UNIVERSITY PEDs Estrogen and Prolactin Modulation Lesson Overview • • • • • • • • • • • • • • AAS Stack Design Review Estrogen Benefits and Side Effects Stimulus and Inhibitory Inputs for Gynecomastia AAS Effects on Gynecomastia Other Factors as Input Signals Relationship of Estrogen, Progesterone and Prolactin Types of Gynecomastia Aromatase Inhibitor (AI) Review Selective Estrogen Receptor Modulator (SERM) Review Health Effects of AI and SERMS Prolactin Regulation Effects of High Prolactin Levels and Stimulus for Increase Dopamine Agonist Withdrawal Syndrome Framework for Estrogen and Prolactin Management Overview of Stack Design Framework IF using the cycle design framework we have established prior You should not need to damage control once your cycle has begun Test is our anchor up until you need estrogen control Then a DHT derivative is implemented to modulate estrogen Then a 19-nor derivative is implemented to further androgen levels To get to higher levels of usage if needed or at the later stages of contest prep you might have brief moments of time needing to manage estrogen and prolactin This should be compounds implemented short term on an as needed basis if stack design can not be manipulated to further see out our physique goals Estrogen Benefits Neuroprotective Cardiovascular protective Needed for Erection and Libido Regulates Body Fat Needed for GH/IGF-1 Axis Needed for insulin sensitivity Bone Health Wakefulness and Alertness Estrogen Low or High? Testosterone normal range males: 300-1000 ng/dL Estradiol normal range males: 20-55pg/mL It will be normal at supraphysiological testosterone levels to have supraphysiological estradiol levels and that is acceptable if you are asymptomatic for high estrogen Signs of Low Estrogen: Fatigue No sex drive and erectile dysfunction Fat accumulation Depression and Irritability Forgetfulness Joint Pain Signs of High Estrogen: Libido present and erectile dysfunction Nipple sensitivity, breast swelling (gynecomastia) Water retention Elevated blood pressure Night sweats Estrogen via Aromatization Gynecomastia Imbalance in Inputs Figure from: Swerdloff 2019 AAS and Gyno Stimulation Anabolic Androgenic Steroids Aromatizing Compounds Testosterone Nandrolone Boldenone Dianabol Compounds with Progesterone and Prolactin Stimulation Nandrolone Trenbolone Non-Aromatizing Compounds Primobolan Masteron Anavar Proviron Winstrol Halotestin Ancillary Compounds Aromatase Inhibitors Anastrozole Exemestane Letrozole Selective Estrogen Receptor Modulators Compounds with Estrogen Receptor Nolvadex Interaction Anadrol Nandrolone Dopamine Agonist Cabergoline Pramipexole Other Factors to Consider Estrogen, Prolactin, Progesterone and Gyno Estrogen will be primary driving cause for gynecomastia Prolactin has a permissive role and estrogen is the stimulator for Prolactin increase Also the prolactin receptor is expressed minimally in most gynecomastia cases (Ferreira 2018) Constantly assessing and pinching nipples will be a direct stimulus for irritation and prolactin increase as well Progesterone is involved in more of luminal epithelium of the breast, which is cells of the milk ducts, but does not contribute to the glandular tissue of gyno Also we have studies in men receiving 100mg test enanthate with the progestin levonorgestrel 0.5mg daily for months and no gyno formation (Bebb 1996) All in all, main gyno focus should be around estrogen management, however prolactin should be addressed as it can be increase unrelated to estrogen in situations Compounds to Address Estrogen Aromatase Inhibitors Exemestane (Aromasin) steroidal suicidal inhibitor, bind to aromatase and deactivates it 25mg or 50mg daily in men, 60% and 56% reduction in estradiol (25mg max dosage needed) Terminal half life of hours 24 hours after one 25mg dose, estrogen levels are reduced by 70-80%; 72 hours later estrogen levels are still 40% below the baseline; 120 hours after initial dose, estrogen levels return to baseline Mild androgenic effect and lowers SHBG In postmenopausal breast cancer patients Exemestane suppress estradiol by 92.2%; Arimidex and Letrozole 90% All three commonly used AIs seem to suppress estradiol in men to a similar degree when taken on a daily basis Side effects very similar amongst all three, preference to Aromasin for a suicidal inibitor and prevent estrogen