Natural Hormones Replacement - acainfo.org · •P4>MPA: VM sxs, anxiety, ... •Biest (50/50): 0.5mg to 2mg •Progesterone Recommended QD Dose(s): •20, 40, 60mg . E N T R E P

E N T R E P R E N E U R S H I P | M E N T O R I N G | E D U C A T I O NE N T R E P R E N E U R S H I P | M E N T O R I N G | E D U C A T I O N

Natural Hormones ReplacementAn Evidence and Practice Based Approach

Andres Ruiz, PharmD, MSc, FACA

President/Partner

Stonegate Pharmacy

COPYRIGHT© ACA This document is the property of the American College of Apothecaries.

These materials may not be copied, photocopied, reproduced, translated, or distributed in any form or by any means without the prior written consent of the American College of Apothecaries.

PRESENTED BY THE

AMERICAN COLLEGE OF APOTHECARIES

2830 SUMMER OAKS DRIVE

BARTLETT, TN 38134WWW.ACAINFO.ORG


Disclosures

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

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


Learning Objectives

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

–Evaluate the various routes of female BHRT administration

–Evaluate the various routes of Testosterone administration

–Discuss the appropriate labs to monitor female BHRT and Testosterone replacement outcomes

–Discuss the appropriate symptoms to follow for optimal female BHRT and Testosterone replacement outcomes


WOMEN


Effectiveness and Monitoring• Oral

• Topical

• Sublingual


Effectiveness: Oral• Estrogen Recommended Dose(s):

•E2: 0.5mg, 1mg, and 2mg •E3: 2mg •Biest (70/30): 2mg, 3mg

• Progesterone Recommended Dose(s):

•100mg, 200mg, 300mg, 400mg


Effectiveness of Oral BHRT: P4 & E2

Takahashi

• E3 and Natural Menopause: decreased severity (50%, p< 0.01)

• E3 and Surgical Menopause: decreased severity (80%, p< 0.01)

Padwick

• E2+E3: decreased Hot Flashes (41%, p<0.01), night sweats (56%, p<0.05), and anxiety (44%, p< 0.01)

Hargrove

Fitzpatrick

• E2+P4>CEE+MPA: VM sxs (p< 0.01)

• E2+P4: VM sxs & mood (p< 0.01)

• P4>MPA: VM sxs, anxiety, & mood (p< 0.001)

• P4: VM sxs, anxiety, & mood (p< 0.001)


Effectiveness of Progesterone


Oral BHRT: E2 & P4 PK

Simon & de Ligniéres

• P4: 10% BA; 2hr tmax; Term t½ ~17hrs; ~7ng/ml Cmax*; Food increases BA ~5 to 10%

• 5α and 5β pregnanolone: 30%; GABAA

Price

• E2: 10% BA, 7hr tmax; Term t½ ~20hrs; ~35pg/ml Cmax; 1:5 = E2:E1 ratio


Monitoring: Oral

• Patient History and Physical• Questionnaire on symptoms: VM, somatic, and

psychological symptoms• Physical symptoms generally vary greatly from individual

to individual

• Serum Labs recommended


Monitoring: Oral

• Serum Labs: Cycling: draw labs on day 20• BMP, CBC with Hct/Hgb, lipid panel• E2, P4, Testosterone (free and total), DHEA-S, fasting am

cortisol, T4, free T3, and TSH• Caution: Labs are a tool not the goal

•Serum levels to Target:• E2 (30-70pg/ml), P4 (10-20ng/ml), Ttotal (30-50 ng/dl),

Tfree (3-5pg/ml), DHEA-S (75-150ug/dl)


See the Forest



• Topical

• Sublingual


Effectiveness: Topical

• Estrogen Recommended QD Dose(s):•Biest (80/20): 0.5mg to 3mg•Biest (70/30): 0.5mg to 2mg•Biest (50/50): 0.5mg to 2mg

•Progesterone Recommended QD Dose(s):•20, 40, 60mg


Effectiveness of BHRT: Topical

Ruiz

• All Topical(N=37) and 3 to 6 months follow-up

• 25% decreased emotional lability (p= 0.04); 25% decreased irritability (p= 0.05)

• Non-Sig decrease 12% anxiety (p= 0.27); 14% NS (p= 0.27); 10% HF (p= 1.0)

• No ADE (i.e. BCA or CHD) noted on follow-ups

Ruiz

• No significant reductions at 1 to 3 months follow-up

• 3 to 6 months: decreased 31% emotional lability (p<0.01); 29% irritability (p=0.02); 31% night sweats (p=0.04)

