FOUNDATIONAL PRINCIPLES OF BIO-IDENTICAL HORMONE REPLACEMENT THERAPY: THE WHO, WHAT, WHERE, WHEN, AND WHYS. Dr. Kristy A. Prouse, MD, FRCSC (OB/Gyn)

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2 FOUNDATIONAL PRINCIPLES OF BIO-IDENTICAL HORMONE REPLACEMENT THERAPY: THE WHO, WHAT, WHERE, WHEN, AND WHYS Dr. Kristy A. Prouse, MD, FRCSC (OB/Gyn) 2

3 HOUSEKEEPING Cell Phones Download the Slides Questions No photography, audio, or video recordings 3

4 DISCLAIMER DISCLAIMER: The information contained in this program, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding, is FOR EDUCATIONAL PURPOSES ONLY and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO MEDICAL OR ALLIED HEALTH PROFESSIONAL: Any treatments, therapies, or standards of practice must be fully investigated and prescribed by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia. 4

ACCREDITATION PHARMACIST & PHARMACY TECHNICIAN CREDITS CPE Consultants, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education and

5 ACCREDITATION PHARMACIST & PHARMACY TECHNICIAN CREDITS CPE Consultants, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education and complies with the Accreditation Standards for continuing education activities. Activity Type Pharmacist Pharmacy Technician Pharmacist UAN L01-P L01-T Credits 1 CPE Hours = 0.1 CEUs 1 CPE Hours = 0.1 CEUs Release Date October 28 th 2018 October 28 th 2018 Expiration Date October 28 th 2019 October 28 th

6 ACCREDITATION HOW TO OBTAIN CREDITS Create your LP3 Account Register for WCC 2018 Workshops Note the Tacking Code at the END OF THE PRESENTATION Submit a completed Evaluation (within 14 days) online for each Workshop. 5 Statement of credits will be provided within 30 days. 6

7 KRISTY A. PROUSE, MD, FRCSC Associate Professor, University of Toronto- Faculty of Medicine B.A. Psychology and B.Sc. In Genetics and Cell Biology Specialized in Anti-aging and Regenerative Medicine Established the Institute for Hormonal Health in 2011 and the IHHeLP Initiative I have no financial relationships to disclose 7

8 LEARNING OBJECTIVES PHARMACISTS 1. Define differences between bioidentical hormones and non-bioidentical hormones. 2. Review steroidogenic pathway. 3. Compare conventional HRT with bioidentical HRT in terms of clinical efficacy, breast cancer risk, and cardiovascular risk. 4. Recognize the importance of diagnostic testing. 5. Identify principals of prescribing BHRT, dosing BHRT, applying BHRT, and troubleshooting BHRT. 8

9 LEARNING OBJECTIVES PHARMACY TECHNICIANS 1. Define differences between bioidentical hormones and non-bioidentical hormones 2. Recognize the clinical benefits and demand for personalized BHRT. 3. Identify elements that should be found in a BHRT prescription, including dosage strength and dosage form. 4. Evaluate common challenges encountered with BHRT formulations. 9

10 PHYSIOLOGY OF SEX HORMONES 10

11 PHYSIOLOGY OF THE MENSTRUAL CYCLE By Lyrl - Derived from Image:MenstrualCycle.png, an image made by the user Chris

12 STEROIDOGENIC PATHWAYS cholesterol Testosterone Progesterone Aldosterone Cortisol Estrogens 12

13 CLASSIFICATION AND SYMPTOMATOLOGY OF SEX HORMONE IMBALANCES 13

14 CLASSIFICATION IMBALANCE AND DEFICIENCIES IMBALANCES IMBALANCES Estrogen Dominance Relative Estrogen Dominance Elevated Androgens Estrogen Progesterone Testosterone 14

15 SYMPTOMATOLOGY ESTROGEN DOMINANCE Perimenopausal Sx Anovulation PMS Menorrhagia Dysmenorrhea Cyclical breast tenderness Consequences of Estrogen Dominance Endometriosis Fibroids Breast/cervical/uterine cancer Thyroid related problems ELEVATED ANDROGENS (FEMALE) Male pattern hair loss Male pattern hair growth Acne/oily skin Irritability/Aggressiveness Breast tenderness Hypersexuality Clitoromegaly Deepening voice 15

SYMPTOMATOLOGY LOW ESTROGEN OR PROGESTERONE Hot flashes Memory decline Anxiety Insomnia Weight gain Vaginal dryness Painful intercourse Decreased libido Crawly skin Frequent

16 SYMPTOMATOLOGY LOW ESTROGEN OR PROGESTERONE Hot flashes Memory decline Anxiety Insomnia Weight gain Vaginal dryness Painful intercourse Decreased libido Crawly skin Frequent bladder infections LOW TESTOSTERONE (FEMALE) Decreased libido Decreased arousal/orgasm Decreased nipple sensation Loss of muscle mass Loss of vitality Decreased exercise tolerance 16

