Estrogen-progestin Replacement Therapy Research Articles

ACOG Committee Opinion No. 262: Risk of Breast Cancer with Estrogen-Progestin Replacement Therapy

ACOG Committee Opinion No. 262: Risk of Breast Cancer with Estrogen-Progestin Replacement Therapy

Anti-ischemic effect of chronic oestrogen replacement therapy alone or in combination with medroxyprogesterone acetate in different replacement schemes

Background: Oestrogen replacement therapy in postmenopausal women has a protective effect upon the cardiovascular system and improves exercise-induced myocardial ischemia. Although in hormone replacement schemes progestins are required to reduce the likelihood of uterine malignancies, little is known on the cardiovascular effect of progestins. The purpose of this study was to evaluate the effect of oestrogen replacement alone and two different estrogen–progestin replacement therapy schemes upon exercise induced myocardial ischemia. Material and method: The study population included 18 female menopausal patients with coronary artery disease. After a baseline exercise test patients received conjugated equine estrogens (CEE) 0.625 mg alone for 30 days when they underwent a second exercise test and were randomized to receive in a cross-over design medroxyprogesterone acetate (MPA) either in continuous combined therapy (2.5 mg/daily) for 28 days or in cyclical therapy (10 mg o.d. from day 16 to day 28). Results: After CEE alone two patients with a previously positive exercise test showed a negative exercise test. CEE increased time to 1 mm ST compared to baseline (352±185 vs 265±133 s, P<0.01). In the 2 pts in whom the exercise test was negative after CEE the test remained negative during continuous combined MPA therapy while become positive during cyclical MPA. CEE+continuous combined MPA increased both time to 1 mm ST and exercise time compared to baseline (386±165 vs 265±133 s, P<0.01 and 545±198 vs 465±186 s, P<0.05, respectively). No difference was found between baseline and CEE+cyclical MPA in either time to 1 mm ST or exercise time (268±164 vs 265±133 s, P=NS and 455±223 vs 465±186 s, P=NS, respectively). Conclusion: Continuous combined therapy with CEE+MPA improves exercise-induced myocardial ischemia in female patients with coronary artery disease while the beneficial effect of CEE is reduced by cyclical therapy.

Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women

Objective: To evaluate the effects of dehydroepiandrosterone (DHEA) supplementation on the growth hormone-releasing hormone–growth hormone (GHRH-GH) axis in lean and obese postmenopausal women.Design: Prospective study.Setting: Postmenopausal women in a clinical research environment.Patient(s): Thirty-one postmenopausal women were divided in two groups by age (50 to 55 and 60 to 65 years). Within each group, lean and obese patients were considered.Intervention(s): All patients underwent hormonal evaluations before and at the third and sixth month of therapy (50 mg of DHEA orally each day) and a GHRH test (1 μg/kg) before and at the sixth month of treatment. Ultrasound and bone mass density (BMD) examinations were performed before and after the sixth month of therapy.Main Outcome Measure(s): Plasma dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), E1, E2, androstenedione (A), testosterone (T), osteocalcin, GH, insulin-like growth factor 1 (IGF-1) concentrations.Result(s): The levels of all of the steroids that derived from DHEA metabolism (E1, E2, A, T, DHEAS) and osteocalcin were increased in plasma under DHEA supplementation. The supplementation protocol also increased the levels of GH and IGF-1. However, GHRH-induced GH and IGF-1 responses were not modified by DHEA supplementation.Conclusion(s): Administration of DHEA significantly affects several endocrine parameters in early and late postmenopausal women independently from body mass index. Our data support the hypothesis that DHEA treatment acts similarly to estrogen-progestin replacement therapy on the GHRH-GH-IGF-1 axis. This suggests that DHEA is more than a more than a simple “diet supplement” or “antiaging product”; rather it should be considered an effective hormonal replacement treatment.

Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer

Estrogen replacement therapy (ERT) increases a woman’s risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT increases a woman’s risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer risk, progestins have been added to ERT (estrogen-progestin replacement therapy; EPRT) 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). We conducted two large case-control studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. 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. The sharp contrast between the effects of 7 days and 10 days of progestin in SEPRT suggests that the extent of endometrial sloughing or of ‘terminal’ differentiation at the completion of the progestin phase may play a critical role in determining endometrial cancer risk. This may provide an explanation of why endometrial cancer risk increases so sharply with age in young women even in countries where obesity-associated anovulation is very uncommon; extended periods of unopposed estrogen is not an explanation but less than 10 days of an ‘adequate’ progesterone level may be. EPRT significantly increased the risk of breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 2 1 2 -fold greater than the effect of ERT, which we had previously predicted on theoretical grounds. This effect could also be predicted from the results on mammographic densities seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densities to a much greater extent than 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. The vaginal route will provide adequate endometrial progestin levels with low blood levels so that the effects of the progestin on the breast should be small; with the direct endometrial route the blood progestin levels are even lower, and the effects of the progestin on the breast will be effectively zero. 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.

