Clinical Review

Hormone Replacement Therapy In Women: The Evidence

Sangeeta Pati MD FA COG graduated at the top of her medical class at the University of Maryland School of Medicine, Baltimore, and completed her residency at Georgetown University School of Medicine, Washington, D.C. She practiced obstetrics-gynecology in the Washington, D.C. area for 14 years before opening Sajune Medical Center in Orlando, Florida. where she is currently President & Medical Director

Abstract

Restoration of low thyroid, insulin and cortisol is the medical

standard. So, it seems logical to also replace low estrogen. progesterone and testosterone: however the evidence leaves

cl inicians at a loss for c lear direc tion. because of conflicting results from studies using varying types of hormone . routes

and ages. This paper analyses the data and puts forth an argument as to why physiologic hormone ratios are safe to

women and can be achieved by the use of bio-identical hormones, transdermal estrogen and a start in early menopause before disease sets in .

Introduction: Why restore Hormone Bala nce

Hom10ne receptors for estrogen, progesterone and testosterone

are present on the cells of the heart. blood vessels. bone. nerves, muscles, skin and most ce lls in the body. So, when

these hormones become imbalanced. women acquire an increased r isk of heart attacks. strokes, cognitive decline.

osteoporos is and breast cancer. A comprehensive analysis of data shows that restoration of normal physiologic ratios of

hormones is beneficial in alleviating symptoms and more importantly degenerative disease. But. what type is protective?

What route is protective and to which women?

Normal Protective H01·mone Ratios

There are three predominant estrogen in non-pregnant,

premenopausal women. These are estrone (E I). estradiol (E2)

and estriol (E3) at a ratio ofEI 10-20%, E2 10-20% and E3 60-RO% (see Tahle 1)1• This ratio is protective. since the bulk of

estrogen is in the form of the weakest estrogen, E3, which is

also the most clot and breast protective. E2 is the strongest

estrogen and E I is the storage form of estrogen. which also has the abil ity to stimulate breast proliferation and c lots. E I can be

metabol ized to methylated products which are excreted safe ly by the liver2, however if the liver systems a rc overwhelmed or

methyl groups are deficient. E l is converted to qui nones (i.e. 4-0H or 16-0H) which arc mutagenic and carcinogenic.J.4

Hormone ratios in the peri-menopause and menopause

Hormone decline starts around age 30 when progesterone

levels stan to wane. This can produce a myriad of symptoms

which are often not recognized as progesterone deficiency,

including anxiety, insomnia. pan ic attacks, heavier bleeding.

cysts (ovarian and breast), PMS. weight gain. fibroids and bone

loss. This period is characterized by an overabundance of estrogen-'

As menopause approaches, the ovarian production of estrogens dec lines; however due to the continued production of

E I by the adrcnals and fat tissue, 60-80% of estrogen is E I with E2 and E3 each reduced to I 0-20%. ll is precisely the

overabundance of E I and the lack of E3 and progesterone that

predisposes menopausal women to breast cancer. stroke and heart attack.

J[AA!\1 & BAA \1.1 Issue 3

32

Clinical Review

Bio-identical hormones can mimic protective ratios

Horse-derived, soy and yam honnones do not fi t into the hu man receptor exactly. Bio-identical hormones are exactly

identical to the hormones of the human body, molecule by

molecule. Since, they fi t the hormone receptor like a key fi ts into its lock; the body can not d isti nguish between a bio­

identical hormone and the hormones it makes itse lf. They are

often created from soy or yam hormones by removing any

molecules that do not exist on the human bonnone counterpart.

They can also be made synthetically in the laboratory, for

example Climara patch o r Vivelle Dot which are both bio­

identical 17-beta cstradioi.6 To reestablish the normal

protective ratio, a 20:80 ratio ofE2 to E3 can be used, avoiding

E I altogether. Transdermal estrogen mimics nonna l ratios better than

oral, since oral estrogen tirst passes through the liver where

50% is converted into estrone sulfate (EI) before circulating to

tissues. Transdermal estrogen enters the circulation at the ratio

applied to the skin. A body of literature suggests that

transdennal estrogen decreases thrombosis, b lood pressure,

tr iglycerides and vascular resistance as opposed to oral

estrogen which increases thrombosis, blood pressure, CRP, triglycerides, gall stones and liver binding proteins7,8,9,10.11 ,12,13,14

What's wrong with the Women's Health Initiative (WHJ)15?

