TESTOSTERONE REPLACEMENT FOR MEN
TESTOSTERONE and Prostate Cancer
(The following is adapted from two excellent lectures by urologist Kenneth Janson, MD, FACS, given at the November 2010 and May 2013 Age Management Medical Group conferences, as well as a lecture by Harvard urologist Abe Morgentaler at the December 2012 A4M conference.)
In the past it was accepted belief that raising testosterone would increase the risk of prostate cancer. This was largely because in 1941 Huggins, Hodges and Scott showed that orchiectomy (surgical castration– and thus elimination of testosterone production) caused regression of metastatic prostate cancer. They also gave testosterone to three men with prostate cancer. Of those three men, they only published the results for two. They showed that alkaline phosphatase went up in those two men, supposedly a sign that the cancer was getting worse.
(Alkaline phosphatase is an outdated blood test for prostate cancer. We don’t use it anymore because it is quite unreliable. These days we use PSA instead, though the guidelines for PSA monitoring are also changing.)
But one of those two men had already been castrated previously, which means he is not comparable to men who still make their own testosterone. In other words, his results don’t really “count.”
Nevertheless, in 1966 Huggins won the Nobel Prize for “fundamental discoveries concerning the hormone dependence of normal and neoplastic cells in animals, and their practical application to the treatment of human prostatic and breast cancer.” Their results led to decades of unchallenged belief that raising testosterone would increase the risk of prostate cancer. What never made the news was that this belief was based on Huggins and Hodges work with… one single patient!
In 1981 Fowler and Whitmore re-opened the discussion: they did a study showing that in men with prostate cancer who were treated with chemical castration (i.e. given medicine to shut down all testosterone production), testosterone therapy caused disease progression, just like Huggins and Hodges had shown. However, testosterone therapy in non-castrated men did not cause progression. (In other words: in men that still had some testosterone of their own, adding more did not cause prostate cancer progression.)1
Because of that paper, some questions started to be asked about the assumption that testosterone therapy is always detrimental in patients with prostate cancer:
In 2000, articles from the Massachusetts Male Aging Study were published showing no correlation between PSA and testosterone levels even with testosterone levels up to 2800ng/dL.2,3 (For perspective: Age Management Medicine protocols generally do not push levels past 1200ng/dL, so this study used more than double the typical maximum levels for HRT.)
In 2002 the Mayo Clinic stated,4
There is no clinical evidence that testosterone replacement causes prostate cancer.
In 2004, things started really getting interesting. Harvard urologists Morgentaler and Rhoden published a review article on testosterone replacement therapy in the New England Journal of Medicine.5 They wrote:
Despite decades of research, there is no compelling evidence that testosterone has a causative role in prostate cancer.
…there appears to be no compelling evidence at present to suggest that men with higher testosterone levels are at greater risk of prostate cancer, or that treating men [with testosterone] increases this risk. In fact, it should be recognized that prostate cancer becomes more prevalent exactly at the time of a man’s life when testosterone levels decline.
Dr. Morgentaler continued treating patients with testosterone, and in 2009 he went a bold step further: he published a case report of an 84-year old attorney who was diagnosed with prostate cancer and decided to not treat it– and to remain on testosterone therapy. After 24 months his PSA decreased and his prostate cancer was deemed stable.6
Morgentaler proposed the Saturation Theory: in patients with no testosterone (chemically castrated or levels less than 90ng/dL), testosterone replacement may cause disease progression—that first little bit may stimulate receptors on the cancer. HOWEVER, those receptors quickly saturate; therefore if patients are NOT castrated, and have testosterone already circulating, then additional testosterone doesn’t stimulate the receptors any further.7,8,9
Dr. Morgentaler makes the useful analogy of a houseplant that has been deprived of water: A man whose testosterone level is extremely low (i.e. total T below 100ng/dL) may have a dormant, small prostate cancer, and giving such a person testosterone could be like watering the shriveled houseplant: that first little bit of water causes the plant to flourish. However in a plant that already has enough water, you can pour buckets of water on it and it still won’t grow any faster: similarly, in men who have more than 100ng/dL circulating testosterone, adding more testosterone will not cause any prostate lesions to grow.
That same year (2008) Cornell, Baylor and University of Toronto published a study showing that Testosterone therapy in hypogonadal men after radical prostatectomy for prostate cancer resulted in no increase in PSA and no increase in prostate cancer progression.10
Also that year, Marks et al published a study showing that tissue levels of Testosterone in the prostate were tested before and after testosterone therapy, and even though blood levels of testosterone went up significantly, there was no change in testosterone levels in the prostate.11
In 2010 the American Urological Association published work by Morgentaler on 13 patients already diagnosed with prostate cancer, who were treated with testosterone replacement and followed for 30 months: they showed no progression of their prostate cancer on subsequent biopsies and no increase in PSA!12
Furthermore: there is significant evidence to suggest that LOW testosterone INCREASES the risk of prostate cancer:
- In 2001 Schatzl showed that lower testosterone levels were associated with more aggressive prostate cancer.13
- In 2006 Morgentaler and Rhodes published a paper14 showing that low levels of testosterone actually increase the risk of prostate cancer:
Among 345 hypogonadal men with low levels of total or free testosterone, Prostate cancer was present in more than 1 of 7 of the men even though their PSA was less than 4.0.
An increased risk of prostate cancer was associated with more severe reductions in testosterone.
- In the Baltimore Longitudinal Study of Aging, men with the highest levels of Testosterone were at the LOWEST risk of developing prostate cancer.15
- A study in Korea looked at 568 patients who underwent prostate biopsy. Patients with lower levels of serum testosterone had a higher risk of prostate cancer than did patients with high serum testosterone.16
And even more recently,17 in 2011 Salonia et al found that in men with low testosterone compared with men with normal testosterone levels,
- The risk of high-grade prostate cancer was increased by >50% (33% vs 19.8%, p< .0009),
- local invasion nearly doubled (21% vs 11%, P < .003),
- and for men with more severe T deficiency, the risk of high grade cancer tripled (59.5% vs 19.8%, P < .0001).
2. Massachusetts Male Aging Study, Diabetes Care 2000; 23: 490-494.
3. Hoffman, M, DeWolf, W, Morgentaler, A. Is Low Serum Free Testosterone a Marker for High Grade Prostate Cancer? J Urology 2000,163:824-827
4. Mayo Clin Proc 2002 Jan:75:583-87
5. Rhoden E, Morgentaler, A. Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring. New England Journal of Medicine 2004,350:482-492
6. Morgentaler, A. Two years of Testosterone Therapy Associated with Decline in Prostate-specific Antigen in a man with Untreated Prostate Cancer. J Sexual Medicine 2009,6:574-577
7. Morgentaler, A. Guilt by Association: A Historical Perspective on Huggins, Testosterone Therapy and Prostate Cancer. J Sex Med 2008, 5:1834-1840
8. Morgentaler, A. Testosterone Therapy in Men with Prostate Cancer: Scientific and Ethical Considerations. J Urology 2009, 181:972-979
9. Morgentaler, A. Shifting the Paradigm of Testosterone and Prostate Cancer: the Saturation Model and the Limits of Androgen-Dependent Growth. European Urology 55 (2009) 310-321
10. Roddam, A and the Endogenous Hormones and Prostate Cancer Collaborative Group. J National Cancer Institute 2008, 100:170-183
11. Marks LS, Mazer NA, Mostaghel E. et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 2006; 296: 2351
12. Morgentaler A, Morales A: Should hypogonadal men with prostate cancer receive testosterone? J Urology October 2010, 184; 1257-1260
13. Schatzl et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate 47:52-58, 2001
14. Morgentaler A, Rhoden E. Prevalence of Prostate Cancer Among Hypogonadal Medn with PSA levels of 4.0ng/mL or Less. Urology 68:1263-1267, 2006
15. Laughlin GA, Barrett-Connor E and Bergstrom J: Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68
16. Bo Sung Shin, et al: Is a Decreased Serum Testosterone Level a Risk Factor for Prostate Cancer? A Cohort Study of Korean MenKorean J Urol 2010 December; 51(12): 819–823
17. Morgentaler A. Turning Conventional Wisdom Upside-Down: Low Serum Testosterone and High-Risk Prostate Cancer. Cancer Volume 117, Issue 17, pp 3885–3888, 1 September 2011
IT IS IMPORTANT TO UNDERSTAND that clinical tumor recurrence or increase in PSA DOES OCCUR in a small percentage of patients treated with testosterone— but the rate is not higher than previously published statistics in men not receiving testosterone. In other words: whether they get testosterone or not, some men will get (initial or recurrent) prostate cancer. The literature simply indicates that testosterone replacement is not the cause.
One group that needs to be especially vigilant: men who have been treated in the past with Lupron, and still have an exceedingly low testosterone level. In keeping with Morgentaler’s “saturation theory”, those patients are the most likely to see an increase in PSA when started on testosterone. If such a patient wants testosterone replacement, I would be very careful to clarify that they will need frequent monitoring. My preference is to monitor via MRI, and for this reason I refer patients with elevated PSA to Dan Sperling, MD at Sperling Prostate Center.
In any patient on long-term testosterone replacement therapy, regular prostate exam is necessary. Referral to a Urologist is warranted for any concerns. At present, most Urologists who are also trained in Age Management Medicine (a small group, to be sure) would likely NOT stop testosterone therapy even if PSA went up, but that decision would of course be made by the patient after an informed discussion with his doctors.
In the interest of balance it should be noted that, as of this writing, the Endocrine Society Clinical Guidelines still state that testosterone therapy is contraindicated in patients with prostate cancer.
500mg of Sustanon and 30mg of D’bol (Dianabol) would be considered a moderate dosage for me. As a professional bodybuilder my dosages are considered very low, compared to other pros. For instance, the most testosterone I have ever taken is 1,250mg a week, and this is considered nothing since I am a pro.
Professional athletes who use steroids are injecting a cocktail of synthetic medications that the human body has never seen, or using testosterone at levels no human was meant to deal with. Then they use other medications to try to address the side effects. These are modern-day gladiators sacrificing their bodies for our entertainment (and our money). A preventive medicine practice, by contrast, is simply replenishing the level of testosterone that your body was used to seeing when you were younger. Not only is this safe, it lowers your risk of heart attack, type 2 diabetes, and osteoporosis. If you would like to review some of the studies on testosterone levels and your health, please see the Testosterone Studies page.
Of course, when you were in your 20s and 30s, you had plenty of testosterone and had no concerns about suddenly having too much estrogen. This is because your body knows how to manage normal, human levels of testosterone, which is all that you will receive in our practice. Bodybuilders found out the hard way that when they injected massive doses of testosterone, they wound up with more estrogen than they would like, so they started taking Arimidex and other medicines to block the conversion to estradiol. In my practice that is rarely necessary, because I increase levels slowly (so your body’s enzymes have time to adjust) and I don’t exceed the normal human range.
