1. Menopause and Hormone Therapy
Power Surges and Profit Margins;
And, The Devil Is in the Details

2. Some definitions Perimenopause
Early perimenopause - change in menstrual cycle length of more than 7 days from baseline cyclicity.
Late perimenopause - one or more skipped menstrual periods, or greater than 60 days of amenorrhea
Menopause – no menses x 1 year (a retrospective dx.)

3. Alternative Terminology
Reproductive stage: menarche to the beginning of the perimenopause (when cycles become variable).
Menopausal transition: ↑FSH, ↑variability in cycle length, 2 skipped cycles with > 60 days amenorrhea (absence of menstruation), or both.
Postmenopause: Begins at the time of the FMP (final menstrual period), although it is not recognized until after 12 months of amenorrhea.

4. Does Menopause Need to be Treated?

5. Disease State vs. Normal Lifecycle Stage
Some feel menopausal women are estrogen deficient
Some feel premenopausal women are estrogen toxic to facilitate childbearing
One’s attitude clearly will influence approach to treatment, though our opinion may be less important than the patient’s

6. History of HRT
Initially marketed to help women prevent aging changes and loss of attractiveness
Feminine Forever, Robert A. Wilson 1966
The annual number of HT prescriptions filled increased from 58 million in 1995 to 90 million in 1999 and estrogen became the biggest selling prescription drug. Annual Review of Public Health Vol. 26:

7. The Power of a Reframe. . . Crone Power
What the caterpillar calls the end of the world, the master calls a butterfly.  Richard Bach
Crone Power
Magical Menopause
Embracing Menopause
Menopause: Initiation into Power – Joan Borysenko

8. But is there evidence of any actual benefit to HRT?
Symptom management – efficacy undoubted
Hot flashes
Vaginal atrophy
Urinary tract infections (vaginal estrogen)
Observational studies have suggested a role for preventing heart disease, osteoporosis, etc.
RCT’s have been troubled by methodologic problems

9. Cardiovascular disease
Cardiovascular disease (CVD) remains the leading overall cause of death in women, with 27.2% and 7.5% of all female deaths in 2004 caused by heart disease and stroke, respectively
Although acute cardiovascular events are rare in nonobese, nondiabetic premenopausal women, they increase markedly after the menopause
Collins P., Rosano G., Casey C., et al:  Management of cardiovascular risk in the perimenopausal women: a consensus statement of European cardiologists and gynecologists.  Climacteric 10. (6):

10. Observational Trials Meta-analysis:
Decreased risk of CHD for E and E+P
Annual Review of Public Health Vol. 19:

13. Randomized Controlled Trials
Widely interpreted as indicating HRT increased risk of CHD
Methodology and these conclusions have been questioned by many

14. HERS - Heart and Estrogen/Progestin Replacement Study
There is debate about the validity of these additional data because they were unblinded, patients dropped out, and patients crossed over to the opposite arm. 14

15. HERS - Heart and Estrogen/Progestin Replacement Study
There is debate about the validity of these additional data because they were unblinded, patients dropped out, and patients crossed over to the opposite arm.

16. Cardiovascular and Global Index Events by Years Since Menopause at Baseline
Rossouw, J. E. et al. JAMA 2007;297:
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17. The same point, expressed graphically

18. And not just the WHI
J Gen Intern Med 2006; 21:363–366.

19. Nurses’ Health Study <1 year HRT - 25% ↑risk recurrent CHD
> 2 years - ↓risk recurrent CHD. Longer duration of use was associated with lower risk.
*after controlling for age, smoking, blood pressure, and body weight
Nurses’ Health Study 2001 Annals of Internal Medicine (volume 135, pages 1-8)

20. Osteoporosis
Each standard deviation below mean bone density doubles fracture risk
Bone density tends to be lost rapidly in the first few years after menopause

21. HRT and Osteoporosis
Hormone therapy with estrogen or estrogen/progestin ↓ risk for osteoporosis-related hip fracture by 25% and for vertebral fractures by over 50%
In observational studies:
fracture risk reduction may require use of HRT for at least 5 years
fracture risk reduction appears to diminish rapidly after cessation of HRT

