Everything That’s Wrong With Your PCT

by Eric M. Potratz

Discussion of pharmaceutical agents below is presented for information only. Nothing here is meant to take the place of advice from a licensed health care practitioner. Consult a physician before taking any medication.

In the world of steroid users, it has become mandatory to follow post cycle therapy (PCT) upon cessation of steroid use. Many great PCT protocols have been outlined over the years, and many individuals have had great success with following such protocols. Nevertheless, what works can always work better. This is especially the case for those that have had a lack of success following popular advice. In this article I will address the major problems with popular PCT protocols and clarify exactly how we should use the items at our disposal for optimum recovery from AAS. Three main topics will be covered in this article –

hCG on cycle -- I will show you the best way to use HCG, which will protect your "testicular real-estate", and prime your HPTA for the fastest and most complete recovery possible.
SERMs. -- Drugs such as Clomid and Nolvadex are some of the most toxic drugs in a steroid-users cabinet. I will present the evidence of this toxicity and provide alternatives.
Peptides for PCT -- Peptides such as Growth Hormone and IGF-1 have much more of a role in PCT than most people realize. Besides preserving muscle gains, these hormones can actually help restore testicular function after a cycle.
HCG unraveled

Human Chorionic Gonadotropin (hCG) is a peptide hormone that is used in place of LH to stimulate hormone production from the gonads.1 LH is the primary signal sent from the pituitary to the testes, which stimulates the leydig cells within the testes to produce testosterone. When steroids are administered, LH levels rapidly decline. The absence of an LH signal from the pituitary causes the rapid onset of testicular degeneration. The testicular degeneration begins with a reduction of leydig cell volume, and is then followed by rapid reductions in intra-testicular testosterone (ITT), peroxisomes, and Insulin-like factor 3 (INSL3) – All important bio-markers and factors for proper testicular function and testosterone production.2-6,19 However, this degeneration can be prevented by a small maintenance dose of hCG ran throughout the cycle. Unfortunately, most steroid users have been engrained to believe that hCG should be used after a cycle. Though, we will learn that a faster and more complete recovery is possible if hCG is ran during a cycle.

Firstly, we must understand the clinical history of hCG to understand the most efficient way to use it. Many popular "steroid profiles" advocate an hCG dose of 2500-5000iu once or twice a week. These were the kind of dosages used in the historical hCG studies for hypogonadal men who had reduced testicular sensitivity due to prolonged LH deficiency.85,86 That is, testes desensitize when not presented with a sufficient LH signal. In men with normal LH levels and testicular sensitivity, the maximum increase of testosterone is seen from a dose of only ~250iu, with minimal increases obtained from 500iu or even 5000iu.2,11 (It appears the testes maximum secretion of testosterone is about 140% above base line.12-18) So, if you have allowed your testes to desensitize over the length of a typical steroid cycle, (8-16 weeks) then you would require a higher dose to elicit a response in an attempt to restore normal testicular size and function – but there is cost to this, and a high probability that you won’t regain full testicular function.

To get an idea of how quickly testicular degeneration occurs from your average multi-AAS cycle, consider this: LH levels are rapidly decreased by the 2nd day of steroid administration.2,9,10 By shutting down the LH signal and allowing the testis to be non-functional over a 12-16 week period, leydig cell volume decreases 90%, ITT decreases 94%, INSL3 decreases 95%, while the capacity to secrete testosterone decreases as much as 98%.2-6 It should be mentioned that visually analyzing testes size is a poor method of judging your actual testicular function, since testicular size is not directly related to the ability to secrete testosterone.4 This is because the leydig cells, which are the primary sites of testosterone secretion, only make up about 10% of the total testicular volume. Therefore, testicular size may appear normal on a cycle, but the testes ability to secrete testosterone upon LH or hCG stimulation can actually be significantly diminished.3-5



The decreased testosterone secretion capacity was well demonstrated in a study on power athletes who used steroids for 16 weeks, and were then administered 4500iu hCG post cycle. It was found that the steroid users were about 20 times less responsive to hCG, when compared to normal men who did not use steroids.8 In other words, their testosterone secretion capacity was dramatically reduced because they did not receive an LH signal for 16 weeks. The testes essentially became desensitized and crippled. Case studies with steroid using patients show that aggressive long-term treatment with hCG at dosages as high as 10,000iu E3D for 12 weeks were unable to return full testicular size.7 Other studies with men using low dose steroid implants for 6 weeks showed unsuccessful return of Insulin-like factor-3 (INSL3) concentration in the testes upon 5000iu/wk of HCG treatment for 12 weeks.6

These studies show that postponing hCG usage until the end of a cycle, increases your need for a higher dose of hCG, and decreases your odds of a full recovery. As a consequence to using a higher dose of hCG, estrogen will be increased disproportionately, which then causes further HPTA suppression while increasing the risk of gyno.11 For example, high doses of hCG are known to raise estradiol 165%, while only raising testosterone 140%.11 Higher doses of hCG are also known to reduce LH receptor concentration and degrade the enzymes responsible for testosterone synthesis within the testes12,13,19 (the last thing someone wants during recovery). While these negative effects of hCG can be partly mitigated by the use of a drug such as tamoxifen, it will create further problems associated with using a toxic SERM. (covered in the next section)

