What Are the Pros and Cons of Estrogen Replacement Therapy after a Hysterectomy?

In combination with estrogen tablets, the indication is suitable for the treatment of the following diseases: 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Treatment of vulvar and vaginal atrophy. When used only to treat symptoms of vulvar and vaginal atrophy, products for topical vaginal use should be considered. 3. Prevention and control of osteoporosis. When only for the prevention and control of osteoporosis, it should be considered only in women with a significant risk of osteoporosis and in women who are considered unsuitable for non-estrogen therapy. 4. Treatment of hypoestrogen caused by hypogonadism, castration or primary ovarian function decline. 5. Treat appropriately selected women and men with metastatic breast cancer (for symptomatic relief only). 6. Treatment of advanced androgen-dependent prostate cancer (for symptomatic relief only). Hormone replacement therapy should not or continue to be used to prevent cardiovascular disease or dementia. The pros and cons of hormone replacement therapy must always be carefully weighed, including the risks that may arise when continuing treatment (see [Cautions]-Warnings). The use of estrogen alone or in combination with progestin requires the lowest effective dose and shortest course of treatment in the context of individual women's treatment goals and risks.

Drug Name: Estrogen tablets

Drug type: Prescription drugs, medicines for medical workers' injuries
Use classification: Estrogen

Combined with estrogen tablets

Main ingredients of this product: Combined with estrogen. Premarin (combined with estrogen tablets) is an oral preparation containing a mixture of estrogen extracted from the urine of pregnant horses and a mixture of water-soluble estrogen sodium sulfate. It is a mixture of sodium estrone and sodium maleestrone. It also contains sodium sulfate conjugate, 17-dihydroestrenone, 17-estradiol, and 17-dihydroestrenone.

Combined estrogen tablet traits

This product is dark green (0.3mg) or fuchsia (0.625m) oval-shaped sugar-coated tablets.

Combined with estrogen tablets specifications

(1) 0.3mg (2) 0.625mg

Combination with estrogen tablets

This product is a prescription drug and is prescribed by a doctor.
When estrogen therapy is given to postmenopausal women with a uterus, progestin should be added at the same time to reduce the risk of endometrial cancer. Women without a uterus do not need to add progestin. The use of estrogen alone or in combination with progestin requires the lowest effective dose and shortest course of treatment in the context of individual women's treatment goals and risks. Patients should be re-evaluated regularly (eg every 3 or 6 months) based on clinical needs to determine if treatment is still needed (see [Caution]-Warning). For women with a uterus, when there is a long-term or recurrent vaginal abnormal bleeding of unknown diagnosis, adequate diagnostic measures, such as endometrial biopsy, should be taken to rule out the possibility of malignant disease.
1. Treat moderate to severe vasomotor symptoms associated with menopause and / or vulvar and vaginal atrophy. When used only to treat symptoms of atrophy of the vulva and light tunnel, products for topical vaginal use should be considered.
Patients should be given the lowest effective dose. It is usually advisable to start with 0.3 mg of bemeril daily, and subsequent dose adjustments should be based on individual patient response. Doctors should periodically re-evaluate the dose of the drug to determine if treatment is still necessary.
According to the patient's individual situation and medical needs, Premarin treatment can be used continuously or periodically (such as medication for 25 days and then discontinued for 5 days).
2. Prevention and control of osteoporosis:
When it is only for the prevention and control of osteoporosis, it should only be considered in women with a significant risk of osteoporosis and in women who are considered unsuitable for non-estrogen therapy. Patients should be treated with the lowest effective dose, usually starting from 0.3 mg Premel® daily, and subsequent doses should be adjusted based on the patient's individual clinical response and response to bone mineral density. The dose should be evaluated regularly by a doctor to decide whether treatment is still necessary.
Depending on the patient's individual situation and medical needs, Premill can use continuous therapy or a periodic medication regimen (such as the therapy for 25 days and then discontinuation for 5 days).
3 Treatment of hypoestrogen caused by hypogonadism, castration or primary ovarian decline:
Hypogonadism in women: 0.3mg or 0.625mg per day, taken periodically (such as one week after taking the medicine for three weeks). Adjust the dose according to the severity of the symptoms and the response of the endometrium.
In clinical studies of delayed puberty due to hypogonadism in women, a low dose of 0.15 mg can induce breast development.
Over a period of 6-12 months, the dose can be gradually increased until a proper increase in bone age and final epiphyseal closure is achieved. Clinical studies suggest that the dosages are 0.15mg, 0.30mg, and 0.6mg, and the corresponding bone age and age ratios ( BA / CA) are 1.1, 1.5, and 2.1. (Bellimer has no 0.15mg product). Existing data suggest that combined with the sequential use of progestins, long-term administration of 0.625 mg of Premarin is sufficient to generate artificial cycles and maintain bone mineral density after bone maturation.
Castration or primary ovarian decline: 1.25 mg daily, taken periodically. Adjust the dose up or down based on the severity of the symptoms and the patient's response. In order to maintain efficacy, the dose can be adjusted to the lowest dose effective in controlling the disease.
4 Treatment of appropriately selected women and men with metastatic breast cancer (for symptomatic relief only):
It is recommended to take 10 mg three times a day for at least three months.
5. Treatment of advanced androgen-dependent prostate cancer (only to relieve symptoms):
Three times a day, 1.25 mg to 2 x 1.25 mg each time. Efficacy can be judged based on the results of phosphatase test and improvement of patients' symptoms.
Patients should be regularly evaluated by a physician to determine the need to continue symptomatic treatment.