In addition, blocking estrogen is not a good idea, because estrogen has tremendous benefits in men as well, preventing heart disease and osteoporosis, as well as fighting prostate cancer. (In fact a 2013 NEJM article showed that estrogen also helps men decrease visceral body fat.) Having levels of estradiol as high as 50 is not harmful and may be beneficial in men. I have a few patients who have briefly used very low doses of Arimidex to keep their estrogen levels at the upper end of normal range; I don’t have any patients using Arimidex to suppress their estrogen levels below, say, 25.
Some people hardly convert any testosterone to DHT: they have minmal activity of the enzyme responsible for that conversion, 5-alpha-reductase. If, like me, you are one of the unlucky ones that convert a lot of testosterone into DHT, you may battle androgenic alopecia, or male pattern baldness. In that case, if we increase your testosterone, it is possible that your DHT levels will go even higher, which can worsen hair loss.
Is there a way to prevent that? Absolutely. We will track your DHT levels, and if they start to climb, we can inhibit the 5-alpha-reductase enzyme with medications like dutasteride (similar to Propecia but more effective).
Changes in the International Index of Erectile Function and Male Sexual Health Questionnaire composite scores and erectile, orgasmic, ejaculatory, intercourse, or overall satisfaction scores did not differ significantly between the dutasteride and placebo groups.
…In other words, as long as they had enough testosterone circulating, dutasteride did not hurt sexual function. And that was using 2.5mg/day of dutasteride, the highest possible dose. I would actually only use 0.5mg, and probably not even every day, because the half-life is so long that it isn’t necessary to take it daily.
Effect of Testosterone Supplementation With and Without a Dual 5a-Reductase Inhibitor on Fat-Free Mass in Men With Suppressed Testosterone Production: A Randomized Controlled Trial. Bhasin et al. JAMA, March 7, 2012—Vol 307, No. 9[/expandsub1]
HORMONE REPLACEMENT THERAPY FOR WOMEN:
We take synthetic medications all the time!”]Certainly many synthetic medications can be beneficial. Hormones are in an unusual category, however, in that a great deal of misinformation has been disseminated about them. Provera®, a patented, altered imitation of progesterone, has been shown (like many other synthetic progesterone imitators, collectively called “progestins”) to slightly increase a woman’s risk of breast cancer. Progesterone itself, however, has been shown NOT to increase the risk of breast cancer, and in some studies has actually protected against it! Similarly, Premarin® (a collection of estrogens made from horse’s urine) increases the risk of blood clots, while transdermal bio-identical estrogen does not. Thus, the distinction that it is “bio-identical” is not merely intended to appeal to the Woodstock generation of naturalists; it identifies a category of therapy that is safer than the patented alternatives.
The Women’s Health Initiative used synthetic alternatives for natural (human) estrogen and progesterone. Instead of bio-identical estrogen they used Premarin®, a synthetic estrogen made from horse’s urine. And instead of bio-identical progesterone they used an altered, patented imitation known as medroxyprogesterone acetate (MPA for short), patented as Provera®.
In the Women’s Health Initiative, the synthetic horse estrogens, when used alone without Provera®, did not cause an increased incidence of breast cancer. However, when they combined it with Provera®, they reported a small increased risk in breast cancer. Whether that small increased risk is ‘real’ or not has been the subject of much debate (and will be discussed in detail below); what is not debated is the fact that, if there was an increase in breast cancer, Provera was the cause.
Progesterone is a natural, bio-identical hormone and absolutely does not cause cancer. Provera®, and many other synthetic progestins, have been shown in multiple trials to increase the risk of breast cancer. Again: Provera® and other synthetic progestins are NOT progesterone! Natural progesterone has never been shown to increase the risk of cancer, and in many studies has conferred a benefit in preventing cancer. The medical community has done a very poor job of explaining this distinction, and so unfortunately thousands of women have been scared away from the health benefits of hormone replacement therapy. (Suzanne Somers deserves a lot of credit for helping to educate women on this subject, via her books and interviews.)
Bio-identical progesterone is not just safe—many studies show it protects women from cancer of the breast, ovaries and uterus! In addition, it has a beneficial effect on HDL (‘good’) cholesterol, appears to help reduce heart disease and stroke, and helps prevent osteoporosis.
Though it has taken many years, this is finally, in 2012, becoming accepted by the “mainstream.” Note this recent paper:
The original conclusions of the Women’s Health Initiative study have been questioned… Guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and specific guidelines from the European Menopause and Andropause Society for the management of menopausal women with a personal or family history of [blood clot] all contain positive statements regarding both transdermal estradiol and micronized progesterone. Unlike oral estrogens, transdermal estradiol has been shown not to increase the risk of blood clot or stroke, and to confer a significantly lower risk for gallbladder disease. Unlike some progestogens, [bioidentical] progesterone is also not associated with an increased risk of blood clot, or with an increased risk of breast cancer. Based on these data, which are now included in the guidelines, the use of transdermal estradiol and micronized progesterone could reduce or possibly even negate the excess risk of blood clot, stroke, cholecystitis, and possibly even breast cancer associated with oral HRT use.
J.A. Simon. What’s new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone. CLIMACTERIC 2012;15(Suppl 1):3–10
I would add to that: bio-identical testosterone is an additional piece in the puzzle. The overall message is this: keeping your hormone levels (including estrogen, progesterone and testosterone) within the normal range for healthy women in their 30s, using only bioidentical hormones, helps prevent most of the common diseases of aging (heart disease, stroke, Alzheimer’s disease and osteoporosis), lowers all-cause mortality, and does not increase the risk of breast cancer– in fact, may very well reduce it.
The Endocrine Society released a position statement on Hormone replacement therapy in 2010, and the following line from that statement is an eye-opener:
Menopausal Hormone Therapy was associated with a 40% reduction in mortality in women in trials in which participants had a mean age below 60 yr or were within 10 yr of menopause onset.
Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. JCEM July 1, 2010 vol. 95 no. 7 Supplement 1
That is an astounding assertion: women who start HRT within ten years of menopause have a 40% reduction in mortality from any cause compared to women not on HRT! What else do you really need to know?
(You say you need to know a lot more? Then read on…)
Micronized progesterone does not increase cell proliferation in breast tissue in post- menopausal women compared with synthetic medroxyprogesterone acetate (MPA). Experimental evidence suggests that the opposing effects of MPA and micronized progesterone on breast tissue are related to the non-specific effects of MPA, including glucocorticoid activity and differences in the regulation of gene expression.
Micronized progesterone and its impact on the endometrium and breast vs. progestogens. Gompel A, CLIMACTERIC 2012;15(Suppl 1):18–25
Journal of Steroid Biochemistry and Molecular Biology, July 2005
The addition of natural progesterone does not affect breast cancer risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. More importantly, medroxyprogesterone acetate [Provera®] can potentiate the proliferative action of estrogens.
Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. Campagnoli et al. J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.
Journal of Steroid Biochemistry and Molecular Biology, December 2005
…synthetic progestins (i.e. Provera®), when added to HRT for menopausal complaints, increase breast cancer risk more than estrogen alone. However, recent findings suggest that natural progesterone, whether produced during pregnancy or administered outside pregnancy, does not increase breast cancer risk, and could even be protective.
J Steroid Biochem Mol Biol. 2005 Dec;97(5):441-50
Breast Cancer Research and Treatment, 2008
This was a large prospective cohort study of over 100,000 women in France. About 70% of the women used HRT for about 7 years, starting at age 52 (on average). They were then followed for about 8 years. This study found that if they combined bio-identical estrogen with synthetic progestins (Provera® /MPA or norethindrone), the risk of cancer was much worse: relative risk of 1.48 to 2.11!
However if they combined estrogen with natural progesterone instead of Provera®, the relative risk of breast cancer was 1.00: no increased risk.
Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. See Table 3.
International Journal of Cancer, 2005
This study assessed the risk of breast cancer in relation to different types of Hormone Replacement Therapy (HRT) in 54,548 postmenopausal women who were part of the E3N-EPIC cohort study.
The relative risk (RR) of developing breast cancer was 1.2 if they used transdermal estrogen alone, and decreased to 0.9 when estrogen was combined with bio-identical progesterone. Those differences did not reach statistical significance: essentially estrogen either alone or with bioidentical progesterone had no effect on breast cancer risk. However, when estrogen was combined with synthetic progestins (such as MPA/Provera®), relative risk of breast cancer increased to 1.4, which was statistically significant.
(In the image above, TD-E2 stands for Transdermal Estrogen.)
Fournier A. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005 Apr 10;114(3):448-54.
To evaluate the risk of breast cancer associated with the use of estradiol plus (bio-identical) progesterone, which is commonly prescribed in France (rather than MPA/Provera), a cohort of 3175 postmenopausal women was followed for a mean of 8.9 years (28,367 woman-years). There was no increase in the risk of breast cancer in the natural, bio-identical hormone users (RR 0.98, 95% confidence interval (CI): 0.65-1.5). The author concluded that HRT with natural estradiol and natural progesterone is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile.
de Lignières B et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002 Dec;5(4):332-40.
Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. However,
the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. Recent evidence shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for synthetic progestins (like Provera®). …Recent trials (also) indicate that natural progesterone confers less or even no risk of breast cancer, as opposed to synthetic progestins.
Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review.
Maturitas. 2008 Jul-Aug;60(3-4):185-201.
Breast Cancer Research and Treatment, 2007
The goal of this study was to compare the effects of oral estradiol given with either MPA or micronized progesterone on risk for breast cancer in a postmenopausal primate model. Compared to placebo, Estrogen + MPA resulted in significantly greater breast tissue proliferation, while Estrogen + bio-identical progesterone did not. These findings suggest that oral micronized progesterone has a more favorable effect on risk biomarkers for breast cancer than medroxyprogesterone acetate. These findings provide growing support for micronized progesterone as an alternative to MPA in hormone therapy regimens.
Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007 Jan;101(2):125-34.
Elevated serum progesterone concentrations were associated with a statistically significant reduction in breast cancer risk.
(OR for highest versus lowest quartile = 0.61, 95% CI = 0.38 to 0.98; P(trend) = .06)
J Natl Cancer Inst. 2005 May 18;97(10):755-65. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).
Cancer Epidemiology, Biomarkers and Prevention, 2002
This study directly evaluated the association between progesterone levels during third trimester of pregnancy and maternal risk of developing breast cancer later in life. Elevated progesterone levels were associated with a decreased incidence of breast cancer [odds ratio (OR) for progesterone >/=270 ng/ml, 0.49; 95% confidence interval (CI), 0.22-1.1] relative to those in the lowest decile.
Steroid hormone levels during pregnancy and incidence of maternal breast cancer. Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):361-8.
Fertility and Sterility, 1998
Estradiol and progesterone regulate the proliferation of human breast epithelial cells.
Double-blind randomized study to study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo.
METHOD: Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding aesthetic breast surgery or excision of a benign lesion. The surgical procedure allowed them to then measure breast tissue proliferation.
RESULTS: Topical progesterone reduced the estradiol-induced proliferation of normal breast epithelial cells by 400% and down-regulated breast receptor sites to reduce breast cancer risks.
Foidart JM, Colin C, Denoo X, Desreux J, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998 May; 69(5):963-969.
