"Opioid Modulation & Potential for Preventing AAS Induced HPTA Suppression"
- 06-26-2007, 05:23 PM
"Opioid Modulation & Potential for Preventing AAS Induced HPTA Suppression"
Anabolic Steroids - MESO-Rx Steroid Profiles, Steroid Pictures, Steroid Books, Bodybuilding
Opioid Modulation & Potential for Preventing anabolic steroids Induced HPTA Suppression
by Eric M. Potratz
Post Cycle Therapy (post cycle therapy) is a key component in a steroid cycle, as suppression of the Hypothalamus, Pituitary, Testicular Axis (HPTA) is seemingly unavoidable to a steroid user. What I will be presenting in this article is a new idea to the world of anabolic steroids users. This exciting new concept addresses the possibility of limiting and possibly preventing suppression of the (HPTA) during cycle. More specifically, we will learn how we can actively modulate the hypothalamus & pituitary pulse generator during cycle and how this can prime our endocrine system for a quicker, smarter, and healthier recovery from anabolic androgenic steroids (AAS).
For a moment, let’s forget the concept of "post cycle therapy", and embrace the idea of "constant cycle therapy" – active therapy throughout a steroid cycle. The HPTA involves a constant biological interplay of responses and feedback loops that can ultimately become shutdown and degraded during exogenous hormone administration. However, research suggests suppression of the hypothalamus and pituitary may be preventable during steroid use. Before we delve into the details, lets first take a quick recap on the HTPA and how it responses to AAS.
HPTA – The basics
When the hypothalamus senses low hormone levels, it secretes gonandotropin releasing hormone (GnRH). This GnRH then travels a short distance to the nearby pituitary gland to stimulate gonadotrope receptors. These, in turn, secrete the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). These gonadotrophins travel all the way down to the testis, to activate their respective leydig and seritoli cells. LH initiates testosterone production via the leydig cell receptor (steroidogenesis), while FSH initiates sperm production via the sertoli cell receptor (spermatogenesis).
AAS’s inhibit hormone production just as endogenous hormones do. Testosterone interacts with the androgen receptor (AR) and estrogen interacts with the estrogen receptor (ER). When these hormones are in high concentration, they cause the hypothalamus to decrease its release of GnRH, which decreases LH and FSH production from the pituitary.1 This cuts off the signal to the testis and halts all hormone production. This process is a daily event for the rhythmic endocrine system. Spikes in LH & FSH are followed by spikes in testosterone, and spikes in testosterone result in a reduction of LH & FSH release until testosterone levels decline and LH & FSH is released again. The caveat with most steroids, is that hormone levels remain chronically high (24/7) and do not allow release of LH or FSH, thus leaving the pituitary and testis in a dormant state for as long as the steroids are administered.
While low-dose on-cycle hCG is a good protocol to mimic LH and keep the testis from atrophy, (to be covered in a future article) it does nothing to prevent pituitary atrophy. We forget that the pituitary is susceptible to the same degradation and atrophy as the testis. That is, when the GnRH secretion from the hypothalamus stops (during a steroid cycle), the pituitary reduces its number of GnRH receptors and becomes less and less responsive to GnRH stimulation as weeks pass.11 This is analogous to atrophy of the testis, during absence of an LH or FSH signal. On the same accord, both the pituitary and testis will decrease receptor concentration during over stimulation as well, as its been found from too much hCG use or too much GnRH stimulation.12,13 The point here, is that only minor stimulus is required for preservation of function and sensitivity. Perhaps a completely neglected and suppressed pituitary may explain the lack of full and prompt recovery for many steroid users, despite adherence to a "tried and true" hCG, Clomid + Nolvadex regimen. So the question is – How can we prevent suppression of the pituitary, and better yet, how can we prevent suppression of the hypothalamus?
