Male Lab Testing Made Easy

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2 Medical Disclaimer: The medical information in this lecture is provided as an information resource only and is not to be used or relied on for any diagnostic or treatment purposes. This lecture contains general information about medical conditions and treatments. The information is not advice and should not be treated as such. This information is not intended to be patient education, does not create any patient-physician relationship, and should not be used as a substitute for professional diagnosis and treatment. The medical information in this lecture is provided as is without any representations or warranties, express or implied. Precision Analytical, Inc (DUTCH) and Dr. Carrie Jones makes no representations or warranties in relation to the medical information in this lecture. Copyright 2019: Carrie Jones ND, MPH 2

4 Male basics: The hypothalamus tells the pituitary LH binds to Leydig cells in the testes Testosterone, androstenedione and DHEA FSH binds to Sertoli cells in the seminiferous tubules to nurture developing sperm cells through the stages of spermatogenesis There are 6 stages to seminiferous development and going from stage 1 to stage 6 is called a Cycle. Each Cycle takes about 16 days and most sperm need 4.6 cycles to mature = 74 days Sperm are then shuttled to the epididymis for maturation, storage, then transport out through the vas deferens to the prostate and out the penis on ejaculation. Copyright 2019: Carrie Jones ND, MPH 4

6 More male basics Ejaculate contains about 2-5ml of semen Each milliliter contains zero to 300 million sperm depending on his case Testosterone is highest at puberty then starts to decline 1-2% yearly at 30yo This process can be sped up through poor lifestyle habits, dietary choices, exposures, lack of exercise and increased stress resulting in men in their 20 s and 30 s experiencing the fallout of a low testosterone level. Male factor infertility is 30% of the cause of infertility between couples Prostate cancer is 2 nd most common cancer in men after non-melanoma skin cancer Copyright 2019: Carrie Jones ND, MPH 6

8 The last date was 14 years ago imagine testosterone now in 2019? Travison TG, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab Jan;92(1): Epub 2006 Oct 24 Copyright 2019: Carrie Jones ND, MPH 8

9 Ask, what you are looking for Serum: Good for basic sex hormones = P, T, E2 Can do DHT, prolactin, SHBG, LH, FSH, PSA etc Can not get estrogen metabolites/pathways, OATs, melatonin Cortisol is a mix of bound and unbound and only a single point Saliva: Good for sex hormones depending on the method used Can not get estrogen metabolites/pathways, OATs Can not get androgen metabolites/pathways Cortisol is free cortisol only, able to get 4-point rhythm, no cortisone, no metabolized cortisol Can not get SHBG, prolactin, DHT, PSA, LH, FSH etc Dried Urine: Good for sex hormones Able to get estrogen metabolites/pathways Able to get androgen metabolites/pathway Able to get OATs, melatonin Able to get metabolized cortisol Able to get free cortisol and cortisone Able to do 4 or 5 point cortisol rhythm Able to get melatonin Can not get SHBG, prolactin, LH, FSH etc Copyright 2019: Carrie Jones ND, MPH 9

11 Immunoassay vs Mass Spectrometry Important to understand if the lab you choose is using immunoassay vs LC/MS (or LC-MS/MS) and GC/MS (or GC-MS/MS) In a nut shell: Immunoassay is generally much cheaper and easier to set up however it s less sensitive and less precise Mass Spectrometry is more expensive to set-up however it s considered the most sensitive and precise MS tends to have less interference from other steroid hormones PMID: PMID: Copyright 2019: Carrie Jones ND, MPH 11

12 As this study recently said The era of steroid analysis via immunoassay is drawing to a close as these unspecific assays are replaced by high-throughput, specific, sensitive mass spectrometry (MS) analyses. Indeed, a recent statement by The Endocrine Society had attempted to implement a policy toward introducing LC-MS as the diagnostic standard for publication of steroid measurements, although this position was later relaxed because many laboratories do not have the technology to achieve such accurate analysis. Mueller J, et al. The Regulation of Steroid Action by Sulfation and Desulfation. Endocrine Reviews. 2015;36(5): , Copyright 2019: Carrie Jones ND, MPH 12

Testing: FSH What? A pituitary hormone that stimulates sperm formation via Sertoli cells Inhibited by inhibin B Why test? Low sperm count Serum results? Normal adult range: 1.5-8.

