Female Hormone Protocol © 2015, Pamela W

Female Hormone Protocol 3 By Pamela W. Smith, MD, MPH, MS

Disclaimer

• The suggested dosages are for educational purposes only.

• They are suggestions for patients with normal renal and hepatic function.

• They are based upon my research and my personal and professional experiences after reviewing over 20,000 saliva tests.

• They are not intended as a substitute for a personalized approach to each patient but are designed instead to be a guideline. A complete medical history including patient symptomology should be taken and considered when prescribing hormones for patients.

• PCCA and Pamela W. Smith, M.D., MPH, MS are not responsible for any adverse effects or consequences resulting from the use of any of these suggestions or preparations.

How to Use this Protocol

This protocol is designed for women who are not currently on natural hormone replacement. It is divided into three sections of women with the following possible diagnoses being considered.

• PMS/PCOS/Infertility/PMDD

• Peri-menopause

• Menopause

©2015 (Updated 02-16) This protocol is protected by Federal United States Copyright laws and International Copyright laws. No portion of this protocol can be copied or disseminated in any form without the express permission of Pamela W. Smith, MD Any dissemination of this seminar or contents of this seminar without express permission from Pamela W. Smith, M.D. will result in a $10,000 fine.

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Table of Contents

The Triad...... 6

Education...... 7

Pre-Menopause (PMS, PCOS, Infertility, PMDD)...... 11

Peri-Menopause...... 17

Menopause...... 23

Other Important Hormones...... 30

Appendix...... 39

Studies...... 43

Forms/References...... 51

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The Triad The foundation of the profession.

Patient

Relationships

Prescriber Pharmacist

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Prescribing Hormones Before prescribing hormones, it is very important to know how much of each hormone that the body makes in a day.

24-Hour Production Rates of Sex Steroids in Women at Different Stages of the Menstrual Cycle

Sex Steroids Early Follicular Preovulatory Midluteal

Progesterone (mg) 1.0 4.0 25.0

17-hydroxy-progesterone (mg) 0.5 4.0 4.0

Dehydroepiandrosterone (mg) 7.0 7.0 7.0

Androstenedione (mg) 2.6 4.7 3.4

Testosterone (mcg) 144.0 171.0 126

Estrone (mcg) 50.0 350.0 250.0

Estradiol (mcg) 36.0 380.0 250.0

Start Low and Go Slow! It Is All About Balance!

Traditional Estrogen Dosing Information Biest is commonly prescribed in estrogen replacement and is a combination of estradiol (E2) and estriol (E3). Traditionally the prescription is written as 80% E3 and 20% E2. The compound prescription should be guided by the results of the patient saliva tests and can be any percentage of E2/E3 that is suitable for the patient. Compounded estrogen for hormone replacement always needs to be prescribed transdermally or transvaginally. Always prescribe with VersaBase®, which was designed for hormone replacement therapy.

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A Quick Warning for Estrogen Given by Mouth. It Could... Increase blood pressure Increase triglycerides Increase estrone (E1) Cause gallstones Elevate liver enzymes Increase sex hormone binding globulin (SHBG) (decreases testosterone) Interrupt tryptophan metabolism and consequently serotonin metabolism Lower growth hormone Increase prothrombic effects Increase c-reactive protein (CRP) Increase carbohydrate cravings

Tips for Dispensing Hormones Transdermally It is best to dispense to patients in 1 mL syringes. Doing so allows hormones to be dispensed over a wider area for better absorption. It is best not to dispense in less than 0.5 mL syringes and larger syringes make it harder for patients to see the needed dosage. Another dosage option is the PCCA MegaPump or PCCA Mini MegaPump line (see pages 48 or 49 for information). • Sizing and approximate dispensing information for the PCCA MegaPump family: 150 mL dispenses approximate at 1.0 mL 30 mL and 75 mL dispenses at approximately 0.5 mL 10 mL and 15 mL dispense at approximately 0.2 mL

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Methocel™ E4M CR (E4M) Dosing Immediate release capsules are designed to release the medication quickly for systemic absorption. However, the low bioavailability of some hormones in these capsules would require frequent daily dosing, and the side effects of this dosing would not be desirable. Therefore, many patients will benefit from slow release oral capsules.

This can be achieved by using Methocel™ E4M CR in the capsule, which creates a hydrophilic matrix system that allows for consistent drug release over a longer time period.

However, this dosage form is not available as such in the pharmaceutical industry and would have to be compounded. When an encapsulated formulation consisting of an API, Methocel™ E4M CR and an inert filler comes in contact with fluid in the intestine, a gel matrix forms. This gel continually allows water to penetrate into the mass and maintains uniform drug release.

When using E4M dosing make sure the patient has a healthy GI tract or the medication will not be well dispersed. If the gut is not healthy, do a GI effects test and then use the 4R program for GI health. As can be seen in the dosing suggestions throughout this protocol, it is important for the prescriber to write E4M on the prescription.

Effect of LoxOral™ and Lactose on In Vitro Dissolution Studies of Progesterone Sustained Release Capsules LoxOral and lactose monohydrate oral delivery systems showed similar in vitro sustained progesterone release profile from capsules. Based on the performances of both formulations, there is a great potential of interchangeability between LoxOral and lactose monohydrate as excipients of sustained release progesterone capsules. However, LoxOral confers advantages in compounding progesterone formulations because it is a base with enhanced quality attributes, such as excellent flowability, reduced static and minimum hygroscopicity. For the full study, see page 47.

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Pre-Menopause (PMS, PCOS, Infertility, PMDD)

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28-Day Saliva Testing

This test contains all three estrogens (estrone, estradiol, and estriol) as well as progesterone, testosterone, DHEA, cortisol and melatonin. 28-day saliva testing is a very beneficial test for younger women. • PCOS • PMS • Infertility • PMDD

Example of a 28-Day Saliva Test of a PCOS Patient Estradiol Progesterone Testosterone

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Norms for Estradiol on 28-Day Saliva Test Follicular: 2.8–8.8 pmol/L Peak: 4.5–19.1 pmol/L Luteal: 2.8–8.2 pmol/L Menopausal: 3.7–9.4 pmol/L

Cycling Women with Low Levels of Estrogen Cycling women very rarely need estrogen replacement, but if they do, see below for some useful information. Usually this is an indicator that insulin is not working effectively in the body. Measure Fasting Blood Sugar (FBS), fasting insulin, HgBA1C and postprandial insulin. Normalizing insulin will help bring up estrogen levels. Start these women on a low GI program and exercise three times a week • Chromium 1,200–1,600 mcg (dose is for patients with normal renal function) • And/or alpha lipoic acid 300 mg • And/or Metagenics Insinase® if insulin level is high • And/or berberine 200 mg BID

How to Lower High Estrogen Levels in Cycling Women If progesterone is low, balance the estrogen dominance with progesterone Start these women on a liver detoxification Weight loss if the patient is overweight Decrease exposure to environmental estrogens Decrease intake of foods that are phytoestrogens

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Guidelines for Younger Female Patients Not on Progesterone PMS/PCOS/Infertility/PMDD

Progesterone • Oral administration of Progesterone E4M capsules 25 to 300 mg Give cyclically days 14 through 25 at bedtime • Topical administration 5 to 30 mg cream Give cyclically days 14 through 25 in the morning

Norms for Progesterone on 28-Day Saliva Test

Follicular: 120–593 pmol/L Peak: 328–1385 pmol/L Luteal: 145–797 pmol/L Menopausal: 163–669 pmol/L Progesterone can be given transdermally, orally or transvaginally. Doses are for transdermal and oral.