22. WHI Reduction in hip fractures (NNT 2,000 per year)
Vertebral fractures (NNT 1,429 per year)
Osteoporotic fractures (NNT 228 per year)
Note study stopped early. . .(just when efficacy might start to be seen)

23. Since WHI Fractures rising since 2002 (publication of WHI)
Menopause Volume 16(1), January 2009, pp 77-83

24. Breast Cancer
HRT (E+P) associated with increased invasive breast cancers (0.38% HRT pts/year vs. 0.3% placebo pts/year; NNH 204 over 5.6 years) but no further increased risk after cessation of trial
borderline statistical significance and not significant in adjusted analysis
Estrogen alone does not have increased risk of breast cancer, based on trial with 10,739 women with prior hysterectomy

25. HRT Prescriptions in the US
Year
Dispensed retail hormonal prescriptions13,77,78
US women aged 55 and older: N (thousands)103,104
Ratio: Rx per women age 55+
1966
17.8 million
19 778
0.90
1975
30.7 million
24 060
1.28
1980
16.3 million
26 796
0.61
1983
21.4 million
28 140
0.76
1992
34.5 million
30 254
1.14
2000
87.3 million
32 852
2.66
2003
59.6 million
33 892
1.76

26. Breast Cancer Incidence Trend
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Breast Cancer Incidence Trend
Krieger, N. Int. J. Epidemiol : ; doi: /ije/dyn055
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27. Other Benefits of HRT Decreased risk of diabetes
Decreased risk of colon cancer
Decreased tooth loss
Possible decreased osteoarthritis
Decreased dry skin, skin wrinkling
Decreased cataracts

28. Other risks of HRT VTE Stroke
Possibly Dementia: 40 HRT patients (1.8%) vs. 21 placebo patients (0.9%) developed probable dementia (p = 0.01 NNH 111), rate 45 vs. 22 per 10,000 person-years (NNH 435 for 1 year) (Observational studies suggest >10 years use may be assoc. w/decreased risk of dementia)

29. WHI in Perspective

30. WHI

31. Bottom Line: Do No Harm
In the past, I gave patients a worksheet to look at their personal risk factors for breast cancer, osteoporosis, and heart disease, to use this to help guide them in a decision about HRT vs. none
Now, with the above data, it is a little murky, and I will now add to the murkiness:

32. But, are all hormones created equal?
Bioidentical Hormone Replacement Therapy
The Sexy Years, Oprah, etc.
Bottom line: not well-studied
Rationale: our detox systems are designed to deal with human hormones in a certain proportion
Synthetic or exogenous hormones may therefore have side effects different than endogenous hormone exposure
We already do this with thyroid, adrenal insufficiency, insulin, male HRT and erythropoietin

33. Progestins vs. Progesterone
From PEPI:
progesterone did not interfere with HDL raising from estrogen, whereas MPA(provera) did
MPA raised 2-hour postprandial glucose (P did not)
MPA binds to androgenic and other receptors in ways natural progesterone does not
Estrogen and progesterone are neuroprotective against excitotoxicity, whereas the synthetic progestin medroxyprogesterone acetate (MPA; Provera) is not Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling, PNAS (18):10506
Etc.

34. Estrogens
CEE: Estrone (75-80%), equilin (6-15%), Estradiol and two other equine estrogens (5-19%).
Premenopausal human females: Estriol, Estrone, and Estradiol, 90%; 3%; 7%
Metabolism and receptor binding are different for different estrogens (note the SERMs)
As an example: Unsaturation in the B ring alters the regiochemistry of P450-catalyzed hydroxylation from primarily 2-hydroxylation for endogenous estrogens to 4-hydroxylation for equine estrogens
Cytotoxic effects of the catechol estrogens from estrone, equilin, and 2-hydroxyequilenin were similar, whereas 4-hydroxyequilenin was a much more potent cytotoxin ( approximately 30-fold)
Chemical research in toxicology 1999;12(2):204-13