In light of the above evidence, it becomes obvious that we must take preventative measures to avoid this testicular degeneration. Besides, with hCG being so readily available, and such a painless shot, it makes you wonder why anyone wouldn’t use it on cycle. Based on studies with normal men using steroids, ~100iu HCG administered everyday was enough to preserve full testicular function and ITT levels, without causing desensitization typically associated with higher doses of hCG.2 It is important that low-dose hCG is started before testicular degeneration occurs, which appears to rapidly manifest within the first 2-3 weeks of steroid use.

Recap – For optimal preservation of testicular function during cycle, use 100iu hCG ED starting 3 days after your first AAS dose. Drop the hCG a week before the AAS clear the system. For example, you would drop hCG a week after your last Testosterone Enanthate shot. Or, if you are ending the cycle with orals, you would drop the hCG a week before your last oral dose. This will allow for a sudden and even drop in hormone levels, while initiating LH and FSH production from the pituitary, making for a seamless recovery.

A more convenient alternative to the above recommendation would be a weekly shot of 500iu hCG, throughout the entire cycle. Beyond this dose, one could calculate a rough estimate for their required hCG dosage by multiplying 40iu x days of LH absence. (40iu x 60 days = 2400iu HCG dose)

As an alternative to the on cycle hCG protocol, you could follow a plan based on modulation of the gonadotropin pulse generator. (seen here)

Note: If following any of these protocols, hCG should NOT be used after the cycle.

Clomid & Nolva; A closer look

The use of Clomid and Nolvadex, as Selective Estrogen Receptor Modulators (SERMs), has gradually become well established in the steroid using community. The popular push of these drugs has almost made them mandatory. They have essentially become hormonal vitamins – vitamins that can do no wrong and provide seemingly endless benefits of testosterone support, bloat reduction, gynecomastia prevention and cholesterol health. It seems that we are all well educated about the benefits of Clomid and Nolvadex, so in this segment, I will present the risks and consequences from the short and long term use of Clomid and Nolvadex.

Upon examination of the research available for Clomid (clomiphene) and Nolvadex (tamoxifen) we find that the research is quite extensive, and contradicting.21 We see many early studies with tamoxifen done on breast cancer patients, which show an acceptable "safety profile", with an apparent lack of adverse effects.22 On the other hand, many of the early in vivo animal studies showed severely toxic effects, with the development of cancer in the liver, uterus, or testes upon tamoxifen administration.30-34,41 However, this evidence was largely disregarded by ex vivo (test tube) research on human cell-lines which appeared to show a lack of toxic effects.21

For example, tamoxifen was generally accepted as being non-toxic to human liver upon the conclusion that tamoxifen did not cause noticeable DNA adducts (damage) during short-term ex vivo studies with human liver cells.35,36 This was in contrast to the in vivo animal studies showing dramatic carcinogenic effects on the liver.30-34,41 As scientists learned that the toxic effects from tamoxifen are from the metabolism and buildup of the a-hydroxytamoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen metabolites. It became apparent that ex vivo research was largely flawed due to low-rate metabolism.21 The carcinogenic effects of tamoxifen proved to be even more unusual and elusive, when it was hypothesized that tamoxifen had both genomic and non-genomic toxicity, which affecting different animals, in different organs.21 This created an obvious clinical challenge for measuring genotoxicity in a test tube. Eventually, it was established that tamoxifen was a bona-fide carcinogen in all species, at least in one way or another.21,37-39 Recent human studies have shown tamoxifen treated women to have 3x the risk of developing fatty liver disease, which appeared as soon as 3 months into therapy at only 20mg/day.24-26 In some cases, the disease lasted up to 3 years, despite cessation from tamoxifen therapy. Five and ten year follow-ups with patients on long term tamoxifen therapy showed cases of deadly hepatocellular carcinoma.27-29 In a 2000 case study involving tamoxifen induced liver disease, D.F Moffat et al made a profound statement –


"In addition, hepatocellular carcinoma in tamoxifen treated patients may be under-reported since there may be reluctance to biopsy liver tumours which are assumed to be secondary carcinoma of the breast."

In other words, it appears that the liver carcinoma from a large number of breast cancer patients on tamoxifen therapy has been misdiagnosed as a metastasis infection from the breast cancer itself.28 Upon closer examination it was found that the cancerous lesions in the livers of the long-term tamoxifen therapy case studies were identical to those seen in the early animal studies showing tamoxifen to be a potent hepatotoxin.28-34 Although the effects took much longer to manifest, it became obvious that tamoxifen was toxic to the human liver.

