9/22/2019 1 Menopausal hormone therapy and pharmacist responsibilities in supporting women's health Prepared and presented by: Dragana Skokovic-Sunjic RPh, NCMP Disclosure • Nothing to disclose • No specific products will be discussed • No funding received related to topic of presentation After listening this presentation, pharmacists will be able to: • Understand the effects of menopausal symptoms on overall health • Appreciate latest recommendations for menopausal hormone therapy (MHT) and correlation between benefits and risks • Dispel common misconceptions associated with MHT and provide evidence-based advice to patients and prescribers • Adopt the pharmacist’s role in advising patients deciding on appropriate approaches in menopausal symptom management 1 2 3
Transcript
9/22/2019
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Menopausal hormone therapy and pharmacist responsibilities in
supporting women's health
Prepared and presented by:
Dragana Skokovic-Sunjic RPh, NCMP
Disclosure
• Nothing to disclose
• No specific products will be discussed
• No funding received related to topic of presentation
After listening this presentation, pharmacists will be able to:
• Understand the effects of menopausal symptoms on overall health
• Appreciate latest recommendations for menopausal hormone therapy (MHT) and correlation between benefits and risks
• Dispel common misconceptions associated with MHT and provide evidence-based advice to patients and prescribers
• Adopt the pharmacist’s role in advising patients deciding on appropriate approaches in menopausal symptom management
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Menopause: definition
• Permanent cessation of menstruation due to loss of ovarian activity and the depletion of follicles
• During menopause women produces less hormones (estrogen and progesterone)
“If a menopausal woman has pain or makes trouble, pound her hard on the jaw”
Quote from Egyptian medical text, 2000 B.C.
Hormonal changes throughout a woman’s lifetime
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The Stages of Reproductive Aging in women
Source: Santoro NC, et al J Clin Endocrinol Metab 1996;81:1496-1501
Progesterone
Estrogen Follicle stimulating
hormone FSH
Luteinizing hormone LH
Pre-menopause - 180 days monitored
Source: Santoro NC, et al J Clin Endocrinol Metab 1996;81:1496-1501
Estrogen
Progesterone
Follicle stimulating
hormone FSH
Luteinizing hormone LH
Post-menopause – 180 days monitored
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Source: Santoro NC, et al J Clin Endocrinol Metab 1996;81:1496-1501
Perimenopause – 180 days monitored
Symptom distributionSymptoms Pre-
menopause
Late Peri-
menopause
2 years Post-
menopause
Lack of energy 43 43 43
Depression 26 38 32
Aches and joint pain 41 53 57
Insomnia 31 38-39 43
Memory changes 31 44 42
Vasomotor 10 42-58 41-48
Vaginal dryness 3 21 32
Bladder control 12 14 26
Sexual dysfunction 42 88
Dry mouth 18 23 29Ref: Dennerstein et al. Obstet Gyn 2000; 96:351Woods et al. Am J Med 2005 Suppl 125, Asplund R et al. Maturitas 2005; 50 85-90
Why is this important?
Fluctuating hormones have been an issue for generations, what is the big deal now?
Brinton RD et al. Nat Rev Endocrinol 2015;11:393-405
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VMS in menopause: Is it a big deal?
• Moderate to severe VMS associated with:–Higher incidence of CVD
–Negative impact on sleep
–Higher incidence of depression
– Impaired sexual functioning
Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: A comprehensive review. Health QualLi fe Outcomes. 2005;3:47. doi:10.1186/1477-7525-3-47.
VMS and CVD risk
• VMS are triggered by low estrogen induced changes in hypothalamic temperature control >
• Accompanied by drastic changes in sympathetic/parasympathetic nervous function >
• Resulting in changes in heart rate and increased blood pressure reactions >
• Severe VMS and related CV effects increase soft plaque instability and increase the risk of CV events
1. Tuomikoski P. et al. Evidence for a role of hot flushes in vascular function in recently postmenopausal women. Obstet Gynecol 2009;113:902–8
2. Thurston R. et al .Hot flashes and subclinical cardiovascular disease:findingsfrom the Study of Women's Health Across the Nation Heart Study. Circulation 2008;118:1234–40
3. Hoikkala H. et al. Association between vasomotor hot flashes and heart rate variabil ity in recently postmenopausal women. Menopause 20 10;17:315–20
VMS and CVD risk
• The mechanisms are not fully understood
• Possible that VMS become a determinant for cardiovascular health through effects on sympathetic/parasympathetic activity
1. Tuomikoski P. et al. Evidence for a role of hot flushes in vascular function in recently postmenopausal women. Obstet Gynecol 2009;113:902–8
2. Thurston R. et al .Hot flashes and subclinical cardiovascular disease:findingsfrom the Study of Women's Health Across the Nation Heart Study. Circulation 2008;118:1234–40
3. Hoikkala H. et al. Association between vasomotor hot flashes and heart rate variabil ity in recently postmenopausal women. Menopause 20 10;17:315–20
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If we treat VMS, do we reduce CVD risk?