The WHl included 16,600 women in 40 centers from 1997-

2002 of average age 63. They used Conjugated Equine Estrogen

(CEE) with 50% E I, Y,% E2, no E3 and 40% horse equilins

(see Table 1). They a lso used a non-bio-identical progestin,

medroxy-progesterone acetate (M PA) which is both

thrombogenic and carcinogenic. This may partly explain 8

more breast cancers, 8 more strokes, 7 more heati attacks and

Table l : Estrogen Ratios I

Estrone (Ell Estradiol (E2) Estriol (E3)

Pre-menopausal 10-20% 10-20% 60-80%

Non-p regnant

Post-menopausal 60-80% 10-2 0% 10-20%

Premar in (CEE) SO% 0.5% 096

Ora l

18 more peripheral clots per 10,000 women. Interestingly, the

WHI released results for the estrogen-only arm in 2002,

showing an almost significant decrease in breast cancer and

cardiovascular disease.16 WHL showed a decreased ri sk of hip

fracture and colon cancer of 6 per 10,000 women. Additionally,

reanalysis revealed that the decreased mortality from hip and

colon cancer far offset the increased mortali ty from breast cancer.

The WH l greatly int1nenced the way in which Ameri can

doctors prescribe hormones and the way in w hich American

women receive them, with millions of women stopping

hormone replacement therapy (HRT) after the results were

heralded by the media. And although the results were not as bad

as initially thought, there arc several changes which would have

increased the applicability and the positivity ofthe findings:

I) they should have studied qual ity of li fe.

2) they should have used estrogens in favora ble ratios

and transdermally. 3) they should have used a bio-identical progesterone

instead of a synthetic, non-bio-idcntical progestins which is

known to be thrombogenic and carcinogenic. 4) they should have started women on hormones before

they developed significant vascular disease (by age 55) instead

of at average age 63 and average age 71 in the memory study.

5) And. they should have insisted on media coverage of

the positive fi ndings they later found in the estrogen-only ann .

Progestins -vs- bio-identical progesterone

Progestins are vastly different in molecular

funct ion fi·om bio-identical progesterone.

structure and

Bio-identical

progesterone was preferred by 34% of women previously on

MPA i11 a Mayo Clinic Study. Rio-identical progesterone results in less bleed ing, less bloating, less mood swings 17,18

and bette r sleep l9,20 than MPA. It also leads to less breast cell

proliferation and less cell adhesion 21,22,23. From a vascular

standpoint, it decreases LDL24, vasodilates 25 and inh ibits

vascular smooth muscle 26 and vasospasm 27. 29 com~;>ared with

MPA. MPA actua lly stimulates vascular smooth muscle in

coronary arteries 28, opposes vasodilation 30, decreases N031

and increases CRP32 compared with bio-identical

progesterone 33,34. The WH I study demonstrated the increased

vascul ar consequences of progestin since the estrogen-only

ann did not demonstrate the increased cardiovascular risk seen in the CEE-MPA arm_15. 16

Several studies support an increased breast cancer risk with progestins, incl uding the WHl 15,16, Breast Cancer

Demonstration Project 35 and Swedish Record Review 36 with

a 2, 8, and 2.5 fold increased risk of breast cancer respectively

when using MPA with CEE compared to CEE alone. So,

progestins are more mitogenic and thrombogen ic than bio­identical progesterone.

Breast Cancer

The number one fear expressed by women when discuss ing

H RT is the fear of breast cancer. In perspective, the two-year

morta lity for hip fracture is much greater than the ten-year

morta li ty from breast cancer, and osteoporotic fractures occur

8 times more frequently than breast cancer.

In review of the data regarding breast cancer and HRT (see Table 2), a few things stand out:

l) The relative risks are not huge: RR 0.5 to 1.46 37.38

which was found in a subset of women who drank 3-4 glasses

of alcohol per week in the Nurses Health Study 2) Progestin is a possible culprit: WHl 15,16, BCDDP 35

and Swedish Record 36 Review all report increased risk due to

the add ition of progestins to CEE40 , and the breast mitotic index increases more when progestin is added to CEE. 39

3) HRT does not increase recurrence eve11 in breast cancer patients. Nine independent studies in "five countr ies (the Uni ted

States, Australia, South Africa, and Finland) fail to demonstrate

any increased incidence o f recurrent breast cancer with HRT. 41,42

.TEAAJ\1 & BAAMJ Issue 3

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Clinical Review

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34

Clinical Review

bone formation 88_ Studies (using both bio-identical and non­

bio- identical estrogen) show that estrogen prevents bone loss

by inhibiting osteoclasis and bone resportion 90, 91. 92_ E2 is

significantly stronger than E3 in this protective effect. Estrogen

also protects against loss of cartilage and osteoarthritis.