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Dosing Progesterone in the Luteal Phase PMS/PCOS/Infertility/PMDD (continued)

For results between 328–450 pmol/L dose: • 25–30 mg progesterone cream days 14–25 • 200–250 mg progesterone E4M days 14–25 For results between 450–700 pmol/L dose: • 20–25 mg progesterone cream days 14–25 • 140–200 mg progesterone E4M days 14–25 For results between 700–900 pmol/L dose: • 15–20 mg progesterone cream days 14–25 • 120–150 mg progesterone E4M days 14–25 For results between 900–1,000 pmol/L dose: • 5–10 mg progesterone cream days 14–25 • 90–120 mg progesterone E4M days 14–25 For results between 1,000–1,385 pmol/L: • No progesterone is usually needed. Herbal therapies like chasteberry are commonly used if the patient has symptoms. • If using progesterone dose: 3–5 mg progesterone cream days 14–25 35–50 mg progesterone E4M days 14–25

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Younger Female Patients Not on HRT: Testosterone

Normal: 34–148 pmol/L Goal is around 70–100 pmol/L Always give transdermally or transvaginally Doses are for transdermal application Apply to thigh or buttock and rub in for two minutes It is important to rotate sites or women may grow hair at the site of application

Dosing Testosterone

For results <30 pmol/L, dose: • 1–2 mg testosterone cream qd For results between 30–40 pmol/L, dose: • 0.75 mg–1 mg testosterone cream qd For results between 40–60 pmol/L, dose: • 0.5–0.75 mg testosterone cream qd For results between 60–75 pmol/L, dose: • 0.25–0.5 mg testosterone cream qd For results 75 pmol/L or higher: • Does not need testosterone

How to Lower Testosterone Levels if They are Elevated

Confirm the patient is not getting testosterone by transference from her partner

Decrease exercise if the patient exercises daily

Recommend that the patient start saw palmetto 240–260 mg BID

Metformin 250 mg compounded as the starting dose • If patient is insulin resistant or FBS and fasting insulin levels are not optimal

Spironolactone 100 mg BID • As a last resort to lower testosterone

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Peri-Menopause

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Six-Day Saliva Testing

If peri-menopausal woman do not want to do a 28-day test, then this test is very beneficial since their hormones may change over time. This test contains all three estrogens (estrone, estradiol, and estriol) as well as progesterone, testosterone, DHEA, cortisol and melatonin.

Start the test on day 16 of their cycle if their cycle is a 28-30 day cycle. Specimens are collected on days 16, 18, 20, and 21. If the patient’s cycle is shorter then begin the test on day 14 of their cycle. If the patient’s cycle is longer than 30 days then start their test on day 18 of their cycle. A one-day test can still be used for these women if 28-day and six-day are not an option. Start the one-day test on day 20 or 21 of their cycle. If the patient really needs to do a 28-day test but will not do one for one reason or another, then have them do a one-day test on day four of their cycle and another one-day test on day 21 of their cycle. For younger women, a 28-day always gives you more information.

Norms for Estrogens on Six-Day Test Estradiol • Follicular: 2.8–8.8 pmol/L • Peak: 4.5–19.1 pmol/L • Luteal: 2.8–8.2 pmol/L • Menopausal: 3.7–9.4 pmol/L Estrone • 4.7–18.9 pmol/L Estriol • <133 pmol/L

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Peri-Menopausal Patients Not on HRT: Estradiol Cycling women very rarely need estrogen replacement. The exception to this is menstrual migraines at peri-menopause. If the patient develops menstrual migraines or if they become more common or much more severe peri-menopausally, then start: • Biest Cream 0.10 mg per 1 mL in VersaBase®. • Sig: apply qd to thigh. Rub in for two minutes. Rotate sites.

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General Dosing Guidelines Peri-Menopause

Oral administration of Progesterone E4M capsules (if issues with insomnia and better breast protection) • Progesterone E4M 25 to 200 mg days 14–25 • May need to give low dose days 4–13 Topical administration • Progesterone 10–30 mg days 14–25 May need to give low dose on days 4–13

Norms for Progesterone on Six-Day Saliva Test

Follicular: 120–593 pmol/L Peak: 328–1,385 pmol/L Luteal: 145–797 pmol/L Menopausal: 163–669 pmol/L Can be given transdermally, orally, or transvaginally. Doses are for transdermal and oral.

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Dosing Progesterone for Peri-Menopause: Not on HRT

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Peri-Menopausal Patients Not on HRT: Testosterone

Normal: 34–148 pmol/L Goal is around 70–100 pmol/L Always give transdermally or transvaginally Doses are for transdermal application Apply to thigh or buttock and rub in for two minutes Important to rotate sites or the woman will grow hair at the site of application

Peri-Menopausal Patients Not on HRT: Dosing Testosterone For results <30 pmol/L, dose: • 1–2 mg testosterone cream qd For results between 30–40 pmol/L, dose: • 0.75 mg–1 mg testosterone cream qd For results between 40–60 pmol/L, dose: • 0.5–0.75 mg testosterone cream qd For results between 60–75 pmol/L, dose: • 0.25–0.5 mg testosterone cream qd For results 75 pmol/L or higher: • Does not need testosterone

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One-Day Saliva Testing

For menopausal women, a one-day saliva test is perfect. The one-day test includes all three estrogens (estrone, estradiol, and estriol) along with progesterone, testosterone, DHEA, cortisol and melatonin. Should be completed on day 20 or 21 of cycle.

Example of a One-Day Saliva Test for a Menopausal Patient

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Norms for Estrogens on 1-Day Test

Estradiol • Follicular: 2.8–8.8 pmol/L • Peak: 4.5–19.1 pmol/L • Luteal: 2.8–8.2 pmol/L • Menopausal: 3.7–9.4 pmol/L Estrone • 4.7–18.9 pmol/L Estriol • <133 pmol/L

General Dosing Guidelines Menopause

Topical administration • Bi-estrogen cream (80% E3:20% E2) 0.25–2.0 mg daily qd After six months, give patient a hormonal holiday • Progesterone cream 20 to 30 mg qd After six months, give patient a hormonal holiday • Testosterone cream 0.25 to 2.0 mg daily qd After six months, give patient a hormonal holiday Oral administration • Progesterone 25 to 150 mg E4M • After six months, give patient a hormonal holiday For peri-menopausal and menopausal women, oral progesterone offers breast protection.