Another well known risk of tamoxifen therapy is the increased risk of developing endometrial cancer (uterine cancer).23,42 This is due to tamoxifen actually acting as an estrogen agonist in the uterus, presumable from the 4-hydroxytamoxifen metabolite.33,40 This estrogenic metabolite triggers abnormal growth of the uterus and the formation of cancer causing DNA adducts.33 As male bodybuilders we assume this presents no risk. On the contrary, the implications are quite scary when we realize the male equivalent to the uterus is the prostate -- differentiating from the same embryonic cell line and sharing the same oncogene, Bcl-2, and high concentration of the estrogen receptor. It is likely that tamoxifen has the same estrogenic action, and DNA damaging effects within the prostate.60-62 It is no wonder that tamoxifen failed as a treatment for prostate carcinoma.43

Aside from restoring testosterone levels post cycle, tamoxifen is often used to combat gyno during cycle when "flare ups" occur. While tamoxifen may provide immediate inhibition of growth, and serve as valuable tool, it also has the ability to up-regulate the progesterone receptor.54-56 This is a true contradiction, which dramatically increases your chances of bringing upon gyno in future cycles when utilizing Nandrolone (Deca) or Trenbolone, both of which act upon the progesterone receptor. It is interesting to speculate: is tamoxifen use directly related to the increased gyno occurrences seen with modern day steroid users?

When we bring our attention to Clomid, we find less research is available on long term human toxicity, probably because of the relatively short term (3-4 week) clinical application for ovarian stimulation,59 although long term follow ups with patients who received Clomid for ovulation induction have shown an increased risk of developing uterine cancer.74 This is to be expected, since many of the same carcinogenic tendencies found with tamoxifen are the same effects seen with clomiphene.44,45,57,58 Upon analysis of anecdotal reports from Clomid and nolva users, we see the typical short term side effects of low libido, erectile dysfunction, and emotional instability – despite many men showing normalized testosterone and estrogen levels during the use of these SERM’s. Research on male breast cancer patients also shows frequent reports of low libido, thrombosis (arterial blockage), and hot flashes with tamoxifen use.47 Another common side effect associated with both SERMs, but more common with Clomid, is the loss of visual accuracy and development of visual "tracers", due to the ocular toxicity.46

As the medical community became more aware of the side-effects associated with clomiphene and tamoxifen treatment, newer and safer SERMs, such as toremifene and raloxifene hit the developmental fast track. Toremifene appears to be less liver toxic, but it is an analog of tamoxifen, so it also carries many of the related genotoxic effects.48,49 Raloxifene appears to be even safer by being the least liver toxic, and not having any potential issue with the uterus or prostate.50-52 Unfortunately, raloxifene has been associated with a higher incidence of thromboembolism52 (arterial blockage), and also has very low oral absorption, making it an expensive alternative at a typical 120mg/day dose.53 Still, raloxifene could presumably be equally effective as Clomid or Nolvadex at restoring HPTA function, while imparting less side effects.53 Newer SERMs are already being evaluated such as bazedoxifene, arzoxifene, and lasofoxifene, in hopes of reducing risk even further.

Another SERM that may be useful for post cycle therapy is resveratrol.87,88 Resveratrol is a natural polyphenol extracted from grape skin, that has recently been under heavy research for its cancer fighting effects in the breast, prostate and liver.63-69 Contrary to Nolva or Clomid, resveratrol appears to actually have beneficial effects on the liver,70 as well as having multiple benefits on cardiovascular health by limiting LDL oxidation and improving endothelial function.71-73 Improved blood vessel function may be a mechanism by which resveratrol improves erectile function in many men. Research also suggests that resveratrol may actually extend life, by reducing oxidative stress on organs such as the heart,77 and preventing the metabolic syndrome by fighting insulin resistence.79,80 It’s becoming well known that insulin resistance is a leading cause of low testosterone.82 More specifically, improving insulin sensitivity will increase your leydig cell sensitivity, and therefore increase the testes response to LH.81

It should be pointed out that resveratrol may not be the best choice to combating emergency gyno, due to its lower binding affinity to the human ER of about 90x less than tamoxifen, and about 30x less than clomiphene.75,76 However, considering that resveratrol is a pure estrogen antagonist at the pituitary,89 while Clomid has mixed agonist/antagonistic effects,90-94 resveratrol could be a suitable substitute for PCT. Aside from acting as a SERM, resveratrol can also help control estrogen by actually limiting aromatase enzyme production.82 Based on the research, it appears that at least 100mg/day would needed to increase LH, FSH and testosterone production.84 This is comparable dose of resveratrol found in an advanced topical based product, Dermacrine Sustain (found here - http://www.primordialperformance.com).

Admittedly, no steroid users are dropping dead from a 4 week protocol of Nolva or Clomid, and many will say "the consequences far outweigh the benefits" -- but why deal with the potential consequences when alternatives are available?

Peptides for testicular recovery

It’s a common practice these days for experienced bodybuilders to implement some dosage of IGF-1 either during or after a cycle to "pick up" a lagging body part, or to preserve gains in muscle. Growth Hormone (GH) is also a versatile drugd for cutting or bulking, with increasing popularity as it becomes more affordable. The value of IGF-1 and GH becomes so much more significant when we realize there integral role in testicular function. In fact, it seems that these hormones are more effective at building testes, than muscles.