14 Testing: FSH What? A pituitary hormone that stimulates sperm formation via Sertoli cells Inhibited by inhibin B Why test? Low sperm count Serum results? Normal adult range: miu/ml ( same for IU/L) Sometimes is the upper limit (I m concerned when it s <5.0 (brain issue?) >8.0 = testes aren t listening, brain is fine Copyright 2019: Carrie Jones ND, MPH 14

15 Testing: LH What? A pituitary hormone that stimulates testosterone production from the Leydig cells in the testes Why? When his testosterone levels are low to determine brain from testicular cause (although it can be both) Results? Done in the serum Normal adult range: miu/ml I m concerned when it s <5.0 (brain issue?) >9.0 = brain is fine, testes aren t listening if T is low If he s on testosterone replacement, this will lower LH levels Copyright 2019: Carrie Jones ND, MPH 15

Clinical pearl: FSH and LH are all about communication!

17 Hypogonadotropic hypogonadism When the hypothalamus and/or pituitary are not producing hormones Common causes: Any injury to the brain (accident, military, sport, trauma etc) Medications: Accutane, Opioids, Steroids (high dose/long term), men on Testosterone Elevated prolactin levels Elevated prolonged stress Excessive exercise Primary hypothyroidism Long term inflammation or infection in brain (including brain autoimmune) EMF/Cell phone to the head (PMID: ) Endocrine disrupting hormones ( s/endocrine/index.cfm) Hemochromatosis Anorexia/low body weight Genetic (ie. Kallmann s) Tumor PMID: Copyright 2019: Carrie Jones ND, MPH 17

18 If it all starts with the brain Address the prior slide! Follow a strict circadian rhythm Get your gut healthy and work on the vagus nerve Improve blood flow in the brain Exercise cardio, weights and inversion poses Stop smoking Normalize your blood sugar Neurofeedback Acupuncture/chiropractic/massage Test for iron overload (esp. men) Reduce EMF/Cell phone to the head exposure Copyright 2019: Carrie Jones ND, MPH 18

19 It all starts with the brain: supplements Bacopa monnieri (doi: /rej ) Fish oil (doi: /j.biopsycho ) Pyrroloquinoline quinone (PQQ) (doi: / _29) Rosemary ( Ginkgo biloba (doi: /s ) Cordyceps sinensis (doi: /2015/575063) Maca lepidium (doi: /2012/193496) Copyright 2019: Carrie Jones ND, MPH 19

Testing: Prolactin Pro-lactation hormone Tested in serum The only ant.

21 Prolactin Causes of mild elevations in prolactin: Elevated estrogens (or estrogen replacements) Low dopamine Transient high stress Hypothyroid Kidney disease (can t clear it) Prolactinoma (usually very high levels) Elevated BPA (and similar) levels Why test it? Mildly elevated prolactin can cause low testosterone and low sperm count! Copyright 2019: Carrie Jones ND, MPH 21

22 How do you address prolactin? Is his dopamine low? Test HVA levels in urine Is his estrogen high? See estrogen slides How is his stress/hpa axis on testing? How is his thyroid? Testing? Medication? Supplements? Does he need a brain MRI? Have you tested his BPA levels? Other endocrine disruptors? Copyright 2019: Carrie Jones ND, MPH 22

High Estrogen in Men Made in adipose tissue (mainly) via aromatase enzyme Testosterone aromatase estrogen Increased levels: excess insulin, excess adipose tissue, increased stress, alcohol Symptoms

24 High Estrogen in Men Made in adipose tissue (mainly) via aromatase enzyme Testosterone aromatase estrogen Increased levels: excess insulin, excess adipose tissue, increased stress, alcohol Symptoms of increased estrogen: fatigue, low mood, low libido, weight gain, breast development, erectile dysfunction Tested in serum, saliva or urine Serum range: pg/ml (I prefer <30 pg/ml) Copyright 2019: Carrie Jones ND, MPH 24

25 What does aromatization look like on testing? What s his story? *Early 40 s male on the testosterone injection weekly *Complains of weight gain, poor erections, low libido and fatigue Copyright 2019: Carrie Jones ND, MPH 25

26 What does aromatization look like on testing? What s his story? *Early 40 s male on the testosterone injection weekly *Complains of weight gain, poor erections, low libido and fatigue Copyright 2019: Carrie Jones ND, MPH 26

27 What does aromatization look like on testing? What s his story? *Early 40 s male on the testosterone injection weekly *Complains of weight gain, poor erections, low libido and fatigue Copyright 2019: Carrie Jones ND, MPH 27

Why is estrogen metabolism important? 1.Understand estrogen dominance 2.