35. Routes of Administration
Oral
Transdermal
Vaginal
Intrauterine

36. Matched Odds Ratios (95% CI)
TABLE 2. Impact of Hormone Therapy on VTE Risk by Route of Estrogen Administration and Type of Progestogens
Cases
(n=259)
Controls N=623
Matched Odds Ratios (95% CI)
Crude
Adjustment 1
Adjustment 2
Nonuse
146
384 1
Oral estrogen use 45 39
3.6 (1.5–8.8)
4.0 (1.6–10.1)
4.2 (1.5–11.6)
Transdermal estrogen use 67
180
0.8 (0.4–1.6)
0.8 (0.4–1.8)
0.9 (0.4–2.1)
No progestogens 14 40
...
Micronized progesterone 19 63
1.0 (0.4–2.3)
0.9 (0.4–2.2)
0.7 (0.3–1.9)
Pregnane derivatives (incl MPA) 79
0.9 (0.4–2.3)
Norpregnane derivatives
40*
3.8 (1.6–8.7)
4.0 (1.7–9.4)
3.9 (1.5–10.0)
Users of oral estrogen combined with nortestosterone derivatives (12 cases, 7 controls) were excluded (OR, 6.7; 95% CI, 2.1 to 21.9 vs nonusers). Estrogen-by-progestogen interaction terms were not significant. Adjustment 1: adjustment for obesity status, familial history of VTE, and history of varicose veins. Adjustment 2: adjustment for obesity status, familial history of VTE, history of varicose veins, education, age at menopause, hysterectomy, and cigarette smoking.
*Twenty-two cases received nomegestrol acetate, and 18 cases received promogestone.
Nineteen controls received nomegestrol acetate, and 18 controls received promogestone.
Norpregnane: nomegestrol acetate or promegestone
Climarapro – levonorgestrel (nortest deriv)

37. So then is HRT safe after all?
Bottom line:
We don’t know. (A Climara patch with micronized progesterone at night might be safe and effective, but there are no large trials to confirm.)
So in practice:
Inform your patient – I have a handout for those who are interested
Share the decisions (and the risks) with your patient

38. Some pearls from my experience:
Consider a slow (over 2-3 years) taper of estrogen in people with a lot of symptoms who do not want long-term estrogen therapy
Pay attention to which symptoms are most bothersome – tiny doses of vaginal estrogen can be really helpful
Use progesterone at night
Emphasize stress management when menopausal sx. flare after previous control on a given dose

39. Alternatives Depends on Goals of Therapy
Most are studied only for symptom management
For Heart Disease, Osteoporosis, Breast cancer: vegetarian diet and regular exercise are helpful in preventing all of these. Vitamin D and calcium, fish oil might be considered.

40. Symptom Control Hot Flushes - ”Power surges” Vaginal atrophy
Bladder changes, UTI

41. DDX Hot Flushes
Systemic Diseases - Carcinoid syndrome, Mastocytosis, Pheochromocytoma, Medullary carcinoma of the thyroid, Pancreatic islet-cell tumors, Renal cell carcinoma
Neurological - Spinal cord injury, Migraine, Parkinson's disease, Brain tumors, Emotional (e.g., anxiety)
Drugs/Vitamins and Alcohol –
CCBs, SSRIs, Cholinergic drugs, Cephalosporins, Niacin
Hormonal –SERMs, Lupron, Arimidex, Tamoxifen
Eating/Food Additives - Dumping syndrome, Hot beverages, Spicy foods, MSG, Sodium nitrate, Sulfites

42. Phytoestrogens Isoflavones: soybeans, chickpeas, red clover and
other legumes (beans and peas).
Lignans: Oilseeds such as flaxseed, cereal bran,
whole cereals, vegetables, legumes and fruit.
Mechanisms – (note complexity; final impact not easily predicted)
Bind estrogen receptors like SERMs
Inhibit aromatase, change SHBG levels
Alter gut flora, which affects estrogen detox
Are altered by gut flora (diadzein → equol) – may work in only a percentage of women

43. Epidemiology
Populations that consume a diet high in phytoestrogens have lower rates of cardiovascular disease, osteoporosis and breast, colon, endometrial and ovarian cancers
These are plant-based diets – the phytoestrogens may or may not be the explanation

44. Eat Food, Not Supplements
AHA does not recommend use of isoflavone supplements in food or pills to reduce the risk of cardiovascular disease.
In contrast, soy products such as tofu, soy butter, soy nuts and some soy burgers should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins and minerals, and low content of saturated fat.