A closer look –
In should be mentioned that another mechanism in which AAS inhibit LH and FSH release from the pituitary is by direct suppression upon the pituitary GnRH receptors and consequent quenching of LH & FSH secretion.35,38 However its appears that AAS which bind strictly to the AR, do not exert a direct negative effect on pituitary function or sensitivity.34,37,39 This agrees with the theory that non-aromatizing steroids such as Primobolan, Proviron or Masteron are not nearly as suppressive as an aromatizing AAS’s such as testosterone or Dianabol. Evidence suggests that estradiol is about 200x more suppressive than testosterone on a molar basis37, and that administration of Arimidex can greatly reduce testosterones suppression on GnRH and LH release.42 So, we know anti-estrogens can limit suppression of AAS, but this only solves half the problem.
When it comes to suppression of the hypothalamus, and what seems to be basic endocrinology, we find it is not so simple upon closer examination. There is more than a simple on-off switch for the hypothalamus control center, a lot more. Evidence suggests that there isn’t even a direct AR or ER action upon GnRH release.2-6 That is, steroid hormones do not directly influence GnRH release from the GnRH neurons.7
It was well summarized here by A.J Tilbrook et al,
"It follows, that the actions of testicular steroids on GnRH neurons must be mediated via neuronal systems that are responsive to steroids and influence the activity of GnRH neurons."
And again here by FJ Hayes et al
"It was thus postulated that estrogen-receptive neurons were acting as intermediaries in the non-genomic regulation of GnRH by estrogen"
There is a network of neurogenic intermediaries in the hypothalamus for GnRH release that communicate the inhibitory effects of steroid hormones. More specifically, it is the combined efforts of neuro-active peptides and catecholamines which send the message of "suppression" to the GnRH neurons once activated by steroid hormones.16 These primary messengers are known as a group of neuro-active peptides called endogenous opioid peptides (EOP’s).7,16 The EOP’s consist of the three main peptides -- b-endorphin, dynorphin, and enkephalins, which act upon their respective u-opioid, k-opioid, and s-opioid receptors. It appears that the most influential EOP in GnRH modulation is b-endorphin, acting upon the u-opioid receptor. 8-10 For this reason, b-endorphin will be the main focus of the article, although there are other intermediates involved.
When steroid hormones reach the hypophysial portal, they activate the EOP’s, which suppress GnRH. We know that steroid hormones must communicate with these opioid receptors in order for them to inhibit the release of GnRH from the GnRH neurons, since the GnRH neurons do not have AR or ER receptors. What’s most interesting here is that the suppression on GnRH neurons can actually be intercepted by a u-opioid receptor antagonist – such as naloxone, and the orally active congers naltrexone, and nalmefene.
This is accomplished by blocking the u-opioid receptor and preventing the inhibitory effects of b-endorphin upon the GnRH releasing neuron. It should be noted that this "antagonism" of suppression is not due to antagonism of the AR or ER itself, since u-opioid antagonists to not bind to these hormone receptors.15,32
The effect of a u-opioid receptor antagonist on the HPTA can be seen here --
Essentially, a u-opioid antagonist such as naloxone takes the brakes off of GnRH release and allows pulses of GnRH to occur as if no steroid hormones are present.17 Naloxone, and related u-opioid antagonists have consistently proven to block the suppressive effects of testosterone, DHT, and estrogen administration in both animals and humans.18-25 It also appears that these drugs have the ability to increase pituitary sensitivity to GnRH.26,27
U-opioid antagonists have long been used for treatment of opioid dependence; not only to control cravings of narcotics, but to restore a suppressed endocrine system.28,29 It’s well known that strong opioid based drugs such as methadone, cocaine, heroin and alcohol can suppress GnRH and therefore suppress LH & FSH. It seems that this decease of GnRH is due to the same EOP mechanisms seen with AAS induced suppression.33 In alcoholics, cocaine and heroin users, naltrexone and naloxone have been used to restore LH and testosterone levels.28,29 Naltrexone has even been proposed as a treatment for male impotence and erectile dysfunction.30,31
Naloxone, naltrexone and nalmefene seem progressively more powerful in their potency to dis-inhibit LH release, respectively14,18 Naloxone lacks oral bioavailability therefore injection is required. An injectable preparation could easily be made with BA water due to the water solubility of the compound. A 40mg subcutaneous injection would be a typical dose of naloxone. Naltrexone is orally active, with a safe and effective oral dose being about 100mg for a 220lb male.18 While a lower dose of about 25-50mg of nalmefene would seemingly have the same benefit.20,24 Increasing the dose with either of these drugs will surely increase the likelihood of side-effects without notably increasing the benefit. An every 3rd day protocol would seem appropriate with these drugs, as only to increase GnRH and LH release enough to prevent pituitary and testicular shrinkage – Just enough to keep them in the "ball game". Also, a twice a week dosing protocol would most likely limit the increased opioid sensitivity induced by the long-term use of the drugs.