31 Detox Analogy: Picture a claw foot tub Phase 1 is the water filling up the tub Is the right type of water filling up the tub? How fast or slow is it filling up? Phase 2 is the drain How open or closed is the drain? Is it open wide enough? Copyright 2019: Carrie Jones ND, MPH 31

32 What affects your CYP1 family? Iron CYP are heme dependent Environmental toxicants PAHs, PCBs, xenoestrogens (phthalates, BPA) Smoking Charred meats (BBQ) Grapefruit juice Copyright 2019: Carrie Jones ND, MPH 32

33 DIM/I3C Phase 1 metabolism primarily I3C needs stomach acid to then convert into 15+ compounds, of which the most predominant is DIM 10-60% of I3C converts to DIM DIM: An acid catalyzed dimer of I3C DIM increases in brassica family if the food is chopped or mildly heated Out of the body within about 24hrs DIM increases the conversion of E1/E2 into 2-OH-E1 via CYP1A DIM binds to aryl hydrocarbon receptor (AhR) = Nrf2 Dosage in research: mg/day PMID: = read me to learn everything DIM does in the body Copyright 2019: Carrie Jones ND, MPH 33

36 What slows down/affects COMT? COMT mutation (+/+) Being estrogen dominant (even elevated estrogen catechols) Gut infections phenols from gut bacteria Certain Phenols from foods/supplements Green tea, quercetin High levels of SAH (blocks methyltransferases) Consider Sam/SAH ratio Bisphenol and PCB exposure Serotonin can competitively block SAM receptors in COMT (PMID: ) COMT inhibitors (medications) Really anything that affects the methionine cycle PMID: , PMID: , PMID: Copyright 2019: Carrie Jones ND, MPH 36

38 Dietary and other considerations? Brassica family Broccoli, kale, Brussels sprouts etc Broccoli sprouts Artichoke Leafy greens Raw unpeeled carrots Onions/garlic Foods high in fiber Ground flax seeds Fermented foods Glucoraphanin/Sulforaphane Broccoli sprouts NAC/Liposomal glutathione Resveratrol Calcium-D-glucarate (check beta glucuronidase levels in stool) Copyright 2019: Carrie Jones ND, MPH 38

Speaking of What about Estrogen and the Gut Microbiome?

40 What does beta-glucuronidase do to estrogen? It is an enzyme in colonocytes It deconjugates things Estrogen My Analogy: The body puts estrogen in a box and ties it up with a bow to be excreted in the stool (glucuronidation). Beta-glucuronidase unties the bow and opens the lid allowing estrogen to escape and get reabsorbed Copyright 2019: Carrie Jones ND, MPH 40

41 What increases beta-glucuronidase? Low consumption of: o Fruits and vegetables o Fiber o Pre and probiotic foods/supplements High consumption of: o Sugar o Processed foods o Standard American Diet o Alcohol o Toxicants o Antibiotics!! o Alcohol Copyright 2019: Carrie Jones ND, MPH 41

Supplement: Calcium-d-Glucarate MOA: Keeps the glucuronide group on the hydrophobic molecule for excretion (urine/gi) Dosing is VERY high: 1500-3000mg/day at a minimum (in animal studies, they were

42 Supplement: Calcium-d-Glucarate MOA: Keeps the glucuronide group on the hydrophobic molecule for excretion (urine/gi) Dosing is VERY high: mg/day at a minimum (in animal studies, they were on much higher doses based on mg/kg of body weight) Foods high in CDG (but not anywhere near therapeutic doses): oranges, carrots, apples, grapefruit, and cruciferous vegetables Copyright 2019: Carrie Jones ND, MPH 42

43 Where are androgens made in men? >95% of testosterone is made in the testicles Bound to SHBG (primarily) and albumin (minor) 80% of DHEA (no S ) is made in the adrenals 20% of DHEA (no S ) is made in the testicles 100% of DHEA-S is made in the adrenal glands Copyright 2019: Carrie Jones ND, MPH 43

