Addressing the Nutritional Needs of BHRT and TRT Patients

Mazen Baisa, PharmD, MBA, ABAAHP, FAARFM, CPE, FACA, FMNM Director of Clinical Services MedWell Health Solutions

Mazen Baisa “declare(s) no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.”

The American College of Apothecaries is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

At the conclusion of this program, the participating pharmacist or technician will be able to:

• Examine the importance of nutrients and diet on the hormonal balance • Discuss the nutrients that aid in the optimal metabolism of selected hormones • Identify the recommended nutrients for patients on BHRT and TRT regimens • Recognize the difference between food grade and professional grade nutrients/supplements

Selected Selected Supplements for Supplements for BHRT Support TRT Support

Nutrigenomics Supplements and Lifestyle Evaluation and Impact Selection

Source- The American Academy of Antiaging Medicine

– Memory

– Mobility

– Vision

– Hearing

1- Said YES to the previous slide questions 2- Complement actions of hormones 3- Enhance healthy metabolism

• Heart Disease • Obesity • Type II Diabetes • Cancer • PMS & Menopause • Osteoporosis

The Nutritional Cost Of Drugs: A Guide To Maintaining Good Nutrition While Using Prescription And Over-The-Counter Drugs Perfect Paperback – June 7, 2004 ©2016 American College of Apothecaries Nutrition and Estrogen Metabolism

After menopause, the metabolism of estrogen can change.

Consequently a women may respond differently to estrogen replacement.

• Strong estrogenic activity • Turns on estrogen receptor • Greater likelihood of estrogen-dependent conditions

• Very weak estrogenic activity • Protective against breast cancer • Potent antioxidant • Inverse correlation with atherosclerosis

• Post-menopausal women at baseline who went on to develop breast CA showed 15% lower 2:16-OHE1 ratio than controls (Meilahn EN 1998)

• Women with breast CA at all ages show increased 16α-hydroxylation (Zumoff B 1994 and Kabat GC Epidemiology. 2006)

The Supplement Pyramid: How to Build Your Personalized Nutritional Regimen Paperback – March 15, 2014 ©2016 American College of Apothecaries ©2016 American College of Apothecaries Estrogen Supporting Supplements

©2016 American College of Apothecaries ©2016 American College of Apothecaries 2-Hyhdroxlation Support • Broccoli derivatives: Indole-3-carbinol (I3C), diindolylmethane (DIM), sulforaphane glucosinolate • Flaxseed lignans • Omega-3 fats • Tumeric/Curcumin • Exercise • Weight control • Vitamin D

• Cruciferous vegetables such as broccoli, cauliflower, cabbage, kale, and Brussels sprouts can help detoxify dangerous estrogen breakdown products that promote cancer growth

©2016 American College of Apothecaries Am J Clin Nutr. 2009 May;89(5):1553S-1557S. Epub 2009 Mar 18. Cruciferous Vegetables and Estrogen • Cruciferous vegetables contain compounds that promote a healthier pathway for the breakdown of estrogens in the body, thus protecting against cancer • A chief component of cruciferous vegetables, indole-3-carbinol (I3C), prevents the conversion of estrogen to its breast cancer promoting 16-alpha-hydroxyestrone form, while increasing conversion to its cancer- fighting 2-hydroxyestrone form

J Natl Cancer Inst. 1997 May 21;89(10):718-23. ©2016 American College of Apothecaries Epidemiology. 2000;11(6):635–640. Indole-3-carbinol (I3C) • I3C is a naturally occurring compound found in numerous cruciferous vegetables, such as broccoli, cauliflower, and kale

• Following ingestion of I3C, the body converts it to several different metabolites, one of which is diindolylmethane (DIM)

• Both of these compounds, as well as many other I3C metabolites, have been shown to impact metabolic shifts and cellular activities for improved health outcomes

• I3C has also been shown to temper estrogen signals by competing for binding sites and inhibiting the activity of estrogen receptors

• A study published in the Journal of Nutrition unveiled evidence that I3C supports healthy cellular function related to estrogen metabolism

