $10 at 866-319-0566 yet these books dont have the lab values, but they do have the recipes and guidance to follow the Delgado Protocols which took us over 12 years to perfect.
Im not trying to be commercial here we are just directing you to the best sources to get this info, as to my knowledge Dr Ron Klatz stated it best, no other reference books have published the ideal ranges except ours. A few clinical companies for the sack of their clients have listed an optimum or ideal range above the usual reference range on the printed lab reports. The problem is many other labs have asked me to establish what ideals would be, yet when i asked them to provide me the range for those healthy individuals age 22 to 28 the labs haven't responded, and i cant do there work for them.
09-04-2007, 05:44 PM
www.ultimatemedicalresearch.com and read the book Hormone Solution by Theirry Hertoghe as well to tie it all in. In a prior book we published all the expected ideallys for lab, yet each lab has different ranges and nomenclature. So please dont ask me to go line by line for your lab values for these reasons.
Yes it is a great idea to followup and get your downstream metabolite levels (We have the most experience with urine lab values from Rhein lab of Oregon, yet Genova has a blood test to get the 2 and 16 ratios, we used a few times, also some of the research was published using blood values. A snap shoot with blood can help, and the urine adds the full load during 24 hours.
09-04-2007, 07:16 PM
[ame="http://www.amazon.com/gp/offer-listing/1400080851/104-3141280-6068716"]Amazon.com: Used and New: The Hormone Solution: Stay Younger Longer with Natural Hormone and Nutrition Therapies[/ame]
The Hormone Solution: Stay Younger Longer with Natural Hormone and Nutrition Therapies (Paperback)
by Thierry Dr Hertoghe (Author)
09-05-2007, 03:27 PM
09-06-2007, 12:36 PM
Last edited by DrDelgado; 09-06-2007 at 12:40 PM. Reason: typo
09-06-2007, 01:02 PM
How many times do you have to leak per day (i.e. do you have to go back and forth to the lab for a day to get a numebr of samples)?
Do you take the samples at home?
How much does the urine testing cost?
09-06-2007, 02:19 PM
Yes, we have the oncology panel and stuff like SHBG that can't be measured by urines, and thats fine. Lets grab that up with bloods.
But for the rest, its urines, by a landslide.
09-06-2007, 02:49 PM
with ADL lab we can send the test kit with invoice, this is a comprehensive test of nuerotransmitters and all key hormones the test is around $850.
With Rhein consulting you have to have the ordering doctor and test hormones (estrogen, testosterone, DHEA, cortisol) around $225, plus $75 for Thyroid.
09-06-2007, 03:39 PM
Do you have opinion on
Genova Diagnostics, former Great Smokies Diagnostic Laboratory
New name - same great company
GDX Endocrinology Laboratory Assessments
Reviewing their website I find many fascinating panels, logically compiled with powerful presentation of their reports.
Is there any particular shortcoming one would face when using their services?
I find two of their panels particularly interesting (but I think they could be had as a one set)
Hormonal Health Assessment
09-07-2007, 07:50 PM
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