44 Why does Testosterone decrease? Age Increased aromatization to estrogen (increased with fat tissue, insulin and stress) Zinc deficiency Possible Vitamin D deficiency (PTH) Possible low vitamin A levels Low cholesterol levels (cholesterol is the back bone) Decreased blood supply to the glands Steroid use (performance and corticosteroids) Testosterone supplementation (negative feedback to HPG) Opioid pain medications Elevated SHBG (= decreased free testosterone) Hypogonadism and/or removal of testes Testicular infection ie. mumps, orchitis Radiation to the groin area, chemo at-large Diabetes Hypothyroid High prolactin Regular alcohol use Ketoconazole (anti-fungal) Environmental exposure ie. phthalates, BPA EMF exposure/wifi Copyright 2019: Carrie Jones ND, MPH 44

45 The common reasons I see in YOUNG men: Age Increased aromatization to estrogen (increased with fat tissue, insulin and stress) Zinc deficiency Possible Vitamin D deficiency (PTH) Possible low vitamin A levels Low cholesterol levels (cholesterol is the back bone) Decreased blood supply to the glands Steroid use (performance and corticosteroids) Testosterone supplementation (negative feedback to HPG) Opioid pain medications Elevated SHBG (= decreased free testosterone) Hypogonadism and/or removal of testes Testicular infection ie. mumps, orchitis Radiation to the groin area, chemo at-large Diabetes Hypothyroid High prolactin Regular alcohol use Ketoconazole (anti-fungal) Environmental exposure ie. phthalates, BPA EMF exposure/wifi Copyright 2019: Carrie Jones ND, MPH 45

Did you know BPA alone can Estrogen Prolactin SHBG

gov/m/pubmed/25213476/ https://www.ncbi.nlm.nih.

i=3&from=/25213476/related https://www.ncbi.nlm.nih.

47 What causes increased Testosterone? 1.He may make robust levels naturally 2.Supplementation or natural support 3.Increased/healthy Growth Hormone levels 4.Resistance training/hiit 5.Low levels of SHBG = higher levels of free testosterone Copyright 2019: Carrie Jones ND, MPH 47

48 How much testosterone do men make per day? 4-7mg/day Testosterone is made at night during sleep Testosterone Serum Range per Quest labs: Total Testosterone Age Male (ng/dl) (nmol/l) >18 years Free Testosterone Age Male (pg/ml) (pmol/l) Years >69 Years Bioavailable Testosterone Age Male (ng/dl) (nmol/l) Years >69 Years SHBG Age Male (nmol/l) years >55 years Copyright 2019: Carrie Jones ND, MPH 48

50 What is SHBG? (Sex Hormone Binding Globulin) Glycoprotein binding globulin made primarily in the liver that requires calcium and zinc. *Main job is to preferentially bind up: DHT, testosterone, androstenediol (not androstenedione), estradiol, and then estrone in that order. DHEA, but not DHEA-S, can bind weakly to SHBG. Degraded in the extra-cellular space Copyright 2019: Carrie Jones ND, MPH 50

51 SHBG (Sex Hormone Binding Globulin) SHBG increased by: 1. High estrogens 2. Liver disease 3. Hyperthyroid or too much thyroid medication, 4. Dilantin (phenytoin), 5. Ground flax seeds (not the oil) 6. There is also a genetic mutation that slows the half-life causing more to float around the blood stream. SHBG decreased by: 1. Glucocorticosteroids 2. Other steroid use 3. Hypothyroid 4. High insulin (or too much medication) 5. Obesity 6. Cushing s Disease 7. Healthy levels of growth hormone and IGF-1 8. Avena sativa (mixed research but mg daily) 9. Urtica dioica ( mg daily). Copyright 2019: Carrie Jones ND, MPH 51

52 What is Epi-Testosterone? It s an epimer of testosterone Weak competitive antagonist to the androgen receptor (anti-androgen) Most males have an endogenous production of epitestosterone to testosterone ratio of roughly 1:1 Tested in urine (not serum or saliva) It does not increase with testosterone replacement Copyright 2019: Carrie Jones ND, MPH 52