Note that progesterone levels during the third trimester of pregnancy approach 300ng/dL, and that is clearly safe for the mother as well as protective against breast cancer. Age Management protocols in post-menopausal women aim to maintain serum progesterone levels at a minimum of 10ng/dL. Although that seems quite low in relation to the levels during pregnancy, progesterone creams are nevertheless unable to accomplish this; the above study is an exception in that gel applied directly to the breast did seem to significantly reduce cell proliferation. This was a very short term study: only two weeks. In my practice I find that creams may barely provide adequate levels to prevent endometrial proliferation (approximately 2ng/dL), but are inadequate to yield levels that provide progesterone’s other benefits on breast tissue, bone and vasculature. Sublingual or oral progesterone is the way to go, contrary to what some websites may say. –Trutt
The following three papers show that having low progesterone levels increases the risk of breast cancer. This is particularly relevant to women with PolyCystic Ovary Syndrome (PCOS), which involves a deficiency of progesterone. These women have an increased risk of breast cancer if not appropriately treated.
International Journal of Cancer, 2004
Endogenous sex hormones and subsequent breast cancer in premenopausal women:
This study recruited 5,963 premenopausal women to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study; they provided a blood sample in the 20-24th day of their menstrual cycle. After 5.2 years of follow-up, 65 histologically confirmed breast cancer cases were identified and matched to randomly selected controls.
Progesterone was inversely associated with adjusted Relative Risk for breast cancer– so much so that in women with regular menses (i.e. higher levels of progesterone), adjusted RR was just 0.12! (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of breast cancer in premenopausal women.
NOTE: “ovarian hyperandrogenism associated with luteal insufficiency” is medical-ese for Polycystic Ovary Syndrome (PCOS) —Trutt.
Int J Cancer. 2004 Nov 1;112(2):312-8.
American Journal of Epidemiology, 1981
Researchers at Johns Hopkins studied 1083 women who had been evaluated for infertility from 1945-1965 and were followed prospectively through 1978 to ascertain their breast cancer incidence. These women were categorized as to the cause of infertility into two groups: those with progesterone deficiency (PD) and those with nonhormonal causes (NH). Women with progesterone deficiency had 5.4 times the risk of premenopausal breast cancer. Women with progesterone deficiency also experienced a 10-fold increase in deaths from all malignant neoplasms compared to women in the NH group. The incidence of postmenopausal breast cancer did not differ significantly between the two groups.
Cowan LD et al. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol. 1981 Aug;114(2):209-17
Breast Cancer research and Treatment, 1986
Estrogen and progesterone, when secreted in an adequate balance, permit the complete and proper development of the mammary gland. Progesterone may also have an antagonistic activity against estradiol, mediated through a decrease in the replenishment of the estrogen receptor, and also through increased 17 beta-hydroxysteroid dehydrogenase which leads to accelerated metabolism of estradiol to estrone… Thus, it can be inferred that long periods of luteal phase defect (i.e progesterone deficiency/ anovulation as is seen in PCOS) leading to an unopposed estrogen effect on the breast might promote breast carcinogenesis. Breast Cancer Res Treat. 1986;8(3):179-88 Mauvais-Jarvis P, et al. Antiestrogen action of progesterone in breast tissue.
The following papers discuss in vitro (lab, not human) studies that explain how progesterone protects against cancer.
“Progesterone alone or combined with estradiol induces cellular apoptosis (causes the death of breast cancer cells).”
Franke HR, Vermes I. Differential effects of progestogens on breast cancer cell lines. Maturitas. 2003 Dec; 46(1):S55-58.
Molecular and Cell Biochemistry, 1999
Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis…
These results demonstrate that progesterone at relative high physiological concentrations, comparable to those seen during the third trimester of human pregnancy, exhibited a strong antiproliferative effect on breast cancer cells and induced apoptosis.
(In other words, progesterone prevented breast cancer cells from proliferating.)
Mol Cell Biochem. 1999 Dec;202(1-2):53-61. Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis.
Journal of Cell Biochemistry, 2001
Apoptosis induced by progesterone in human ovarian cancer cell line SNU-840:
Progesterone has been used as an ingredient of anticancer drug for patients with ovarian carcinoma. In this study, the effects of progesterone on ovarian cancer cells, SNU-840, were investigated. The level of the p53 mRNA reached its maximum at 12 h after incubation with progesterone. …Progesterone inhibits the proliferation and elicits apoptosis of human ovarian cancer SNU-840 cells. Also, it up-regulates p53 mRNA transiently.
(In other words, progesterone also prevented ovarian cancer cells from proliferating.)
J Cell Biochem. 2001;82(3):445-51.
European Journal of Cancer Prevention, 2002
“These results suggest that MCF-7 human breast cancer cells become more sensitive to progesterone and die by apoptosis due to inhibition of the PI3-kinase/Akt pathway.”
Eur J Cancer Prev. 2002 Oct;11(5):481-8. Alkhalaf M et al.
FEBS Letter, 2005
Progesterone inhibits human breast cancer cell growth through upregulation of CDK inhibitor p27Kip1 gene.
Progesterone derivatives selectively activating the p27 gene promoter could be promising drugs against breast cancer progression.
FEBS Letter 2005 Oct 24; 579(25):5535-41
American Journal of Physiology-Endocrinology and Metabolism, 2005
This in-vitro study suggests that bio-identical progesterone together with estrogen is actually more protective against breast cancer than just progesterone alone: Progesterone increases the production of something called Breast Cancer Resistance Protein, and in combination with estradiol its production is increased even further. (Look at the study below this one for another take on this concept…)
Am J Physiol Endocrinol Metab 2005 Dec 13 Regulation of BRCP/ABCG2 Expression by Progesterone And 17beta-estradiol in Human Placental BeWo Cells.
Proceedings of the National Academy of Sciences, 1999
Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy.
Full term pregnancy early in life is the most effective natural protection against breast cancer in women. Because the mammary gland is exposed to the highest physiological concentrations of estradiol and progesterone during full term pregnancy, it is these elevated levels of hormones that likely induce protection from mammary cancer. Thus, it appears possible to mimic the protective effects of pregnancy against breast cancer in nulliparous rats by short term specific hormonal intervention.
Guzman RC, et al. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2520-5.
Japan Journal of Cancer Research, 1985; 76:669-04
Estrogen-induced mammary tumors could be shrunk equally using either Tamoxifen or bio-identical progesterone.
Fertility and Sterility, 1995
Estradiol stimulates ductal proliferation 230% — but bio-identical progesterone decreased proliferation 400%!
Fertil Steril. 1995 Apr;63(4):785-91. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo.[/expandsub1][/expand] [expand title=”So natural progesterone actually helps prevent breast cancer. Does it have any other benefits?”]Progesterone drastically reduces incidence of endometrial cancer. (In fact, that is the reason doctors started adding synthetic progestins to HRT in the 1980s.) Progesterone also helps reduce heart disease, stroke and osteoporosis:
Data suggest that, in addition to estradiol, progesterone may play a significant role in the interrelationship between the ovaries and the skeleton in women. Indeed, the differentiation of human osteoblasts from perimenopausal women has been shown to be dose-dependent on progesterone at physiological concentrations.
Data in peri-menopausal women also suggested that higher progesterone levels… may be associated with more bone formation and with slightly less bone resorption than anovulatory cycles in which progesterone levels are low
V. Seifert-Klauss et al. Progesterone and bone: a closer link than previously realized. CLIMACTERIC 2012;15(Suppl 1):26–31
And incidentally, cancer prevention is not the only area where natural progesterone has the opposite effect of synthetic Provera®; they also have opposite effects when it comes to preventing heart disease and stroke:
Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
This was a 3-year, multicenter, randomized, double-blind, placebo-controlled trial involving 875 healthy postmenopausal women aged 45 to 64 years.
Conclusions: Estrogen with natural bio-identical progesterone has the most favorable effect on HDL-C (compared to synthetic MPA) and no increased risk of endometrial hyperplasia.
In other words, when they used natural bio-identical progesterone instead of synthetic MPA (Provera), the result was a better effect on lipids, and also no increased risk of uterine cancer. Natural Progesterone is much more effective than synthetic Provera in improving HDL levels. This benefit is so pronounced that Elizabeth Connor, one of the cardiologists involved in the PEPI trial, said
If I were treating a woman primarily because she was worried about heart disease, I would probably see if she wanted to take micronized (natural) progesterone. I was quite impressed with the better effect.
JAMA. 1995 Jan 18;273(3):199-208.
Journal of the American College of Cardiology, 2000
In women with heart disease, exercise time to myocardial ischemia improved when they were given estrogen, and improved even more with combination estrogen/progesterone therapy (92 seconds [35 to 149 [p = 0.001)).
Natural Progesterone, but not Medroxyprogesterone Acetate (Provera®), Enhances the Beneficial Effect of Estrogen on Exercise-Induced Myocardial Ischemia in Postmenopausal Women. J Am Coll Cardiol 2000 December; 36(7)
The Journal of Reproductive Medicine, 1999
Endometrial hyperplasia. Risks, recognition and the search for a safe hormone replacement regimen:
“The synthetic progestins have been associated with uncomfortable side effects, reversal of some of the cardiovascular and metabolic benefits of estrogen, and unwanted bleeding. The use of natural progesterone alleviates the former two drawbacks… In Europe, where natural progesterone has been in use for some time, a cyclic combined regimen of estrogen and 100mg micronized progesterone administered on days 1-25 has been shown to decrease the risk of uterine cancer, with minimal bleeding and a high rate of tolerability.” J Reprod Med. 1999 Feb;44:191-6.
(Note: While the above regimen can be used, and is safe, I would simply continue the progesterone daily rather than cycle it. This prevents withdrawal bleeding (most women would rather not go back to getting their period!) and affords the protective benefits of progesterone on uterus, breast and ovaries every day rather than just 25 days a month.– Trutt)
All women on micronized progesterone had a decrease in total cholesterol and an increase in high-density lipoprotein cholesterol. Those on MPA (Provera®) had no significant change in total cholesterol. Progesterone increases estrogen’s beneficial effects on cholesterol, whereas MPA reverses estrogen’s benefits.
Hargrove JT, Maxson WS, Wentz AZ, Burnett LS. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstet Gynecol. 1998 Apr;73(4):606-612.
Estrogen and progesterone are neuro-protective against cerebral damage. These beneficial effects were blocked by MPA (medroxyprogesterone).
National Academy Science USA; 2003 Sept. 2;100(8):10506-11.
Journal of Vascular Surgery, 2002
Progesterone may have a protective role against the atherosclerotic changes associated with type II diabetes.
Carmody BJ, Arora S, Wakefield MC, Weber M, et al. Progesterone inhibits human infragenicular arterial smooth muscle cell proliferation induced by high glucose and insulin concentrations. J Vasc Surg. 2002 Oct; 36(4):833-888.[expandsub1 title=”What about side effects?”]
Due to the side effects of synthetic progestins, natural progesterone is preferred. Progesterone has proven bio-availability and no side effects, making it the preferred hormone for menopause.
American Family Physician 2000; 62:1939-1946
Progesterone raises good HDL cholesterol, whereas MPA (Provera®), lowers good cholesterol. Progesterone increases estrogen beneficial effects whereas MPA reverses estrogen’s benefits. Progesterone has no side effects, whereas MPA has many.