Research has shown GH to be vitally important in testicular function, 95-97 but it is generally accepted that the beneficial effects are directly mediated by hGH’s conversion to IGF-1.98 As many of you know, IGF-1 is created in the liver by GH, upon interacting with insulin. So, we will be focusing on the usage and benefits of IGF-1, rather than GH, as it seems more cost effective and directly related to our purpose of optimizing recovery.

In short, IGF-1 increases steroidogenic acute regulatory protein (sTAR),98 and cholesterol side chain cleaving enzyme (CYP 11A)99. These are both rate-limiting steps and are critical factors for converting cholesterol into hormones, such as testosterone. IGF-1 also has the ability to increase the concentration of steroidogenic enzymes in the testes, such as 3b HSD.100 IGF-1 can also increase the testes sensitivity to LH and hCG by increasing the number of LH receptors.99-102

These positive effects on testicular function make IGF-1 an ideal drug for PCT. A dose of IGF-1 Lr3 at 80mcg/day, split two times per day, would likely be the most cost effective dose.

In conclusion, we have learned that utilizing hCG during a steroid cycle will significantly prevent testicular degeneration. This helps create a seamless transition from "on cycle" to "off cycle". Then, by avoiding the deleterious SERMs such Clomid and Nolvadex and opting for safer alternatives, you can seemingly avoid any sort of post cycle crash, while maintaining a strong libido and uncompromised emotional health.

References

1. Pierce JG, Parsons TF 1981 Glycoprotein hormones: structure and function. Annu Rev Biochem 50:466–495

2. Low-Dose Human Chorionic Gonadotropin Maintains Intratesticular Testosterone in Normal Men with Testosterone-Induced Gonadotropin Suppression. Andrea D. Coviello, et al J. Clin. Endocrinol. Metab., May 2005; 90: 2595 - 2602.

3. Luteinizing hormone on Leydig cell structure and function. Mendis-Handagama SM . Histol Histopathol 12:869–882 (1997)

4. Leydig cell peroxisomes and sterol carrier protein-2 in luteinizing hormone-deprived rats. SM Mendis-Handagama, PA Watkins, SJ Gelber, and TJ Scallen; Endocrinology, Dec 1992; 131: 2839.

5. Effect of long term deprivation of luteinizing hormone on Leydig cell volume, Leydig cell number, and steroidogenic capacity of the rat testis. Keeney DS, Mendis-Handagama SMLC, Zirkin BR, Ewing LL. Endocrinology 1988; 123:2906–2915.

6.The Effects of Gonadotropin Suppression and Selective Replacement on Insulin-Like Factor 3 Secretion in Normal Adult Men. Katrine Bay, et al. J. Clin. Endocrinol. Metab., Mar 2006; 91: 1108 - 1111.

7. Successful treatment of anabolic steroid–induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Dev Kumar Menon, M.D. FERTILITY AND STERILITY VOL. 79, SUPPL. 3, JUNE 2003

8.. Testicular responsiveness to human chorionic godadotrophin during transient hypogonadotrophic hypogonadism induced by androgenic/anabolic steroids in power athletes. Hannu et al. J. Steroid Biochem. Vol. 25, No. 1 pp. 109-112 (1986)

9. Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate of testosterone cypionate. Schulte-Beerbuhl M, Nieschlag E 1980. Fertil Steril 33:201–203

10. Effects of chronic testosterone administration in normal men: safety and efficacy of high dosage testosterone and parallel dose-dependent suppression of luteinizing hormone, follicle-stimulating hormone, and sperm production. Matsumoto AM 1990. J Clin Endocrinol Metab 70:282–287

11. Effect of human chorionic gonadotropin on plasma steroid levels in young and old men. Longcope C. Steroids 21:583–590 (1973)

12. Regulation of peptide hormone receptors and gonadal steroidogenesis. Catt KJ, Harwood JP, Clayton RN, Davies TF, Chan V, Katikineni M, Nozu K, Dufau ML. Rec Prog Horm Res 1980; 36:557–622

13. [Effect of human chorionic gonadotropin on the endocrine function of Papio testes] GV Katsiia, VM Gorlushkin, TN Todua, and NP Goncharov. Probl Endokrinol (Mosk), Sep 1984; 30(5): 68-71.

14. Reproductive function in young fathers and grandfathers. Nieschlag E, Lammers U, Freischem CW, Langer K, Wickings EJ. J Clin Endocrinol Metab 55:676–681 (1982)

15. The aging Leydig cell III Gonadotropin stimulation in men. Nankin HR, Lin T, Murono E, Osterman J 1981. J Androl 2:181–189

16. Reproductive hormones in aging men. I. Measurement of sex steroids, basal luteinizing hormone, and Leydig cell response to human chorionic gonadotropin. Harman SM, Tsitouras PD 1980. J Clin Endocrinol Metab 51:35–40

17. Prolonged biphasic response of plasma testosterone to single intramuscular injections of human chorionic gonadotropin. Padron RS, Wischusen J, Hudson B, Burger HG, de Kretser DM 1980. J Clin Endocrinol Metab 50:1100–1104

18. Gonadotrophins and plasma testosterone in senescence. In: James VHT, Serio M, Martini L, eds. The endocrine function of the human testis. Mazzi C, Riva LP, Bernasconi D 1974., New York: Academic Press, Inc.; 51–66

19. Androgen biosynthesis in Leydig cells after testicular desensitization by luteinizing hormone-releasing hormone and human chorionic gonadotropin.