53 What is 5a-Reductase? Located in the reproductive tract, gonads, skin, and nervous system 5a Reductase pathway Converts testosterone to more potent DHT (tested in serum or urine) Converts androstenedione to androsterone (tested in urine) Increased via: genetics, inflammation, insulin, obesity 5b reductase pathway Less androgenic pathway Copyright 2019: Carrie Jones ND, MPH 53

54 What is 5a-DHT? Free Testosterone is reduced to 5a-DHT by 5a-reductase in target tissue cells About 5% of free testosterone naturally turns into DHT Binds more strongly to androgen receptor and tougher to knock off than T Action is approximately 2-5x stronger than testosterone Side effects if elevated: Male pattern baldness, acne, anger/irritation worsened, prostate problems Copyright 2019: Carrie Jones ND, MPH 54

55 Testosterone Elevated 5a-reductase levels: Androsterone, 5a-DHT and 5a-Androstanediol Address the cause Saw Palmetto Stinging Nettle Root Zinc Pygeum EGCG from Green Tea Reishi Mushroom Copyright 2019: Carrie Jones ND, MPH 55

56 DHEA (no S) versus DHEA-S DHEA-S is the sulfate ester of DHEA DHEA DHEA-S via the SULT2A1 snp and sulfotransferase enzyme DHEA-S DHEA via the sulfatase enzyme (STS) in adrenals, liver and intestines DHEA supplementation converted to DHEA-S in liver and intestines DHEA-S is the most abundant circulating steroid in the body DHEA-S cannot cross into the brain via the blood brain barrier, can cross out once made from within the brain DHEA-S has no diurnal pattern but DHEA (no s) does Copyright 2019: Carrie Jones ND, MPH 56

57 DHEA/DHEA-S Causes of higher DHEA: DHEA supplementation Elevated cortisol Non-Classical Congenital Adrenal Hyperplasia High prolactin Alcohol Nicotine Medications: Alprazolam, Anastrozole, Methylphenidate, Amlodipine, Diltiazem and Bupropion Causes of lower DHEA: Age naturally declines with aging HPA Axis dysfunction Inflammation inflammation lowers sulfation (this DHEA-S but DHEA SULT2A1 problems Medications: Glucocorticosteroids, Opioids, Pulmicort (inhaler), Metformin/Glucophage ( Copyright 2019: Carrie Jones ND, MPH 57

58 DHEA and DHEA-S DHEA-S more commonly tested due to its lack of a circadian rhythm Can be tested in serum, saliva and urine Levels tend to decline with age Reminder: 80% of DHEA (no S ) is made in the adrenals 20% of DHEA (no S ) is made in the testicles 100% of DHEA-S is made in the adrenal glands DHEA-S Serum Range: mcg/dl or umol/l Copyright 2019: Carrie Jones ND, MPH 58

PSA Testing Screen for prostate cancer done in serum Often done with PSA Velocity or doubling time = change in PSA over time Elevated results: prostate cancer, BPH, prostatitis, activities that

59 PSA Testing Screen for prostate cancer done in serum Often done with PSA Velocity or doubling time = change in PSA over time Elevated results: prostate cancer, BPH, prostatitis, activities that affect the prostate such as biking, anal sex or a DRE prior to testing, A high total PSA with a low free PSA percent = much higher risk for prostate cancer Serum Total PSA: age 49 or younger: ng/ml age 50 to 59: ng/ml age 60 to 69: ng/ml age 70 or older: ng/ml Serum Free PSA Percent: 0-10% = very concerning 10-24% = depends on risk, DRE, symptoms >25% = less risk, considered less concerning Murrell D. What is a free PSA test and what is it for? MedicalNewsToday Retrieved from Copyright 2019: Carrie Jones ND, MPH 59

60 Summary: 1. Make sure you test his testosterone levels first thing in the morning! 2. There are SEVERAL reasons for low testosterone don t just jump to HRT or supplements that allegedly raise testosterone. Address the cause if you can! 3. It takes almost 3 months to make a sperm for fertility, make sure your treatments are at least 3 months to ensure turnover of the old for the new 4. You can get a lot of information out of serum testing however it is missing key pieces 5. You can get a lot of information out of saliva testing however it is missing key pieces 6. You can get a lot of information out of urine testing - it does include metabolites (ie. estrogen detoxification), month long testing, organic acids etc. 7. Understand if he needs help with phase 1, phase 2 and/or phase 3 estrogen detoxification treatments are NOT the same and men get estrogen excess. Copyright 2019: Carrie Jones ND, MPH 60

