Endocrinology Reproductive Menopause

1. Menopausal
Hormone
Replacement
Therapy: Hero or
villain?
Olfat Fawzy

2. Objectives
• Describe menopausal symptoms & comorbidities
• Identify different formulas of hormones for HRT
• Summarize the indications & benefits of HRT
• Describe AEs & contraindications of HRT
• Ensure the safe use of HRT & improve outcomes

8. What is
Hormone
Replacemen
t Therapy
Supplementing women with hormones
that are lost during the menopausal
transition

10. Basics of Menopausal HRT

11. HRT: Basics
HRT includes an estrogen & progesterone
component to mimic hormones created by the
human ovary.

12. Estrogen alone or Estrogen +
Progestin?

13. Estrogen Therapy
Estrogen formulations include
 Human estrogens (17B-estradiol, E2)
 Estrone (E1)
 Estriol (E3)
 Synthetic estrogens (ethinyl estradiol EE)

14. Oral Estrogen Therapy
Most widely used formulation
Estradiol is converted to estrone at 1st pass metabolism
Thus, estrone is the major hormone found in circulation

15. Risks of oral estrogens stem from first
pass metabolism through the liver
↑ production of coagulation factors
↑ production of various inflammatory markers
Hypertriglyceridemia
↑ risk of venous thromboembolism (VTE)
↑ risk of gallstones

16. Transdermal & Topical
in contrast to oral Estrogens
Bypass first pass metabolism
Can be dosed lower than oral estrogen
Less impact on TG, coagulation factors & GB disease
May not ↑ VTE risk

17. Vaginal Estrogen Therapy
• Cream, ring, tablet or capsule
• Treats vaginal dryness & dyspareunia
• No systemic estrogen levels
• Progesterone is not necessary with vaginal
estrogen (minimal absorption & low risk of
endometrial cancer)

18. Progestogens therapy:
• Progesterone made by the human ovary
• Progesterone-like substances, or
progestins

19. Why give
progestogens?
•For a woman who has an
intact uterus, progestogen
should be added with
estrogen
•It protects the uterus from
endometrial hyperplasia or
malignancy

20. How does Progestogen therapy protect from
endometrial cancer?
• ↓ estrogen receptors in target tissues
• Inhibiting LH surge that → ↑ ovarian estrogen production
• ↑ 17B-hydroxysteroid dehydrogenase activity → conversion
of estradiol to estrone in endometrium
• Estrone’s weaker estrogen activity → ↓ endometrial
stimulation

21. Progestogen Therapy: Actions
•Has mild sedating effects
•↓ VMS
•Relieves symptoms of sleep disturbance & mood
instability
• Transdermal progesterone do not provide adequate
endometrial protection & should not be used in combination
therapy.

22. Combination Formulations

23. Combination Formulations
• Continuous-cyclic estrogen- progestogen
• Short cycle: daily estrogen + progestogen added cyclically for 12-14
days/month
• Long cycle: daily estrogen + progestogen added cyclically q 2-6 months for 14
d
Withdrawal or breakthrough bleeding often results after progestogen cessation
• Continuous-combined estrogen-progestogen
• Daily estrogen and progestogen
No withdrawal bleeding & Most women get amenorrhea
• Intermittent combined estrogen-progestogen:
• Daily estrogen with cycles of progestogen for 3 days & off progestogen for 3 d
→ ~ 80% amenorrhea rates after 1 year

24. Monitoring
•Estradiol & progesterone
levels are not measured to
monitor HRT.
•Relief of menopausal
symptoms & absence of
AEs signify adequate
medical response.