Meng Q, Qi M et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E- cadherin/catenin complexes. J Mol Med. 2000;78(3):155-65. ©2016 American College of Apothecaries Ashok BT Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol. Nutr Cancer. 2001;41(1-2):180-7. Diindolylmethane (DIM) • Diindolylmethane (DIM) is a phytonutrient and plant indole • Found in cruciferous vegetables with potential for enhancing proliferation of healthy cells and cellular activities • As a dimer (formed chemical structure of two substances) of indole-3-carbinol, DIM promotes beneficial estrogen metabolism in both sexes supporting the formation of healthy estrogen metabolites and enhancing the potential for greater antioxidant activity

Hong C, Firestone GL, Bjeldanes LF. Bcl-2 familymediated apoptotic effects©2016 of 3,3’ -Americandiindolylmethane College (DIM) of Apothecariesin human breast cancer cells. Biochem Pharmacol. 2002 Mar 15;63(6):1085-97. Calcium D-Glucarate

• Calcium D-Glucarate is the supplemental calcium salt form of D-glucaric acid, a substance produced naturally in the body and obtained through consumption of certain fruits and vegetables

• Calcium D-glucarate has been extensively studied and has been shown to inhibit beta-glucuronidase, an enzyme found in certain bacteria that reside in the gut

• This activity supports the body’s ability to detoxify estrogens, foreign molecules and fat-soluble toxins

• Lignans can slow the growth of breast cancer in women

• A comprehensive review of 21 studies found that postmenopausal women with higher lignan intake were significantly less likely to get breast cancer

• A study found that a combination of lignans, I3C, and calcium-d- glucarate along with other supportive herbs favorably altered the 2/16-hydroxyestrone ratio in pre- and post-menopausal women

• Vitamin D confers significant protective effects against breast cancer

• In the referenced study, women with higher vitamin D levels had a nearly 70% reduction in their risk of breast cancer compared to women with the lowest levels

Individual differences in biochemistry, genetic influence, and environmental influences must be considered

• Vitamin B12: 1000 – 2000 mcg daily • Folate (B9): 800 – 1600 mcg daily • Broccoli; standardized extract: 400 – 800 mg daily • Indole-3-carbinol (I3C): 200 – 400 mg daily ( May need higher dosing if used a lone) • 3,3’-Diindolylmethane (DIM): 50 – 100 mg daily ( May need higher dosing if used a lone) • Lignan extract (flax or Norway spruce): 50 – 100 mg daily • Vitamin D3: 5000 – 8000 IU daily • Omega-3 fatty acids: 2000 – 6000 mg daily ( consider the ratio of EPA/DHA) • Calcium D-glucarate: 200 – 600 mg daily • Also keep the supplement pyramid in mind

• 56 yo female, hx extreme menopausal symptoms x 4 years • Strong FHx Breast Ca – 2 sisters • Concerned about continuing her BHRT and risk of breast cancer • No significant PMH • BRCA neg • What would you recommend for her?

• 53 y/o Caucasian female works as a local court judge complaining of, fatigue, vaginal dryness, and foggy memory • Ht. 5’6: Wt. 215 Ib • She has been on BHRT for 3 months now • Her friends told her to come see you

Decrease Leydig Cell T Production Decrease Gonadotropin Secretion Corticosteroids Corticosteroids Ethanol Ethanol Ketoconazole Estrogens Progestins (Megace)

Bind to the Androgen Receptor Rx that raise prolactin

Spironolactone (opiates, metoclopramide, psych meds) Flutamide Cimetidine

• Number Leydig cells ↓ ↓Testosterone secretion

• LH signaling to Leydig cells ↓ ↓Testosterone secretion

• SHBG ↑ ↑ Nonspecific bound fraction of testosterone ↓Bioavailable testosterone

• Zinc: This mineral is involved in almost every aspect of male reproduction, including testosterone metabolism, sperm formation, and sperm motility

• Some men require higher levels of zinc to adequately suppress aromatase

• More than 7 types of zinc supplements are available. Zinc citrate and chelated zinc formulations seem to have good absorption profile

J Coll Physicians Surg Pak. Nov 2005;15(11):671-3

©2016 American College of Apothecaries Biol Trace Elem Res. 2011 Apr;140(1):18-23. ©2016 American College of Apothecaries In this study which had 399 men over 65 y/o, The results showed that higher levels of magnesium were associated with higher levels of testosterone (both free and total) and of insulin-like growth factor (IGF-1).

