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Aromatase Inhibitors The Steroidogenic Pathways THE KEY TO UNDERSTANDING HORMONES BY WILLIAM CLEARFIELD D.O. Objectives 01 Provide an Overview of the Steroidogenic Pathway 02 Review the Enzymes Involved in the Genesis of Active Steroid Hormones 03 Case Histories No Relevant Relationships with a Commercial Interest to Disclose In Memorium: The Johnny Castle Memorial Lecture Johnny Castle (1952-2009) Our Prime Directive What Issues Do We Deal With? 20’s ▶ Teen Years ▶ PCOS Acne ▶ ▶ Worsening PMS ▶ PCOS ▶ Infertility ▶ Endometriosis ▶ Hypothyroid ▶ Weight gain ▶ Endometriosis ▶ Fibroids ▶ Irregular periods ▶ Heavy periods ▶ Menstrual cramps ▶ Painful periods ▶ PMS ▶ Weight gain Common Hormonal Complaints 30s and 40s Acne Weight gain Infertility Hair loss PMS Facial hair PCOS Hypothyroid Fibroids Perimenopause Endometriosis Common Complaints Hormonal Etiology 50’s 60+ Hot flashes Osteoporosis Night sweats Decreased libido Weight gain Sexual dysfunction Depression Insomnia Insomnia Migraine headaches Vaginal dryness Mood swings/anxiety Low libido Hair loss/Hair in places it shouldn’t be Hypothyroid Erectile dysfunction What You Need to Know What You Need to Ask Estrogen Estrogen Excess Progesterone 1.Hot Flashes 1. Cysts 1. Agitation 2.Night Sweats 2. Breast Tenderness 2. Irritability a. Ovarian, Breast 3. Sleep Disturbance 3.Brain Fog b. Uterine (Fibroids) 4. Panic Attacks 4. Belly Fat c. Gallstones 5. Poor Libido 3. Anxiety 6. Headaches 5. Memory Loss 4. Spotting, Irreg menses 7. Short Tempered 6. Bone Loss Cramping 5. Infertility 7. Heart S/S DOE 6. Joint pain 7. Wt. Gain 8. PMS What You Need to Ask Testosterone Testosterone Excess Thyroid 1. Anxiety 1. Oily Skin 1. Dry Skin 2. Depression 2. Oily Hair 2. Dry Hair 3. Poor Sense of Well 3. Acne 3. Hair loss evenly on scalp Being 4. Skin Breakout 4. Fingernails 4. Muscle Tone neck and shoulder a. Crack/Break 5. Urinary 5. Road rage 5. Constipation Incontinence 6. Higher BPs 6. Weight Gain 6. Vaginal 7. ASVD (Long term) 7. Tired All Day Dryness/ED 8. Acne 8. Eyebrows Thin At outer 7. Poor Libido edge 8. Poor Sexual 9. Oral Temp <97.6 Performance What You Need to Ask Cortisol Growth Hormone Insulin 1. Tired Upon Rising 1. Strength/Energy 1. Excess 2. Need Stimulant in 2. Memory a. Thirst mid morning 3. Task Initiation b. Excess Urination 3. Nap in afternoon 4. Planning and Prioritizing c. Abdominal Pain 4. Exhausted by 5. Organization d. Visual Disturbance Dinner time 6. Ability to Switch Between 5. Second Wind after Tasks 2. Deficiency 8 PM 7. Completing Tasks a. Sweating 6. Sugar/Salt 8. Paranoia b. Tired Cravings 9. Dark Moods c. Hunger 7. Nods off easily 10. OCD d. Easily Irritable e. Feels Shaky 1. Deficiency a. Lightheaded b. Needs to Eat Every 2 hours c. Irritable d. Moodiness What You Need to Ask DHEA Pregnenolone Low Prolactin 1. Flabby Muscles 1. Memory loss 1. Treatment Resistant: 2. Aging Faster than 2. Stress intolerant a. Anxiety Peers 3. Crave Salty Food b. Depression 3. Prone to Infections 4. Thing are dim vs. 2. Poor Immune Responses 4. Feels less well the past 5. Noise intolerant 5. Less hair High Prolactin 1. Unexplained headaches. 2. Visual impairment. 3. Reduced sex drive or fertility problems. 4. Erectile dysfunction 5. Abnormal lack of body and facial hair. 6. Irreg or no menses 7. Galactorrhea 8. Menopausal S/s Types of Steroid Hormones Understanding Steroid Hormones All Steroid Hormones: ▶ Are derived from Cholesterol ▶ Differ in the ring structure and attached side chains ▶ Are lipid soluble ▶ Are not stored in cells Holst, Jennifer P et al. “Steroid hormones: relevance and measurement in the clinical laboratory.” Clinics in laboratory medicine vol. 24,1 (2004): 105-18. doi:10.1016/j.cll.2004.01.004 Steroid Hormone Functions ★ “In Health” ○ Glucocorticoids-Carbohydrate Regulation, Anti-inflammatory, Energy Production ○ Gonadal Steroids-Reproduction ○ Mineral Balance-Mineralocorticoids, Maintains BP and Blood Volume, Reabsorbs Sodium ○ ★ “In Sickness” ○ Inflammation ○ Stress Response ○ Bone Deterioration ○ ASVD ○ Behavioral Issues ■ Cognition ■ Agitation/Irritability ■ Mood Hu, J., Zhang, Z., Shen, WJ. et al. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab (Lond) 7, 47 (2010). https://doi.org/10.1186/1743-7075-7-47 Lipid Based Steroid Hormones Travel in Bloodstream Linked to Binding Globulins ❖ Sex Hormone Binding Globulin carries Testosterone and Estrogen ❖ Corticosteroid Binding Globulin carries Cortisol Hammond, Geoffrey L. “Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action.” The Journal of endocrinology vol. 230,1 (2016): R13-25. doi:10.1530/JOE-16-0070 The FIrst Step in Steroid Hormone Production The “Mom and Pop” of the Steroidal Hormones Cholesterol ▶ Healthy fats and an adequate cholesterol levels to make hormones ▶ Very low cholesterol levels contribute to poor hormone production ▶ Statins, Red Yeast Rice, Binders, and genetically low cholesterol ▶ Associated with increased risk for cancer, suicide, cancer, memory concerns Conversion of Cholesterol Modulated by To Pregnenolone Cytochrome P450 Let’s Go Back to “The Way It Was” DeBose-Boyd, Russell A. “Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase.” Cell research vol. 18,6 (2008): 609-21. doi:10.1038/cr.2008.61 Added “Off Topic Bonus” Statins Effect on the Steroidogenic Pathway Statins inhibit HMG CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol Sniderman, A.D., Thanassoulis, G. Do statins lower testosterone and does it matter?. BMC Med 11, 58 (2013). https://doi.org/10.1186/1741-7015-11-58 Statins Effect on Cholesterol https://www.intechopen.com/books/cholesterol-lowering-therapies-and-drugs/cholesterol -lowering-drugs-and-therapies-in-cardiovascular-disease Cholesterol to Pregnenolone Transfer of Chol. from Outer to Inner Membrane of Steroid Cells Steroidogenic Acute Regulatory Protein STaR: The Rate Limiting Step Organs: Adrenal cortex, Gonads, Brain, Nonhuman placenta Inhibited by Endocrine Disruptors: ETOH, DES, Arsenic, BPA Kallen CB, Billheimer JT, Summers SA, Stayrook SE, Lewis M, Strauss III JF (October 1998). "Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein". J. Biol. Chem. 273 (41): 26285–8. doi:10.1074/jbc.273.41.26285. PMID 9756854. Cholesterol to Pregnenolone STaR: The Rate Limiting Step Steroidogenic Acute Regulatory Protein 1. Cytochrome P450 2. Co-Factors- NADPH + 3 H + 3 O 2 Hanukoglu I (December 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis". The Journal of Steroid Biochemistry and Molecular Biology. 43 (8): 779–804. doi:10.1016/0960-0760(92)90307-5. PMID 22217824 Old Enzymes-New Names Pregnenolone MOA: Inhibits tonic (NMDA) receptor-mediated neurotransmission Provides neuroprotection Preferentially metabolizes to allopregnanolone. ALLO levels triple two hours post oral administration of 400 mg pregnenolone Pregnenolone protects the brain from cannabis intoxication 1. Marx CE, Keefe RS, Buchanan RW, Hamer RM, Kilts JD, Bradford DW, et al. Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia. Neuropsychopharmacology 2009 2. Marx CE. 2007 unpublished data. 3. Vallee, M., et al., “Pregnenolone can protect the brain from cannabis intoxication,” Science 2014; 343(6166):94-8. Pregnenolone Indications Dose Memory 1. Maintenance-25-50 mg/25-50 mg/d Neuroprotection 2. Memory Enhancement- 150 mg/d Anti-stress, anti-anxiety, anti-depressive 3. Fatigue-150-200 mg 2x/d) x 4 mo. Anti-arthritic 4. Depression/Anxiety 400 mg/d Lowers Lipids Improves mental alertness Improves psychomotor performance Anti-fatigue https://selfhacked.com/blog/top-11-scientific-health-benefits-pregnenolone-including-drawbacks/accessed January 29, 2021 Tai, P., 8 Powerful Secrets to Anti-Aging, Health Secrets USA, Tucker, GA; 2007:89. https://www.grc.com/health/research/Pregnenolone/The_Promise_of_Pregnenolone.pdf, accessed January 29, 2021 1. https://selfhacked.com/blog/top-11-scientific-health-benefits-pregnenolone-including-drawbacks/accessed January 29, 2021 2. Tai, P., 8 Powerful Secrets to Anti-Aging, Health Secrets USA, Tucker, GA; 2007:89. 3.https://www.grc.com/health/research/Pregnenolone/The_Promise_of_Pregnenolone.pdf, accessed January 29, 2021 To Progesterone and Testosterone and Beyond! 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Converts Pregnenolone to Progesterone Converts 17-OH Pregnenolone to 17-OH Progesterone Converts DHEA to Androstenedione Androstenediol to testosterone Androstadienol to androstadienone To Progesterone and Testosterone and Beyond! 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Decreased by: Progestins, ETOH, Metformin, Isoflavonoids, PCB’s Increased by: PCOS, Hyperinsulinemia, IL-4 and IL-13 (allergies), Hyperthyroidism, Forskolin, SSRIs, SNRIs, Congenital Deficiency=Virilism, Adrenal Hyperplasia Santín-Márquez, Roberto et al. “Sulforaphane - role in aging and neurodegeneration.” GeroScience vol. 41,5 (2019): 655-670. doi:10.1007/s11357-019-00061-7 Progesterone MOA: Calming/Improves Sleep Lowers High Blood Pressure Helps Body Use and Eliminate Fats-Lowers Cholesterol Balances Estrogen- Bioidentical-Not Progestins) Stimulates new bone production Enhances thyroid function Improves libido Restores cell oxygen levels Induces conversion of E1 to inactive E1S form Promotes Th2 immunity Deficiency S/S Agitation Poor Libido Headache Short Temper Irritability Insomnia Progesterone
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