Basic principles of hormone replacement therapy in the postmenopause

17 beta-estradiol, conjugated equine estrogens, esterified estrogens, and estriol constitute postmenopausal replacement therapy, all of which are in clinical use as oral preparations. Non-oral routes--matrix and reservoir patches, gel--were developed for estradiol, as was the intravaginal administration of estriol and estradiol. Daily doses of 1 mg estradiol(valerate) or 25 micrograms estradiol delivered via a patch or 0.5 mg gel or 0.3 mg conjugated equine estrogens are often sufficient to alleviate climacteric symptoms. Bone resorption may be effectively reduced and bone mineral density maintained by 1 mg estradiol or 25 micrograms transdermal estradiol. Maximal bone sparing dosages are 2 mg estradiol, 50 micrograms transdermal estradiol, 0.625 mg conjugated equine estrogens, and 1.25 mg estrone Estriol, predominantly used for the prevention and or treatment of urogenital symptoms, has no bone sparing effect at the doses in clinical use. Non-oral administration of estradiol may be superior in diabetic women and those with hypertriglyceridemia due to the different metabolism which does not mainly involve the hepatic first pass effect. Epidemiological data do not support any preference of oral versus non-oral routes of administration regarding side-effects such as venous thromboembolism. Progestogens--natural progesterone, derivatives structurally related to progesterone and testosterone, respectively--are necessary for endometrial protection. Sequential use of a progestogen for at least 10 days per month, preferably 12-14 days abolishes the increased incidence of endometrial hyperplasia which is likely to develop with unopposed use of estrogen. Observational studies do not suggest any superiority of a given progestogen regarding cardiovascular risk, prevention of osteoporosis, and cognitive function in postmenopausal women on estrogen replacement therapy. Tibolone, a derivative of norethindrone, is yet another option for replacement therapy. The recommended dose for treatment of climacteric symptoms and prevention of bone loss is 2.5 mg. Controlled clinical studies do not suggest that this compound is superior in achieving amenorrhea compared with continuous combined estrogen progestogen replacement therapy, as available data are inconsistent. In early postmenopause the sequential use of a progestogen in conjunction with an estrogen is the preferred treatment option. With advancing postmenopausal age either continuous combined replacement or tibolone may be choices in case withdrawal bleeding is no longer acceptable for women. However, there are no rigid age limit when to change treatments, the selection of which is largely influenced by the preference of the individual's acceptance of withdrawal bleeding.

Cardioprotective effects of ovarian hormones and the HERS in perspective

The increased population of women in menopause living in the industrialized countries is associated with an increase of diseases which are dependent or facilitated by a state of estrogen deficiency such as cardiovascular and cerebrovascular diseases. Several studies have shown that estrogen replacement therapy reduces the occurence of coronary and may be of cerebrovascular disease by nearly 50% in treated women compared to non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls as well as a direct effect on the vessel wall. Progestins may, in some cases, counteract the beneficial effect of estrogens upon cardiovascular functions. More androgenic progestins may have a detrimental effect upon vascular reactivity while less androgenic progestins seem not to reduce the beneficial effect of estrogens. Of interest, continuous combined administration of hormone replacement therapy seem to be preferable for women with coronary artery disease or for those with increased cardiovascular risk. Case-control and cohort studies have shown that estrogen progestin therapy is associated with a significant reduction of cardiovascular mortality and morbidity. The HERS study has added critical data regarding the cardioprotective effect of hormone replacement therapy in elderly women with proven coronary artery disease. Because of the several methodological and statistical flaws of the HERS study, further studies are warranted to evaluate the effect of hormone replacement therapy on cardiovascular prognosis. Large scale randomized studies will evaluate the effect of estrogen and estrogen–progestin replacement therapy upon cardiovascular events in menopausal women. Until completion of these studies hormone replacement therapy in women with increased cardiovascular risk should be seen with no enthusiasm but also with no fear.