A word of caution: The opioids antagonists mentioned in this article are recognized as safe and non-toxic at the given dosages, however they can cause severe withdrawal symptoms in opiate users (methadone, morphine, cocaine, and heroin addicts.) Caution is also advised when using opioid antagonists prior to sedation or surgery as they can reduce effectiveness of anesthetics. Temporary nausea, headache or fatigue, are occasional side-effects associated with the use of these drugs. Naltrexone has been reported to heighten liver enzymes, while naloxone and nalmefene do not appear to have this issue. At any rate, a twice a week protocol for 4-16 weeks is unlikely to cause any liver issues that may be associated with naltrexone.
A few point to consider -
For those who choose to embark on a every 3rd day protocol of an opioid antagonist several things should be considered. First, total prevention of HPTA suppression is unlikely in a cycle of 1gm or more per week of AAS. However, by following smart cycling guidelines, suppression will at least be minimized to the point where normal HPTA function could be regained within days of AAS clearance, rather than months. The protocol suggested in this article would at least allow steroid users to limit the usage of classic SERM’s for post cycle therapy, as these drugs can have obvious undesired effects. Several things shall be considered when planning an AAS protocol designed to limit suppression.
It appears that progestin based AAS such as trenbolone and nandrolone which bind not only to the AR, but also to the progesterone receptor (PR) also have a directly suppressive effect on pituitary sensitivity36 (similar to estrogens). It also appears that no opioid receptor antagonist or anti-aromatase can prevent suppression via the PR. Therefore, a multiple gram stack of testosterones and nandrolones is no doubtingly going to completely suppress HTPA function by causing suppression via the ER, AR and PR.40,41 If one hopes for a prompt and full recovery post cycle, perhaps nandrolones are better avoided, or at least not stacked with heavily aromatizing AAS without the concurrent use of a strong AI.
As it was pointed out earlier in this article, estrogen has a markedly stronger effect on suppression of LH release compared to androgens since estrogens suppresses the hypothalamus and pituitary. Usage of an AI such as anastrozole, letrozole, or exemestane (Aromasin) can reduce estrogen and greatly reduce suppression on GnRH, LH and FSH release by preventing excessive ER activation in the hypothalamus and desensitization of the pituitary gonadotropes. 35,37,38 Anastrozole has ~50% maximal total estrogen suppression at 1mg/day. Exemestane has ~50% maximal total estrogen suppression at 25mg/day. While letrozole has ~60% at 1mg/day. These are averages based on compiled data from several studies. Similar estrogen suppression can also been seen from only twice a week administration of these AI’s.43-47
1. Hypothalamic Gonadotropin-Releasing Hormone: Basic and Clinical Aspects. Yen SSC. Raven Press, New York, pp 245–280 (1991)
2. Absence of androgen receptors in LHRH immunoreactive neurons. Huang X, Harlan RE. Brain Res 1993; 624:309–311
3. Augmented hypothalamic proopiomelanocortin gene expression with pubertal development in the male rat: evidence for an androgen receptor-independent action. Kerrigan JR, Martha PM, Krieg RJ, Queen TA, Monahan PE, Rogol AD. Endocrinology.128:1029-1035. (1991)
4. Distribution of estrogen receptorimmunoreactive cells in the preoptic area of the ewe: co-localisation with glutamic acid decarboxylase but not luteinizing hormone-releasing hormone. Herbison AE, Robinson JE, Skinner DC. Neuroendocrinology 1993; 57:751–759.