61 References: Resolve. (2016). Male Factor. Retrieved on October 11, 2016 from Centers for Disease Control and Prevention. (2016). Prostate Cancer Statistics. Retrieved on October 11, 2016 from Ogden C, Carroll M, Fryar C, Flegal K. (2015). Prevalence of Obesity Among Adults and Youth: United States, Retrieved on October 11, from Stanworth RD, Jones TH. Testosterone for the aging male; current evidence and recommended practice. Clinical Interventions in Aging. 2008;3 (1): Newman T. (2015). DHT (Dihydrotestosterone): What is DHT s Role in Male Pattern Baldness? Retrieved on October 11, 2016 from Guilliams, T. (2015). The Role of Stress and the HPA Axis in Chronic Disease Management. Stevens Point, WI: Pointe Institute. Abdel-Rahman M and Lucidi R. (2015). Androgen Excess. Retrieved on October 11, 2016 from Bahar A, Akha O, Kashi Z, and Vesgari Z. Hyperprolactinemia in association with subclinical hypothyroidism. Caspian J Intern Med Spring; 2(2): Zeitlin S, and Rajfer J. Hyperprolactinemia and Erectile Dysfunction. Rev Urol Winter; 2(1): Hirsch I. (2016) Male Hypogonadism. Retrieved on October 11, 2016 from Quest Diagnostics. (2016). Testosterone, LC/MS/MS. Retrieved on October 11, 2016 from Quest Diagnostic. (2016). DHEA sulfate, Immunoassay. Retreived on October 11, 2016 from Quest Diagnostics. (2016). Dihydrotestosterone, LC/MS/MS. Retrieved on October 11,2016 from Quest Diagnostics. (2016). Prolactin. Retrieved on October 11, 2016 from Starka L. Epitestosterone. J Steroid Biochem Mol Biol Oct;87(1): Balunas M, Su B, Brueggemeier R, and Kinghorn A. Natural Products as Aromatase Inhibitors. Anticancer Agents Med Chem Aug; 8(6): Zhao J, Dasmahapatra A, Khan S, Khan I. Anti-aromatase activity of the constituents from damiana (Turnera diffusa). J Ethnopharmacol Dec 8;120(3): Yeksan M, Polat M, Turk S, Kazanci H, Erdogan Y and Erkul I. Effect of vitamin E therapy on sexual functions of uremic patients in hemodialysis. Int J Artif Organs Nov;15(11): Brandao Neto J, de Mendonca B, Shuhama T, Marchini J, Madureira G, Pimenta W, Tornero M. Zinc: an inhibitor of prolactin (PRL) secretion in humans. Horm Metab Res Apr;21(4):203-6 Fujita R, Shimizu K, Konishi F, Noda K, Kumamoto S, Ueda C, Tajri H, Kaneko S, Suimi Y, and Kondo R. Anti-androgenic activities of Ganoderma lucidum. J Ethnopharm. 2005;102: Schernhammer E and Hankinson S. Urinary Melatonin Levels and Postmenopausal Breast Cancer Risk in the Nurses Health Study Cohort. Cancer Epidemiol Biomarkers Prev Jan; 18(1): doi: / EPI Sephton S, Sapolsky R, Kraemer H, and Spiegel D. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. JNCI J Natl Cancer Inst (2000) 92 (12): doi: /jnci/ Travison, TG, AB Araujo, AB O Donnell, V Kupelian, JB McKinlay A population-level decline in serum testosterone levels in American men. Journal of Clinical Endocrinology and Metabolism 92: Copyright 2019: Carrie Jones ND, MPH 61

Issues. What is a low testosterone? Who needs testosterone therapy? Benefits/adverse effects of testosterone replacement Treatment options

Issues. What is a low testosterone? Who needs testosterone therapy? Benefits/adverse effects of testosterone replacement Treatment options Male Hypogonadism Jauch Symposium Waterloo, IA May 17, 2013 Janet A. Schlechte, M.D. Disclosure of Financial Relationships Janet A. Schlechte, M.D. has no relationships with any proprietary entity producing