Sood

• P4: 100mg compounded equal to 100mg Prometrium

• 3mg Biest (80:20): Closest to 0.05mg Vivelle-Dot

• 3mg Biest (80:20): avg increased 50 pg/ml; Vivelle-Dot: avg increased 49 pg/ml


Effectiveness of BHRT: Biest vs Vivelle-Dot


Effectiveness of Topical BHRT: P4

Leonetti

• 20mg P4: resolution of vasomotor symptoms at 4 months (83% vs 19%; p<0.001)

Wren

• 32mg P4: Non-sig reduction in VS (-1.0 vs. 0; p=0.07) and anxiety (-1.0 vs. 0; p= 0.10) in 12 weeks

Benster

• 5,20,40,60mg P4: Non-sig reduction in VS 5mg (-0.4; p= 0.22), 20mg (-0.4; p= 0.23), 40mg (-0.6 p= 0.06), and 60mg (-0.4; p=0.23)


Effectiveness of Compounded BHRT to Alleviate Moderate to Severe Menopausal Symptoms


Effectiveness of Topical BHRT to Alleviate Moderate to Severe Menopausal Symptoms


Effectiveness of Topical BHRT to Alleviate Moderate to Severe Mood, VM, & QOL Symptoms at 1-3 months

59%$

63%$

30%$

70%$

38%$

30%$

29%$

44%$

33%$

37%$

64%$

63%$

44%$

63%$

41%$

44%$

25%$

59%$

52%$

48%$

0%$ 10%$ 20%$ 30%$ 40%$ 50%$ 60%$ 70%$ 80%$ 90%$ 100%$

Libido$(n=22)$

Fatigue$(n=27)$

Memory$Loss$(n=27)$

Sleep$Disturbances$(n=27)$

Hot$Flashes$(n=29)$

Night$Sweats$(n=27)$

Depression$(n=24)$

Irritability$(n=27)$

Emotional$Lability$(n=27)$

Anxiety$(n=27)$

Proportion(with(Moderate(to(Severe(Symptoms(

Menopausal(Sym

ptom

s(

Baseline$$ 1$to$3$Months$

p=0.45$

p=0.06$

p=0.38$

p=1$

p=0.29$

p=1$

p=0.73$

p=0.29$

p=1$

p=0.1&


Effectiveness of Topical BHRT to Alleviate Moderate to Severe Mood, VM, and QOL Symptoms at 3 to 6 months

54%$

46%$

33%$

71%$

38%$

31%$

25%$

33%$

28%$

28%$

66%$

64%$

45%$

68%$

48%$

51%$

33%$

62%$

59%$

46%$

0%$ 10%$ 20%$ 30%$ 40%$ 50%$ 60%$ 70%$ 80%$ 90%$ 100%$

Libido$(n=35)$

Fatigue$(n=39)$

Memory$Loss$(n=40)$


Hot$Flashes$(n=42)$


Depression$(n=36)$



Anxiety$(n=39)$


Menopausal(Sym

ptom

s(

Baseline$$ 3$to$6$$Months$

p=0.09$

*p<0.01$

*p=0.02$

p=0.55$

*p=0.04$

p=0.39$

p=1$

p=0.23$

p=0.09$

p=0.34'


Monitoring: Topical• Patient History and Physical

• Questionnaire on symptoms: VM, somatic, and psychological symptoms

• Physical symptoms generally vary greatly from individual to individual

• Salivary Labs recommended for topical


Monitoring: Topical• Serum Labs: Cycling: draw labs on day 20

• BMP, CBC with Hct/Hgb, lipid panel

• E2, P4, Testosterone (free and total), DHEA-S, fasting am cortisol, T4, free T3, and TSH

• Caution: Labs are a tool not the goal

• Serum levels to Target:

• E2 (0.8-12pg/ml), P4 (200-3000pg/ml), T (40-150pg/ml), DHEA-S (75-150ug/dl)

• 12 wks after initial treatment then 6 and 12 months

• Follow directions on kit very carefully



• Topical

• Sublingual


Effectiveness: Sublingual

• Estrogen Recommended Dose(s)-Divided:• Biest (70/30) or (50/50): 0.25mg to 1mg

• Dose increase by 0.25mg increments

•Progesterone Recommended Dose(s)-Divided:•100mg to 200mg


Effectiveness of BHRT: Sublingual

Gass

• E2 effectively reduces HF (0.05mg, 0.1mg, 0.2mg, and 0.4 mg/day)

• Digital thermography: 56%, 55%, 57% and 80% reduction in HF frequency, compared to baseline (p<0.05)