Effect of Estrogen-Progestin Replacement Therapy on Plasma Lipids and Lipoproteins in Postmenopausal Women

Serum levels of cholesterol (Chol), triglycerides (TG), low-density lipoprotein cholesterol (LDL) high-density lipoprotein cholesterol (HDL), both apolipoproteins A1 and B (Apo A1, Apo B), follicle-stimulating hormone (FSH) luteinizing hormone (LH), estradiol (E2), progesterone (P), testosterone (T) and steroid hormone binding globulin (SHBG) were measured in postmenopausal women, before and after four different estrogen-progestin replacement therapies. Each woman was her own control to avoid genetic or socioeconomic differences. Our results showed that serum E2 and TG significantly increased and serum FSH, LH, LDH, Apo B, and Chol significantly decreased after all treatments. Serum P and T did not significantly change after any of the treatments. HDL, Apo A1 and SHBG significantly increased in the groups treated with medroxiprogesterone acetate (MPA) but not in the group treated with Norgestrel. We conclude that estrogen-progestin replacement therapy in postmenopausal women leads to profound and beneficial changes in plasma lipids and lipoproteins and that treatments with cyclic or continuous MPA could provide greater protection against coronary heart disease (CHD).

Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk

Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk

Influence of Continuous Combined Estradiol-Norethisterone Acetate Preparations on Insulin Sensitivity in Postmenopausal Nondiabetic Women

Estrogen-progestogen replacement therapy (HRT) may be associated with deterioration of insulin sensitivity in comparison to estrogens alone, which tend to improve insulin sensitivity in postmenopausal women. Insulin sensitivity with the use of continuous combined 17-beta estradiol/norethisterone acetate (E2/NETA) preparations has not been examined before in postmenopausal women. In a double-blind randomized parallel study, we evaluated the effect of 2 mg E2/1 mg NETA (high dose E2/NETA), 1 mg E2/0.5 mg NETA (low dose E2/NETA), or placebo (P) on the insulin sensitivity index (SI) in three groups (18 women/group) of postmenopausal nondiabetic women (follicle stimulating hormone [FSH] > 40 mIU/mL, mean +/- SD) aged 56 +/- 3 years, BMI 25 +/- 4 kg/m2, cholesterol 233 +/- 42 mg/dL, and triglycerides 87 +/- 36 mg/dL. Insulin sensitivity was measured by means of a two-step hyperinsulinemic euglycemic glucose clamp (insulin infusion rate, 0.25 and 1.0 mU/kg/min for 120 min each) at baseline and after 3 months of daily administration of high dose E2/NETA, low dose E2/NETA, or P. Analysis was performed assuming equivalence of start-end changes of insulin sensitivity among treatment groups (Anderson-Hauck test). SI was 7.7 +/- 2.9, 7.5 +/- 3.4, 6.8 +/- 2.2 at baseline and 6.3 +/- 3.0, 7.9 +/- 2.5, 7.1 +/- 3.1 mL/min/m2 per mu U/mL 3 months after the administration of high dose E2/NETA, low dose E2/NETA, and P, respectively. The low dose E2/NETA group had start-to-end changes of SI which were equivalent to the P group (0.4 [95% confidence interval [CI] -0.8; 1.7] vs. 0.4 [-0.3; 1.0]) (p = 0.02). For the high dose E2/NETA group, equivalence could not be shown with either the P (p = 0.89) or with the low dose E2/NETA group (p = 0.90). SI within the high dose E2/NETA group decreased by -1.5 (95% CI -2.7; -0.2) mL/min/m2 per mu U/mL. HbAlc decreased from 5.3 +/- 0.3 to 5.1 +/- 0.3% within the high dose E2/NETA group (p < 0.03) and remained unchanged within the low dose E2/NETA and P group. Fasting plasma glucose, fasting serum insulin, and C-peptide, as well as triglycerides and BMI were comparable among the groups at baseline and after 3 months. Total cholesterol decreased by 12% and 8% in women treated with high dose and low dose E2/NETA (p < 0.02), respectively, and remained unchanged within the P group. These results indicate that 3 months use of a low dose continuous E2/NETA preparation does not change insulin sensitivity in postmenopausal women. At high dose of E2/NETA, a modest decrease seems possible. The effects of E2/NETA on other parameters of carbohydrate and lipid metabolism are neutral or favorable.