Obstetrics Gynecology 1989;73:606-611.
Synthetic progestins (like Provera®) cause many side effects: breast swelling and tenderness, uterine bleeding, depression and mood disturbance, weight gain, bloating and edema. Natural progesterone has no side effects.
Female Patient 2001 Oct; 19-23.
The synthetic progestins have been associated with uncomfortable side effects, reversal of some of the cardiovascular and metabolic benefits of estrogen, and unwanted bleeding. The use of natural progesterone alleviates the former two drawbacks…
J Reprod Med. 1999 Feb;44:191-6.
Please note: any of us in this field will tell you, the reality is that natural progesterone can have some side effects, depending what form you take it in, and how your body metabolizes it. However, the side effects are trivial compared to those of Provera.[/expandsub1]
Here is what they found:
Among women with a family history of breast cancer, those who currently used HRT and had done so for at least 5 years developed breast cancer at an age-adjusted annual rate that was not statistically significantly higher than the rate in women who had never used HRT.
Among women with a family history, those who used HRT had a significantly lower risk for total mortality than did women who had never used HRT (relative risk, 0.67 [CI, 0.51 to 0.89]), including total cancer-related mortality (relative risk, 0.75 [CI, 0.50 to 1.12]). The age-adjusted annual mortality rate for women using HRT for at least 5 years was 46 deaths per 10,000 person-years (CI, 19 to 74 deaths); this is roughly half the rate seen in women who had never used HRT (80 deaths per 10,000 person-years [CI, 69 to 92 deaths]).
These data suggest that HRT use in women with a family history of breast cancer is NOT associated with increased incidence of breast cancer, and IS associated with a significantly reduced total mortality rate.
The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med. 1997 Dec 1;127(11):973-80.
Those results are probably exactly opposite to what you have heard on the news, from your friends and, unfortunately, from your doctor. Here is another study that also looked specifically at HRT in women with a strong family history of breast cancer:
This study looked at 3300 women who had benign breast biopsies at the start of the study, and followed them for quite a long time– median of 17 years. Here again, the relative risk of breast cancer was lower in the women who used estrogen replacement therapy. But that is not the most interesting part:
The table below shows the interaction between estrogen usage and a history of breast cancer in a first degree relative (mother, sister, or daughter):
The women with a strong family history of breast cancer were the ones who benefited the most from estrogen! These results are fairly remarkable. Dozens of studies have looked for a possible relationship between HRT and breast cancer; the majority are statistically non-significant, and very few have as clear a statistical significance as this one.
Exogenous estrogens reduced breast cancer risk in both women with and without a family history of breast cancer. However, the protective effect of estrogens was more pronounced among women with a family history.
Influence of exogenous estrogens, proliferative breast disease, and other variables on breast cancer risk. Cancer. 1989 Mar 1;63(5):948-57.[expandsub1 title=”But why would that be? It seems counterintuitive… “]The relationship between HRT and breast cancer is incompletely understood; for example, the available evidence suggests that BRCA1 mutation carriers would be better off using HRT:
Journal of the National Cancer Institute, 2008
We conducted a matched case–control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer.
Among postmenopausal women with a BRCA1 mutation, Hormone Therapy use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.
Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst. 2008 Oct 1;100(19):1361-7
Granted, this was a small study. But the study was statistically significant (unlike much of the WHI results), and there is a plausible mechanism by which HRT might protect against breast cancer risk in BRCA1 mutation carriers: estrogen increases expression of BRCA1. In cells that retain one normal BRCA1 allele, estrogen could serve to increase the level of the wild-type protein, and thereby promote genetic stability.
Here is another BRCA1 study:
The authors identified 462 women with BRCA1/BRCA2 mutations. 155 of the women decided to have their ovaries removed prophylactically, which has been shown to greatly decrease breast cancer risk. However, these women all decided to use HRT afterwards to avoid premature menopause symptoms. The women were followed to see if breast cancer developed. The authors found that after having their ovaries removed, the women were protected from breast cancer– and that using HRT did not change that.
CONCLUSION: Short-term HRT use does not negate the protective effect of (ovary removal) on subsequent breast cancer risk in BRCA1/2 mutation carriers.
Rebbeck et al. Effect of short term HRT on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23:7804-7810
Some have suggested that the reason that BRCA1 mutation carriers are protected, is that their tumors are usually estrogen receptor-negative. That sounds reasonable, except it implies that women on HRT get ER-positive tumors more often than women not on HRT; this turns out not to be true. It also suggests that if an ER-positive cancer develops in a women on HRT, she would do very poorly– after all, ER-positive tumors are treated with estrogen blockers! Yet the truth is that most breast cancers are ER-positive, and despite that, surprisingly: women who get breast cancer while on HRT do much better than women who get breast cancer while NOT on HRT.
For example, in 2009 Sener et al reviewed 1055 women who developed breast cancer; half of them had used HRT. Estrogen Receptor status was positive in 66% of HRT users and 64% of non-users. Yet HRT users had a much lower risk of death than HRT nonusers (hazard ratio .438, 95% confidence limit .263 to .729, P = .002).
(The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival. Am J Surg 2009;197:403–7)
Others propose that women on HRT are much more vigilant due to anxiety about breast cancer, and thus they may be catching their tumors sooner, and therefore having a better outcome. This is not the whole story either, as you will see below: when women develop breast cancer while on HRT, their tumors actually have more favorable histology than tumors in women not on HRT.
Some of these details remain to be elucidated; the bottom line for now is that women on HRT appear to get breast cancer less often, and when they do get it they have fewer metastatic cancers and fewer fatal cancers.
For many more papers showing improved survival in women on HRT, see the FAQ question below, “What if I do get breast cancer? Won’t HRT make it worse?”
(Spoiler alert: The answer is No.)[/expandsub1]
The current data supports waiting until you are cancer-free for five years, and then initiating HRT– even if your cancer was ER positive or you have a BRCA1 mutation. The five-year mark is probably somewhat arbitrary, but that is how the studies to date have been done, and it’s best to stick with the literature.[expandsub1 title=”HRT for breast cancer survivors?? I can’t believe you’re saying this! Show me the studies, in detail!”]As you wish:
Journal of Obstetrics and Gynaecology Canada, 2004
HRT after treatment of breast cancer has not been demonstrated to have an adverse impact on cancer recurrence or mortality.
Use of Hormonal Therapy after treatment of breast cancer. J Obstet Gynaecol Can. 2004 Jan
Estrogen replacement therapy in breast cancer survivors: a matched-controlled series.
Estrogen Replacement Therapy did not increase the rate or time to cancer recurrence, new primary cancer, or systemic metastases. Overall survival favored the Estrogen Replacement Therapy group (p=0.02).
Menopause 2003 Jul-Aug: 10(4) 269-70
Medical Journal of Australia, 2002
1122 women who had breast cancer and used HRT for up to 26 years, were followed for up to 36 years (median of 6 years). Compared with non-users, HRT users had reduced risk of cancer recurrence and reduced all-cause mortality.
Continuous combined HRT was associated with a reduced risk of death from primary tumor (RR 0.32) and all-cause mortality (RR 0.27), both of which were statistically significant.
HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.
Hormone Replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. MJA 2002 177(7):347-351
Journal of Reproductive Medicine, 2004
A review of literature prior to March 2003 found 10 uncontrolled studies and 11 case-controlled studies, encompassing 1,558 breast cancer survivors treated with HRT or Estrogen RT.
In this review, the cancer recurrence rate was 11% in patients who received estrogen and 20% in patients not given estrogen.
Hormone therapy for women after breast cancer: a review. J Reprod Med 2004; 49:510-526
American Journal of Obstetrics and Gynecology, 2002
The study group consisted of 123 women who were diagnosed with breast cancer at an oncology practice in Georgia and subsequently used estrogen replacement therapy (estradiol, not Premarin). Average age at diagnosis of breast cancer was 57, and the follow-up of those who received ERT was on average 6.4 years (longest follow up was 32 years). Receptor status was known in 23 patients: 16 patients were estrogen-receptor positive.
Estrogen replacement therapy apparently does not increase the risk of recurrence or of death in patients with early breast cancer.
These patients may be offered estrogen replacement therapy after a full explanation of the benefits, risks, and controversies.
Estrogen Replacement Therapy in Women with Early Breast Cancer. Am J Obstet Gynecol 2002 Aug; 187(2):289-94
Journal of the National Cancer Institute, 2001
We observed that women who used HRT after a diagnosis of breast cancer had lower risks of breast cancer recurrence, breast cancer mortality, and total mortality than nonusers. …the results suggest that HRT after breast cancer has no adverse impact on recurrence or mortality.
Note that all of those findings were statistically significant:
–The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis, and 30 per 1000 person-years in nonusers (adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85).
–Breast cancer mortality rates were five per 1000 person-years in HRT users, and 15 per 1000 person-years in nonusers (RR = 0.34; 95% CI = 0.13 to 0.91).
–Total mortality rates were 16 per 1000 person-years in HRT users, and 30 per 1000 person-years in nonusers (RR = 0.48; 95% CI = 0.29 to 0.78).
The relatively low rates of recurrence and death were observed in women who used any type of HRT: oral only (41% of HRT users), vaginal only (43%), or both oral and vaginal (16%).
Hormone Replacement Therapy After a Diagnosis of Breast Cancer in Relation to Recurrence and Mortality. J Natl Cancer Inst 2001 93(10) 754-761
The Journal of Family Practice, 2002
This meta-analysis of observational studies found no increased risk of breast cancer recurrence and a statistically significant reduction in mortality for breast cancer survivors who take hormone replacement therapy compared to those who do not.
(…Again, probably the exact opposite of what you have heard!)
Cancer Recurrence and mortality in women using hormone replacement therapy after breast cancer: Meta-analysis. Meurer et al. The Journal of Family Practice, Dec 2002. Vol 51, No. 12
American Journal of Clinical Oncology, 2000
This study was a matched cohort analysis to evaluate the impact of HRT on mortality in breast cancer survivors. Patients with breast cancer who received HRT after diagnosis of breast cancer were identified. Control subjects were identified from the regional cancer registry. The cohorts were matched for age at diagnosis, stage of breast cancer, and year of diagnosis. One hundred twenty-five cases were matched with 362 controls. The median duration of HRT was 22 months (range 1-357 months).
The risk of death was lower among the HRT users.
Odds ratio 0.28 (95% confidence interval 0.11-0.71), statistically significant.
Breast cancer survival and hormone replacement therapy: a cohort analysis. Am J Clin Oncol. 2000 Dec;23(6):541-5.
Objective: To determine the risk of recurrence of breast cancer associated with hormone replacement therapy in women previously treated for breast cancer who were taking Tamoxifen or who were estrogen receptor-positive.
The use of HRT was not associated with an increased risk of recurrence of breast cancer in women taking Tamoxifen or who were estrogen receptor positive.
Tamoxifen, hormone receptors and hormone replacement therapy in women previously treated for breast cancer: a cohort study. Dew et al. Climacteric 2002; 5:151-155
American Journal of Obstetrics and Gynecology, 2002
Estrogen Replacement Therapy apparently does not increase the risk of either recurrence or of death in patients with early breast cancer. These patients may be offered ERT after a full explanation of the benefits, risks and controversies.