It is progesterone decline that accounts for bone loss

occurring 1 0-15 years before menopause. Progesterone

actually stimulates osteoblasts and bone formation 88. 89_

Similarly, testosterone stimulates bone fom1atioo 93. 94. Clinical

studies support the use of both synthetic and bio-identical

progesterone. estrogen and testosterone for the prevention of

osteoporosis and bone fracture even when started late (i.e. WHT study with 35% fracture reduction)t5_

C olon C ancer

The WHT study reported six fewer colon cancers per I 0,000

women in the HRT group 15_ NAMS meta-analysis reviewed 18 studies to conclude that H RT reduces colorectal cancer up to

34% compared with women who never used 1-1 RT 95. One case­

control study shows that the risk reduction from rransdenna I estrogen is greater than that with oral 96_

Sexual and urogenital function

Twelve ran domized controlled trials have shown a significant

bene fit to sexual function with the restoration of testosterone

97, 98,99 Numcroli-S stud ies have shown the restorative effects

of estrogen on the vaginal epithelium 100, 10 1. 102. 106_ Therefore

estrogen (particularly through the vaginal route) is used

effectively to relieve vaginal dryness, vaginal relaxation, loss of urine 103, 104,105 and recurrent urinary tract infectionsiOI_ Jn

fact, the use of vaginal E3 re lieves st ress urinary incontinence in a matter of weeks.

Conclusion

The closer we mimic the normal physiologic ratios of

hormones, the better the prevention of disease. Non­

bioidentical, oral estrogens (i.e . CEE) provide too much E t {up

to 50%) partly due to their inherent makeup and partly due to

the liver pass effect via the oral route. Bio-ident ical estrogens,

especially transderrna l, m imic nonnal ratios bette r. They have

favorable anti-thrombotic and vascular effects . Although,

progestins add cardiovascular risk; bio-identical progesterone

is anti-thrombotic and breast cancer protective. T he best

strategy for preven tion of breast cancer lies in restoring a protective balance of hormones and nutrients and avoiding and

removing toxins. Although, bio-identical hormones mimic

norrna l ratios better, even studies using CEE support the use of

early HRT (<Syears from menopause) to reduce the r isk of

heart attacks. stroke and cognitive decline. Physiologic

hormone ratios a re safe to women and can be a.chieved by the

use of bio- identical hormones, transdermal estrogen and a start

in ear ly menopause before disease sets in.

References

1. Wright J, et al. Comparative Measurmenl of serum estriol. estradiol

and estrone in non-pregnant, premenopausal women: a preliminary

investigation, Alternative Medicine Review, 1999; 4(4):266-70

2. Longscope C. et al, The metabolism of estradiol : oral compared to

intravenous administration. J Steroid Biochem 1 985;23: 1 065-1 070

3. Chen Y. et al. Metabolites of Synthetic Conjugated Estrogens are

linked to development of breast carcinoma. Chern Res Toxtco/ 1998

Sept; 11 (9)94-101,1105-11

4. Cavalieri E, el al. Molecular origin of cancer: Catechol estrogen-3,4

quinones as endogenous tumor initiators. Cell Mol Ute Sci

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592-3

6. Reed-Kane D. In/ J Pharm Camp 2001; 5 (5), 332-341

7. Erenus M, et al, Comparison of effects of continuous combined

transdermal with oral estrogen and oral progesterone replacement

therapies on serum lipoproteins and compliance.Ciimacteric

2001 ;4:228-234

8. Adami S. et al, Long term effects of trar~sdermal and oral estrogen on

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9. Meschia M, et al, Effects of oral and transdermal hormone

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12. Vongpatanasin W , et al, Differential effe<:ts of oral versus transdermal

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13. Post MS, et al, Effect of oral and transdermallherapy on hemostatic

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hormone therapy on vascular function: a randomized. placebo­

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15. Writing Group for the Women's Initiative Investigators. Risks and

benefits of estrogen plus progestin in healthy postmenopausal

women. Principal resulls from the women's Initiative randomized

controlled trial. JAMA 2002;288:321-333

16. Anderson GL, et at, Effects of CEE in postmenopausal women with

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17. Fitzpatrick L, et al, Comparison of regimens containing oral

micronized progesterone or medroxyprogesterone acetate on the

quality of life in postmenopausal women: a cross-sectional survey. J

Women 's Health Gend Based Med 2000;9:381-7

t8. Cummings J. Comparison of physical and emotional side effects of

progesterone or medroxyprogesterone in early postmenopausal

women. Menopause. 2002 Jui-Aug; 9(4):253-63.

19. Montplaisir J, et al, Sleep in Menopause: differential effects of two

fonns of hormone replacement therapy. Menopause 2001 Jan­

Feb;8:10-16

20. Arafat ES, et al, Sedative and hypnotic effects of oral administration

of micronized progesterone may be mediated through its metabolites.

Am J Obstet Gyneco/, Nov 1988;159(6): 1203-1209

21 . British J Cancer 1996; 73:1552-5-P inhibits breast cells

22. Chang Kj, et al, Influences of percutaneous administration of

estradiol and progesterone on human breas1 epithelial cell cycle in

vivo. Fertil Steri/1995;63:765-791

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