MHT and CVD
• Several sub-analyses of the WHI* study indicate that MHT provides CAD protection against cardiac events if initiated close to menopause
• MHT reduces the progression of atherosclerosis and accumulation of CAD in recently menopausal women
*WHI – Women’s Health Initiative study
Schierbeck L. et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409
MHT and CVD• 2015 review compared CVD death risk in almost half
a million estradiol-based HT users with that in an age-matched female background population
• The risk for CAD death in HT users was reduced in an exposure-dependent manner up to 54%
• To get maximal cardio-protective efficacy of MHT, treatment should initiate as soon as symptoms occur, and preferably within the first 10 postmenopausal years
Mikkola T. et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and allcausemortality. Menopause 2015;22:976–83Mikkola T et a l REVIEW:New evidence for cardiac benefit of postmenopausal hormone therapy, CLIMACTERIC, 2017 VOL. 20, NO. 1, 5–10
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Menopause and diabetes
• Currently as many as 1/3 of the average patient load is postmenopausal patient population
• Since 1980, the prevalence of diabetes in adults has increased from 108 million (1980) to 422 million (2014)
• In adult women, the age-standardized prevalence of diabetes increased by 60%
REVIEW: Menopause, hormone therapy and diabetes Stuenkel C. CLIMACTERIC, 2016, VOL. 20, NO. 1, 11–21
Menopause, MHT and risk of diabetes
• Observational studies reported an association of current HT use (oral and transdermal) with lower risk of developing T2DM
• Earlier meta-analysis (RCTs 1966 and 2004) concluded that HT (oral more effectively than transdermal) reduced insulin resistance (as measured by HOMA-IR) and new-onset diabetes by 30%
• A second meta-analysis (studies 1997-2011) reported similar findings, a 39% reduction in incidence of diabetes
1. Manson J et al. A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent DM. Ann Epidemiol 1992;2:665–732. de Lauzon-Guillain B et al. Menopausal hormone therapy and new-onset diabetes in the French Etude Epide de Femmes de MGEM (E3N) cohort. Diabetologia 2009;52:2092–1003. Rossi R et al. Transdermal 17-B-estradiol and risk of developing T2DM in a population of healthy, nonobese postmenopausal women. Diabetes Care 2004;27:645–94. Salpeter SR, Walsh JM, Ormiston TM, et al. Meta-analysis: effect of HRT on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 2006;8:538–545 Xu Y, Lin J, Wang S, Xiong J, Zhu Q. Combined ERT on metabolic control in postmenopausal women with diabetes mellitus. Kaohsiung J Med Sci 2014;30:350 –61
Menopause, MHT and diabetes
• Women with T2DM receiving oral HT appear to have neutral or improved effect on fasting glucose
• Less evidence is available about transdermal estrogen, and very little is known about HT in women with T1DM
REVIEW: Menopause, hormone therapy and diabetes Stuenkel C. CLIMACTERIC, 2016, VOL. 20, NO. 1, 11–21
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40% reduced
If MHT within first 10 years
Risk of heart disease and risk of dying of any cause
Why is hormonal therapy in menopause still controversial?
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Reflection: Years leading to 2002*
• Typical Rx provided to patients going through “the change”
*First arm of WHI stopped in 2002
Brief history of MHT• 1890 - Doctors start to experiment with
testicular extracts for men and ovarian extracts for women
• 1929 – First crystalline preparation of estrogen extracted from urine of pregnant women
• 1939 – pregnant mares urine became a major source for commercial production of estrogen
• 1941 – FDA approves estrogen for treatment of menopausal symptoms
• 1942 - First estrogen pill (Premarin™) was introduced in US
1966: Bestselling book “Feminine Forever” by Dr Robert Wilson
• Dr. Wilson described post-menopausal women “castrates” whose bodies were “truly a galloping catastrophe …in living decay”.
• Estrogen would make these women “much more pleasant to live with and ... not dull and unattractive”.