Estrogen Replacement Therapy in patients with early breast cancer. Am J Obstet Gynecol 2002; 187:289-95
Journal of Clinical Oncology, 2001
We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group.
HRT did not seem to affect breast cancer recurrence risk.
(RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15)
Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol. 2001 Apr 15;19(8):2357-63.
International Journal of Gynecology & Obstetrics, 1999
Twenty-four patients who had previously been treated for breast cancer 8-91 months prior to their initiating ERT have been observed for 24-44 months. There were 15 patients with stage 1, eight with stage 2 and one with stage 4 breast cancer. There have not been any recurrences to date.
Breast cancer survivors did not have their outcome adversely affected by Estrogen Replacement Therapy during an observation period of 24-44 months.
Estrogen replacement therapy in breast cancer survivors. Int J Gynecol Obstet. 64 (1999) 59-63
Annals of Surgical Oncology, 2001
Estrogen Replacement Therapy After Breast Cancer: A 12-Year Follow-Up
Background: In the United States, estrogen replacement therapy (ERT) is discouraged in breast cancer survivors because of concerns that hormones may reactivate the disease. Because ERT can improve quality of life and decrease morbidity from osteoporosis and cardiovascular disease, however, this policy is increasingly being challenged.
Methods: 607 breast cancer survivors were interviewed concerning ERT usage. Sixty-four patients had received some form of ERT after their breast cancer diagnosis. Medical records for these patients were analyzed for disease stage, surgical treatment, adjuvant treatment, estrogen and progesterone receptor status, date of initiation of ERT, type of ERT, recurrence, and final outcome. Patients receiving ERT were followed prospectively.
56 patients received ERT as conjugated estrogens, an estradiol patch, estropipate, or birth control pills. The median follow-up from cancer diagnosis was 12.8 years (range, 4.7-38.9 years). The median time on ERT since cancer diagnosis was 6.4 years (range, 1.0-20.9 years); 38% of the patients initiated Estrogen Replacement Therapy within 2 years of cancer diagnosis. Estrogen receptors were positive in 28 (74%) of the 38 cases with available information. At time of diagnosis, the cancer was stage 0 in 15 cases (27%), I in 27 (48%), and II in 14 (25%). Twenty-six patients (47%) received adjuvant chemotherapy or hormonal therapy. One local recurrence and one contralateral breast cancer occurred during the follow-up period (13.5 and 9.6 years, respectively), with no regional or distant recurrences, for a 15-year actuarial disease-free survival rate of 92.5%. There were no breast cancer deaths.
Use of Estrogen Replacement Therapy in breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even over a long follow-up period.
Ann Surg Oncol. 2001 Dec;8(10):828-32.
The authors conducted a prospective, 5-year clinical trial to assess the safety and efficacy of prolonged ERT in a group of menopausal women with localized (Stage I or Stage II) breast carcinoma and a minimum disease free interval of 2 years if the tumor was estrogen receptor-negative, or 10 years if estrogen receptor status was unknown. The women used Premarin for estrogen replacement, and were followed for 5 to 10 years.
Two of the 56 (3.6%) women on Estrogen Replacement Therapy developed a contralateral, new breast carcinoma. In the group that was not on ERT, 33 of 243 women (13.5%) developed new or recurrent breast carcinoma. This was right on the cusp statistical significance (p=.053); essentially there was no difference between the two groups.
ERT did not compromise disease-free survival in patients who were treated previously for localized breast carcinoma. Larger scale randomized trials are needed to confirm these findings.
Estrogen replacement therapy for menopausal women with a history of breast carcinoma: results of a 5-year, prospective study. Cancer. 2002 Nov 1;95(9):1817-26.
Journal of Clinical Oncology, 1999
Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively.
ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer.
J Clin Oncol. 1999 May;17(5):1482-7.
American Journal of Obstetrics and Gynecology, 1999
As we have noted, whether you use hormones or not, some people will get breast cancer. This study followed 76 women with breast cancer; 18 of the women had never used HRT, and 50 had been using estrogen for up to 32 years. (The other 8 women had used hormones other than estrogen.) All of them started (or continued) bio-identical estrogen replacement therapy despite their cancer diagnosis. In this study most of the women were also put on testosterone, and most of them also took a synthetic progestin.
Estrogen replacement therapy apparently does not increase either recurrences or mortality rates. Adding progesterone may even decrease recurrences. Women with early breast cancer should be offered hormone replacement therapy after a full explanation of the benefits, risks and controversies.
(Note: The above quote actually had the word “progestogen” in place of “progesterone”. I changed it because the word “progestogen” is confusing. Progestogen can mean bio-identical progesterone but can also refer to altered synthetics such as medroxyprogesterone acetate (Provera). MPA has been shown in multiple other studies to increase the risk of breast cancer, cause multiple side effects, and negate the beneficial effects of estrogen on lipids and cardiovascular health. We would never recommend the use of synthetic progestins in our practice; I only prescribe bio-identical progesterone. I suspect the results in this study were so good in part because they added testosterone, which was able to counteract the proliferative effect of the progestin. Transdermal testosterone has been shown to have a powerful protective effect against breast cancer; in this study they used it to treat menopausal symptoms (decreased libido), but as a side effect it very likely helped suppress their breast cancer. I recommend low doses of transdermal testosterone for all of my post-menopausal patients. –Trutt)
Estrogen replacement therapy in women with previous breast cancer. Am J Obstet Gynecol. 1999 Aug;181(2):288-95.
This is another retrospective observational study which suggests that
the addition of testosterone to conventional HRT for postmenopausal women does not increase and may indeed reduce hormone therapy-associated breast cancer risk.
Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Dimitrakakis et al. Menopause Vol 11, No, 5 pp 531-535
Journal of the National Cancer Institute, 2008
Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers.
Background: Hormone replacement therapy (HRT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. Any association of HRT with breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HRT after undergoing prophylactic surgical oophorectomy at a young age.
METHODS: We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HRT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural).
Among postmenopausal women with a BRCA1 mutation, HRT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.
J Natl Cancer Inst. 2008 Oct 1;100(19):1361-7.
NOTE: Comments on this trial included multiple mentions of the HABITS trial, a Scandinavian trial of hormone replacement in breast cancer survivors. The HABITS trial used synthetic norethisterone as the progestin. The HABITS trial, like the WHI trial (and most trials using MPA/Provera), showed a definite increase in breast cancer, which proves yet again that synthetic, altered progestins are dangerous and should not be used—unlike bio-identical progesterone, which is safe and entirely beneficial. If a study exists showing harm from the use of bio-identical progesterone, I have yet to see it.
At the same time the HABITS trial was done, a sister trial called the Stockholm trial was also conducted with breast cancer survivors using HRT– but in that trial they discouraged the use of progestins. Not surprisingly, in contrast to the HABITS trial, the Stockholm trial found that the use of menopausal hormone therapy did not increase the risk of breast cancer recurrence among patients with early-stage breast cancer.
Journal of Clinical Oncology, 2010
This study does not directly deal with breast cancer survivors, but will likely be of interest to them. The authors looked at women in the Women’s Health Initiative who took CEE alone (Premarin, estrogens derived from horses’ urine), to see whether they ended up getting more mammograms or biopsies than average. They found that Premarin does not cause an increase in cancer, but it does increase breast tissue density. Therefore, every so often a radiologist would see something suspicious on their mammogram and order a repeat study. Because of this, compared to women not taking Premarin, the group who took Premarin for 5 years wound up getting one extra mammogram for every 11 women, and one extra biopsy for every 50 women. The biopsies were generally negative; a crucial point is that the women on Premarin developed actual breast cancer less often than the women NOT on Premarin. I included this study because this phenomenon of increased breast density and occasional extra mammograms while on estrogen is something breast cancer survivors should be aware of, as no doubt a ‘suspicious’ mammogram would be highly stressful to them.
Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy. J Clin Oncol. 2010 Jun 1;28(16):2690-7.[/expandsub1]
Regarding Endometrial cancer:
716,738 postmenopausal women in the UK without previous cancer or previous hysterectomy were recruited into the Million Women Study in 1996-2001, provided information about their use of HRT, and were followed up for an average of 3.4 years.
Compared with women who had never used HRT, risk of endometrial cancer was:
reduced if they used continuous combined estrogen/progesterone (relative risk 0.71 [95% CI 0.56-0.90]; p=0.005);
increased if they used estrogen only (1.45 [1.02-2.06]; p=0.04);
and not significantly altered if they used cyclic combined estrogen/progesterone (1.05 [0.91-1.22]; p=0.5).
In other words: estrogen dramatically lowers heart attacks, Alzheimer’s and osteoporosis– but it does increase the risk of endometrial cancer. However, we can get around that problem: if you use progesterone for 2 weeks of every month (“cyclic” progesterone) it is enough to make your risk of endometrial cancer the same as the risk for women who don’t use any estrogen. And if you use progesterone the ENTIRE month, it makes your risk of endometrial cancer LOWER than the typical woman who doesn’t use estrogen. Progesterone protects against endometrial cancer. Note that synthetic Provera should not be used because, although it protects quite well against endometrial cancer, it increases the risk of breast cancer. Bio-identical progesterone should be used instead.
Obstetrics and Gynecology, 2001
Suriano et al at UC Irvine compared outcomes between two groups of endometrial cancer survivors. 130 women received Estrogen Replacement Therapy and 49% received ERT plus progesterone. Over 5.5 years follow-up, there were no recurrences among patients who started HRT within the first 6 months of cancer treatment, whereas there were 11 recurrences among the women not using HRT.
Obstet Gynecol 2001 Apr 97(4):555-60
(Although this study started HRT at 6 months, many doctors now would recommend that following hysterectomy for localized uterine cancer, women should wait 1 year to be certain there is no early recurrence, and then begin estrogen replacement therapy. Bio-identical progesterone therapy can begin immediately.)[/expand] [expand title=”What if I do get breast cancer? Won’t HRT make it worse??”]Great question–
I hope that the answers above make clear that using estrogen with bio-identical progesterone does not increase your risk of breast cancer. Nevertheless, obviously, some women will get breast cancer, whether they use hormone therapy or not. But even in these women, HRT turns out to be good news:
If you compare a woman who is on HRT with a women who is not, if both women develop breast cancer, the woman who is on HRT is much less likely to die from it. This too has been looked at in multiple studies. Here is a graphical representation of those results:
From: Natrajan P, Soumakis K, Gambrell D. Estrogen Replacement Therapy in Women With Previous Breast Cancer. Am J Obstet Gynecol, Aug 1999, p 292
The chart shows the results of nine different studies on survival from breast cancer that developed while the women were on hormone replacement therapy.(1-9)
The center of the graph (‘1.0’) is the baseline risk of mortality from breast cancer in women not on HRT. As you can see, all of these studies show that, for women on HRT, risk of dying from breast cancer is “less than 1.0”, meaning lower than baseline. (The statisticians among you will point out that the confidence intervals on two of the studies touch or cross the 1.0 line, meaning those two studies just barely missed statistical significance. Nevertheless, the overall picture is clear.)