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Traditional Estrogen Dosing for Menopausal Women

Biest is used for estrogen replacement: estradiol (E2) and estriol (E3). Put in VersaBase®, which is designed for hormones. Traditionally the prescription is written as 80%E3 and 20%E2. You can make the prescription any percentage of E2/E3 that you want it to be, guided by your saliva test result. Always give estrogen for hormone replacement transdermally or transvaginally. Re-measure in 90 days and adjust accordingly.

Estrogen Dosing: Menopause for Women Not on HRT

Do not replace E1. Dosing for E2: Estradiol level needs to be at least 6 pmol/L to be functional. Estradiol levels: • For results between 2.8–3.8 pmol/L, dose: Biest cream 0.75–1.0 mg 50%E2/50%E3 • For results between 3.8–4.8 pmol/L, dose: Biest cream 0.25–0.5 mg 50%E2/50%E3 • For results between 4.8–6.0 pmol/L, dose: Biest cream 0.25–0.75 mg 80%E3/20%E2 • For results between 6.0–8.2 pmol/L, dose: Biest cream 0.25 mg–0.75 mg 90%E3/10%E2 • For results > 8.2 pmol/L, dose: Does not need estrogen

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Estrogen Dosing: Menopause

E3 is given in ratio to E2 according to results of saliva testing. Commonly you start with 80%E3 and 20%E2, but the ratio of E3 to E2 can be any ratio that you want it to be. For example, if the lab results show that the level of E3 is 0 and the level of estradiol is 5.7, then use 90%E3/10%E2. After six months, give a hormonal holiday.

Norms for Progesterone on One-Day Saliva Test

Follicular: 120–593 pmol/L Peak: 328–1385 pmol/L Luteal: 145–797 pmol/L Menopausal: 163–669 pmol/L • You do not want to dose for menopausal normal. You want to turn back the clock so the patient maintains function. Can be given transdermally, orally, or transvaginally. Doses are for transdermal and oral.

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Dosing Progesterone for Menopause: Women Not on HRT

For results between 328–450 pmol/L dose: • 25–30 mg progesterone cream qd • 140–200 mg progesterone E4M days qd For results between 450–700 pmol/L dose: • 20–25 mg progesterone cream qd • 125–140 mg progesterone E4M qd For results between 700–900 pmol/L dose: • 110–140 mg progesterone E4M qd • 15–20 mg progesterone cream qd For results between 900–1,000 pmol/L dose: • 90–110 mg progesterone E4M qd • 5-10 mg progesterone cream qd For results between 1,000–1,385 pmol/L • No progesterone is usually needed. Herbal therapies like chasteberry are commonly used if the patient has symptoms. • If using progesterone dose: 3–5 mg progesterone cream qd 35–50 mg progesterone E4M qd After six months, give a hormonal holiday.

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Menopausal Patients Not on HRT: Testosterone

Normal: 34–148 pmol/L Goal is around 70–100 pmol/L Always give transdermally or transvaginally Doses are for transdermal application Apply to thigh or buttock and rub in for two minutes

Important to rotate sites or the woman will grow hair at the site of application Dosing Testosterone for Women Not on HRT

Hormonal Holiday

Giving women a hormonal holiday is beneficial to overall health if she is not going to cycle after menopause. Two methods for hormonal holiday: select one or the other • Take all of the hormones (pregnenolone, DHEA, estrogen, progesterone, testosterone) Monday through Saturday and none on Sunday. • Give all the hormones (pregnenolone, DHEA, estrogen, progesterone, testosterone) days 1–25 of the month with four days off.

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Dehydroepiandrosterone (DHEA)

Is a hormone made by the adrenal glands. A small amount is also made in the brain and skin. DHEA production declines with age starting in the late twenties. By the age of 70 the body may only make one-quarter of the amount of DHEA it made earlier. DHEA makes estrogen and testosterone in both women and men. DHEA levels may also change when the patient has stress at any age.

Functions of DHEA

Decreases cholesterol Decreases formation of fatty deposits Prevents blood clots Increases bone growth Promotes weight loss Increases brain function Increases lean body mass Increases sense of well-being Helps one deal with stress Supports the immune system Helps the body repair itself and maintain tissues Decreases allergic reactions Lowers triglycerides

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Cortisol and DHEA

Example of a 24-Hour Salivary Cortisol and DHEA Test of a PCOS patient

Note: This is included in the 28-day Saliva Test

DHEA Replacement

DHEA should be in the middle of the green section for optimal health. Normal DHEA: 71–640 pg/mL. Women are much more sensitive to DHEA than men. So start with low dosages. In younger women you may not need to replace DHEA since the cause of low DHEA is usually due to stress. Balance cortisol and the DHEA level will rise.

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DHEA Replacement for Women Not on HRT

For results between 0–40 pg/mL dose: • 10 mg DHEA E4M qam For results between 40–80 pg/mL dose: • 7.5 mg DHEA E4M qam For results between 80–120 pg/mL dose: • 5 mg DHEA E4M qam For results between 120–140 pg/mL dose: • 3.5 mg DHEA E4M qam For results between 140–200 pg/mL dose: • 1.0–2.5 mg DHEA E4M qam If the patient has normal or high testosterone then use ketoDHEA at the same dosages. DHEA can be given orally or transdermally but is usually given orally. DHEA can be mixed with pregnenolone in the same capsule.

Clinical Pearls on DHEA

DHEA balances cortisol. If cortisol levels are abnormal, then treat. Do not just give DHEA hoping that cortisol levels will come up. If cortisol is abnormal and you just give DHEA without working on the abnormal cortisol levels then the next time that you measure DHEA, the levels will be even lower.

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Functions of Cortisol

Balances blood sugar Weight control Immune system response Bone turnover rate Stress reaction Helps with good sleep hygiene Protein synthesis Improves mood and positive thinking Influences testosterone/estrogen ratio Influences DHEA/insulin ratio Affects pituitary/thyroid/adrenal system Participates with aldosterone in sodium reabsorption Is an anti-inflammatory

Treatment of Hyperadrenalism

Replace DHEA (if levels are low) with adrenal support Adaptogenic herbs Calming herbs Stress-reduction techniques If cortisol is high in the evening then add phosphatidylserine 300 mg, which may be taken any time of the day. Nutrients • Vitamin C • Selenium • B vitamins • Copper • Calcium • Sodium • Magnesium • Manganese • Zinc

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Treatment of Hypoadrenalism

Stress-reduction techniques Adaptogenic herbs Adrenal extracts (if adaptogenic herbs do not work) Calming herbs Licorice (cannot use if the patient has hypertension) Replace DHEA Nutrients • Vitamin C • Selenium • B vitamins • Copper • Calcium • Sodium • Magnesium • Manganese • Zinc

Cortef® (last resort after you have tried all the other therapies). When giving Cortef®, continue adrenal extracts.