• MHT formulation, route, and timing of initiation produce different effects
• Absolute risks for MHT use in healthy women ages 50-59 are low
• MHT initiation in older women carries greater risks
• ET can be considered for longer duration of use because it carries a lower risk for breast cancer
NAMS position statement. Menopause 2017.
What happened between 2002-2012?Consequences of WHI
10 years after WHIMHT use 80%
Sprague et al. Obstet Gynecol 2012;120(3):595–603.
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10 years after WHIHip fracture 55%
Karim et al 2011, Menopause 18(11): 1172-1177.
10 years after WHI18,000-91,000
Died prematurely
Sarrel et al 2013, Am J Public Health 103(9): 1583-1588.
Hormone therapy
Contraindications to MHT Non-contraindications to MHT
• Unexplained/undiagnosed vaginal bleeding• Confirmed or suspected breast cancer• Acute liver disease• Active thromboembolic disease• Acute cardiovascular disease• Recent stroke or MI• Pregnancy
• Smoking• Diabetes• Hypertension• Migraine
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Dose & Route of Administration
• Therapeutic goal is lowest effective estrogen dose, plus appropriate progestogen dose for women with a uterus
• All routes of administration of ET can effectively treat menopausal symptoms
• Transdermal ET may be associated with lower risk of DVT, stroke, and MI
• Multiple progestogen options for endometrial protection
NAMS position statement. Menopause 2012. 2017*
appropriate*
ET – oral vs transdermal (TD)
• Transdermal route provides more constant blood levels of estrogen
• Transdermal route is devoid of increased risk of deep vein thromboembolism
• Head-to-head comparisons between oral and transdermal estradiol with CAD events as primary endpoints are needed
1. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005;8(Suppl 1):3–632. Stevenson JC. Type and route of estrogen administration.Clima cteric 2009;12(Suppl 1):86–903. Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause 2014;21:753–62
Routes of Administration
:
Non-oral route Oral Route
No First-pass Effect First-Pass Effect
Less of an effect on:
- Clotting factors
- Triglycerides
- C-reactive protein
- Sex hormone-binding globulin
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Consider using transdermal estrogen:
1. First line therapy for VMS and for patients with:- High risk of DVT or PTE
- High triglyceride levels
- Gall bladder disease
- Hypertension
2. Need for “steady state” drug release: daily mood swings, migraine headaches, shift workers
3. Inability to use oral tablets : stomach upset, problems with taking a daily pill
Progestogen indications
• Endometrial protection from unopposed ET–Generally not indicated with ET post-
hysterectomy
–Adequate doses recommended with intact uterus
• Not necessary with vaginal ET therapy
NAMS position statement. Menopause 2017.
ProgestogensProgestogens – any substance that has progestational activity
Progesterone(“natural”, bioidentical)
Progestins(synthetic)
Oral progesterone is broken down in GI tract, rendered inactive;Once micronization was introduced, progesterone could be given orally
Developed as a synthetic equivalent, not broken down in the GI tract, derived from progesterone or testosterone precursors
• 1st year after stopping HT risk of stroke and cardiac death increased compared with HT users
• Risk returned to baseline in the second year
When to stop?
• A recent large-scale population study revealed that women who stopped estradiol-based HT relative to women who continued it had a 2.3-fold greater risk of CAD death within the first post-HT year
• Risks were markedly higher in women who had been younger than 60 years at the discontinuation of HT use
1.Mikkola T. et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J Clin Endocrinol Metab 2015;100:4588–942.Mikkola T. et al Review:New evidence for cardiac benefit of postmenopausal hormone therapy, Climacteric, 2017 VOL. 20, No. 1, 5–10
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When to stop?
• The longer HT is used, the larger is the cardiac benefit
• The safety of annual or biennial pausing to test the persistence of hot flushes is potentially dangerous, because acute withdrawal of estrogen may predispose to cardiac events
1.Mikkola T. et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J Clin Endocrinol Metab 2015;100:4588–942.Mikkola T. et al Review:New evidence for cardiac benefit of postmenopausal hormone therapy, Climacteric, 2017 VOL. 20, No. 1, 5–10
5 years ?Appropriate dose
Appropriate length of time
Patient’s risk/benefit
profile
49%
84%
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Need help to start
the conversation?
In summary:
• Many women experience vasomotor symptoms in menopause that are bothersome enough to consider therapy
• Primary care providers have an opportunity to advise patients on the function of hormones and the role of HT, differences between therapies, what to expect from treatment, safety of HT, and long-term health impact