17 DIAGNOSIS OF SEX HORMONE IMBALANCES 17

18 DIAGNOSIS Symptomatology: Imbalances/Deficiencies Physical Examination: breast and pelvic Saliva: historically gold standard for baseline Dried urine spot: baseline or for those on hormone replacement Bloodwork: underestimates hormone levels 18

19 CASE STUDY #1 CASE INFORMATION 47 y/o peri-menopausal female not on any hormone replacement therapy complaining of heavy periods with breast tenderness in the week before her period. She is complaining of new onset anxiety and sleeplessness. 19

20 CASE STUDY #2 CASE INFORMATION 57 year old PM female complaining of hot flashes, sleep disruption and vaginal dryness. Further questionig reveals decreased sex drive unrelated to vaginal dryness and painful intercourse. 20

21 CASE STUDY #3 CASE INFORMATION 47 yo post-menopausal female started on Estrogel 1 pump and Prometrium 100mg po by her family doctor without testing. She is largely asymptomatic however with questioning she does note occasional breast tenderness. She has not had any PV bleeding and endometrial thickness is 4mm. 21

22 BIO-IDENTICAL HORMONE REPLACEMENT THERAPRY (BHRT) 22

23 DEFINITIONS Bio-identical Hormone: have a chemical structure identical to endogenous human hormones but are chemically synthesized such as estriol, estradiol, progesterone and testosterone. Non-bio-identical hormones: are not structurally identical to human hormones and may either be chemically synthesized such as MPA (progestin) or derived from a nonhuman source such as CEE (conjugate equine estrogens). Progesterone: our own endogenous hormone. Progestins: synthetic chemicals that mimic the effects of progesterone by binding to progesterone receptors e.g., MPA Progestogens: an umbrella term for both progesterone and progestins. 23

24 BIO-IDENTICAL VS CONVENTIONAL HRT Bio-identical Progesterone Synthetic Progestins Clinical Efficacy Best Good Physiologic actions on breast tissue Risk of breast cancer Protective Protective Negative Increased Risk of CVD Protective Increased Risk of DVT None None Bio-identical E2/E3-TD Synthetic Estrogens Breast cancer risk Protective Increased DVT risk None Increased Holtorf, K. Postgraduate Medicine,

25 FDA/HEALTH CANADA APPROVED HORMONES Brand Name Estrace po/pv Esclim TD patch Climara TD patch Estraderm TD patch Vivelle TD patch Estrogel TD gel Estrasorb TD cream Estring vaginal ring Femring vaginal ring Vagifem vaginal tablet Prometrium po Procheive 4% vaginal gel Type/Source Bio-identical? 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes 17 Beta-estradiol/plant Yes Estradiol acetate Yes Estradiol hemihydrate Yes Progesterone micronized Yes Progesterone Yes Holtorf, K. Postgraduate Medicine,

26 FDA/HEALTH CANADA APPROVED HORMONES Brand Name Premarin po/pv Estinyl po Provera po Ovrette po Micronor po Prempro po FemHRT po Combipatch TD Climara Pro TD Type/Source Bio-identical? Conjugated equine estrogens No Ethinyl estradiol No Medroxyprogesterone acetate (MPA) No Norgestrel No Norethindrone No CEE and MPA No Ethinyl acetate and norethindrone acetate No 17 beta estradiol and norgestimate No 17 beta estradiol and levonorgestrel No Holtorf, K. Postgraduate Medicine,

27 COMPOUNDED BIO-IDENTICAL HRT BiEst (Estradiol/Estriol) TD Estriol pv Progesterone po/td Testosterone TD 7-keto DHEA SL/TD DHEA SL/TD 27

29 PRINCIPLES OF PRESCRIBING HRT Start low and go slow Balance Physiologic ranges Understand downstream hormones Avoid down regulation of receptors Conversion dosing TD po (x4-5) Perform baseline investigations 29

30 BASELINE INVESTIGATIONS Trans-vaginal pelvic ultrasound (TVUS) PAP smear Mammogram or thermography Bone Mineral Density (BMD) 30

31 PROGESTERONE 31

PROGESTERONE Used to balance estrogen and to support cortisol production TD or po applications most common Prescribed orally for sleep/anxiety Given

32 PROGESTERONE Used to balance estrogen and to support cortisol production TD or po applications most common Prescribed orally for sleep/anxiety Given cyclically to menstruating woman Given daily (with a day of rest) to post-menopausal woman Initiate dose according to test results and titrate to symptoms 32

33 TYPICAL PROGESTERONE DOSING Pre-Menopausal Compounded progesterone mg SR po qhs D15-28 (or until menses begins if before day 28) **increments of 25mg Compounded progesterone cream 5-30mg TD qhs D15-28 (or until menses begins if before day 28) **increments of 5mg Post-Menopausal Compounded progesterone mg SR po qhs Monday to Saturday **increments of 25mg Compounded progesterone cream mg TD qhs Monday to Saturday **increments of 5mg 33