Dose of Cortef® for Hypoadrenalism

The dose of Cortef® is for augmentation and not replacement since the patient dose not have Addison’s disease. Suggested dose of Cortef® • AM: 7.5 mg • Noon: 5 mg • 5 PM: 2.5 mg The patient should be on Cortef® only for six to nine months and not longer. The patient has to be weaned off of Cortef®.

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Melatonin Normal Melatonin

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Melatonin Replacement in Women

Normal range for melatonin • 7 AM–9 AM: £ 10.50 pg/mL • 3 PM–5 PM: £ 0.88 pg/mL • 2:30 AM–3:30 AM: 2.53–30.67 pg/mL Suggested dosages for melatonin replacement if middle of the night level is low. • 0–2.53 pg/mL: 2 mg qhs • 2.53–5 pg/mL: 1 mg qhs • 5–10 pg/mL: 0.5 mg qhs (may need to compound) • 10–15 pg/mL: 0.25 mg qhs (will need to compound) • >15 pg/mL: no melatonin is needed High levels of melatonin in the morning usually mean that cortisol levels were too low in the AM. If melatonin levels are too high any time of the day or night, then serotonin levels may go down. Middle of the night level is done with the lights off; otherwise, the reading will not be accurate.

Functions of Melatonin

Affects the release of sex hormones Aids the immune system Acts as an antioxidant Blocks estrogen from binding to receptor sites Decreases cortisol levels Helps balance the stress response Helps prevent cancer Improves mood Improves sleep quality Increases the action of benzodiazepines Stimulates the parathyroid gland Stimulates the production of growth hormone Cardioprotection

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Pregnenolone

Pregnenolone Replacement at Any Age

Pregnenolone is a serum test. Pregnenolone levels in some labs are not age dependent. • Normal: 15–132 ng/dL Pregnenolone levels in other labs may be age dependent. • Normal for pre-menopause: 7–188 ng/dL • Normal for post-menopause: 13–111 ng/dL Pregnenolone needs to be at least 50 ng/dL to maintain memory. Start with pregnenolone 10 mg E4M qam in most patients and repeat levels in 90 days. Adjust accordingly. Pregnenolone can be given transdermally, but is not commonly given this way. In younger patients, you may not need to replace pregnenolone if the patient has normal pituitary function since the cause of low pregnenolone is usually due to stress. Balance the cortisol level, and the pregnenolone will usually normalize in these patients without replacement.

Functions of Pregnenolone

Regulates the balance between excitation and inhibition in the nervous system Increases resistance to stress Improves energy both physically and mentally Enhances nerve transmission and memory Reduces pain and inflammation Blocks the production of acid-forming compounds Modulates the neurotransmitter GABA Helps to repair nerve damage Promotes mood elevation Improves sleep Modulates NMDA receptors

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Appendix

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What to do if levels come back too high?

If estrogen levels are too high, then detox the liver and weight loss if the patient is overweight. If progesterone is too high, then use herbal therapies such as chasteberry. If testosterone levels are too high • Saw palmetto 240–260 mg BID • Metformin 500 mg qam if the patient already has insulin resistance Must also give coenzyme Q-10 100 mg Must also start patient on B complex BID • Spironolactone 100 mg BID if the other therapies do not work If DHEA is too high, this can be due to stress, but it can also be due to an adrenal tumor. The patient may need to have a urine test for metanephrines and MRI of the adrenals. If pregnenolone is high, then repeat the study. If it is still elevated, then the patient needs to have an MRI of the pituitary to rule out a pituitary tumor.

Converting Administration Routes

Dosage comparisons difficult due to multiple influences on relative bioavailabilities Approximate ratio for topical: sublingual: oral • For progesterone, estrogen, DHEA: topical 1: sublingual 2: oral 4–5 • For testosterone: topical 1: subligual 2: oral 5–6 • Starting guideline only Switching to topical dosing may require higher initial dosing • Estrogen: 5–10 days • Progesterone and testosterone: 3 – 6 weeks Lab results may be confusing

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Prescribing Hormones

Many hormones can be mixed in the same capsule, syringe, or pump. If the patient is just starting hormones, then give the hormones separately and do not mix them in case you need to change the dosage of one of the hormones. After the dose is established, then it is more cost effective and convenient for the patient to mix some of the hormones together. For example, biest and testosterone can be mixed in the same syringe or pump. After the dose is established, it is more cost effective for the patient to give them a 90-day supply at a time. When you first prescribe hormones, re-measure the levels in 90 days. After this the hormones should be re-measured every six months.

Vaginal Dryness

Most common therapy used is estriol vaginal cream 0.5 mg to 2 mg. Most common dose is 1 mg. Estriol Vaginal Cream (or suppository) 1 mg in 50% VersaBase® and 50% MucoLox™ • Ex: 1 mg/0.5 mL vaginal cream. 0.5 mL is an appropriate volume for intravaginal delivery. Sig: Insert vaginally nightly for two weeks, Monday and Thursday for two weeks, then PRN. See page 52 for the use of MucoLox™ for Vulvovaginal Atrophy (VVA)

References Chollet, J., et al., “Efficacy and safety of vaginal estriol and progesterone in postmenopausal women with atrophic vaginitis,” Menopause 2009; 16:978–83. Chuery, A., et al., “Efficacy of vaginal use of topical estriol in postmenopausal women with urogenital atrophy,” Clin Exp Obstet Gynecol 2011; 38:143–45.

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Vaginal Administration

Vaginal administration has good absorption systemically. There is documented effectiveness for progesterone in luteal phase defect. You do have to worry about transference to partner.

Plasma Levels of Progesterone after Vaginal and Oral Administration of Progesterone

4 Vaginal

1 Oral Progesterone (ng / ml) / (ng Progesterone

0 24 26 28 30 0 2 4 6 Hours 48 Nahoul et al. Profiles of plasma estrogens, progesterone, and their metabolites after oral or vaginal administration of estradiol and progesterone. Maturitas 16: 185-202, 1993

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Studies

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PCCA VersaBase®/Progesterone Base Study PCCA BASE STUDIESSTUDY

PCCA VersaBase® Cream, Cosmetic HRT™, VersaBase® Gel and Special Micronized Progesterone Study® PCCA Cream Bases Now Proven to Transport Progesterone Into and Through Human Skin Better Than Vanicream®

Study Evaluation Of The Percutaneous Absorption Of Progesterone, In Vitro, Using The Human Cadaver Skin Model (Study performed by PRACS Institute, Ltd., an independent contract research facility.)

Summary The study was designed to evaluate the percutaneous absorption pharmaco- kinetics of progesterone. Absorption was measured in human cadaver skin, in vitro, using the finite dose technique and Franz Diffusion Cells.