Dufau ML, Cigorraga S, Baukal AJ, Sorrell S, Bator JM, Neubauer JF & Catt KJ

Endocrinology 105 1314–1321 (1979)

20. Insulin-Like Factor 3 Serum Levels in 135 Normal Men and 85 Men with Testicular Disorders: Relationship to the Luteinizing Hormone-Testosterone Axis
K. Bay, S. Hartung, R. Ivell, M. Schumacher, D. Jürgensen, N. Jorgensen, M. Holm, N. E. Skakkebaek, and A.-M. Andersson
J. Clin. Endocrinol. Metab., Jun 2005; 90: 3410 - 3418.


21. Understanding the genotoxicity of tamoxifen?
David H. Phillips
Carcinogenesis, Jun 2001; 22: 839 - 849.

22. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors
B Fisher, J Costantino, C Redmond, R Poisson, D Bowman, J Couture, NV Dimitrov, N Wolmark, DL Wickerham, ER Fisher, and et al.
N. Engl. J. Med., Feb 1989; 320: 479 - 484


23. Tamoxifen treatment and its consequences
Adrian Shulman, Ilan Cohen, Ron Maymon, and Marco M. Altaras
Hum. Reprod., Aug 1995; 10: 2174 - 2175


24. Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance.

Elefsiniotis et al.

European Journal of Gastroenterology and Hepatology 2004;16:593-598.

25. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled

in Italian tamoxifen chemoprevention trial

Savino Bruno el al.

BMJ 2005;330;932-; originally published online 3 Mar 2005;

26. Fatty liver and transaminase changes with adjuvant tamoxifen therapy.

Liu, Chien-Liang a c; Huang, Jon-Kway b; Cheng, Shih-Ping a

Anti-Cancer Drugs. 17(6):709-713, July 2006

27. The association between tamoxifen and the development of hepatocellular carcinoma: case report and literature review.

Law CH, Tandan VR.

Can J Surg 1999;42:211-4.

28. Hepatocellular carcinoma after long-term tamoxifen therapy

D. F. Moffat, K. A. Oien, J. Dickson, T. Habeshaw and D. R. McLellan

Volume 11, Number 9 / September, 2000

29. Tamoxifen-associated hepatocellular damage and agranulocytosis.

Ching,C.K., Smith,P.G. and Long,R.G. (1992)

Lancet, 339, 940.

30. Tamoxifen induces hepatocellular carcinoma in rat liver: a 1-year study with two antiestrogens.

Hirsimaki P, Hirsimaki Y, Nieminen L, et al.

Arch Toxicol. 1993; 67: 49–4


31. Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis.
VP Tryndyak, O Kovalchuk, L Muskhelishvili, B Montgomery, R Rodriguez-Juarez, S Melnyk, SA Ross, FA Beland, and IP Pogribny
Mol Carcinog, Mar 2007; 46(3): 187-97

32. Antiestrogens and the formation of DNA damage in rats: a comparison.
Kim SY, Suzuki N, Laxmi YR, Umemoto A, Matsuda T, Shibutani S.
Chem Res Toxicol. 2006 Jun;19(6):852-8.

33. Activation of 4-hydroxytamoxifen and the tamoxifen derivative metabolite E by uterine peroxidase to form DNA adducts: Comparison with DNA adducts formed in the uterus of Sprague-Dawley rats treated with tamoxifen
Deena N. Pathak, Krisztina Pongracz, and William J. Bodell
Carcinogenesis, Sep 1996; 17: 1785 - 1790

34. Activation of the Tamoxifen Derivative Metabolite E to Form DNA Adducts: Comparison with the Adducts Formed by Microsomal Activation of Tamoxifen
Krisztina Pongracz, Deena N. Pathak, Takemichi Nakamura, Alma L. Burlingame, and William J. Bodell
Cancer Res., Jul 1995; 55: 3012 - 3015.

35. Activation of tamoxifen and its metabolite -hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes.

Phillips,D.H., Carmichael,P.L., Hewer,A., Cole,K.J., Hardcastle,I.R., Poon,G.K., Keogh,A. and Strain,A.J.

Carcinogenesis, 17, 88–94. (1996)

36. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers.