34 OVER-REPLACEMENT OF PROGESTERONE Slow to wake up or groggy in the morning Breast tenderness Cystic acne Low mood Swelling in hands and legs Sluggish bowels/bloating Hot flashes (body interprets estrogen as too low) Insulin resistance and weight gain 34

35 BI-EST 35

36 ESTROGEN METABOLISM 36

daily (with a day of rest) to post-menopausal woman Initiate dose according

37 BI-EST Used to replace estrogen when objectively deficient Combination of estradiol and estriol (20:80) or (50:50) Transdermal application only Given daily (with a day of rest) to post-menopausal woman Initiate dose according to test results and titrate to symptoms Must be balanced with progesterone 37

38 TYPICAL BIEST DOSING Pre-Menopausal Compounded BiESt cream 80:20 (E3/E2) mg TD OD day 1-25 **Increments of 0.05mg Post-Menopausal Compounded BiEST cream 80:20 (E3/E2) mg TD BID Monday to Saturday **Increments of 0.5mg Surgical menopause may require higher doses to manage symptoms 38

39 OVER-REPLACEMENT OF ESTROGEN Irritability or weepiness Acne Breast tenderness Swelling Post-menopausal vaginal bleeding 39

40 TROUBLESHOOTING ESTROGEN Hot flashes worse at a certain time of day Transition from peri to post-menopausal dosing Timing of switch from cyclic to daily hormones 40

41 ESTRIOL 41

ESTRIOL FOR UROGENITAL ATROPHY Used for vaginal atrophy resulting in bothersome vaginal dryness, painful intercourse or recurrent urinary tract infections

42 ESTRIOL FOR UROGENITAL ATROPHY Used for vaginal atrophy resulting in bothersome vaginal dryness, painful intercourse or recurrent urinary tract infections Transvaginal application Administered in tapering doses at bedtime May be transferred to sexual partner May initiate without testing based on symptoms and physical examination 42

43 TYPICAL VAGINAL ESTRIOL DOSING Compounded Estriol vaginal cream mg qhs x 2 weeks, then twice weekly thereafter 43

44 TESTOSTERONE 44

TESTOSTERONE REPLACEMENT Used to replace testosterone when proven deficient AND with symptoms of deficiency Transdermal application only Administered Monday to Saturday Initiate dose according to

45 TESTOSTERONE REPLACEMENT Used to replace testosterone when proven deficient AND with symptoms of deficiency Transdermal application only Administered Monday to Saturday Initiate dose according to test results and titrate to symptoms Woman must have adequate endogenous estrogen and if not, then estrogen replacement to balance Elevated dihydrotestosterone (DHT) Downstream impact on estrogen 45

46 OVER-REPLACEMENT OF TESTOSTERONE Angry/aggressive Acne/oily skin Clitoromegaly Hirsutism Deepening of the voice 46

Administered Monday to Saturday Initiate dose according to test results

47 TESTOSTERONE REPLACEMENT Used to replace testosterone when proven deficient AND with symptoms of deficiency Transdermal application only Administered Monday to Saturday Initiate dose according to test results and titrate to symptoms Elevated Dihydrotestosterone (DHT) Downstream impact on estrogen 47

TYPICAL TESTOSTERONE DOSING Female Compounded testosterone cream 0.5-1.25mg TD qam Monday to Saturday **increments of 0.

48 TYPICAL TESTOSTERONE DOSING Female Compounded testosterone cream mg TD qam Monday to Saturday **increments of 0.25mg Male Compounded testosterone cream mg TD qam Monday to Saturday **increments of 40mg ***desired fertility-do not use testosterone ****controlled substance 48

49 DELIVERY METHODS 49

50 CARRIER BASES FOR BHRT Carrier bases Fillers Vaginal (E3) Application sites 50

51 CARRIER BASES FOR BHRT Use base creams specified for HRT for stability of API and penetration Allows for consistency in dosing Allows for consistent potency over time Can be used both transdermally and transmucosally Choose hypoallergenic cream Choose paraben-free 51

52 PROGESTERONE CAPSULE FILLERS Progesterone is a BCS Class IV Drug (Class 4: Low Solubility Low Permeability) Lactose (non-specific excipient) should be avoided for those with lactose allergies Poor powder blend flowability May interact negatively with various APIs Cellulose is considered a neutral filler Minimal if any adverse reations Does not improve dosage form (eg.,enhance drug dissolution, improve chemical stability, increase efficiency, reduce static of actives, etc.) Blended Excipients 52

53 VAGINAL APPLICATION Use a suppository base to avoid vaginal irritation (instead of gels/creams) Hormones are lipophilic and so preparation with a lipophilic base will provide slower release 53

54 ESTROGEN/PROGESTERONE APPLICATION SITES 54

55 TESTOSTERONE APPLICATION SITES 55

56 TRACKING CODE WCC2018HRT2 56

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