5. Unmasking the neural progesterone receptor in the preoptic area and hypothalamus of the ewe: no colocalization with gonadotropin-releasing neurons. Skinner DC, Caraty A, Allingham R. Endocrinology 2001; 142:573–579.
6. Multimodal influences of estrogen upon gonadotropin releasing hormone neurons. Herbison AE. Endocrine Reviews 1998; 19:302–330.
7. Negative Feedback Regulation of the Secretion and Actions of Gonadotropin-Releasing Hormone in Males. A.J. Tilbrook and I.J. Clarke. Biol Reprod, Mar 2001; 64: 735
8. Steroid Control of Gonadotropin-Releasing Hormone Secretion: Associated Changes in Pro-Opiomelanocortin and Preproenkephalin Messenger RNA Expression in the Ovine Hypothalamus
James A. Taylor, Marie-Laure Goubillon, Kevin D. Broad, and Jane E. Robinson. Biol Reprod, Mar 2007; 76: 524
9. Do gonadotropin-releasing hormone, tyrosine hydroxylase-, and ß-endorphin-immunoreactive neurons contain oestrogen receptors? A double-label immunocytochemical study in the Suffolk ewe. Lehman MN, Karsch FJ. Endocrinology 1993; 133:887–895
10. -Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release. Alicia G. Faletti, Claudio A. Mastronardi, Alejandro Lomniczi, Adriana Seilicovich, Martha Gimeno, Samuel M. McCann, and Valeria Rettori. PNAS, Feb 1999; 96: 1722.
11. The frequency of gonadotropin-releasing hormone stimulation determines the number of pituitary gonadotropin-releasing hormone receptors. Katt JA, Duncan JA, Herbon L, Barkan A, Marshall JC. Endocrinology. 116:2113–2115. (1985)
12. Exogenous gonadotrophin-releasing hormone (GnRH) stimulates LH secretion in male monkeys (Macaca fascicularis) treated chronically with high doses of a GnRH-antagonist. Weinbauer GF, Hankel P, Nieschlag E. J Endocrinol. 133:439–445. (1992)
13. Chronic administration of the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix decreases gonadotrope responsiveness and pituitary LHRH receptor messenger ribonucleic acid levels in rats. Pinski J, Lamharzi N, Halmos G, et al. 1996. Endocrinology. 137:3430–3436.
14. Acute effects of testosterone infusion and naloxone on luteinizing hormone secretion in normal men.
GB Kletter, CM Foster, IZ Beitins, JC Marshall, and RP Kelch. J. Clin. Endocrinol. Metab., Nov 1992; 75: 1215 - 1219.
15. Naloxone-induced increases in serum luteinizing hormone in the male: mechanisms of action
TJ Cicero, CE Wilcox, RD Bell, and ER Meyer. J. Pharmacol. Exp. Ther., Mar 1980; 212: 573.
16. Endogenous opioids participate in the regulation of the hypothalamic-pituitary-luteinizing hormone axis and testosterone’s negative feedback control of luteinizing hormone. CICERO, T. J., SCHAINKER, B. A. AND MEYER, E. R. Endocrinology 104: 1286-1291, (1979)
17. Opiatergic control of LH secretion is eliminated by gonadectomy. BHANOT, R. AND WILKINSON, M.: Endocrinology 112: 399-401, (1983)
18. Role of endogenous opiates in the expression of negative feedback actions of androgens and estrogen on pulsatile properties of luteinizing-hormone secretion in man. Veldhuis JD, Rogol AD, Samojlik E, Ertel MH. J Clin Invest. 74:47–55 (1984)
19. Counteraction of gonadal steroid inhibition of luteinizing hormone release by naloxone. VAN VUGT, D. A., SYLVESTER, P. W., AYLSWOWRH, D. F. AND MNRRAS J. J. Chro- naloxone. Endocrinology 34: 274-278, 1982
20. Unexpected effects of nalmefene, a new opiate antagonist, on the hypothalamic-pituitary-gonadal axis in the male rat. P Limonta, CW Bardin, EF Hahn, and RB Thau. Steroids, Dec 1985; 46(6): 955-65.
