Very low dose estrogen with drug holidays appear to be a safe and the most effective treatment for hot flashes and vaginal dryness.  Estrogens combined with progesterone agents cause an increase in the death rate.  Estrogen alone is much safer in women without a uterus and probably in non-smoking women with a uterus when the very low dose strategy is used with drug holidays.  Estrogens, especially in higher dosages, in smokers and if no drug holidays, can cause an increase in uterine cancer.  Estrogens should not be used in women with breast cancer or at a high risk of breast cancer.  

The use of estrogen should be restricted only to those women whose hot flashes are otherwise not tolerable.  However, some research does continue to support a more general long-term, low-dose estrogen use.

For the treatment of hot flashes, see Menopausal Symptoms.

Estrogen Treatment Lowers Parkinson's Risk After Hysterectomy: 72 female patients who developed Parkinson’s disease found an increase in the disease in women with hysterectomies but the increase offset by estrogen replacement therapy. Men have a 50% higher rate of Parkinson's, possibly due to women being protected by estrogen. Demetrius Maraganore, September 2001 Movement Disorders. 

Elderly Estrogen Users Lived Longer: In a 22-year follow-up of 8,801 women in the Leisure World Cohort (median age, 73 y), 6,626 died during follow-up. Estogen users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P <0.001). The risk was lowest among long-term (> or =15 y) users (RR = 0.83 for 15-19 y and RR = 0.87 for 20+ y). Lower-dose users (< or =0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84 vs RR = 0.91). Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study. Paganini-Hill A, et al. University of Southern California. . Menopause 2006 Jan-Feb;13(1):12-8.

No Increase in Breast Cancer, But Very Slight Increase in Blood Clots and Stroke: In a 7-year follow-up DB PC Women's Health Initiative study of 10,739 women who had had hysterectomies and using only estrogen, not progesterone, there was no increase in breast cancer. JAMA 4/12/06. The increase in blood clots large enough to block a vein was 0.30% vs. 0.22% or one more case per 2000 women.  I don't have the stroke numbers, but I suspect it is also very slight.

Estrogen Increased Breast Cancer 41% in African-American Women After 10 Years: In a study of 23,000 women, those on estrogen alone still had an increased rate of cancer.  I don't think that the study of a controlled DB study, but rather an epidemiologic one. Arch Int Med 4/10/06.

Estrogen Helps Verbal Performance: Improved oral reading and verbal memory performance were found in a DB PC crossover of 60 women 33-64 postmenopausal, Yale, 9/03, Menopause, Sally Shaywitz

Estrogen Safe After Breast Cancer: Use of estrogen replacement therapy in a cohort of 64 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 13 year follow-up period. Univ. Texas SW. Estrogen replacement therapy after breast cancer: a 12-year follow-up. Peters GN, Fodera T, Sabol J, Jones S, Euhus D. Ann Surg Oncol. 2001 Dec;8(10):828-32

Vaginal Dryness: Estrogen Cream Didn't Increase Breast Cancer Recurrence: Study of 1461 women treated for breast cancer of whom 69 used estrogen cream for vaginal dryness. Cancer recurrence was actually less in those using cream (HR 0.57). Although the small numbers of this study preclude a definitive result, topical estrogen usage does not appear to be associated with an increased risk of recurrence of breast cancer. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Dew JE, Wren BG, Eden JA. Climacteric. 2003 Mar;6(1):45-52; Vaginal tablets or rings were preferred over other preparations. There were no serious adverse events reported. J Womens Health (Larchmt). 2002 Dec;11(10):857-77. 

Estrogen-Medroxyprogesterone Increases Mortality: In one year, for every 10,000 women who take the estrogen-progestin combination Prempro there will be eight more breast cancers, eight more strokes and seven more heart attacks - and six fewer colon cancers and five fewer hip fractures - compared with 10,000 women who didn't take the pills. Prempro increased the risk of stroke by 41%, a heart attack by 29% and breast cancer by 26%.  It decreased hip fractures 34%, colorectal cancer 37%, and prevents osteoporosis. This comes from a 5.2 year study of 16,000 women with an average age of 63 on HRT or placebo. NIH Study, JAMA 7/9/02 288:321

Estrogen OK, Not Prempro: Women’s Health Initiative Prempro arm stopped due to increased harm, however, estrogen by itself in another arm of the study for women with hysterectomies was continued because of no sign of harm. Medroxyprogesterone interferes with the beneficial effects of estrogen. A different progestin may cause fewer side-effects and less interference. Only medroxyprogesterone of several progestins blocked the favorable anti-dementia effect. Scientific American 10/03

Estrogen Low Dose No Net Harm or Benefit in Postmenopausal with Hysterectomy: In a 6.8 year DB PC study of 10,739 postmenopausal women who had undergone hysterectomy, 0.625 mg/day of conjugated equine estrogen (CEE) resulted in a greater reduction in low-density lipoprotein cholesterol (-13.7% vs. -1.0%) and a greater increase in high-density lipoprotein cholesterol (15.1% vs. 1.1%). Estimated hazard ratios (HRs) for CEE versus placebo were 0.91 for CHD, 1.39 for stroke, 1.34 for pulmonary embolism (PE), 1.08 for colorectal cancer, 0.61 for hip fracture and 0.77 for breast cancer. The global index of risks and benefits, including primary outcomes plus stroke, PE, colorectal cancer, hip fracture, and deaths from other causes, was 1.01. Effects of Conjugated Equine Estrogen in Postmenopausal Women Having Undergone Hysterectomy: The Women's Health Initiative Randomized, Controlled Trials. Obstet Gynecol Surv. 2004 Aug;59(8):599-600.