PREMATURE OVARIAN FAILURE

In 1% of women, premature ovarian failure develops by 40 years of age, a condition causing amenorrhea, infertility, sex steroid deficiency, and elevated gonadotropins. Early loss of ovarian function has significant psychosocial sequelae and major health implications. These young women have a nearly two-fold age-specific increase in mortality rate. Among women with spontaneous premature ovarian failure who have a normal karyotype, half have ovarian follicles remaining in the ovary that function intermittently. Indeed, pregnancies have occurred after the diagnosis of premature ovarian failure. Thus, premature ovarian failure should not be considered as a premature menopause. Young women with this disorder have a 5% to 10% chance for spontaneous pregnancy. Attempts at ovulation induction using various regimens fail to induce ovulation rates greater than those seen in untreated patients; however, oocyte donation for women desiring fertility is an option. Young women with premature ovarian failure need a thorough assessment, sex steroid replacement, and long-term surveillance to monitor therapy. Estrogen-progestin replacement therapy should be instituted as soon as the diagnosis is made. Androgen replacement should also be considered for women with low libido, persistent fatigue, and poor well-being despite taking adequate estrogen replacement. Women with premature ovarian failure should be followed up for the presence of associated autoimmune endocrine disorders such as hypothyroidism, adrenal insufficiency, and diabetes mellitus.

Increased activity of lecithin: Cholesterol acyltransferase during short-term oral estrogen progestin replacement therapy in a group of postmenopausal women

The aim of the study was to assess the short-term effect of estrogen-progestin therapy on the plasma level of lecithin: cholesterol acyltransferase ([LCAT] EC 2.3.1.43), a key enzyme in the cholesterol reverse-transport process. The trial included 21 women with at least 6 months of menopause, which was confirmed by anamnesis, physical evaluation, and follicle-stimulating hormone (FSH) determination. Women receiving pharmacological treatment or who had any kind of endocrine disorder were excluded. In addition, we evaluated and confirmed normal Papanicolaou and mammography tests in all 21 women included in the trial. They received conjugated equine estrogen 0.625 mg daily, plus cyclic medroxyprogesterone acetate (5 mg daily) for 12 days each month. Plasma levels of LCAT, cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apoB, and apoAl were evaluated before and after 1 and 3 months of therapy. Pretherapy and posttherapy results were analyzed statistically by Wilcoxon's rank-sum test for paired samples. No significant changes were observed either for body mass index or for blood pressure. A significant increase in plasma LCAT activity was found at the first and third month posttherapy ( P < .005). In addition, after 3 months of therapy, HDL-C significantly increased ( P < .005), in contrast to the significant decrease detected in total cholesterol ( P < .025), LDL-C ( P < .005), cholesterol to HDL-C and LDL-C HDL-C ratios ( P < .005). Triglyceride levels did not show significant modification. In conclusion, our results indicate that short-term estrogen-progestin therapy produces a significant increase in plasma LCAT activity, as well as beneficial changes in the lipid profile, in postmenopausal women.

Strategies to reduce the incidence of endometrial cancer in postmenopausal women

Objective: The purpose of this study was to develop strategies to reduce the incidence of endometrial cancer in postmenopausal women by reviewing methods to diagnose women at risk and providing therapies that are effective. Study Design: A literature search for studies between 1975 and 1995 of the association between hormone therapy and endometrial cancer was performed with MEDLINE. There were nine reports with a total of 66 cases of endometrial cancer developing during use of estrogen-progestogen replacement therapy. Results: The cases of endometrial cancer diagnosed during use of estrogen-progestogen therapy because of abnormal bleeding occurred when the dosage or duration of the progestogen was less than that considered optimum. The minimum effective dosage of medroxyprogesterone acetate is 10 mg and the minimum effective dosage of norethindrone acetate to 2.5 mg. The minimum effective duration of the progestogen is 12 to 14 days when it is used sequentially. Continuous combined therapy with low dosage estrogen and progestogen may not be fully endometrial protective. Conclusions: The progestogen challenge test is an effective test to identify women at increased risk for endometrial cancer. There are no adverse effects on lipids and lipoproteins from added progestogen when adequate dosages of estrogen are given. Side effects of progestogens can be managed with mild diuretics or by changing the type, dosage, or route of administration. Cyclic combined therapy may be more endometrial protective than continuous combined hormone replacement is.

Estrogen-progestin replacement therapy and endometrial cancer.

It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per "month" in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy. We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer. A population-based, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50-74 years when first diagnosed with invasive endometrial cancer or were aged 50-74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors. The adjusted OR was 2.17 (95% confidence interval [CI] = 1.91-2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32-2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82-1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80-1.43) (94 case subjects and 81 control subjects). The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.