• Digital thermography: 0.4mg/day vs. placebo (0.17 vs. 0.65; P < 0.01)

Ahokas

• E2: 1mg SL QD achieved serum levels of 108pg/ml

• 2wks: 19 of 23 women recovered from post-partum depression (MADRS)

• 8wks: all recovered via total MADRS

Price

• 0.25mg E2: ~80% BA, 1hr tmax; Term t½ ~8hrs; ~294pg/ml Cmax; 3:1 = E2:E1 ratio

• 1mg E2:~80% BA, 1hr tmax; Term t½ ~18hrs; ~451pg/ml Cmax; 3:1 = E2:E1 ratio


Effectiveness of BHRT: Sublingual

Ruiz

• 1-3m: reduced 42% anxiety, 38% emotional lability, 36% irritability, 38% night sweats, 31% hot flashes, 35% sleep disturbances, 35% memory loss, 33% fatigue, and 26% loss of libido (p<0.05)

Wren

• 100 P4: 80% BA, 1hr tmax; Term t½ ~8-10hrs; ~9ng/ml Cmax


Effectiveness of SL BHRT: Estradiol


Effectiveness of SL BHRT to Alleviate Moderate to Severe Mood, VM, and QOL Symptoms at 1 to 3 months

0%# 10%# 20%# 30%# 40%# 50%# 60%# 70%# 80%# 90%# 100%#

Libido#(n=23)#

Fatigue#(n=23)#

Memory#Loss#(n=23)#

Sleep#Disturbances#(n=23)#

Hot#Flashes#(n=26)#

Night#Sweats#(n=26)#

Depression#(n=25)#

Irritability#(n=25)#

Emotional#Lability#(n=26)#

Anxiety#(n=26)#


Menopausal(Symptoms(

Baseline## 1#to#3#Months#

*p<0.01#

*p<0.01#

*p=0.01#

p=0.07#

*p<0.01#

*p=0.04#

*p<0.01#

*p<0.04#

*p=0.04#

*p=0.03#


Effectiveness of SL BHRT to Alleviate Moderate to Severe Mood, VM, and QOL Symptoms at 3 to 6 months

23%$

43%$

30%$

58%$

21%$

30%$

21%$

33%$

18%$

18%$

70%$

80%$

63%$

81%$

64%$

67%$

46%$

67%$

61%$

64%$

0%$ 10%$ 20%$ 30%$ 40%$ 50%$ 60%$ 70%$ 80%$ 90%$ 100%$

Libido$(n=23)$

Fatigue$(n=23)$

Memory$Loss$(n=23)$


Hot$Flashes$(n=33)$


Depression$(n=33)$



Anxiety$(n=33)$


Menopausal(Symptoms(

Baseline$$ 3$to$6$$Months$

*p<0.01$

*p<0.01$

*p=0.01$

*p=0.02$

*p<0.01$

*p<0.01$

p=0.09$

*p=0.02$

*p=0.01$

*p<0.01'


Monitoring: Sublingual• Patient History and Physical

• Questionnaire on symptoms: VM, somatic, and psychological symptoms

• Physical symptoms generally vary greatly from individual to individual

• Serum Labs recommended

• No salivary testing-saturates salivary glands


Monitoring: Sublingual• Serum Labs: Cycling: draw labs on day 20

• BMP, CBC with Hct/Hgb, lipid panel• E2, P4, Testosterone (free and total), DHEA-S, fasting am cortisol, T4,

free T3, and TSH• Caution: Labs are a tool not the goal

• Serum levels to Target:• E2 (30-70pg/ml), P4 (10-20ng/ml), Ttotal (30-50 ng/dl), Tfree (3-

5pg/ml), DHEA-S (2-23ng/ml) • 6 wks after initial SL treatment then 6 and 12 months• Labs 3 to 5 hours after morning sublingual therapy


Intake/Questionnaire• Greene climacteric scale

• Evaluates VM, somatic and psychological components

• Can also score for clinical depression or anxiety (score >10)

• Test at baseline and follow-up – Likert Scale

• Other Questionnaires

• NAMS menopause health questionnaire

• The Menopause Rating Scale

• Kupperman index


8/5/2014 WARMI: GUARANTEED RELIEF OR YOUR MONEY BACK | Warmi | Better Menopause Relief

http://www.bettermenopause.com/warmi-guaranteed-relief-or-your-money-back 2/2

Next: The Warmi Story (node/9)

Reference: J. G. Greene: Maturitas 61 (1-2) 2008 78-84. Not all Warmi Clinical Trial Results are Statistically Significant