Important Note: This study should not be used as a means of determining dosing of progesterone topically. It is a study intended to evaluate the ability of certain cream vehicles to transport progesterone across a human skin sample, in vitro. It is not a substitute for in vivo pharmacokinetic studies. It also is important to note the formulations in this study are NOT rubbed into the skin, but simply applied to the skin via a pipette and left to diffuse. ■ VersaBase® Cream PCCA # 30-3641

Bases Tested The bases used in the testing were: VersaBase® Cream, Cosmetic HRT™, a mixture of VersaBase® Cream and VersaBase® Gel (95% Cream/5% Gel) and the commercial cream Vanicream®*. The progesterone used was Progesterone USP, PCCA Special Micronized. Pentylene glycol was used as a wetting agent at a concentration of 10%. The concentration of progesterone in each preparation was 50 MG/GM.

Study Skin Preparation Percutaneous absorption was measured using the in vitro cadaver skin finite dose technique. Human cadaver trunk skin without obvious signs of skin disease, obtained within ~24 – 48 hours of death, was used in this study. It was dermatomed, prepared for cryo-preservation, sealed in a water impermeable plastic bag, and stored at ≤ -70° C until the day of the experiment. Prior to use it was thawed in ~37° C water, then rinsed in tap water to remove any adherent blood or other material from the surface. ■ VersaBase® Gel PCCA # 30-3656

Donor Demographics INTEGRITY DONOR ID AGE RACE SEX TEST RESULT* DA100405 34 Caucasian Male 0.24 ± 0.05 MM011907 48 Caucasian Male 0.72 ± 0.22 BS120705 53 Caucasian Male 0.54 ± 0.24

3 2 * Results are reported as µL-equ H20; Acceptance ≤ 1.56 µl-equ/cm

Cosmetic HRT™ Base Progesterone USP, ■ PCCA # 30-3337 PCCA Special Micronized ■ PCCA # 30-3530

USA© :2013 1.800.331.2498 PCCA. All Rights Reserved. www.pccarx.comPCCA USA l | www.pccarx.comCanada: 1.800.668.9453 PCCA CANADA www.pccarx.ca | www.pccarx.ca PCCA l Australia AUSTRALIA: 02.9316.1500| www.pccarx.com.au www.pccarx.com.au Female Hormone Protocol 45 By Pamela W. Smith, MD, MPH, MS

PCCA VersaBase®/Progesterone Base Study STUDIES PCCA BASE STUDY

PCCA VersaBase® Cream, Cosmetic HRT™, VersaBase® Gel and Special Micronized Progesterone Study® cont’d PCCA Cream Bases Now Proven to Transport Progesterone Into and Through Human Skin Better Than Vanicream®

Results The data indicate that progesterone does penetrate into and through human skin, in vitro, from the test formulations evaluated in this study.

In general the penetration profile from all formulations is characterized by a rise in absorption to a peak at approximately 7 hours after dose application followed by a slow decline in flux over time. A transient lower secondary peak of penetration is observed at approximately 28 hours after dose application at approximately half the flux than seen at the maximum.

WOWThe WOW Factor When comparing the bases’ abilities to transport progesterone deep into the dermis, VersaBase® Cream out-performed all bases, and delivered more than 4 times as much progesterone as the commercial base Vanicream®.

Peak flux of progesterone into receptor compartment at approximately 7 hours VersaBase® Cream delivered 4.07 times as much progesterone to the dermis as post application. Vanicream®.

Vanicream® is a registered trademark of Pharmaceutical Specialties, Inc., Rochester, Minn.

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Technical Report: Effect of LoxOral™ and Lactose on In Vitro Dissolution Studies of Progesterone Sustained Release Capsules

Abstract: Progesterone is a hormonal steroid used as a lipophilic drug model for evaluation of the effect of two different excipients, LoxOral and lactose monohydrate, on in vitro sustained release drug from pharmaceutical compounded oral capsules. The study was performed over time by monitoring the percentage of progesterone dissolved in simulated gastro-intestinal fluids (SGIF), employing the USP dissolution apparatus 2. In such fluid, the amount of progesterone dissolved increased rapidly up to 480 min from both oral drug delivery systems, although the dissolution rate profiles were statistically similar. The satisfactory and comparable dissolution performances of both progesterone capsule formulations confirm the interchangeability between the two excipients. Nevertheless, the versatile oral base, LoxOral, has advantages over traditional lactose since the compounding process of progesterone formulations becomes easier due to its excellent flowability, reduced static and minimum hygroscopicity.

Introduction: The focus of the present research was to investigate the effect In vitro drug release and dissolution testing play an important of two different excipients, LoxOral and lactose monohydrate, role in pharmaceutical formulation development and quality on the progesterone sustained release from capsules through control. Poorly soluble candidate molecules constitute a major in vitro dissolution rate studies in simulated gastro-intestinal challenge for the formulation development since the fluids (SGIF). Progesterone was selected as a model of a insufficient solubility causes problems for in vitro and in vivo lipophilic drug with poor aqueous solubility and dissolution assays, with consequent increased risk of attrition and costs rate, being an ideal candidate for study of solubility (Di et al., 2012), besides low solubility and low dissolution rate enhancement by using LoxOral as an excipient. Lactose often lead to poor bioavailability (Sarnes et al., 2013). The monohydrate is one of the most commonly used fillers trend in the pharmaceutical industry is to produce more and although it provides poor powder flowability and is shown to more compounds that exhibit high lipophilicity and poor water interact negatively with various drug actives (Ferreira, 2008). solubility, categorizing into Biopharmaceutical Classification Methocel (hypromellose) is one of the most widely used mean System (BCS) classes II and IV (Vogt et al., 2008). of providing prolonged release of API in a solid oral dosage form due to form a hydrophilic matrix system (Novak et al., Progesterone is a naturally occurring steroid hormone used in 2012). the treatment of endometrial hyperplasia and secondary amenorrhea in postmenopausal women as part of a hormone Methodology: replacement therapy. The drug, a BCS class II compound, Materials: Special Micronized Progesterone (lot number suffers from poor aqueous solubility due to its highly lipophilic C152389) was obtained from PCCA (Houston, TX, USA), as structure (cLog P 4.0) (Miller, 2009). Its oral absorption can be well as the excipients Methocel® E4M Premium CR significantly improved by the physical characteristics of the (hypromellose USP, lot number C155691), LoxOral (lot progesterone and the vehicle used in the dosage form. number 1309189) and Lactose Monohydrate (lot number Progesterone for oral administration has been delivered in a C156659). micronized form in order to improve the dissolution rate and oral absorption (Hargrove et al., 1989). Methods: The study of the progesterone sustained release from gelatin capsules was performed in vitro in the SGIF A variety of strategies have been adopted to increase the employing the USP Apparatus 2 (rotating paddle method) aqueous solubility of lipophilic drugs which include the use of (Distek Symphony 7100, North Brunswick, NJ), according to surfactants, lipids, permeation enhancers, micronization, salt the protocol described by Hamoudi et al. (2011) with minor formation, cyclodextrin, nanoparticle and solid dispersions modifications. The following formulations composed of 100 mg (Saxena et al., 2013). Recent studies have approached the of progesterone were tested in duplicate: progesterone in use of amphiphilic excipients as both drug delivery systems LoxOral/Methocel E4M capsules and progesterone in lactose and solubilization agents to improve the aqueous solubility of monohydrate/Methocel E4M capsules. Each capsule was many of these drugs (McCrary et al., 2013). introduced into 500 mL of simulated gastric fluid (SGF) without pepsin pH 1.2, at 37°C under stirring at a speed of 55 rpm. Following the trend of the need for a new generation of After 60 min, 500 mL of pre-warmed simulated intestinal fluid versatile excipients as oral drug delivery system to enable (SIF) without enzyme pH 6.8 were added. For each increased bioavailability of most drug candidates (Lipp, 2013), formulation, samples of 6 mL were withdrawn at different PCCA developed LoxOral. This innovative multifunctional times of incubation over 24 h (30, 60, 90, 240, 480, 720 and excipient for capsule formulations allows enhanced dissolution 1440 min) and were immediately filtered through an rate of all types of active pharmaceutical ingredients (APIs), Acrodisc® syringe - 0.45 µm HT Tuffryn membrane. An equal aggregating excellent physical and chemical stability. LoxOral volume of fresh pre-warmed SGF (first time-point) or SGIF at composition, that confers amphiphilic character to the 37°C was then replaced to maintain a constant volume. The excipient, consists of: isomalt, glyceryl behenate, poloxamer progesterone was assayed directly in the filtered samples, and sodium stearyl fumarate. without dilution, by HPLC (detection wavelength = 242 nm). The cumulative percentage of the API released was calculated.