21. In vivo evidence for a direct effect of naloxone on testicular steroidogenesis in the male rat. TJ Cicero, ML Adams, LH O'Connor, and B Nock. Endocrinology, Aug 1989; 125: 957
22. Endogenous opioids participate in the regulation of the hypothalamus- pituitary-luteinizing hormone axis and testosterone's negative feedback control of luteinizing hormone. TJ Cicero, BA Schainker, and ER Meyer. Endocrinology, May 1979; 104: 1286
23. Effect of naloxone on the plasma levels of LH, FSH, prolactin and testosterone in Beetal bucks.
Singh B, Dixit VD, Singh P, Georgie GC, Dixit VP. Department of Animal Production Physiology, CCS Haryana Agricultural University, 125004, Hisar, India
24. Endocrinology: The effect of nalmefene on pulsatile secretion of luteinizing hormone and prolactin in men. G.R. Graves, T.G. Kennedy, R.F. Weick, and R.F. Casper. Hum. Reprod., Oct 1993; 8: 1598 - 1603.
Check out the highlighted items...What are some thoughts?
- 06-26-2007, 05:24 PM
- 06-27-2007, 06:54 PM
Thats very interesting. Has anyone ever tried these drugs?
There is also a comment on wikepedia that makes me think it improves libido as well. Apparently Naltrexone is somewhat liver toxic in high doses though...
06-27-2007, 07:00 PM
07-02-2007, 04:53 AM
This idea has been bumping around on various boards. Okay without getting too much into my life history I would like to say that for one reason that I find particularly awful it is not a good idea.
Naloxone is an opiod agonist. It is generally given to people who overdose on opiates. WHat does it do throw them immediatelly into withdrawl and horrible horrible pain if they are opiate dependent.
However, this does some pretty bad stuff to people not opiate dependent. Actually im sorry it is a slight overstatment. If you take naloxone you will feel awful. I mean you will feel really damn bad. Mix of depression and general sense of malaise. I do not know if this is the case with nlatrexolone but naloxone will cause this sense of malaise.
That alone would prevent me from using it duing pct.
07-02-2007, 09:59 AM
07-03-2007, 04:49 PM
The SARM's are what I am really looking forward to. The only reason I thought that naltrexolone might work is due to the fact that supposedly it has been used to help opiate addicts get over there addiction by making the use of opiates useless. However I can not find out if it really is the case or if it was a conjecture as I read this on a third party site that a good while back. I still however would be very hesitant to try it. Naltrexolone has an active life of around 50 hours I believe and if it is anywhere as bas as naloxone it would really be a damn awful 50 hours.
07-03-2007, 06:55 PM
yea i'm not even sure if its worth it. Thats probably not anything to mess with. I mean if we can limit\prevent the ON cycle Shutdown from 2 of the 3 places, then its better than 0\3, and trying to kick-start yourself when its almost too late. I just hope some of the reputable research chem companies are looking into SARM's, it would be an interesting research experiment.
07-04-2007, 12:21 AM
I read that article a few months back, and meant to ask Dr. John if he knew anything about it. Very interesting, if nothing else.
I actually find that opiates, especially codeine derivitives, such as oxycodone, very much ease my symptoms of low testosterone. Maybe this is just from an increase in dopamine or maybe it has to do with it's interaction with my hypothalamus/pituitary? I know that opiates supress natural testosterone in normal men, but what about men suffering from secondary hypogonadism?
07-04-2007, 01:38 PM
07-17-2007, 03:56 PM
07-17-2007, 05:43 PM
10-30-2007, 08:37 PM
10-30-2007, 11:41 PM
Similar Forum Threads
- By PHWSSJ in forum General ChatReplies: 36Last Post: 06-10-2006, 02:33 PM
- By freakboy in forum AnabolicsReplies: 11Last Post: 10-31-2005, 03:17 PM
- By JWest0926 in forum General ChatReplies: 17Last Post: 11-12-2003, 12:50 PM
- By YellowJacket in forum AnabolicsReplies: 4Last Post: 02-16-2003, 03:27 AM