45. Red Clover(found in Estroven, $13-25/mo)
Meta-analysis indicates a reduction in hot flush frequency in the active treatment group (40-82 mg daily) compared with the placebo group (weighted mean difference -1.5 hot flushes daily
Phytomedicine Feb;14(2-3): Epub 2007 Jan 18.
Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis.
In rodents, red clover helped decrease bone loss after oophorectomy, and also skin aging changes

46. Hesperidin
900 mg hesperidin, 300 mg hesperidin methyl chalcone, and 1,200 mg vitamin C x 1 month.
Hot flashes completely relieved in 53 percent and reduced in another 34 percent of the women
Smith CJ. Non-hormonal control of vasomotor flushing in menopausal patients. Chic Med 1964;67:
Inhibits Bone Loss and Decreases Serum and Hepatic Lipids in Ovariectomized Mice
2003 The American Society for Nutritional Sciences J. Nutr. 133: , June Nutrient Metabolism
Hiroshige Chiba

47. Black Cohosh More effective than placebo, but study design criticized
Helped vasomotor sx., less benefit to other sx
Appears to work as a SERM
Relative safety compared to estrogen is unclear
German Commission E recommends 6 mos use only

48. Don’t Bother: Panax ginseng Evening Primrose Oil Dong quai
+/- Vitamin E

49. Treatment by an herbalist
Green, J. et al. Fam. Pract : ; doi: /fampra/cmm048
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51. Abdominal Breathing
44% Decrease in hot flushes with 5 minutes morning and night of paced (abdominal) breathing
No change with Biofeedback, muscle relaxation
No adverse reactions
Freedman RR, Woodward S. Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am J Obstet Gynecol†1992;167:

52. Other drugs more effective than placebo for vasomotor sx
Clonidine /d
SSRI’s
Paroxetine
Venlafaxine
Gabapentin 900 mg per day

53. Fig. 1: Top: Total estimated prescriptions dispensed in Ontario for hormone replacement therapy (HRT: oral and transdermal estrogen monotherapy and estrogen-progesterone combination therapy) and serotonergic antidepressants (SAs: citalopram, fluoxetine, sertraline, fluvoxamine, paroxetine, venlafaxine, nefazadone and trazadone) to women years old, from January 2001 to June 2003
McIntyre, R. S. et al. CMAJ 2005;172:57-59
Copyright ©2005 Canadian Medical Association or its licensors

54. A Side Note on DHEA Promoted by “anti-aging” proponents
Falls in humans as we age
Small benefit for bone density
Is effective in treating “mid-life depression”
Arch Gen Psychiatry. 2005;62:
Study used 90+ mg per day – more than is androgenizing for most women
Can be converted to estrogen and testosterone in the body (safety unknown)

55. Libido A topic for another day, but. . .
Testosterone: trials barely reach statistical significance, and there is potential toxicity
Wellbutrin may be effective: 63% vs. 3% reported themselves as much or very much improved in libido and global assessment of sexual function J Sex Marital Ther Winter;13(4):239-52

56. Frequency of sexual activity at 24 weeks of treatment
Braunstein, G. D. et al. Arch Intern Med 2005;165:
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57. Some other options for libido:
ArginMax: L-arginine, ginseng, ginkgo, damiana and 14 essential vitamins and minerals
64 percent reported an improvement in their level of sexual desire, compared to 43 percent in the placebo group
Kyo-Green : one small open-label trial. Would be expected to improve general health
Exzite: Ligusticum, acanthopanax, chrysanthemum
Unpublished placebo-controlled trial. Statistically significant improvement in vaginal lubrication, sexual desire, clitoral sensation, orgasmic potential and sexual satisfaction

58. So. . . . A 50 yo woman presents and the MA writes CC: “Menopause”
What do you recommend?
Elicit her sx and goals