Fornander,T., Rutquist,L.E., Cedermark,B., Glas,U., Mattsson,A., Silfversward,C., Skoog,L., Somell,A., Theve,T., Wilking,N., Askergren,J. and Hjalmar,M.-L. Lancet, i, 117–120. (1989)

37. Reduced genotoxicity of [D5-ethyl]-tamoxifen implicates -hydroxylation of the ethyl group as a major pathway of tamoxifen activation to a liver carcinogen. Phillips,D.H., Potter,G.A., Horton,M.N., Hewer,A., Crofton-Sleigh,C., Jarman,M. and Venitt,S. (1994). Carcinogenesis, 15, 1487–1492

38. Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s.

Styles,J.A., Davies,A., Lim,C.K., de Matteis,F., Stanley,L.A., White,I.N.H., Yuan,Z.-X. and Smith,L.L. (1994)

Carcinogenesis, 15, 5–9.

39. Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells).

Styles,J.A., Davies,A., Davies,R., White,I.N.H. and Smith,L.L. (1997)

Carcinogenesis, 18, 303–313.

40. Effect of tamoxifen on endometrial proliferation
A Decensi, V Fontana, S Bruno, C Gustavino, B Gatteschi, and A Costa
J. Clin. Oncol., Feb 1996; 14: 434 - 440.

41.Safety Testing of New Drugs. Tamoxifen.

Lawrence,D.R., McClean,A.E.M. and Wetherall,M. (eds)

Tucker,M.J., Adam,H.K. and Patterson,J.S.

Academic Press, London, pp. 125–161. (1984)

42. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14.

Fisher,B et al.and other NSABP contributors (1994)

J. Natl Cancer Inst., 86, 527–537.

43. Phase II trial of tamoxifen in metastatic carcinoma of the prostate.
JH Glick, A Wein, K Padavic, W Negendank, D Harris, and H Brodovsky
Cancer, Apr 1982; 49(7): 1367-72.

44. Biotransformation of the Antiestrogen Clomiphene to Chemically Reactive Metabolites in the Immature Female Rat
Peter C. Ruenitz, et. al
Cancer Res., Aug 1987; 47: 4015 - 4019.

45. Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract.
GR Cunha, O Taguchi, R Namikawa, Y Nishizuka, and SJ Robboy
Hum Pathol, Nov 1987; 18(11): 1132-43.


46. Tamoxifen-associated eye disease. A review
SG Nayfield and MB Gorin
J. Clin. Oncol., Mar 1996; 14: 1018 - 1026.

47. Tamoxifen administration is associated with a high rate of treatment-limiting symptoms in male breast cancer patients.Anelli TF, Anelli A, Tran KN, Lebwohl DE, Borgen PI.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.

48. DNA adducts caused by tamoxifen and toremifene in human microsomal system and lymphocytes in vitro.

Hemminki,K., Widlak,P. and Hou,S.-M. (1995)

Carcinogenesis, 16, 1661–1664.

49. Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats.
GC Hard, MJ Iatropoulos, K Jordan, L Radi, OP Kaltenberg, AR Imondi, and GM Williams
Cancer Res., Oct 1993; 53(19): 4534-41.

50. Selective estrogen receptor modulators: mechanism of action and clinical experience. Focus on raloxifene.
D Thiebaud and RJ Secrest
Reprod Fertil Dev, January 1, 2001; 13(4): 331-6.

51. Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial.
RL Shazer, A Jain, AV Galkin, N Cinman, KN Nguyen, RB Natale, M Gross, L Green, LI Bender, S Holden, L Kaplan, and DB Agus
BJU Int, Apr 2006; 97(4): 691-7.

52. Review on raloxifene: profile of a selective estrogen receptor modulator.
M Heringa
Int J Clin Pharmacol Ther, August 1, 2003; 41(8): 331-45.

53. Comparison of effects of the rise in serum testosterone by raloxifene and oral testosterone on serum insulin-like growth factor-1 and insulin-like growth factor binding protein-3.
EJ Duschek, LJ Gooren, and C Netelenbos
Maturitas, July 16, 2005; 51(3): 286-93.

54. Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma.
M Nola, et al
Gynecol Oncol, Mar 1999; 72(3): 331-6.

55. Tamoxifen increases the plasma estrogen-binding equivalents and has an estradiol agonistic effect on histologically normal premenopausal and postmenopausal
Gorodeski, G.I., Beery, F., Lunenfeld, B. and Geier, A.
endometrium. Fertil. Steril, 57, 320-327. (1992)

56. Estrogen and progesterone receptor expressors o£ decidual endometrium in a postmenopausal woman treated with tamoxifen and megestrol acetate.
Cohen, I., Shulman, A., Altaras, M., Tepper, R., Cordoba, M. and Beyth, Y.
Gynecol. Obstet. Invest., 38, 127-129. (1994)

57. Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.
R Homburg, H Pap, M Brandes, J Huirne, P Hompes, and CB Lambalk
Gynecol Endocrinol, September 1, 2006; 22(9): 506-10.

58. In vivo evaluation of the genotoxic effects of clomiphene citrate on rat reticulocytes: a micronucleus genotoxicity.
B Duran, I Ozdemir, Y Demirel, O Ozdemir, A Cetin, and A Guven
Gynecol Obstet Invest, Jan 2006; 61(4): 228-31.