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Technical Report: Effect of LoxOral™ and Lactose on In Vitro Dissolution Studies of Progesterone Sustained Release Capsules

Results and Discussion: Financial Disclosure: PCCA is the full sponsor of the study. The effect of LoxOral and lactose monohydrate as excipients on the in vitro dissolution of progesterone from capsules is References: shown in Figure 1. The progesterone was released Di, L., Fish, P.V., Mano, T. (2012) ‘Bridging solubility between drug sustainably and only the amount dissolved in SGIF was discovery and development’, Drug Discovery Today, 17 (9/10), pp. quantified. 486-495. Ferreira, A.O. (2008) Guia pratico de farmacia magistral. 2nd edition. Comparing the amount dissolved of progesterone from both Sao Paulo, Brazil: Pharmabooks. pp.97-123. capsule formulations, there was not much difference caused Hamoudi, M., Fattal, E., Gueutin, C., Nicolas, C., Bochot, A. (2011) by LoxOral and lactose monohydrate as excipients on the ‘Beads made of cyclodextrin and oil for the oral delivery of drug release and solubilization. The dissolution rate was lipophilic drugs: In vitro studies in simulated gastro-intestinal statistically similar for both delivery systems and influenced by fluids’, International Journal of Pharmaceutics, 416 (2), pp. 507- the dissolution time, but not by the type of medium (SGF and 514. SGIF). The proportion of progesterone dissolved from Hargrove, J.T., Maxson, W.S., Wentz, A.C. (1989) ‘Absorption of oral capsules increased rapidly up to 480 min (8 h), achieving the progesterone is influenced by vehicle and particle size’, American maximum of 9.83% (LoxOral formulation) and 9.55% (lactose Journal of Obstetrics & Gynecology, 161 (4), pp. 948-51. monohydrate formulation) in 1440 min (24 h). Lipp, R. (2013) ‘The innovator pipeline: bioavailability challenges and advanced oral drug delivery opportunities’, The Review of American These cumulative progesterone releases in SGIF at the end of Pharmaceutical Business and Technology [Online]. Available at: 24 h from PCCA formulations were similar to approximately http://www.americanpharmaceuticalreview.com/Featured- 10% progesterone release from PROMETRIUM® oral Articles/135982-The-Innovator-Pipeline-Bioavailability-Challenges- capsules (100 mg progesterone in peanut oil, Abbott Inc.) (Liu and-Advanced-Oral-Drug-Delivery-Opportunities et al., 2010) (Accessed: 6 December 2013) Liu, Z., Gosangari, S.L., Toops, D.S., Fatmi, A. (2010) Progesterone Solutions for increased bioavailability, US patent application number 20100255085 [Online]. Available at: http://www.faqs.org/patents/app/20100255085 (Accessed: 6 December 2013) McCrary, P.D., Beasley, P.A., Gurau, G., Narita, A., Barber, P.S., Cojocaru, O.A., Rogres, R.D. (2013) ‘Drug specific, tuning of an ionic liquid's hydrophilic–lipophilic balance to improve water solubility of poorly soluble active pharmaceutical ingredients’, New Journal of Chemistry, 37 (7), pp. 2196-2202. Miller, J.M. (2009) The impact of molecular complexation on intestinal membrane permeation. Unpublished dissertation thesis. The University of Michigan. Novak, S.D., Sporar, E., Baumgartner, S., Vrecer, F. (2012) Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets. Journal of Figure 1. Percentage of progesterone dissolved obtained from Pharmaceutical and Biomedical Analysis, 66 (1), 136-143. capsules containing different excipients, LoxOral™ and lactose Sarnes, J., Østergaard, J., Jensen, S.S., Aaltonen, J., Rantanen, J., monohydrate, combined with Methocel E4M. Formulations were Hirvonen, J., Peltonen, L. (2013) ‘Dissolution study of nanocrystal incubated 60 min in SGF (simulated gastric fluid) before addition of powders of a poorly soluble drug by UV imaging and channel flow SIF (simulated intestinal fluid) to give the final SGIF (simulated gastro- intestinal fluid). methods’, European Journal of Pharmaceutical Sciences, 50 (3-4), pp. 511-519. Saxena, S., Singh, H.N., Agrawal, V.K., Chaturvedi, S. (2013) ‘Lipid Conclusions: excipients in self emulsifying drug delivery systems’, Asian Journal LoxOral and lactose monohydrate oral delivery systems of Biomedical and Pharmaceutical Sciences, 3 (22), pp. 16-22. showed similar in vitro sustained progesterone release profile Vogt, M., Kunath, K., Dressman, J.B. (2008)’ Dissolution improvement from capsules. Based on the satisfactory and comparable of four poorly water soluble drugs by cogrinding with commonly dissolution performances of both progesterone capsule used excipients’, European Journal of Pharmaceutics and formulations, there is a great potential of interchangeability Biopharmaceutics, 68 (2), pp. 330-337. between LoxOral and lactose monohydrate as excipients of sustained release progesterone capsules. However, PCCA’s new oral base, LoxOral, confers advantages in the process of compounding progesterone formulations in comparison with the traditional lactose, since it is a base with enhanced quality Click the QR to see more attributes such as, excellent flowability, reduced static and PCCA studies and minimum hygroscopicity. reports.