It’s worth noting that when this paper came out, these were the only nine studies to ever look at this, and all nine studies found lower mortality in women who were on estrogen when they got their cancer.
More recent studies have found the same thing:
In 2005, Fletcher at al studied 4022 postmenopausal women diagnosed with breast cancer between 1993 and 2000, and found the multivariate hazard ratio for HRT use and all-cause mortality was 0.69 (95% CI: 0.49-0.96).10
In 2007, Schuetz et al found a “reduced incidence of distant metastases, and lower mortality, in 1072 patients with breast cancer with a history of hormone replacement therapy.”11
And here is a 2009 study:
[expandsub1 title=”Show me the REFERENCES. “](Citations 1-9 are the nine studies on the graph above, from top to bottom.)
HRT use was associated with the development of biologically more favorable cancers than those that developed in nonusers; both overall survival and disease-free survival rates were higher in HRT users than nonusers.12
1. Burch JC, Byrd BF, Vaughn WK. Results of estrogen treatment in one thousand hysterectomized women for 14,318 years. In: Concensus on menopause research. Lancaster (UK): MTP Press; 1976;p. 164–169
2. Gambrell RD. Proposal to decrease the risk and improve the prognosis of breast cancer. Am J Obstet Gynecol. 1984;150:119–128
3. Lauritzen C, Meier F. Risks of endometrial and mammary cancer morbidity and mortality in long-term oestrogen treatment. In: van Herendael HB et al. The climacteric: an update. 1984;p. 207–216
4. Hunt K et al. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynaecol. 1987;94:620–635
5. ergkvist L et al. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol. 1989;130:221–228
6. Henderson BE, Pagannini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75–78
7. Strickland DM, Gambrell RD, Butzin CA, Strickland K. The relationship between breast cancer survival and prior postmenopausal estrogen use. Obstet Gynecol. 1992;80:400–404
8. Willis DB, Calle EE, Miracle-McMahill HL, Heath CW. Estrogen replacement therapy and the risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control. 1996;7:449–457
9. Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffee M, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769–1775
10. Use of hormone replacement therapy (HRT) and survival following breast cancer diagnosis. Breast. 2005 Jun;14(3):192-200.
11. Am J Obstet Gynecol 2007;196:342 e1–9
12. Sener SF, Winchester DJ, Winchester DP, et al. The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival. Am J Surg 2009;197:403–7[/expandsub1]
Studies on hormone replacement therapy and cognitive function are complicated by differences in how the studies are done:
- Is it a preventative study or an interventional study?
- Did they use estrogen alone or estrogen with a synthetic progestin?
- How far post-menopause were the women when they started estrogen?
But one thing all the studies had in common was that almost none of them used bio-identical estrogen. They all used Premarin (or its’ generic equivalent, conjugated equine estrogen). However, last year a study finally came out comparing the effect of Premarin and bioidentical estrogen on memory. As you might suspect, our brain seems to respond better to the natural human version:
Results: Women receiving 17-beta-Estradiol (i.e. bio-identical estrogen) showed significantly better verbal memory performance compared to women receiving conjugated equine estrogens (i.e. Premarin), regardless of age, IQ, years of education, risk factors for Alzheimer’s Disease (including APOE-4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural or surgical menopause status.
Verbal memory performance was better in menopausal women receiving [bio-identical estrogen] compared to [Premarin] in women with risk factors for Alzheimer’s Didease. Genetic risk for AD as well as other confounders did not affect this finding. The results suggest a differential effect of the type of Hormone Therapy on verbal memory, with [bio-identical estrogen] being a preferential compound.
Differences in verbal memory performance in postmenopausal women receiving hormone therapy: 17beta-estradiol versus conjugated equine estrogens. Am J Geriatr Psychiatry. 2011 September ; 19(9): 792–802.
What is surprising about those results is that only 43 women in their study group were taking bioidentical estrogen– and seven of those women were also taking Provera. There is strong evidence to suggest that Provera worsens verbal memory1,2, and so it’s rather remarkable that they nevertheless got statistically significant results. I suspect a larger trial using just bioidenticals would produce even stronger results.
1. Coker LH, Espeland MA, Rapp SR, et al. Postmenopausal hormone therapy and cognitive outcomes: the Women’s Health Initiative Memory Study (WHIMS). J Steroid Biochem Mol Biol. 118:304–310.
2. Resnick S, Maki P, Rapp S, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab. 2006; 91:1802–1810.
I did find one other study from 2009 looking at bio-identical estrogen (as opposed to Premarin) and verbal memory:
Tierney MC, Oh P, Moineddin R, et al. A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women. Psychoneuroendocrinology. 2009; 34:1065– 1074.
However, that study also used a synthetic progestin: norethindrone. They found that women who had scored above-average on memory tests at the start of the study, had significantly less decline in verbal memory over the two-year study if they used HRT. This is consistent with the studies showing that you need to start estrogen replacement within 8 years of menopause: once the neuronal function degenerates, estrogen can’t “resuscitate” it.[/expandsub1] [expandsub2 title=”But didn’t the Women’s Health Initiative say that Estrogen causes Alzheimer’s??” trigclass=”references”]
Despite all of these positive studies, the Women’s Health Initiative reported in 2003 that HRT increased the risk of dementia in women 65 and older– as early as 12 months after starting therapy!–yet did not increase the risk of mild cognitive impairment. In other words, they seemed to say that women on HRT blew right past mild cognitive impairment and quickly became fully demented within a year of starting HRT!
(Shumaker SA et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative memory study: a randomized controlled trial. JAMA. 2003;289:2651–2662.)
How do we explain this?
The answer is that the study group in the WHI were older women (average age 62) who had never been on HRT and thus had spent ten years since menopause building up plaques in their vessels. Then these women were placed on two drugs (Premarin and Provera) that are known to increase the risk of clots and strokes. These women did not suddenly develop Alzheimer’s: they developed mini-strokes in that first year on those drugs, and likely developed multiple-stroke dementia. That is why it appeared to be “sudden onset” Alzheimer’s: it wasn’t Alzheimer’s, it was small strokes.
This is completely consistent with what we know about the WHI trial: within the first year of therapy (i.e. with PremPro, not bioidentical hormones), women over age 60 in the WHI trial who had not been on HRT previously did have an increased risk of strokes– because Premarin and Provera cause increased clotting and plaque rupture early on. This is why we instead use transdermal estrogen and bio-identical progesterone, both of which do NOT increase clotting or strokes.[expandsub3 title=”Further detail for those who like to understand the fine print: ” trigclass=”references”] In the Heart and Estrogen-Progestin Replacement Study (HERS), which also used PremPro and relatively older women (relative to menopause) just like the WHI: women who did NOT have a stroke or heart attack in that first year, got progressively LOWER risk of heart attacks/ strokes each subsequent year that they stayed on hormones. So, by year 4 and 5 on hormones, even those older women, who had never been on hormones until roughly age 62, and then began taking (relatively dangerous) Premarin and Provera, were at LOWER risk of stroke and heart attack than women who had never taken hormones. The reason is that Premarin seems to cause “reorganization” of plaques in your blood vessels (by increasing something called matrix metalloproteinase). Therefore in women who had plaque buildup for ten years since menopause (because they had no circulating estrogen/ weren’t on HRT), during that first year, this “reorganization” by Premarin increased their risk of plaque rupture and stroke/ heart attack. But if they made it past that first year, the plaque reorganization led to more stable and apparently smaller plaques that then were LESS likely to rupture every year on hormone therapy.
(Note: oral bio-identical estrogen probably also increases the risk of blood clots, but the data on that is much less clear. The ELITE trial uses oral bioidentical estrogen, and should provide more useful data on this issue when its’ results are out in late 2013.)
But transdermal bioidentical estrogen does not increase the risk of clots. This has been looked at in multiple large studies:
The ESTHER study was a multicenter prospective study comparing oral vs. transdermal estrogen looking at their risk of blood clots.
Oral but not transdermal Estrogen Replacement Therapy is associated with risk of venous clot in postmenopausal women.
Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003 362: 428–32
However, some skeptics pointed out that obese women have a much higher risk of blood clots than thin women. What if the ESTHER study (which took place in France) included only thin women?? So they looked at the data again, to see if heavy women were at higher risk:
Conclusion: In contrast to oral estrogen, transdermal estrogen does not confer an additional risk of venous blood clot in women with increased Body Mass Index.
Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. Journal of Thrombosis and Haemostasis, 4: 1259–1265
In 2010, a review paper looked at all available data on oral vs. transdermal estrogens:
Since 2008, we identified five relevant observational studies. Among them, two large cohort studies confirmed that oral but not transdermal estrogens were associated with venous clot risk among postmenopausal women. In an updated meta-analysis of current data, risk ratio for venous clot was 1.0 (95% CI 0.9-1.1) among transdermal estrogens users, respectively.
(For the non-statisticians, a Risk Ratio of 1.0 means no increased risk.)
But they went a bit further this time: They found that even in women who had already had a blood clot in the past, transdermal estrogen didn’t increase the risk of getting another clot!
In addition, one recent cohort study showed that transdermal estrogens did not confer an excess risk of recurrent VTE among postmenopausal women with a history of venous clot.
And they proposed a mechanism as to why transdermal is safer:
The difference in clot risk between oral and transdermal estrogen users is supported by biological data: whereas oral estrogens can increase thrombin generation and induce a resistance to activated protein C, transdermal estrogens have minimal effects on hemostatic variables
Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol. 2010 Sep;17(5):457-63.
Bottom line: Transdermal bio-identical estrogen does not increase your risk of blood clots.
Even in someone with Factor V Leiden, transdermal bioidentical estradiol is probably safe. Please go over the following studies with a doctor experienced in bioidentical HRT:
1. Strazek et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation,112 (2005), pp. 3495–3500
…the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen.
In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation.
2. Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women. Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2807-12.
Current ‘conventional wisdom’ states that oral estrogens are thrombogenic (as opposed to transdermal) —but that is not based on studies of bioidentical estrogen. Premarin (Conjugated Equine Estrogens, or CEE) certainly is thrombogenic. However, oral bioidentical estradiol may be significantly less thrombogenic than CEE. As I mentioned, the ELITE trial should help answer this question when we get the results late next year. But I just want to point out the following study, which looked at women with Factor V Leiden, who used oral bioidentical estradiol WITH Provera (definitely not recommended!) and still found no significant increase in clot risk:
“Factor V Leiden was associated with a 3.7-fold increase in risk [of blood clot]. After adjusting for confounding factors, use of Premarin [plus Provera] was associated with an additional 2.5-fold increase in risk, whereas use of oral bioidentical estrogen [plus Provera] was associated with a nonsignificant 1.5-fold increase in risk compared with nonuse of hormones.”
To be clear: No doctor is going to give oral estrogen (even bioidentical) to someone with a known clotting disorder– they would (and should) use transdermal, as the safety data is much stronger for transdermal. I mention these papers only to illustrate the extent of misinformation regarding the differences between bioidentical estrogen and Premarin (or worse, PremPro). Not all “estrogen” is created equal.