25. Menopausal
Hormone Therapy:
Evolution

26. Background HRT 1960-1980
• Menopause is an endocrinopathy requiring HRT
• 1960s: Successful OCP introduction
• The “pill” freed women from fear of pregnancy
• HRT freed women from fear of aging
• 1972: Forever feminine by Robert Wilson

28. Background HRT 1980s
• 1980: Expanding uses of HRT
• Initially used to treat hot flashes and vaginal SXS
• Later uses: Protection of bone and heart

29. Background HRT: Late 1980s
• 40 retrospective observational studies, EPT or ET ↓ risk of
heart attacks by 50%
Most studies included women in their 50’s
Studies are subject to selection bias
• Conventional wisdom
All women should receive HRT for heart protection
Women with CVD risk factors should use HRT

30. Background HRT: Late 1990s
•1990: Wyeth requested that FDA add labeling to
HT products that include cardioprotection
•FDA insisted that RCTs should be done to prove
that HRT provided CV benefits

31. Background HRT: Late 1990s
• 2 RCTs were initiated to evaluate cardio-protection
HERS: Secondary Prevention Trial
WHI: Primary Prevention Trial

32. HERS study 1998
Hulley, JAMA 1998
Question: Does EPT ↓ MI in women with CHD?
2763 women randomized to HRT or placebo
Entry: women with CHD
Menopausal, intact uterus, age 44-80 y, FFup 4 y

33. HERS study 1998
Hulley, JAMA 1998
EPT had no benefit in reduction of MI or CV
deaths
3-fold increase in VTE

35. Women’s Health Initiative
•1993-2005: RCT,17,000
women
•Women 50-79 y old
•Endpoints
•1ary prevention of MI &
strokes
•Hip fracture, various

36. WHI: Treatment Arms

37. MAIN OUTCOMES AND MEASURES
Main outcomes
• Coronary heart
disease
• Hip fractures
• Invasive breast
cancer
Global index
• Stroke
• Pulmonary embolism
• Colorectal cancer
• Endometrial cancer
• Hip fracture
• Deaths
• Quality-of-life

38. WHI study results
of EPT released
2002 after 5.2y
• Discontinued early
• Risks more than
benefit
Event Risk/10/y Benefit/10/y
Heart Attack 7
Stroke 8
Breast Cancer 8
TE events 18 6
Colorectal Cancer 5
Hip fractures

39. WHI: ET only
study arm
released 2004
after 7 y
Outcome Change vs Placebo
CHD No difference in risk
Breast Cancer No difference in risk
Stroke Increased risk
Hip Fractures Decreased risk
Dementia Trend toward increased risk

40. Conclusions of
WHI
• Menopausal HRT has a complex
pattern of risks & benefits.
• HRT is appropriate for symptom
management.
• However, its use for chronic
disease prevention is not
supported by the WHI trials.

41. Sub-analysis of
WHI results by
age group
↑ CHD risks applied to
women who started HT
•after age 60 or
•a decade past
menopause

42. Relative risks for CHD events associated with
HRT from meta-analysis of 23 RCTs

43. HRT & the Heart:
The "Timing Hypothesis"
Subsequent studies in Europe &
US showed ↓ CVD & death
when HRT starts within first 4
years of menopause transition.
The "Timing Hypothesis" Starting
HRT close to time of
menopause transition, CV
benefit is seen compared with
later initiation.

44. Indications and Contraindications for
Menopausal HRT

45. Indications of HRT
Treatment of vasomotor symptoms
Treatment of genitourinary syndrome (vaginal and
vulvar atrophy)
Prevention of osteoporosis

46. Contraindications to oral HRT
• Hx of breast cancer
• Hx of estrogen-based cancer, i.e., uterine cancer.
• Active DVT or a history of DVT or pulmonary embolism (PE)
• History of blood clotting disorder (Factor V Leiden mutation)
• Hx of arterial thrombotic diseases such as MI or stroke
• Chronic liver disease or dysfunction
• Migraine with aura

47. Do these
contraindication
s apply for
transvaginal
HRT?
These contraindications do
not apply to transvaginal
based estrogen therapies
Serum concentration of
estrogen from this route is
extremely low.

48. Adverse side effects
• GI symptoms
• Abnormal uterine bleeding
• Fluid retention
• Breast tenderness
• Headaches
• Mood changes

49. Conclusion
• Risk-benefit profile of HRT in symptomatic menopausal women
is impacted by age, time since menopause & existing
comorbidities.
• Shared decision making is critical to determine
• HRT formulation
• Route to use
• When discontinuation is appropriate

50. Conclusion
• Estrogen is the most effective treatment for VMS.
• Women with intact uterus require combined progestogen
therapy with estrogen for endometrial protection.
• For those without a uterus, estrogen alone can be used.