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MegaPump

MegaPump® 30 mL & 75 mL

Metered Pump Dispensers for Creams and Gels

PCCA # 35-4861 Blue Approx. dispensing 30 mL size volume for both PCCA # 35-4864 Pink sizes: 0.5 mL PCCA # 35-5068 Blue 75 mL size

100 percent in-line function testing of all dispensers ensures reliability. The 30 mL size, available in custom cobalt blue and pink, and the 75 mL size, available only in cobalt blue, are exclusive to PCCA, and include a UV protectant coating (protects your compounds from harmful UV).

For accurate dispensing, the MegaPump must be manually calibrated according to the formula being placed in it.

SPECIFICATIONS • Approximate dispensing volume: 0.5 mL • Precise and repeatable dosage • Medium- to high-viscosity pump which dispenses in any position • Easy, TOP-FILL design (filling instructions on reverse) • Reliable dual valve system • Evacuates almost all of product contained, leaving minimal residue • 100 percent plastic; no metal parts; recyclable with mixed plastics • BPA-free and latex-free

ALSO AVAILABLE: 150 mL MegaPump® metered pump dispenser (available in blue only) • Three-piece unit; bottom fill • Approx. dispensing volume: 1.0 mL PCCA # 35-4809

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USA© :2015 1.800.331.2498 PCCA. All Rights Reserved. www.pccarx.com l Canada: 1.800.668.9453 www.pccarx.ca l Australia: 02.9316.1500 www.pccarx.com.au Female Hormone Protocol 49 By Pamela W. Smith, MD, MPH, MS Mini MegaPump

Mini MegaPumps®

Metered Pump Dispensers for Creams and Gels

Approx. dispensing volume for all sizes: 0.2 mL

100 percent in-line function testing of all dispensers ensures reliability. The 10 mL and 15 mL sizes, available in custom cobalt blue, pink and natural, and the 5 mL size, available only in cobalt blue, are exclusive to PCCA, and include a UV protectant coating (protects your compounds from harmful UV).

For accurate dispensing, the MegaPump must be manually calibrated according to the formula being placed in it. Please see PCCA Document #97959 under Resources > Documents on the Members-Only Website for instructions on calibrating devices.

SPECIFICATIONS • Approximate dispensing volume: 0.2 mL • Precise and repeatable dosage • Medium- to high-viscosity pump which dispenses in any position • Easy, TOP-FILL design (filling instructions on reverse) • Reliable dual valve system • Evacuates almost all of product contained, leaving minimal residue • 100 percent plastic; no metal parts; recyclable with mixed plastics • BPA-free and latex-free

USA: 1.800.331.2498 www.pccarx.com l Canada: 1.800.668.9453 www.pccarx.ca l Australia: 02.9316.1500 www.pccarx.com.au

USA: 1.800.331.2498© 2015 PCCA. All Rights www.pccarx.comReserved. l Canada: 1.800.668.9453 www.pccarx.ca l Australia: 02.9316.1500 www.pccarx.com.au 50 Female Hormone Protocol By Pamela W. Smith, MD, MPH, MS

USA: 1.800.331.2498 www.pccarx.com l Canada: 1.800.668.9453 www.pccarx.ca l Australia: 02.9316.1500 www.pccarx.com.au Forms/References Estradiol Comparison Chart

Release Rate/Day Total Estradiol Total Dose/Day Drug Product (mg/24hr) Content/Unit (mg) (mg) Alora® 0.025 0.77 0.22 Climara®* 0.025 2 0.28 Esclim® 0.025 5 1.43 Vivelle® 0.025 2.17 0.62 Vivelle-Dot® 0.025 0.39 0.11

0.75 per application Estrogel®† 0.035 0.75 (dosed once per day)

Esclim® 0.0375 7.5 2.14 Vivelle® 0.0375 3.28 0.94 Vivelle-Dot® 0.0375 0.585 0.17

Alora® 0.05 1.5 0.43 Climara® 0.05 3.8 0.54 Esclim® 0.05 10 2.86 Estraderm® 0.05 4 1.14 Vivelle® 0.05 4.33 1.24 Vivelle-Dot® 0.05 0.78 0.22 4.35 per application Estrasorb®† 0.05 8.7 (dosed twice per day)

Alora® 0.075 2.3 0.66 Climara®* 0.075 5.7 0.81 Esclim® 0.075 15 4.29 Vivelle® 0.075 6.57 1.88 Vivelle-Dot® 0.075 1.17 0.33

Alora® 0.1 3.1 0.89 Climara® 0.1 7.6 1.09 Esclim® 0.1 20 5.71 Estraderm® 0.1 8 2.29 Vivelle® 0.1 8.66 2.47 Vivelle-Dot® 0.1 1.56 0.45

* Climara dosed once weekly. All other patches dosed twice weekly. † Estrogel and Estrasorb are topicals, but not patches. Female Hormone Protocol 53 By Pamela W. Smith, MD, MPH, MS Women’s Health and What You Need to Know*

A new term, Genitourinary Syndrome of Menopause (GSM), has been introduced into the women’s health community that is medically more accurate, all-encompassing and a publicly acceptable term than Vulvovaginal Atrophy (VVA). GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder. It’s the newest term to cover all possible problems women in menopause experience.1

VVA, atrophic vaginitis and vulvodynia have been regarded by many to be inadequate for describing the range of menopausal symptoms associated with physical changes of the vulva, vagina, and lower urinary tract associated with estrogen deficiency. VVA describes what the postmenopausal is the perfect delivery vehicle because it adheres to the vulva looks like, but doesn’t describe the associated symptoms. vaginal mucosal tissue, thereby increasing contact time with Atrophic vaginitis implies a state of inflammation or even the mucosal surfaces. This makes it an ideal choice for use infection, even though neither of these is the primary in oral, rectal (including enemas), and vaginal compounded component of atrophic changes of the vulva and/or vagina. preparations. Many of the treatment options listed below use Vulvodynia is chronic pain in the area around the opening of MucoLox as the base and it can be used alone or with various the vagina (vulva) for which there is no identifiable cause. APIs. SYMPTOMS DETERMINE NEEDS Keeping up with current terminology is important so we are Regardless of the newest nomenclature, by looking at patients’ able to understand how to treat our patients. Many times symptoms we can determine their needs. The symptoms that these “new” names are just a fancier way to describe an women struggle with during peri-menopause and menopause already known health problem. However, we can provide are not all magically fixed by adding estrogen, progesterone solutions to these problems regardless of their catchy name and testosterone. The process of regulating hormone levels using quality products and state-of-the-art bases. can take months in many cases. In addition to evaluating