Current estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis

The cardioprotective effects of combined estrogen/progestin replacement therapy have been questioned. Therefore, we have compared carotid arterial wall thickening and the prevalence of carotid stenosis in elderly women (> or = 65 years old) currently using replacement estrogen/progestins (E + P) with arterial pathology and its prevalence in women using unopposed estrogens (E). This cross-sectional study used baseline data from all 2962 women participating in the Cardiovascular Health Study, a population-based study of coronary heart disease and stroke in elderly adults. Users of hormone replacement therapy (HRT) were categorized as never (n = 1726), past (n = 787), current E (n = 280), or current E + P (n = 73). Maximal intimal-medial thicknesses of the internal and common carotid arteries and stenosis of the internal carotid arteries were measured by ultrasonography. Current E + P users resembled current E users in most respects, although some lifestyle factors were more favorable among E + P users. Current E + P use and current E use (as compared with no use) were associated with smaller internal carotid wall thicknesses (-0.22 mm; P = 0.003; and -0.09 mm; P = 0.05, respectively) and smaller common carotid wall thicknesses (-0.05 mm; P = 0.03; and -0.02 mm; P = 0.1, respectively) and lower odds ratios (OR) for carotid stenosis (> or = 1% vs. 0%); OR = 0.61; 95% confidence interval [CI]: 0.36 to 1.01; and OR = 0.91, 95% CI: 0.67 to 1.24, respectively), after adjustment for current lifestyle and risk factors. When both groups of current HRT users were compared, there were no significant differences in carotid wall thicknesses or prevalence of carotid stenosis. For this sample of elderly women, both current E + P therapy and current E therapy were associated with decreased measures of carotid atherosclerosis. These measures did not differ significantly between the two groups of HRT users.

F020 The effect of tibolone on serum lipid and lipoprotein levels

We investigated the effect of tibolone and estrogen-progestin replacement therapy on serum lipid and lipoprotein levels in postmenopausal women. Ninety-five women were included into the study. Initial serum HDL-C, LDL-C, VLDL-C, total cholesterol and trigliseride levels were dete~ined. Continuous CEE and MPA to 30 women (Group I), continuous CEE and cyclic MPA to 3 1 women (Group II) and tibolone to 34 women (Group III) were administered. Six months later serum lipid and lipoprotein levels were reassessed. All groups were found to be comparable in terms of age, duration of menopause, BMI and the initial serum lipid and lipoprotein levels. When we compared group I and III, there was a signi~c~t decrease in all serum lipid and lipoprotein levels except LDL-C in group III. When we compared group II and III, we determined a significant decrease in the levels of serum VLDL-C and HDL-C in women receiving tibolone. It has shown that tibolone is an alternative to estrogen-pogestin herapy in the postmenopausal women.

Are the antioxidative effects of 17 beta-estradiol modified by concomitant administration of a progestin?

Estrogens are known to exhibit antioxidative effects. At present little information exists on the influence of co-administered progestins upon this effect. Therefore we investigated the influence of levonorgestrel, a potent antiestrogenic progestin, on the inhibition of the low-density lipoprotein (LDL) oxidation by 17 beta-estradiol or 17 beta-estradiol valerate in vitro and ex vivo. After isolation from blood, the in vitro oxidation of LDL was induced by copper ions and measured continuously by monitoring the formation of conjugated dienes. In 21 female ovariectomized White New Zealand rabbits the antioxidative action of 17 beta-estradiol alone or in combination with levonorgestrel after subcutaneous infusion for 3 days was determined using the copper-induced LDL-oxidation as an endpoint. Eleven postmenopausal women were exposed to sequential estrogen-progestin replacement therapy (day 1-21:2 mg estradiol valerate/day, day 10-21: 0.15 mg levonorgestrel/day). Blood samples were collected at three times: on day 1, on day 10, on day 22 (after the combination phase). The lag time of ex vivo oxidation of LDL, the plasma estradiol and estrone levels were estimated. In the chosen cell-free system, 17 beta-estradiol increased the lag time of the LDL-oxidation in a dose-dependent manner. Levonorgestrel showed neither pro-oxidative nor antioxidative effects when administered alone in different concentrations. Co-administration of different doses of levonorgestrel did not modify the antioxidative action of estrogen either. The two ex-vivo models confirmed these results. In rabbits the co-administered 19-nortestosterone derivative levonorgestrel did not impair or reverse the estradiol-dependent effect. In postmenopausal women the daily oral administration of levonorgestrel in conjunction with 17 beta-estradiol valerate did not diminish the antioxidative action of this estrogen given for the first 9 days. The antioxidative potential of estradiol and estradiol valerate is maintained in the presence of levonorgestrel.