Take-home point: The available data indicate that even in women with a clotting disorder, transdermal, bioidentical estrogen is safe. Considering that estrogen replacement yields a 40% decrease in mortality after menopause, if you have Factor V Leiden, you should at the very least have a detailed conversation with your doctor about the risks and benefits of ERT.
1. Using estrogen with synthetic progestins (like Provera or norethisterone) may increase your risk of breast cancer slightly.[expandsub1 title=”What do you mean by ‘slightly’?”]The WHI results for patients on Premarin plus Provera actually were not statistically significant: the Relative Risk for breast cancer was 1.24 but the Confidence Interval was 0.97-1.59 once they adjusted for sequential monitoring, which some have argued is what they should have reported.1 That Confidence Interval crosses 1.0 and is therefore non-significant. Instead they report the unadjusted statistic of 1.01-1.54, which is barely significant.2 (See below, “Why I’ve Stopped Caring About the WHI Trial,” for a more in-depth discussion of what this means.) Nevertheless, other studies have also suggested a RR of about 1.24 with synthetic progestins like Provera. If we accept that number, then the risk of breast cancer would increase 24% for women taking PremPro. (Breast cancer risk went down for women on Premarin alone in the WHI trial. It was only once they added synthetic progestins that they developed a higher incidence of breast cancer.) The baseline incidence of breast cancer for women not on HRT is 30 cases per 10,000 women per year. On PremPro, it would increase to 38 cases per 10,000 women per year of therapy. For every thousand women, 0.8 additional cases per year. On bio-identical progesterone, studies (such as E3N) show zero increased cases. This is why we don’t use synthetic progestins like Provera or norethisterone. [expandsub2 title=”References”]1. Stevenson JC, Hodis HN, Pickar JH, Lobo RA. Coronary heart disease and menopause management: the swinging pendulum of HRT. Atherosclerosis 2009;207:336–40
2. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003;289:3243–53[/expandsub2][/expandsub1]
2. If you use estrogen with bioidentical progesterone, your risk of breast cancer does not increase, and probably decreases. In addition, you will dramatically decrease your risk of endometrial cancer.
3. HRT will greatly reduce your risk of fractures from osteoporosis, and if you start HRT within 6 years of menopause you will lower your risk of Alzheimer’s (a disease for which there is no effective treatment) and heart disease (the number 1 killer of women) by 50%!
4. Perhaps most importantly: Even the WHI trial showed that women who start HRT before age 60 decreased their overall mortality by 35%! A meta-analysis of 30 other studies found the same thing: if you start HRT before age 60, it decreases your risk of death from any cause, by about 40%. Of course this benefit may not last forever, but in a meta-analysis of 30 studies (14,000 women) it lasted for as long as the studies were carried out. (J Gen Intern Med 2004; 19:791-804)
Please note: This last point is not controversial. The Endocrine Society itself stated in it’s 2010 Scientific Statement on HRT,
Menopausal Hormone Therapy was associated with a 40% reduction in mortality in women in trials in which participants had a mean age below 60 yr or were within 10 years of menopause onset.
(Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab, July 2010, 95(Suppl 1):S1–S66)
It is remarkable to me that a finding that dramatic never makes the news, yet a tiny increase in breast cancer (caused by synthetic progestins) is trumpeted endlessly.
5. If you use HRT and are one of the few women to develop breast cancer, your cancer is likely to be less deadly than breast cancer that develops in women who are not using HRT.
6. And last but not least: If you use transdermal estrogen instead of oral, you will not increase your risk of blood clots, even if you have Factor V Leiden or prothrombin II variant.
[/expand] [expand title=”Why I’ve Stopped Caring About the WHI Trial– and You Should Too”]It’s time to strip away some of the mystique from the Women’s Health Initiative trial. It’s gotten an order of magnitude more attention than it deserves… but to explain why, we will have to take a short trip into the sometimes uncomfortable world of statistics.
(For help with this I leaned heavily on two fantastic papers: “Epidemiology Faces Its Limits,” by one of my favorite science writers, Gary Taubes; and a beautiful deconstruction of the WHI trial by oncologist Avrum Bluming, “Hormone replacement therapy: Real concerns and false alarms.” See references below.)
Here we go:
What does the Confidence Interval (CI) tell us?
When a study like the WHI says “women who take PremPro are 1.24 times more likely to get breast cancer than women who don’t take PremPro,” we want to know if that Relative Risk of 1.24 is “real,” or just the result of random chance in their study. The Confidence Interval helps answer that by providing a range for the Relative Risk: statistics tells us that if we allow for variation due to random chance, the Relative Risk will still fall somewhere within that Confidence Interval 95% of the time. (Sometimes the 99% CI is used.)
If the range of the Confidence Interval includes the number 1.0, the result is not considered statistically significant.
Let’s say we are studying whether smoking causes skin cancer. We do a trial and compare 10,000 smokers with 10,000 non-smokers and we find that the smokers had a Relative Risk for skin cancer of 0.8. That means, the smokers were only 80% as likely to get skin cancer as non-smokers. We think, wow! Smoking protects against skin cancer! But then we look at the Confidence Interval: it’s 0.7 to 1.35. If the Confidence Interval in our study falls both above and below 1.0 it means: if we repeat this study multiple times, sometimes skin cancer will occur more often in smokers– Relative Risk will be greater than 1.0– but sometimes the smokers will get skin cancer less often than the non-smokers (Relative Risk less than 1.0), simply due to random chance. In that case, skin cancer is not significantly correlated with smoking in our study.
Now that we’ve cleared up what the Confidence Interval is, there is an important point to make:
Let’s say the Relative Risk in our study on smoking and skin cancer was 0.8, and the Confidence Interval was 0.4 to 0.9 – statistically significant! Does that mean that smoking lowers the risk of skin cancer? No. It simply means that the results of our study were not due to random chance. What if I told you that all the smokers in this study were African-Americans (a population with very low rates of skin cancer), and the non-smokers were all caucasian (who have the highest rate of skin cancer). You’d say, well of course the smokers got less skin cancer! The results are still statistically significant (if you repeated that study 100 times, the African Americans would always get less skin cancer) but that does not mean that smoking lowers the rate of skin cancer. That study is statistically significant, but suffers from poor methodology. So that is point number two:
Even if a study reaches statistical significance, that does not mean the correlation definitely exists! You have to look closely at the study itself.
We are almost ready to look at the WHI results. The last point I want to make is that large epidemiologic studies like the WHI or the Million Women Study are more susceptible to confounding factors and observer bias, than are small double-blind prospective trials. Some examples of this:
- Large epidemiologic trials looking at whether alcohol causes cancer have been confounded by the fact that many people who drink a lot, also smoke.
- Large cohort studies often use questionaires, with no way of validating whether the submitted answers are accurate.
- ‘Recall Bias’: women who are diagnosed with breast cancer may take the time to remember in much greater detail what years they used birth control or HRT, whereas healthy women may not make as much effort to answer with great accuracy. Again, there is often no way to verify their answers.
Because of these issues, in large epidemiologic studies like the WHI, unless the lower limit of the Confidence Interval is at least 3, it generally should not be considered a strong, reliable risk factor.
Even if the results are replicated in multiple trials, a large epidemiologic trial with a RR below 2 should not make the headlines the way the WHI has.
So with that in mind, let’s look at the table below.
(Adapted from Bluming AZ. Tavris C. Hormone Replacement Therapy: Real Concerns and False Alarms. Cancer J. 2009;15:93–104.)
In this table, the association of breast cancer with Conjugated Equine Estrogen (Premarin) in the Women’s Health Initiative has a CI from 0.59 to 1.01, which crosses 1.0 and is therefore (barely) not a significant association. (Premarin certainly did not INCREASE the risk of cancer, as the CI is almost entirely below 1.0, but we can’t say it significantly decreased the risk either; we say instead that there was no significant association.) Premarin/Progestin (PremPro), French Fries and Grapefruit did barely reach statistical significance in those studies. As you can see, if you are worried about taking HRT, you should also certainly worry about eating grapefruit, using an electric blanket, and whatever you do, don’t become a flight attendant.
At the bottom of the chart are two risk factors that are “real”. As you can see, the link between tobacco smoke and lung cancer is incontrovertible. And when a link is “true”, it only gets stronger with subsequent studies. With cancer and HRT you seem to get a new answer every other year (as researchers strive desperately to find a significant link), whereas with smoking and lung cancer, the link only became stronger with each subsequent study.
At the bottom I put the link between estrogen and endometrial (not breast) cancer. This is a true link—estrogen taken without progesterone will certainly increase the risk of endometrial cancer.
**Progesterone—indeed, even synthetic progestins— unquestionably prevent estrogen from causing endometrial cancer. This is not a controversial issue. This is why progestins started being given with estrogen in the 1980s.[expandsub1 title=”Show me the references.”]Much of this post was adapted from
Epidemiology Faces Its Limits, Gary Taubes, Science Vol. 269 July 1995, and
Hormone Replacement Therapy: Real Concerns and False Alarms. Bluming A. Tavris C. Cancer J. 2009;15:93–104.
The references from the table specifically are as follows:
1. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2004;291:1701– 1712.
2. Chlebowski RT, Hendrix SL, Langer RD, et al; for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243–3253.
3. Michels KB, Rosner BA, Chumlea WC, et al. Preschool diet and adult risk of breast cancer. Int J Cancer. 2006;118:749–754.
4. Monroe KR, Murphy SP, Kolonel LN, et al. Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study. Br J Cancer.2007;97:440 – 445.
5. Megdal SP, Kroenke CH, Laden F, et al. Night work and breast cancer risk: a systemic review and meta-analysis. Eur J Cancer. 2005;41:2023–2032.
6. Schernhammer ES, Laden F, Speizer FE, et al. Rotating night shifts and risk of breast cancer in women participating in the Nurses’ Health Study. J Natl Cancer Inst. 2001;93:1563–1568.
7. Pukkala F, Auvinen A, Wahlberg G. Incidence of cancer among Finnish airlinecabin attendants, 1967–1992. BMJ. 1995;311:649 – 652.
8. Mawson AR. Breast cancer in female flight attendants. Lancet. 1998;352: 626.
9. Rafnsson V, Tulinius H, Jo ́nasson JG, et al. Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control. 2001;12:95–101.
10. Kangmin Z, Hunter S, Payne-Wiks K, et al. Use of electric bedding devices and risk of breast cancer in African-American women. Am J Epidemiol. 2003;158:798 – 806.
11. Sasco AJ, Merrill RM, Dari I, et al. A case-control study of lung cancer in Casablanca, Morocco. Cancer Causes Control. 2002;13:609 – 616.
12. N Engl J Med. 1975 Dec 4;293(23):1200-2.
Absolutely. They only need about 1% as much as men, but that 1% goes a long way.
When your production of testosterone shuts down as you age, it dramatically decreases libido in most women. It is well-established that replenishing a woman’s testosterone after menopause restores her libido and sense of well-being, and there is no controversy on that point.
In addition, like estrogen and progesterone, testosterone increases bone mineral density in women– meaning, it helps prevent osteoporosis. Women who use estrogen replacement after menopause are protected from osteoporosis– and women who add testosterone to their regimen are protected even more.[expandsub2 title=”Show me the studies (in detail)”]
Testosterone enhances estradiol’s effects on post-menopausal bone density and sexuality.