Adverse effects in combination with estrogen tablets

According to the classification of the incidence of CIOMS adverse reactions, the list of adverse reactions is as follows:

Contraindications with estrogen tablets

Estrogen should not be used in any of the following situations:
1. Diagnosis of unknown bleeding from reproductive organs.
2. Known, suspected, or previous breast cancer, except for appropriately selected patients undergoing treatment for metastatic breast cancer.
3. New or unknown estrogen-dependent organisms (tumors such as endometrial cancer and endometrial hyperplasia).
4. Active deep vein thrombosis, pulmonary embolism, or a history of this type of disease.
5. Active or newly occurring (such as in the past year) arterial thromboembolic disease (such as stroke and myocardial infarction).
6. Liver function test cannot return to normal liver dysfunction or liver disease.
7. Premel cannot be used in patients who are known to have hypersensitivity to its ingredients.
Known or suspected pregnancy. Premill cannot be used in pregnant women.

Precautions in combination with estrogen tablets

A. Warnings 1. General warnings Estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) are associated with an increased risk of certain cancers and cardiovascular disease. The use of non-antagonistic estrogen (ie, estrogen alone) in women with intact uterus is associated with an increased risk of endometrial cancer.
Hormone replacement therapy should not or continue to be used to prevent cardiovascular disease or dementia. The pros and cons of hormone replacement therapy must always be carefully weighed, including the risks that may arise when continuing treatment. Estrogen alone or in combination with progestin, the lowest effective dose and the shortest course of treatment need to be used in the context of individual women's treatment goals and risks. 2. Cardiovascular risk < br Estrogen replacement therapy (ERT) and stroke and Increased risk of deep vein thrombosis (DVT).
Hormone replacement therapy (HRT) is associated with an increased risk of myocardial infarction (MI), stroke, venous thrombosis, and pulmonary embolism (PE). If these conditions occur or are suspected, estrogen should be stopped immediately.
Risk factors for arterial tuberculosis (such as hypertension, diabetes, smoking, hyperlipidemia and obesity) and / or risk factors for venous thrombosis (if history or family history of VTE, obesity and systemic lupus erythematosus) Patients should be treated appropriately.
Patients at risk for thrombotic disease should be closely monitored.
a. Stroke < br In the WHI's monoestrogen study subgroup, women who reported that estrogen alone had a statistically significant increase in stroke risk compared to the placebo group (45 cases versus 33 cases per 10,000 people- year). Increased risk can be observed in the first year and it continues.
In the WHI estrogen / progestin subgroup, women who reported using estrogen / progesterone had a statistically significant increase in stroke risk compared to the placebo group (31 vs. 24 cases per 10,000 person-years). After the first year, increased risk can be observed and continued.
b. Coronary heart disease < br In the WHI monoestrogen subgroup study, women with estrogen alone compared with placebo did not report overall coronary heart disease (CHD) events (defined as non-fatal myocardial infarction) , Asymptomatic myocardial infarction or death from CHD).
In the WHI estrogen plus progestin subgroup study, the risk of coronary heart disease (CHD) events was not reported in the group taking predominantly (0.625 mg combined with estrogen plus 2.5 mg medroxyprogesterone acetate) per day relative to the placebo group A statistically significant increase (the risk of CHD events per 10,000 person-years was 39 to 33). Relative risk increased in the first year and a decrease in relative risk was reported in the second to fifth years.
A controlled clinical trial of secondary prevention of cardiovascular disease (HERS study) in postmenopausal women diagnosed with heart disease (n = 2,763, mean age 66.7 years), which did not demonstrate a combination of estrogen and methyl acetate The combination of oxyprogesterone has cardiovascular benefits. With a mean follow-up of 4.1 years, premenopausal women with established coronary heart disease did not reduce the overall incidence of CHD events with the treatment with Predominant®. In the first year, the incidence of CHD increased in the predominantly treated group compared to the placebo group, but this did not occur in subsequent years. Of the people participating in the HERS study, 2,321 women agreed to participate in an open, HERS Extended Study (HERS II Study). The HERS II study was followed for 27 years, a total of 6.8 years. In HERS, HERS II, the prevalence of CHD events was similar in the predominant and placebo groups.