Cancer risk in women receiving estrogen-progestin replacement therapy

Cancer risk in women receiving estrogen-progestin replacement therapy

Cancer risk in women receiving estrogen-progestin replacement therapy

Objectives and methods: The epidemiological literature was reviewed in order to evaluate the relationship between hormone replacement therapy and risk of cancer in the breast and reproductive organs. Results: For breast cancer, there is no evidence of an overall increase in the risk. According to several studies, but not all, the duration of intake seems to affect the risk. Many years of intake of both estradiol compounds and conjugated estrogens can be assumed to increase the risk of breast cancer 1.5-2-fold. The addition of progestins does not seem to alter (reduce) the duration-risk relationship. The magnitude of risk increase is likely to be small and may be explained partly by methodological problems, or by differences in study populations. The prognosis in patients with HRT-related breast cancer seems to be more favourable than for non-exposed breast cancer patients. Because of the importance of the issue, and inconsistencies in results, further research is urgent. Especially, there is an urgent need to define sub-groups of women who would be susceptible to an adverse influence of HRT. Regarding endometrial cancer, a duration-dependent strong risk relationship with long-term intake of estrogens only is established. The level of risk increase is about 10-fold after 10 or more years of intake, a risk relationship that seems to decrease after discontinuation of treatment. Added progestins for at least 10 days per cycle can reduce or eliminate the risk increase. Tumors occurring after estrogen replacement have favourable biological characteristics. Future research will be needed to define the long-term safety of various progestin regimens. Ovarian cancer risk does not seem to be affected by HRT. Available data are inconsistent and contradictory. Due to the pronounced protective effect of oral contraceptives, further research is needed to measure effects of estrogen-progestin combined regimens. Cervical cancer risk has not been shown to be affected by HRT. Conclusions: It is concluded that hormone replacement therapy, with estrogens alone or estrogens combined with progestins, may have important effects on the risk of cancer, particularly in the breast and endometrium. Therefore, when making a risk-benefit assessment of long-term HRT, possible risk relationships should be considered.

High bone density in hyperandrogenic women: effect of gonadotropin-releasing hormone agonist alone or in conjunction with estrogen-progestin replacement.

We studied 20 hirsute patients with high levels of serum testosterone (T), calculated free T, androstenedione, and dehydroepiandrosterone sulfate and 19 age-matched nonhirsute normoandrogenic control women. The bone mineral density (BMD) in the lumbar spine, femoral neck, and trochanter major region in hirsute patients was higher than that in the controls. BMD in the lumbar spine and proximal femur correlated positively with the body mass index and with serum T and free T in hyperandrogenic women and the whole study group, but not with serum androstenedione or dehydroepiandrosterone sulfate levels. The hirsute women were treated with a GnRH agonist (goserelin, 3.6-mg implant) for 9 months. After the first 3 months of treatment, half of the patients were randomized to receive estrogen-progestin replacement therapy (HRT), and the other half served as controls. After the first 3 months of trial, BMD was unaffected, and the urinary output of collagen pyridinoline, deoxypyridinoline cross-links, and hydroxyproline (all markers of bone resorption) were increased, but serum markers, the carboxy-terminal telopeptide of type I collagen (marker of bone resorption) and that of bone-specific alkaline phosphatase (marker of bone formation) did not change. After 9 months of goserelin treatment, the lumbar spine had lost 5.4% of its BMD (P < 0.01), but regained bone density 6 months after cessation of treatment. Addition of HRT protected the spine and trochanter major against bone loss. The changes in serum telopeptide and urinary output of pyridinoline and deoxypyridinoline after 3 months of treatment (from prestudy levels) correlated with the decrease in BMD in the femoral neck at 9 months. In conclusion, our data show that patients with ovarian androgen excess 1) have high BMD, 2) lose bone during 9 months of treatment with GnRH agonist, 3) show a decrease in bone density preceded by biochemical alterations in bone metabolism at least 6 months earlier, and 4) can have their bone loss prevented by add-back HRT.

A Case-Control Study of Combined Continuous Estrogen-Progestin Replacement Therapy among Women with a Personal History of Breast Cancer

A Case-Control Study of Combined Continuous Estrogen-Progestin Replacement Therapy among Women with a Personal History of Breast Cancer