Maturitas, 2008 Sep-Oct;61(1-2):17-26.
The title really says it all, but for those of you who want the details, here you are:
To investigate the role of testosterone in increasing bone density and improving low libido in postmenopausal women, we have studied the effects of estradiol and testosterone on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Bone Mineral Density of total body, lumbar vertebrae, and hip area increased significantly in both treatment groups (measured by DEXA scan). However, Bone Mineral Density increased more rapidly at all sites in the group receiving testosterone. Also, a substantially greater total increase in BMD occurred in the Estradiol & Testosterone group for hip (P < 0.005), vertebrae L1-L4 (P < 0.001), and total body (P < 0.008) measurements.
All sexual parameters improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to Estrogen alone for sexual activity (P < 0.03), satisfaction (P < 0.03), pleasure (P < 0.01), orgasm (P < 0.035) and relevancy (P < 0.05).
Total cholesterol and LDL-cholesterol fell in both groups, as did total body fat. Total body fat-free mass improved in the Estrogen & Testosterone group only (not with estrogen alone: in other words, the estrogen group lost some fat, but the estrogen-plus-testosterone group lost some fat and gained some muscle).
We conclude that in postmenopausal women, treatment with combined estradiol and testosterone was more effective in increasing bone mineral density than estradiol alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone for diminished libido in postmenopausal women. Also, the addition of testosterone did not diminish the favourable effects of estrogen on cholesterol, and was also associated with beneficial changes in body composition (improvement in fat-free body mass).
Davis SR. Testosterone enhances estradiol’s effects on post-menopausal bone density and sexuality. Maturitas. 2008 Sep-Oct;61(1-2):17-26.
Another study showed that women who use estrogen alone stop any improvements in bone mass as soon as they stop taking estrogen—however, women who used estrogen along with testosterone continued to have improving bone mass even two years after they stopped therapy.
Gelfand MM. The role of androgen replacement therapy for postmenopausal women. Contemp OB/GYN 2000, Feb: 1-5
The Estratest Working Group studied Premarin (horse estrogens) with or without methyltestosterone. They found that over the course of two years, women who were also receiving testosterone had greater increases in bone mineral density in the hip and spine than women who only received Premarin.
(Note again, Premarin does provide most of the benefits of bio-identical estrogen, including increased bone density—however we don’t use it in our practice due to the increased risk of blood clots and strokes. We use only transdermal, bioidentical estrogen, which confers minimal if any risk of clots, even in patients with Factor V Leiden or Prothrombin II Variant.)
Barrett-Connor E. Interim safety analysis of a two-year study comparing oral estrogen-androgen and conjugated estrogen in surgically menopausal women. J Women’s Health 1996; 5: 593-602[/expandsub2][/expandsub1] [expandsub3 title=”My main concern is breast cancer. How does testosterone affect my risk of breast cancer?” ]As with bioidentical progesterone, natural testosterone does not appear to increase– and may help prevent– breast cancer. We still need more data to evaluate this question, but the available data are very encouraging.
This is not surprising, as a pattern with all of these studies emerges where we see that restoring hormone levels to those of a healthy 30-year-old results in your body behaving more like that of a healthy 30-year-old: i.e. increased bone mineral density, increased libido, decreased Alzheimer’s, decreased heart disease, and decreased cancer. All of the diseases of aging arise after your hormone levels decline—not while your natural hormones are still circulating. The studies appear to support that concept as well: maintaining bioidentical hormone levels delays the onset of disease.[expandsub4 title=”I’m skeptical. Show me more information on testosterone and breast cancer. “]Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy
This study looked at women who used HRT with synthetic, non-bioidentical progestins, which in prior studies seem to have increased breast cancer risk slightly (unlike natural progesterone). But in this study, the women also used testosterone. The authors found that:
the addition of testosterone to [synthetic, non-bioidentical] hormone therapy for postmenopausal women does not increase and may indeed reduce breast cancer risk—thereby returning the incidence to the normal rates observed in the general, untreated population.
Dimitrakakis et al. Menopause, Vol. 11, No. 5, 2004
Breast cancer probably does not form unless breast tissue proliferation occurs first… therefore checking for breast tissue proliferation (i.e. breast density) may be a “quick and easy” way to see if women are at higher risk for breast cancer, without having to wait years to see if cancer develops.
Thus, two studies have evaluated the effect of transdermal testosterone therapy on breast tissue density:
In 2007, a randomized, double-blind, placebo-controlled trial looked at 99 postmenopausal women who were taking estrogen with synthetic progestin (norethisterone) therapy. The women were then also given either transdermal testosterone or a placebo. After six months of treatment, women receiving estradiol and synthetic progestins but no testosterone had a fivefold increase in breast cell proliferation from baseline– whereas the women who were also given testosterone did not have any increase in breast cell proliferation despite the synthetic progestins. The investigators concluded that the results “support the concept that testosterone may counteract the proliferative effect of estrogen and [synthetic progestins] in the breast.”
Hofling M, Hirschberg AL, Skoog L, et al. Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in post- menopausal women. Menopause 2007;14:183-190.
In the Aphrodite study, another randomized, double-blind, placebo-controlled trial, the authors compared the effect of two doses of transdermal testosterone vs. placebo in 279 postmenopausal women who weren’t getting any other HRT. After 1 year, testosterone therapy alone had had no significant effect on breast density.
Davis SR et al. The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. J Clin Endocrinol Metab 2009;94(12):4907–13.
A very interesting study at the NIH looked at rhesus monkeys to try to get a better sense of the interrelationship of various hormones with breast cancer. They used bioidentical hormones, and they used monkeys that were in surgical menopause (their ovaries had been removed).
They gave the monkeys very high doses of estradiol: the serum levels were 400 pg/mL, whereas typically patients in our practice are kept at levels no higher than 75 pg/mL.
Here is what they found:
When they gave the Estradiol alone, it caused a sixfold increase in breast cell proliferation and a modest increase in the expression of estrogen receptor-alpha (which could eventually lead to breast cancer). When they added bioidentical progesterone, it didn’t prevent the proliferative influence of estradiol—but this is not surprising, as the monkeys only achieved levels of progesterone of 3.4 ng/mL, about a third as much as we would use in our practice. So, with extremely high doses of estradiol and unusually low doses of progesterone, breast tissue did proliferate. However when they added testosterone (130 ng/dL) along with the estradiol (instead of progesterone), it reduced breast cell proliferation by approximately 40% and abolished the increased ER-alpha expression. (It would have been nice to see what would have happened if they had given all three hormones to the same subject, but they didn’t.)
The authors concluded that
testosterone [reduced] mammary epithelial proliferation and Estrogen Receptor expression, suggesting that combined estrogen/testosterone hormone replacement therapy might reduce the risk of breast cancer associated with estrogen replacement.
(Note! That last line would seem to indicate that I’m conceding that estrogen replacement therapy causes breast cancer! Not exactly. What that line states is that replacing estrogen in large doses without also balancing the other hormones may increase the risk of breast cancer. That is certainly possible, and ten-year studies of women who received estrogen alone (without progesterone or testosterone) have shown a slight increase in breast cancer risk, from about 1.2 to 1.4 cases per 1000 women treated per year. Over that same period, those 1000 women are spared roughly 27 new cases of Alzheimer’s disease due to the protective effects of estrogen, so the extra 0.2 cases of breast cancer would appear to be worth it; nevertheless, I would not advise taking estrogen alone. Rather, balancing all the hormones is the best way to prevent the diseases of aging, including cancer.)
Zhou et al. Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J. 14, 1725–1730 (2000)
[/expandsub4] [expandsub5 title=”My doctor found some studies showing that higher levels of testosterone in women were associated with a higher risk of breast cancer! Isn’t that the opposite of what you’re saying? “]Not necessarily… but this will take a minute to explain.
One of the factors that lowers your circulating hormone levels is Sex Hormone Binding Globulin. SHBG is a protein that sticks to sex hormones (as the name implies) and renders them unable to bind to receptors in your body. This is not always a bad thing, as long as you have enough sex hormones (testosterone or estradiol) left over to do their jobs. When SHBG levels are high, the amount of free, available testosterone and estradiol will be low (because a lot of it is bound to SHBG). When SHBG levels are low, the amount of free testosterone and estradiol will be high.
What lowers SHBG levels? One of the biggest factors is insulin resistance. When people are overweight and have insulin resistance, SHBG drops—and therefore free testosterone and free estradiol levels in the blood increase. The problem is, obesity (insulin resistance) is a strong risk factors for breast cancer after menopause– especially in women who have never used HRT– and therefore it is not surprising that overweight patients have not only higher rates of breast cancer, but also higher circulating hormones levels. The elevated circulating hormones are just bystanders, due to insulin resistance and lower SHBG—they are not the cause of the cancer. (Correlation does not equal causation.)
Another, similar example is found in patients with PolyCystic Ovarian Syndrome (PCOS). Such patients all have insulin resistance, causing lowered SHBG and elevated testosterone levels. PCOS patients also have an increased risk of breast cancer, which may be partly due to insulin resistance and partly due to their low levels of protective natural progesterone. This is a very different situation from the typical menopausal patient in our practice, who is being given testosterone replacement together with appropriate diet and exercise advice, and for whom any insulin resistance is immediately addressed. In the latter case, the testosterone we give them helps to decrease visceral fat, further eliminating any insulin resistance, thus increasing SHBG, and lowering the risk of cancer. So in all three types of patients, circulating testosterone levels will increase, but in PCOS or obesity SHBG is low, whereas in a typical patient in our practice insulin resistance is eliminated and SHBG tends to be higher. Higher levels of SHBG are also associated with lower risk of heart disease (as we might expect: obesity lowers SHBG levels and obesity clearly increases CVD risk).
A review from 2011 summed up the (somewhat confusing) information concerning testosterone replacement in menopausal women as follows:
Testosterone lowers the risk of cardiovascular disease (CVD) in women, whereas low SHBG increases cardiovascular disease risk. The relationship between testosterone and breast cancer remains unclear, although from studies of women treated with testosterone therapy over the past decade, no clear signal of risk has emerged.
Cardiovascular and cancer safety of testosterone in women
Susan R. Davis Current Opinion in Endocrinology, Diabetes & Obesity 2011, 18:198–203 [/expandsub5][/expandsub3][expandsub6 title=”In summary?”]In menopausal women, testosterone replacement clearly restores libido, lowers cardiovascular risk, and improves bone mineral density above and beyond the benefits that estrogen replacement confers. The two together are powerful weapons against heart disease, Alzheimer’s and osteoporosis. It’s true that we don’t yet have as much data as we might like on testosterone replacement in women as it relates to breast cancer. However, the preponderance of the data indicate that balancing all of your hormones in concert, just as they are balanced prior to menopause, is the best way to prevent the diseases of aging– including cancer.
(Note: Some additional information on Estrogen’s benefits in Heart Disease, Osteoporosis, Alzheimer’s Disease and Vascular Dementia can be found on the Estrogen Studies page.)