Long term treatment (for up to five years) with continuous combined hormone replacement therapy containing oestradiol 2 mg and norethisterone 1 mg daily was associated with neither endometrial hyperplasia nor malignancy.  In women who had complex hyperplasia during previous sequential or unopposed regimens, the endometrium returned to normal during treatment with continuous combined hormone replacement therapy
<snip> The reversal of endometrial hyperplasia (with no recurrence during five years of follow up) seen in our study may relate to this specific combination [of drug types], which has a relatively strong progestogen component.

Estrogen-only therapy should not be prescribed for women with an intact uterus. The reason for this -- the increased risk of endometrial cancer -- should be communicated to women, as some are tempted to drop their progestin because of side effects. Clinicians should be aware of the potential for endometrial cancer in women using cyclic HRT, particularly when progestin is used for less than 10 days per month for more than 5 years. The duration of progestin in women on HRT should be increased to at least 12-14 days in a cycle, or women should use ccHRT, which does not seem to increase the risk of endometrial cancer compared with cyclic progestin.

1: Steroids 2000 Oct - Nov;65(10 -11):659-64 
Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer.
Pike MC, Ross RK. 

USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, MS #44, Los Angeles, CA 90033-0800, USA. [email protected] 

Estrogen replacement therapy (ERT) increases a woman's risk 

• of developing endometrial cancer approximately 120% for each 5 years of use. 
• of developing breast cancer approximately 10% for each 5 years of use. 

• for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential EPRT; SEPRT) 
• or with each dose of ERT (continuous-combined EPRT; CEPRT). 

• As expected CEPRT was not associated with any increased risk of endometrial cancer. 
• SEPRT with the progestin being given for 10 days per month also did not increase endometrial cancer risk. 
• SEPRT with the progestin being given for 7 days per month did increase endometrial cancer risk with only a relatively slight reduction in risk compared to ERT effectively proportional to the reduction in the number of days of unopposed estrogen. 

<snip explanation of how EPRT is associated with 212-fold greater risk of brest cancer than is ERT>

 Progestins need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administration. <snip> If this is unacceptable to a woman, then giving progestins by mouth (or transdermally) for 10 days every 3 to 4 months should provide satisfactory protection of the endometrium when used with standard-dose conjugated estrogen (CE). This regimen has much less effect on the breast than monthly SEPRT or CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that this approach may be satisfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed. 

There is strong and consistent evidence in this review that unopposed oestrogen therapy, at moderate and high doses, is associated with increased rates of endometrial hyperplasia, irregular bleeding and consequent non adherence to therapy. The addition of oral progestogens administered either cyclically or continuously is associated with reduced rates of hyperplasia and improved adherence to therapy.
     Irregular bleeding is less likely under sequential than continuous therapy but there is a suggestion that continuous therapy over long duration is more protective than sequential therapy in the prevention of endometrial hyperplasia. Hyperplasia is more likely when progestogen is given every three months in a sequential regimen compared to a monthly progestogen sequential regimen.Endometrial Cancer Risk Varies According to Estrogen Replacement Regimen

This is a Swedish study reported in J Natl Cancer Inst 1999 Jul 7;91(13):1131-7
Subjects were postmenopausal women aged 50-74 years who used hormone replacement. Data obtained from 709 case patients with incident endometrial cancer and from 3368 control subjects showed: 

At the end of five or more years of treatment the excess risk of endometrial cancer was

•  6.2 for unopposed estradiol (95% confidence interval [CI] = 3.1-12.6)
•  6.6 for unopposed conjugated estrogens (95% CI = 3.6-12.0). 
• for combined estrogen-progestin use,  the OR was
• 1.6 (95% CI = 1.1-2.4)   for 11-15 days use of P per cycle. 
•  2.9;(95% CI = 1.8-4.6)  for 10 days use of P per cycle 
•  0.2; (95% CI = 0.1-0.8) continuous progestin use along with estrogens 

                             note continuous use reduced risk

RECOMMENDATIONS 

1. Office endometrial biopsy should be the initial diagnostic procedure of choice due to its convenience, accuracy, availabil-ity, safety and low cost (Grade B).
2. If an office endometrial biopsy cannot be performed or the sample is insufficient, then patients should be triaged according to their risk for endometrial cancer. Those felt to be at low risk for endometrial cancer or in whom atropy is suspected or who are medically unfit, should proceed to transvaginal ultrasound. Those at high risk (i.e. obese, nulliparous, post-menopausal, diabetic women, or those taking tamoxifen) should proceed to D&C, with or without hysteroscopy, as a negative ultrasound would not necessarily be completely reassuring and a positive ultrasound would require tissue sampling regardless (Grade B).
3. There is no consensus in the literature as to what the cut-off value for normal endometrial thickness should be. It has been reported as anywhere from four mm to eight mm. Obviously, the lower the cut-off, the higher the sensitivity for detection of such abnormalities as endometrial cancer or its precursors, but at a cost of lower specificity (Grade B).
4. Persistent bleeding after negative initial evaluation should not be ignored, and should be investigated further, as at least 10 per-cent of patients will harbour disease (Grade C).
5. Patients taking continous combined HRT who experience vaginal bleeding after the first six months of therapy should be investigated with an endometrial biopsy, as should patients on sequential HRT who experience bleeding outside the expected time, i.e. after completing their progesterone (Grade B).
6. Patients taking tamoxifen who experience vaginal bleeding should be investigated with endometrial biopsy (Grade B).