59. Clomiphene citrate—end of an era? a mini-review
Roy Homburg
Hum. Reprod., Aug 2005; 20: 2043 - 2051

60. Selective estrogen receptor modulators: pharmacological profile in the rat uterus.

Bryant H. U., Wilson P. K., Adrian M. D., Cole H. W., Phillips D. L., Dodge J. A., Grese T. A., Sluka J. P., Glasebrook A. L.

J. Soc. Gynecol. Invest., 3: 152A 1996.

61. Molecular perspectives on selective estrogen receptor modulators (SERMs): progress in understanding their tissue-specific agonist and antagonist actions.

Lonard D. M., Smith C. L.

Steroid, 67: 15-24, 2002.

62. Defining the "S" in SERMS.

Katznellenbogen B. S., Katznellenbogen J. A.

Science (Wash. DC), 295: 2380-2381, 2002

63. Detoxifying Cancer Causing Agents to Prevent Cancer

Margaret Hanausek, Zbigniew Walaszek, and Thomas J. Slaga Integr

Cancer Ther, Jun 2003; 2: 139 - 144.

64. Mechanisms Involved in Resveratrol-Induced Apoptosis and Cell Cycle Arrest in Prostate Cancer–Derived Cell Lines
Dixan A. Benitez, et al
J Androl, Mar 2007; 28: 282 - 293.

65. Resveratrol-induced cell inhibition of growth and apoptosis in MCF7 human breast cancer cells are associated with modulation of phosphorylated Akt and caspase-9.
Y Li, J Liu, X Liu, K Xing, Y Wang, F Li, and L Yao
Appl Biochem Biotechnol, Dec 2006; 135(3): 181-92.

66. Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat.
TG Whitsett Jr and CA Lamartiniere
Expert Rev Anticancer Ther, Dec 2006; 6(12): 1699-706.

67. The proteasome as a potential target for novel anticancer drugs and chemosensitizers.
KR Landis-Piwowar, V Milacic, D Chen, H Yang, Y Zhao, TH Chan, B Yan, and QP Dou
Drug Resist Updat, December 1, 2006; 9(6): 263-73.

68. Potent Inhibitory Effects of Resveratrol Derivatives on Progression of Prostate Cancer Cells. Yoo KM, et al. Arch Pharm (Weinheim) Apr 18;339(5):238-241 (2006)

69. Resveratrol and propolis as necrosis or apoptosis inducers in human prostate carcinoma cells.

Scifo C, et al.

Oncol Res. 2004;14(9):415-26.

70. Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver.
A Kasdallah-Grissa, et al
Life Sci, February 20, 2007; 80(11): 1033-9.

71. Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages
Shu-Er Chow, Ya-Ching Hshu, Jong-Shyan Wang, and Jan-Kan Chen
J Appl Physiol, Apr 2007; 102: 1520 - 1527.

72. "A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase."

Wallerath T, et al.

Nitric Oxide. 2005 Mar;12(2):97-104.

73. "Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease."

Lekakis J, et al.

Eur J Cardiovasc Prev Rehabil. 2005 Dec;12(6):596-600.

74. Uterine Cancer after Use of Clomiphene Citrate to Induce Ovulation
Michelle D. et al
Am. J. Epidemiol., Apr 2005; 161: 607 - 615

75. Comparative study of estrogenic potencies of estradiol, tamoxifen, bisphenol-A and resveratrol with two in vitro bioassays.
W Li, M Seifert, Y Xu, and B Hock
Environ Int, May 2004; 30(3): 329-35

76. Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids.
DH Han, MS Denison, H Tachibana, and K Yamada
Biosci Biotechnol Biochem, Jul 2002; 66(7): 1479-87.

77. Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart
Ralph R. Alcendor, Shumin Gao, Peiyong Zhai, Daniela Zablocki, Eric Holle, Xianzhong Yu, Bin Tian, Thomas Wagner, Stephen F. Vatner, and Junichi Sadoshima
Circ. Res., Apr 2007; 10.1161/01.RES.0000267723.65696.4a.

78. Resveratrol inhibition of Propionibacterium acnes
John J. Docherty, Heather A. McEwen, Thomas J. Sweet, Erin Bailey, and Tristan D. Booth
J. Antimicrob. Chemother., Apr 2007; 10.1093/jac/dkm099.

79. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

M Lagouge, C Argmann, Z Gerhart-Hines, H Meziane, C Lerin, F Daussin, N Messadeq, J Milne, P Lambert, P Elliott, B Geny, M Laakso, P Puigserver, and J Auwerx

Cell, Dec 2006; 127 (6) : 1109-22

80. Resveratrol improves health and survival of mice on a high-calorie diet

Baur JA, et al.

Nature 444:337-342 (2006)

81. Increasing Insulin Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men
Nelly Pitteloud, et al
J. Clin. Endocrinol. Metab., May 2005; 90: 2636 - 2641.