Medroxyprogesterone Every Three Months OK: A Washington University DB PC study of 25 women >74yo with half given estrogen 0.625 mg/d and medroxyprogesterone 5 mg/d for 13 days every three months added to the estrogen found an increase in endometrial lining with hormonal therapy but no signs of dysplasia on biopsy at 18 months. Effects of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy: a pilot study. Pinto AB, A, Binder EF, Kohrt WM, Bronder DR, Williams DB. Am J Obstet Gynecol. 2003 Jul;189(1):11-5

Stroke: Increased Only in Hypertensive Women: The Danish Nurse Study with 19898 women replying and 28% on HRT found that there was no increase in stroke among HT nurses who were normotensive. The Hazard Ratio for hypertensive HT was 2.35 and even higher (HR 3.00) if estradiol plus progesterone. Arch Neurol. 2003 Oct;60(10):1379-84

Million Woman Study Finds Combo Worse: 1,084,011 UK women ages 50-64 were surveyed. 50% had had HRT. Current users of HRT were more likely than never users to develop breast cancer (adjusted relative risk 1.66) and die from it (1.22). Past users of HRT were, however, not at an increased risk of incident or fatal disease (1.01 and 1.05). Incidence was significantly increased for current users of preparations containing estrogen only (1.30), estrogen-progestagen (2.00), and tibolone (1.45). Results varied little between specific estrogens and progestagens or their doses; or between continuous and sequential regimens. The relative risks were significantly increased separately for oral, transdermal, and implanted estrogen-only formulations (1.32; 1.24; and 1.65). In current users of each type of HRT the risk of breast cancer increased with increasing total duration of use. 10 years' use of HRT is estimated to result in five additional breast cancers per 1000 users of estrogen-only preparations and 19 additional cancers per 1000 users of estrogen-progestagen combinations. Lancet. 2003 Aug 9;362(9382):419-27

Sexual Problems: Dramatically Decreases Sexual Dysfunction:  A study from the University of Barcelona of 534 healthy women ages 40-64 of whom 82.8% were peri- or postmenopausal, 23% had received hormone replacement therapy (HRT) and 79.2% were sexually active. Among those who were sexually active a total of 51% presented SD. The prevalence of SD increased with age (from 22% at 40-44-years to 66% at 60-64-years). HRT users and healthy women presented a lower risk of SD (OR: 0.1 and OR: 0.6). The risk increased after the menopause (OR: 3.3) and with age older than 49 years (OR: 3.4), hysterectomy (OR: 3.7) and when male partners presented erectile dysfunction (OR: 3.2). J Obstet Gynaecol. 2003 Jul;23(4):426-30

Vaginal Estradiol Helps Urinary Symptoms: Estradiol is popular in Europe, while conjugated estrogens are popular in the U.S.  Vaginally administered low dose (25 microg) micronized 17beta-estradiol in  a DB PC study of 1612 patients with urogenital complaints for 12 months with patients treated once a day over a period of 2 weeks, and then twice a week for the remaining of the 12 months found an overall success rate in postmenopausal women with vaginal atrophy of 85.5%, with estradiol vs. 41.4% placebo. Urinary atrophy symptoms was 51.9% vs. 15.5%, P=0.001. The maximal cystometric capacity (290 ml vs. 200 ml, P=0.023), the volume of the urinary bladder at which patients first felt urgency (180 vs. 140, P=0.048), and strong desire to void (170 ml vs. 130 ml, P=0.045) were significantly increased subsequent to estradiol. The number of patients with uninhibited bladder contractions significantly decreased following estradiol as compared with pretreatment values (17/30, P=0.013). Side effects 7.8% of patients treated with estradiol. It did not raise serum estrogen level nor stimulated endometrial growth. Int J Gynaecol Obstet. 2003 Aug;82(2):187-97

Estrogen 0.625 mg Daily May Slightly Increase Cognitive Impairment in Elderly: In a DB PC study of 2947 women aged 65-79 with prior hysterectomies, a 5.4 year follow-up found those assigned to conjugated estrogen 0.625 mg daily had very slightly greater loss in cognitive functioning (0.26 points on an MMSE) than women assigned to placebo. The harmful effect was more in women already suffering some cognitive impairment. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J; Wake Forest University. JAMA. 2004 Jun 23;291(24):2959-68