Hi, I am new to this newsgroup.  I am having problems when I take the Provera during the last weeks of my cycle.I feel quite good when I take the Premarin but as soon as I start on the  Provera, I get hot flashes, feel dizzy and just plain rotten.

Miserable isn't it!!! My doctor finally took me off the provera altogether...she said the provera was just so you would have your period at the same time every month.. for those kinds of side effects, who cares? Anyway, have been taking the premarin .9 now by it's self for about 8 months and I feel like a new person.. so hang in there.. it's got to get better.

Just how great a risk? Try10 % **per year** according to one study, [more below]

 fiona 

I found this information in the Journal club discussion session with Dr.  Barrett-Connor, ( Estrogen Replacement Therapy and Heart Disease:A Discussion of the PEPI Trial), online at 
http://www.ama-assn.org/special/womh/library/scan/vol_1/no_1/jcr.htm

The PEPI trial used .625 mg premarin, I assume .9 mg premarin would have an even greater effect on the endometrium. [see next point] 

Last December we discussed the so called low dose estrogen study extensively on the ng. The full text of this study can be found online http://www.ama-assn.org/sci-pubs/journals/most/recent/issues/inte/70361..htm
This 24 month study used unopposed Estratab and not Premarin and found that the higher the dose the greater the number of women who developed hyerplasia. From Table  2 in the study,  out of 102 women taking .625 mg/d, 16 women developed hyperplasia before the 24 months were up and withdrew from the study. I could not read the table for the 1.25 mg/d on my screen, but using a little bit of arithmetic I determined that out of 100 women taking the higher 1.25 mg/d, ***33*** developed hyperplasia. That is 33%.

Schairer C, Adami HO, Hoover R, Persson I Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology 1997 Jan;8(1):59-65 

This is the abstract posted to the ng by Steve Harris under the heading <HRT (combination therapy) and uterine cancer risk> on Sept. 17, 1997. It is in the deja news archives, or look for it on medline.   From the abstract:

"Mortality from endometrial cancer was not related to the prescription of weak estrogens or an estrogen-progestin combination, but mortality was 40% higher in women prescribed more potent estrogens without a progestin."

---

Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol. 1994;170(5 pt 1):1213-1223. 

Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304-313. 

Kathryn

I too thought the PEPI trial found 33% with uterine dysplasias after its short term unopposed estrogen use. And it was much higher in the recent "low estrogen" trials when the doses got beyond 0.3 estrogen. And 50% of the women dropped out of that trial and when it got up to the 1.25 doses I believe is where they realized how dangerous this stuff was to be used unopposed. 

 And two years is way too short to know which of the dysplasias will convert to cancer. It took about 7-10 years to find this out after the 1960's hype of unopposed estrogens. I wonder why this bad unopposed stuff is trying to make a comeback?  They must realize now that trying to stuff the combination down as Prempro was a disaster and now are back to just trying to using it unopposed again and monitoring it more closely. But why? Why not just lay off all the hype that it does anything productive anyway for the non-surgical woman. 

 Oh right, I just got it. There used to be 60% of the women castrated who could take it unopposed and that has now dropped to 30% and hopefully will be dropping even more as women no longer race to get "their" hysterectomies. So the unopposed estrogen market has sharply dropped, is getting competition from "designer" estrogen substitutes and they must be trying like crazy to get a new generation of non-surgical women hooked on their drugs. 

 And to keep in mind that all they used in the "low estrogen"  studies was the ultrasound to check the endometrium, and not endometrial biopsies. There are no long term studies at all to validate the uterine ultrasound findings. They just propose that if the endometrium does not grow more than "x" millimeters when using unopposed estrogens, that it is "okay" but they don't know if this is really true because ......yawn....there are no long term studies.  (Where have I heard this before?) 

 I would love to see this MDs written informed consent form when he prescribes 0.9 mg unopposed estrogen. 

shelly 

1. information on the association between estrogen and cardiovascular disease had been obtained almost exclusively from studies of unopposed estrogen; 
2. excluding women with a uterus from 1 treatment group would limit the inferences that could be drawn from PEPI; and (
3. the American College of Obstetricians and Gynecologists includes unopposed estrogen as a treatment option in women with a uterus, provided an annual endometrial biopsy is obtained.