the female hormones, the practitioner should also check

the patient’s thyroid and adrenal function. Many women REFERENCES experiencing hormone changes could benefit from an adrenal 1. Portman DJ, Gass ML. Vulvovaginal Atrophy Terminology Consensus Conference support supplement (I recommend WW #10244, AdreBoost- Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and NG). the North American Menopause Society. Maturitas. 2014 Nov;79(3):349-54. doi: 10.1016/j.maturitas.2014.07.013. Epub 2014 Aug 19. ADHERING TO THE VAGINAL MUCOSAL TISSUE 2. Sobel JD, Chaim W, Nagappan V, Leaman D. Treatment of vaginitis caused by Candida glabrata: use of topical boric acid and flucytosine.Am J Obstet Gynecol. 2003 Treatment options vary depending on underlying issues, but Nov;189(5):1297-300. getting the API to adhere to the mucosal tissue is important 3. Molteni B, D’Antuono A, Bandini P, Sintini G, Barcellona E, Agnello A, Milani whether we are treating a lack of moisture, an infection or M. Efficacy and tolerability of a new chlorhexidine-based vaginal gel in vaginal infections. Curr Med Res Opin. 2004 Jun;20(6):849-53. pain. One of our newest bases, MucoLox™ (PCCA #30-4782),

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* Reprinted from Apothagram – May 2015 5 54 Female Hormone Protocol By Pamela W. Smith, MD, MPH, MS

USAUSA:: 1.800.331.24981.800.331.2498 www.pccarx.comwww.pccarx.com ll CanadaCanada:: 1.800.668.94531.800.668.9453 www.pccarx.cawww.pccarx.ca ll AustraliaAustralia:: 02.9316.150002.9316.1500 www.pccarx.com.auwww.pccarx.com.au CONFIDENTIAL FEMALE HORMONE EVALUATION

Today’s Date: ______

Name: ______Birthdate: ______Age: ______

Address: ______Street City State Zip

Phone: ______Email: ______

Height: ______Weight: ______Desired Weight: ______

How Often and how much? Do you use tobacco?  Yes  No ______Do you use alcohol?  Yes  No ______Do you use caffeine?  Yes  No ______Do you exercise?  Yes  No ______

Allergies: Please list any allergies and describe the reaction that occurred Drugs: ______Foods: ______Other: ______

Over-the-Counter Medication History: Please list all non-prescription medications that you are taking. (Include vitamins, herbals, and supplements): ______

Medical Conditions/Diseases: Please list any conditions/diseases that you have been diagnosed with or suffer from. (Examples include: Heart disease, high blood pressure, depression, ulcers, arthritis, insomnia, etc). ______

Current Prescription Medications (including hormones): Medication Name and Strength Date Started How Often per day ______Patient Name: ______

List Hormones Previously Taken: Date Started Date Stopped Reason ______

Have you ever used oral contraceptives (birth control)?  Yes  No If you experienced any problems, please describe: ______

How many pregnancies have you had? ______How many children? ______Any Interrupted pregnancies?  Yes  No If yes, please explain:______

Have you had a tubal ligation:  Yes  No If yes, date of surgery: ______Have you had a hysterectomy?  Yes  No If yes, date of surgery: ______Reason: ______Do your ovaries remain?  Yes  No

Do you have a family history of any cancers or osteoporosis? Please list the family member(s): ______

Have you had any of the following tests performed? Mammography  Yes  No Date: ______Outcome: ______PAP Smear  Yes  No Date: ______Outcome: ______Bone Density  Yes  No Date: ______Outcome: ______

What age did your period start? ______How many days is/was your cycle (Example: 28): ______Is/was your menstrual flow heavy or light? ______Any clots?  Yes  No

Have you ever had what YOU would consider to be abnormal cycles?  Yes  No Explain: ______

When was your last period? ______How many days did it last? ______

Do you or have you ever suffered from Premenstrual Syndrome (PMS) symptoms?  Yes  No Explain: ______Patient Name: ______

Absent Mild Moderate Severe Hot Flashes ______Night Sweats ______Vaginal Dryness ______Incontinence ______Bleeding Changes ______Fibrocystic Breast ______Weight Gain ______Fluid Retention ______Dry Skin/Hair ______Hair Loss ______Anxiety ______Depression ______Mood Swings ______Irritability ______Headaches ______Breast Tenderness ______Cramps ______Difficulty Falling Asleep ______Difficulty Staying Asleep ______Fatigue ______Loss of Memory ______Foggy Thinking ______Acne ______Arthritis ______Decreased Sex Drive ______Harder to Reach Climax ______Stress ______

Other: ______Patient Name: ______

What are your goals for taking Hormone Replacement Therapy? 1. 2. 3.

Doctor that we should contact for this therapy: Name: ______Phone: ______Address: ______Street City State Zip

*** Please include a copy of all relevant lab work, especially hormone levels that you have recently obtained. KEY TO HORMONE SYMPTOMS EVALUATION

Fibrocystic Breast � E � P Weight Gain � E � P � TH C Heavy/Irregular menses � E � P Hot Flashes � E �� E � P C Dry Skin/Hair � E TH Anxiety � E � P � E Depression � E � P � T � C � TH Night Sweats � E �� C Vaginal Dryness � E � T Headaches �� E �� P � T � TH Irritability � E �� P Mood Swings � E � P Breast Tenderness � E � P � P Sleep Disturbances/Insomnia � P � E � T C Cramps � P Fluid Retention � P � E Breakthrough Bleeding � P Fatigue � T � TH � P � C Loss of Memory � T � E Bladder Symptoms � E � T P Arthritis � T � P E Harder to Reach Climax � T � E � P Decreased Sex Drive � T � E � C � TH Hair Loss � T �� TH �� E �� P C

E=Estrogen P=Progesterone T=Testosterone C=Cortisol TH=Thyroid

�=Caused by High Level �=Caused by Low Level ��=Caused by Fluctuating Levels

Represents the most common causes of symptoms, as far as Progesterone, Estrogen, Tesosterone and Thyroid only, and is not totally inclusive of all possible causes. © 2004 PCCA-Professional Compounding Centers of America. All rights reserved. Rev. 07/04 60 Female Hormone Protocol Hormone Evaluation Follow-Up ByQuestions Pamela W. Smith, MD, MPH, MS

What are her chief complaints? ______

______

How old is she/what stage of life is she in? ______

What is her height and weight? ______

Has she had a hysterectomy (full or partial)?______

What are her current HRT medications (dosage form, strength, and route of administration, site and volume of topical application)? ______

How long has she been on above therapy? ______

Is she compliant with her current medication? ______

What has she previously taken (dosage forms, strengths, and routes of administration)? ______

______

Why did she change previous medications? ______

______

Has she had any hormone levels taken (saliva, blood, or urine)? ______

What non-HRT medications is she taking? ______

______

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References bit.ly/HormProtocol_Refs

Next Steps For further education on hormone replacement therapy, visit www.pccarx.com/education for a schedule of upcoming events.

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Notes:

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