82. Clinical and Biochemical Assessment of Hypogonadism in Men With Type 2 Diabetes: Correlations with bioavailable testosterone and visceral adiposity
Dheeraj Kapoor, et al
Diabetes Care, Apr 2007; 30: 911 - 917.

83. The Red Wine Polyphenol Resveratrol Displays Bilevel Inhibition on Aromatase in Breast Cancer Cells Yun Wang, Kai Woo Lee, Franky L. Chan, Shiuan Chen, and Lai K. Leung Toxicol. Sci., Jul 2006; 92: 71 - 77.

84. trans-Resveratrol, a Natural Antioxidant from Grapes, Increases Sperm Output in Healthy Rats
M. Emília Juan, Eulalia González-Pons, Thais Munuera, Joan Ballester, Joan E. Rodríguez-Gil, and Joana M. Planas
J. Nutr., Apr 2005; 135: 757 - 760.

85. Stimulation of sperm production by human chorionic gonadotropin after prolonged gonadotropin suppression in normal men. Matsumoto AM, Bremner WJ 1985. J Androl 6:137–143

86. Human chorionic gonadotropin and testicular function: stimulation of testosterone, testosterone precursors, and sperm production despite high estradiol levels.

Matsumoto AM, Paulsen CA, Hopper BR, Rebar RW, Bremner WJ 1983

J Clin Endocrinol Metab 56:720–728

87. Is resveratrol an estrogen agonist in growing rats?

Turner, R. T., Evans, G. L., Zhang, M., Maran, A. & Sibonga J. D.

Endocrinology 140: 50–54. (1999)

88. Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats.

Kubo, K., Arai, O., Omura, M., Watanabe, R., Ogata, R. & Aou, S.

Neurosci. Res. 45: 345–356. (2003)

89. Effects of long-term treatment with resveratrol and subcutaneous and oral estradiol administration on pituitary function in rats
Martina Böttner, Julie Christoffel, Hubertus Jarry, and Wolfgang Wuttke
J. Endocrinol., Apr 2006; 189: 77 - 88.

90. Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men.
A Vermeulen and F Comhaire
Fertil Steril, March 1, 1978; 29(3): 320-7.

91. Aromatase Inhibition in the Human Male Reveals a Hypothalamic Site of Estrogen Feedback
F. J. Hayes, S. B. Seminara, S. DeCruz, P. A. Boepple, and W. F. Crowley Jr.
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3027 - 3035.

92. Evidence for a role of endogenous estrogen in the hypothalamic control of gonadotropin secretion in men.
Winters SJ, Troen P.
J Clin Endocrinol Metab. 61:842–845 (1985)

93. LH and FSH response to synthetic LHRH after consecutive administration of clomiphene citrate in normal males. Hashimoto T, Miyai K, Matsumoto K, Izumi K, Kumahara Y.
J Clin Endocrinol Metab. 41:1110–1112. (1975)

94. Modulation of pituitary responsiveness to exogenous LHRH by an estrogenic and an anti-oestrogenic compound in the normal male.
Dhont M, de Gezelle H, Vandekerckhove D
Clin Endocrinol (Oxf). 5:175–180 (1976)

95. Hereditary isolated somatropin deficiency: effects of human growth hormone adrninistration.

Sheikholislan BM, Stempfel RS 1972

Pediatrics 49:362-374

96. The effects of growth hormone on the Leydig cell response to chorionic gonadotropin in boys with hypopituitarism.

Kulin HE, Samdjlike E, Santen R, Santner S 1981

Clin Endocrinol (Oxf) 45:468-472

97. Testicular function in hypopituitarism.

Rivarola MA, et al

Pediatr Res 6:634-641 (1972)

98. Leydig cells: endocrine, paracrine, and autocrine regulation.

Saez JM

Endocr Rev 15:574–626 (1994)

99. Molecular Mechanisms of Insulin-like Growth Factor-I Mediated Regulation of the Steroidogenic Acute Regulatory Protein in Mouse Leydig Cells
Pulak R. Manna, et al
Mol. Endocrinol., Feb 2006; 20: 362 - 378.

100. Regulation of steroidogenic genes by insulin-like growth factor-1 and follicle-stimulating hormone: differential responses of cytochrome P450 side-chain cleavage, steroidogenic acute regulatory protein, and 3ß-hydroxysteroid dehydrogenase/isomerase in rat granulosa cells. Eimerl S, Orly J . Biol Reprod 67:900–910 (2002)

101. Insulin-like growth factor-I-mediated amplification of follicle-stimulating hormone-supported progesterone accumulation by cultured rat granulosa cells: enhancement of steroidogenic enzyme activity and expression. deMoura MD, Choi D, Adashi EY, Payne DW. Biol Reprod 56:946–953 (1997)

102. Upregulation of human chorionic gonadotrophin-induced steroidogenic acute regulatory protein by insulin-like growth factor-I in rat Leydig cells. Lin T, Wang D, Hu J, Stocco DM . Endocrine 8:73–78 (1998)


Source: mesomorphosis.com