• Magnesium Glycinate - Optimum bioavailability • Magnesium Lysinate - Good bioavailability • Magnesium Orotate - Heart health support • Magnesium Taurate - Heart health support and promotes calmness • Magnesium Aspartate - Helps fight fatigue and promote cellular energy • Magnesium Threonate - Promotes mental sharpness and cognitive health • Magnesium Malate - Supports ATP production and cellular energy

©2016 American College of Apothecaries Vitamin D- the Hidden Anabolic Switch Vitamin D can: • Increase the activity of the androgen receptor and Vitamin D Receptor (VDR) • Reduce the levels of SHBG • Reduce the androgenic activity of testosterone and similar hormones

• Both the activity of the androgen receptor and free testosterone levels, are critical in protein synthesis and muscle hypertrophy

Vitamin D, a steroid hormone, is essential for the healthy development of the nucleus of the sperm cell, and helps maintain semen quality and sperm count. Vitamin D also increases levels of testosterone, which may boost libido

©2016 American College of Apothecaries Keeping Aromatase and SHBG in Check • Chrysin: The bioflavonoid chrysin is a natural aromatase inhibitor, extracted from various plants, found in high concentrations in honey

• At high concentrations, chrysin is reported to be an aromatase inhibitor in vitro. However, studies performed in vivo show that orally administered chrysin does not have much clinical activity as an aromatase inhibitor

• Quercetin: One study showed that red wine inhibits aromatase, thus inhibiting the conversion of testosterone to estrogen. The study attributed this effect to the quercetin and other ingredients

Science. 1984 Sep 7;225(4666):1032-4. J Steroid Biochem Mol Biol. 2001 Sep;78(3):231-9. Ann N Y Acad Sci. 2002 Jun;963:239-46 ©2016 American College of Apothecaries Keeping Aromatase and SHBG in Check ( Cont.) • Nettle root: Lignans contained in nettle root extract may help prevent the binding of sex hormone-binding globulin to testosterone

• Fish oil: A study examined how the essential fatty acids EPA and DHA affected SHBG levels in men 43 to 88 years of age (Nagata et al 2000). After controlling for other variables, the researchers concluded that both EPA and DHA decreased levels of SHBG in middle-aged and elderly men

Phytomedicine. 2007 Aug;14(7-8):568-79. Nutr Cancer. 2000;38(2):163-67. ©2016 American College of Apothecaries Supporting Prostate Health • Indole-3-carbinol (I3C): I3C protects against dangerous estrogen metabolites and subsequent prostate cancer

• Saw Palmetto: In Europe, saw palmetto (Serenoa repens) has been used extensively as a drug for reducing symptoms of (BPH)

• Saw palmetto has multiple mechanisms of action: – inhibition of 5-alpha-reductase – inhibition of DHT binding to the androgen receptor – reduction of the inflammatory component of prostate growth (by inhibiting COX-2 and an enzyme called 5-lipoxygenase) – induction of apoptosis and inhibition of prostate cell proliferation

Eur Urol. 2002 May;41(5):497-506. Cell Biol Int. 2001,25(11):1117-24. ©2016 American College of Apothecaries Prostate. 2000 Nov 1;45(3):259-66. Scenario 1: Low Free Testosterone, High Estradiol, Mid Total Testosterone: • This situation suggests excessive aromatase activity, which converts free testosterone to estrogen. Inhibition of aromatase and reduction in aromatase-containing tissue (fat) is indicated • Suggestions include: • Chrysin: 500-1500 mg orally daily. Could also consider to topical compound at lower dose • Piperine: 10 mg-20mg to enhance absorption of oral chrysin • Zinc: 50 – 90 mg daily • Quercetin: 500 – 1000 mg daily

©2016 American College of Apothecaries Scenario 2: Low Free Testosterone, Low Estrogen, High Total Testosterone: • This situation suggests excessive SHBG levels, making sufficient testosterone unavailable to target tissues

• The elevation of SHBG explains why some older men who are on testosterone replacement therapy do not report a long-term beneficial effect, that is, the administered testosterone becomes bound by SHBG and is not bioavailable to cellular receptor sites where it would normally produce an effect