rebound Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial (Goss, 2013) 25mg Exemestane vs 1mg Anastrozole daily for years No difference in breast cancer outcomes Exemestane less lipid effects, increased bone loss and LFTs Both drugs have toxic effects and should be used short term “For cardiovascular events, pooled data showed that longer durations of aromatase inhibitor use are associated with a statistically significantly higher odds of developing such events compared with tamoxifen alone or a shorter period of aromatase inhibitor use after an initial period of tamoxifen therapy” Aromatase inhibitors may have a direct effect on endothelium that may predispose us to the development of atherosclerosis This is most apparent with longer durations of aromatase inhibitor use, suggesting that it is the cumulative exposure to aromatase inhibitors that is important What about a SERM vs AI efficacy? In a double-blind RCT, prostate cancer patients received either bicalutamide with a placebo, or in combination with tamoxifen (20 mg daily) or anastrozole (1 mg daily) for 48 weeks Gynecomastia developed in 73 % of patients receiving a placebo, 10 % of patients receiving tamoxifen, and 51 % of patients receiving anastrozole As such, anastrozole seems ill-suited in the prevention of gynecomastia, whereas tamoxifen appears to be very effective (Boccardo 2005) Selective Estrogen Receptor Modulator (SERM) Tamoxifen Citrate (Nolvadex): Tamoxifen functions as a competitive antagonist of the estrogen receptor It does not reduce total estrogen simply prevents its binding with the ER Terminal elimination half- life of about to hours 10-20mg Nolvadex ED for 3-9 months has been shown efficacious for up to 90% gyno resolution (Narula 2014) 10mg is likely effective close to physiological normal levels, higher AAS will require high Tamoxifen Minor mentions: Clomid and Raloxifene have minimal data on efficacy for gyno reduction Aromatase Inhibitors haves also performed poorly in reduction of gyno while Nolvadex has shown superior If the problem is estrogen as a stimulatory input, Nolvadex blocks the issue but does not solve it Not a long-term strategy This is when stack modulation comes in place Estrogen and Estrogen Antagonist GH Effects Figure: Birzniece 2017 Prolactin Regulation Endocrinol Metab Clin North Am 1992; 21:877 Training alone can significantly increase prolactin levels Enhanced Bbers had a further increase in prolactin but corresponded with Estradiol increase If estrogen is controlled Prolactin can likely be controlled High Prolactin Levels This has been blamed as the culprit of “deca dick” High prolactin decrease erection quality and increases the refractory period between erections High prolactin can also cause breast lactation More liable culprit of ED related nandrolone use is test suppression or inadequate test base, leading to low estradiol (needed for erections) and higher DHN to DHT (DHT needed for penial vasodilation and sexual drive) However high prolactin can happen Lab work is best to truly test and find the root issue Prolactin and Dopamine Agonist Cabergoline: Dopamine receptor agonist, inhibitory input for prolactin production 3-4 days half life Headache, nausea vomiting Constipation, diarrhea Fatigue, anxiety, depression Can increase sexual interest and refractory period Clinically used at an initial dosage on 500mcg per week divided into weekly dosages Pramipexole: Dopamine receptor agonist, inhibitory input for prolactin production 8-12 hour half life Clinically used at an initial dosage 125mcg 2x daily ED More frequent occurrence of GI distress and nauseas Due to side effect and ease of dosage Cabergoline is preferred Dosing in PM might aid side effect management Dopamine Agonist Withdrawal Syndrome: Implications for Patient Care Nirenberg 2013 “While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy” European Academy of Andrology clinical practice guidelines— gynecomastia evaluation and management 2019 Framework of Action Lab work to assess: Estradiol, Total Estrogen, Prolactin Address the Culprit High Estrogen Micro-dose your AAS to prevent large boluses of steroid exposed to aromatase Lower Aromatizing Compounds (Stimulus) and review AAS for other direct receptor actions Modulate androgen to estrogen ratio with Masteron, Primobolan or Proviron (Inhibitor) Utilize Tamoxifen Citrate lowest effective dosage as you