MEN


Effectiveness

• Topical

• Sublingual

• Supplements


Effectiveness: Topical TRT

• Testosterone Recommended Dose(s):• 50 to 200mg QAM to upper arm and shoulder


Effectiveness of Topical TRT

Guay

• T Gel 1% increases TT and free T into the normal range

• Higher levels are achieved with application to arms/shoulder (548 ± 261 ng/dL) vschest/abdomen (440 ± 173 ng/dL) (P = 0.03) and legs/thighs 398 ± 164 ng/dL) (P = 0.004)

Dobs

• 83% of patients of males achieve normal physiological levels by day 14

• T: 10% BA, 13.6 tmax; Term t½ ~32hrs; ~750pg/ml Cmax; 1:5 = DHT:T ratio

• Increase in SHBG; E2 Levels resorted to normal physiology




Effectiveness

• Topical

• Sublingual

• Supplements


Effectiveness: SL TRT

• Testosterone Recommended Dose(s):• 10 to 50mg BID


Effectiveness of Topical TRT

Korbonits

• In the buccal system group, the mean concentrations at all time points were within the physiological range

• Transdermal patch group, mean concentrations at five timepoints were outside of the physiological range.

• Pts with values outside the physiological range was lower in the buccal system group than transdermal group (P < 0.001)

• T buccally is superior to the transdermal patch

Dobs

• Buccal T significantly elevated levels of T in hypogonadal men and improved both objective and subjective measures of sexual function

• T: 80% BA, 30min tmax; Term t½ ~6rs; ~2790pg/ml Cmax; 1:15 = DHT:T ratio

• No Increase in SHBG; E2 Levels resorted to normal physiology




Effectiveness

• Topical

• Sublingual

• Supplements


Saw Palmetto

• Non-competitively inhibits 5-alpha-reductase (prevents conversion of Testosterone to DHT) which may reduce prostate growth

• However 5-AR levels not reduced in vivo

• Shrinks inner prostatic epithelium (not overall prostate size)

• May inhibit lipoxygenase and COX to reduce inflammation (reduces TNF-alpha and IL-1beta)

• Has anti-estrogen, antispasmodic, and alpha-adrenergic inhibitory properties


Saw Palmetto: Efficacy

• Inconsistent and contradictory evidence

• Mild to Mod improvement of urinary symptoms (freq. urination, painful urination, hesitancy, urgency, perinealheaviness), decreased nocturia, improved urinary flow, lower residual volume.


Saw Palmetto: Safety

• Likely safe

• Pregnancy & lactation – Unsafe• Antiestrogenic effects


Saw Palmetto: Adverse Reactions

• Generally mild and comparable to placebo

• Dizziness, HA, GI(N/V/D/C)

• Asthenia, loss of libido, ejaculation disorders, postural hypotension


Saw Palmetto: Drug Interactions

• Anticoagulants/Antiplatelets - increased risk of bleeding (SP may prolong bleeding time)

• Contraceptives (antiestrogenic effects of SP)

• Estrogens (antiestrogenic effects of SP)

• Conflicting evidence of CYP2D6 & 3A4• In vivo - yes; clinically - no


Saw Palmetto


• Flavonoid

• Found: passionflower, silver linden, some geranium species, and in honey and bee propolis

• Primary activity: Aromatase inhibitor

• Other activity: inhibits UGT1A1, CYP 1A1 and CYP 1A2

Chrysin


• Only theoretical for cancer prevention and performance enhancement

• Oral and topical chrysin have very poor bioavailability

• Ineffective?

Chrysin: Efficacy


• Possibly safe since poorly absorbed

• Orally 300mg QD

• Topicall 50mg to 100mg QD

• Unsafe in pregnancy: no studies to date

Chrysin: Safety


• No reported to date

Chrysin: Adverse Reactions


Chrysin: Drug Interactions

• Moderate: Aromatase inhibitors

• Minor: Glucuronidated drugs and CYP 1A2


Chrysin:Passion Flower


Case• 62y/o male

• History of vasectomy, apathy, ED, mood disturbances, decreased libido, and sleep disturbances

• E2 40pg/ml; T total=107ng/dvl, Tfree 2.7ng/dl, BMP WNL, CBC WNL

• No h/o of HRT

• How should the patient be treated?


Hook'em


Need More Information?

Andres Ruiz, PharmD, MSc, FACA

President/Partner

Stonegate Pharmacies

[email protected]

www.stonegaterx.com

Natural Hormones Replacement - acainfo.org · •P4>MPA: VM sxs, anxiety, ... •Biest (50/50): 0.5mg to 2mg •Progesterone Recommended QD Dose(s): •20, 40, 60mg . E N T R E P

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