• Suggestions include: Inhibit aromatase by following some of the recommendations in the previous section, since low testosterone and high estrogen are involved in excess SHBG activity • Additionally consider the following supplements – Chrysin: 1500 mg daily – Nettle root extract: 240-360 mg daily ( in 2-3 divided doses) – Pygeum extract: 100 mg daily – Cruciferous vegetable extract (I3C): 400 mg daily – Omega 3 Fatty Acids: 2000 mg daily (at least 700 mg EPA, 500 mg DHA) – DHEA: 25 – 75 mg daily, followed by blood tests in 3-6 weeks; consider starting at a lower dose and increase as needed

©2016 American College of Apothecaries Scenario 3: Low Free Testosterone, Low Estrogen, Low Testosterone: • This situation suggests low production of testosterone, with resultant low conversion to estrogen

• Suggestions include: Use TRT (e.g., gels). If tests reveal low levels of LH, consider the possibility of using human chorionic gonadotropin (HCG). HCG functions in a manner similar to that of LH, thus helping to stimulate the leydig cells of the testes to produce more testosterone

• DHEA: 25 – 75 mg daily, followed by blood tests in 3-6 weeks; consider starting at a lower dose and increase as needed

• What else would you suggest for this kind of patients?

• 61 y/o male retired with chief complaint of low libido and decrease muscle mass • Ht. 6’1: Wt. 198 Ib • Hx: Diabetes and chronic diabetic neuropathic pain with opioid use • Dx- secondary hypogonadism (from his doctor) • Been on TRT for 5 weeks • He is feeling a little better but not what he expected… he is asking if there is anything you could do to help him

• Curcumin

• Nicotinamide Riboside

Cell Metab 2012;15:838-847. Annu Rev Nutr 2008;28:115-130. https://www.thorne.com/education/resource-library/product-literature ©2016 American College of Apothecaries Nutrigenomics and Lifestyle Impact

Nutrigenetics

Nutrigenomics

Genetic Factors

Exercise & Nutrition Movement

Behavioural & Lifestyle Choices

• For example the Paleolithic diet, which includes fermented and cultured foods, seem to promote healthy hormone levels and metabolism

• Quality protein from meat and fish, as well as healthy fats such as egg yolk, lard, and butter, could help to improve progesterone and DHEA secretion

• Lower in simple carbs and sugar

Exercise induces a rise in many hormones and peptides. ACTH - adrenocorticotropic hormone; GH - growth hormone; PRL - prolactin; CNS - central nervous system; IL - interleukin; BDNF - brain-derived neurotrophic hormone; FGF 21 - fibrob- last growth factor 21

Sweeteners:

Most low quality supplements contain low grade sweeteners like sorbitol or lab created sweeteners. Studies shows that these artificial sweeteners could damage brain cells, impair thinking, and may even lead to some cancers

Binders:

The word binder describes its self; a binder makes everything stick together. Examples include polyethylene glycol, dextrose (a suger), and diethylene glycol (DEG). The FDA recalled cough syrups and toothpastes because of this dangerous poison. DEG is also used in antifreeze

Lubricants:

The most common of these is magnesium stearate. It helps speed up the flow of the nutrient powder that’s made in tablets or put in to capsules. Some consumers might also have sensitivity or allergy to these lubricants and inactive ingredients

Disintegrators:

These ingredients help break down tablets. A common one in inferior supplements is sodium lauryl sulfate (SLS). This chemical is found in floor cleaners and engine degreasers as well as personal care products

Preservatives:

These are used to help maintain freshness. Watch out for anything containing parabens. Emerging research shows that parabens disrupt human hormones and can even cause cancer. Other preservatives commonly used in supplements include BHA and BHT. Unfortunately these chemicals are often not listed on the label

Coloring:

The use of artificial colors designated as “FD&C” and “Lake” are common in inferior supplements. These colors are known allergens and may trigger asthma attacks, hives, or even deadly allergic reactions in some individuals

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COMPOUNDING ALLOWS FOR THE CONSIDERATION OF INDIVIDUAL DIFFERENCES IN BIOCHEMISTRY, GENETIC INFLUENCES, AND ENVIRONMENTAL FACTORS

Mazen Baisa, PharmD, MBA, ABAAHP, FAARM, CPE, FACA, FMNM

Director of Clinical Services MedWell Health Solutions

Direct Phone: (248) 270-8246 Direct Fax: (248) 605-8100 Email: [email protected]