adjust AAS stack for 7-10 days then reduce dosage 50% every 7-10 days and taper off If lowering dosage is not option implement aromatase inhibitor lowest effective dosage preferable Extremestane Adjust dosage base on needs and still utilize Tamoxifen if gyno is present and taper off High prolactin Address Estrogen first as this is an input for prolactin stimulation Lower input of nandrolone or trenbolone, decrease dosage Add Masteron or Proviron to modulate Prolactin Dopamine Agonist Last Option: Cabergoline 0.5mg twice per week When might we deploy these strategies? Offseason During peak blast AAS levels in advanced cycle design AI, SERM, and dopamine agonist should be removed during cruise periods Pre-contest In later stages of prep if estrogen is limiting fat loss and stack design is unable to be modified Later stages of prep if you are removing aromatizing compounds there is no rationale to increase AI or SERMs Summary Management of Estrogen and Prolactin is not as simple as just take XY drug We must assess all stimulus inputs and inhibitory inputs, confirm with lab work, then address the culprit of the issue AI, SERM, and Dopamine Agonist all have their place, but we have several other strategies we can implement prior to taking a larger health risk References K.M.Lakshman,B.Kaplan,T.G.Travison,S.Basaria,P.E.Knapp,A.B.Singh,M.P.LaValley,N.A Mazer, and S Bhasin The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men The Journal of Clinical Endocrinology & Metabolism, 95(8):3955–3964, 2010 Hengevoss J, Piechotta M, Müller D, Hanft F, Parr MK, Schänzer W, Diel P Combined effects of androgen anabolic steroids and physical activity on the hypothalamic-pituitary-gonadal axis J Steroid Biochem Mol Biol 2015 Jun;150:86-96 doi: 10.1016/j.jsbmb.2015.03.003 Epub 2015 Mar 19 PMID: 25797375 Kanakis GA, Nordkap L, Bang AK, Calogero AE, Bártfai G, Corona G, Forti G, Toppari J, Goulis DG, Jørgensen N EAA clinical practice guidelines-gynecomastia evaluation and management Andrology 2019 Nov;7(6):778-793 doi: 10.1111/andr.12636 Epub 2019 May 16 PMID: 31099174 R A Bebb, B D Anawalt, R B Christensen, C A Paulsen, W J Bremner, and A M Matsumoto Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach.The Journal of Clinical Endocrinology & Metabolism, 81(2):757–762, 1996 M.Ferreira,M.Mesquita,M.Quaresma,andS.Andre.Prolactinreceptorexpressioningynaecomastia and male breast carcinoma.Histopathology, 53(1):56–61, 2008 N.Mauras,J.Lima,D.Patel,A.Rini,E.diSalle,A.Kwok,andB.Lippe.Pharmacokineticsanddose finding of a potent aromatase inhibitor,aromasin (exemestane), in young males The Journal of Clinical Endocrinology & Metabolism, 88(12):5951–5956, 2003 N.Mauras,K.O.O’Brien,K.O.Klein,andV.Hayes.Estrogensuppressioninmales:metaboliceffects The Journal of Clinical Endocrinology & Metabolism, 85(7):2370–2377, 2000 F.Boccardo,A.Rubagotti,M.Battaglia,P.DiTonno,F.Selvaggi,G.Conti,G.Comeri,A.Bertaccini, G.Martorana, P Galassi, et al Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer.Journal of clinical oncology, 23(4):808–815, 2005 Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis J Natl Cancer Inst 2011 Sep 7;103(17):1299-309 doi: 10.1093/jnci/djr242 Epub 2011 Jul PMID: 21743022 Narula HS, Carlson HE Gynaecomastia pathophysiology, diagnosis and treatment Nat Rev Endocrinol 2014 Nov;10(11):684-98 doi: 10.1038/nrendo.2014.139 Epub 2014 Aug 12 PMID: 25112235 P V Plourde, H E Kulin, and S J Santner Clomiphene in the treatment of adolescent gynecomastia: clinical and endocrine studies.American Journal of Diseases of Children, 137(11):1080–1082, 1983 Nirenberg MJ Dopamine agonist withdrawal syndrome: implications for patient care Drugs Aging 2013 Aug;30(8):587-92 doi: 10.1007/s40266-013-0090-z PMID: 23686524 G G T’sjoen, V A Giagulli, H Delva, P Crabbe, D De Bacquer, and J.-M Kaufman Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition The Journal of Clinical Endocrinology & Metabolism, 90(10):5717–5722, 2005 Books: Llewellyn W Anabolics Jupiter, FL: Molecular Nutrition LLC; 2017 Bond P Book on Steroids: A complete evidence based reference PeterBond.org; 2020 Swerdloff RS, Ng CM Gynecomastia: Etiology, Diagnosis, and Treatment [Updated 2019 Jul 7] In: Feingold KR,Anawalt B, Boyce A, et al., editors Endotext [Internet] South Dartmouth (MA): MDText.com, Inc.; 2000- Available from: https://www.ncbi.nlm.nih.gov/books/NBK279105/