In a large-scale prospective clinical trial for men, large doses of estrogen (5 mg per day combined with estrogen) are equivalent to doses for prostate and breast cancer, increasing non-fatal myocardial infarction, pulmonary embolism, and thrombosis Risk of phlebitis.
c. Venous thromboembolism. The WHI monoestrogen subgroup study reported an increased risk of venous thromboembolism (deep vein thrombosis [DVT] and pulmonary embolism) in women taking Premel® (30 versus 22 cases per 10,000 person-years). But only the increase in the incidence of deep venous thrombosis was statistically significant (23 vs. 15 cases per 10,000 person-years). An increase in VTE risk was observed during the first two years. (See [Clinical Trials])
In the WHI combined progestin subgroup study, the incidence of venous thromboembolism in women taking estrogen / progesterone was reported to be more than double the VTE of placebo women (35 vs. 17 cases per 10,000 person-years), a difference There is statistical significance. The risk of deep venous thrombosis (26 vs. 13 cases per 10,000 person-years) and pulmonary embolism (18 vs. 8 cases per 10,000 person-years) also showed an increase and were statistically significant. This risk was observed to increase and persist in the first year.
Where possible, estrogen should be discontinued at least 4-6 weeks before surgery or during prolonged bed rest, which may increase the risk of thromboembolism.
3. Malignant tumors a. Endometrial cancer Women with intact uterus are associated with an increased risk of endometrial cancer. Endometrial cancer is reported to be two to 12 times more likely to occur in women with estrogen than without estrogen, and it is related to the time and dose of estrogen. Most studies have shown that there is no significant increase in the risk of endometrial cancer associated with estrogen use after less than one year of estrogen use. The greatest risk appears to be related to long-term medication, with a 15-24-fold increase in risk for patients with 5-10 years or more, and this risk persists for at least 8-15 years after stopping estrogen therapy.
Differences in equivalent doses of natural and synthetic estrogen in the risk of endometrial cancer have not been demonstrated. Increasing progestin in estrogen replacement therapy has been shown to reduce the risk of endometrial hyperplasia. Endometrial hyperplasia may be a precursor to endometrial cancer (see [ Precautions ]-Women with a uterus should add progestin).
A group of WHI studies (see [ Clinical Trials ]) showed that after an average of 5.6 years of medication, the risk of endometrial cancer in the estrogen / progestin combination group did not increase compared to the placebo group.
Clinical monitoring of all women using a combination of estrogen / progestin is important. Appropriate diagnostic measures, including endometrial biopsy when indicated, should be used for all patients with persistent or repeated vaginal abnormal bleeding of unknown diagnosis, except for the possibility of malignancy.
b. Breast cancer < br In some studies, the use of estrogen and progesterone in postmenopausal women has been linked to an increased risk of breast cancer.
In the WHI monoestrogen subgroup study, after an average of 7.1 years of follow-up, CEE (0.625 mg per day) was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04).
In the WHI estrogen plus progestin subgroup, an average risk of invasive breast cancer was reported after a mean follow-up of 5.6 years (RR 1.24, 95% nCI 1.01-1.54); invasive breast cancer found in the estrogen-progestin combination group Larger than found in the placebo group, and staged later at diagnosis. The absolute risk of the estrogen and placebo groups was 41 to 33 cases per 10,000 person-years. Metastatic lesions are rare and there are no significant differences between groups. Other prognostic factors such as histological typing, grading, and hormone receptor status did not differ significantly between groups.
Epidemiological studies report an increased risk of breast cancer in women treated with estrogen or estrogen plus progesterone for several years. The risk increased over time and seemed to gradually return to baseline levels after 5 years of discontinuation of treatment. These studies also suggest that the use of estrogen and progesterone combined therapy is higher risk than breast cancer with estrogen alone, and the increased risk appears earlier.
Studies evaluating different HRT formulations, regardless of estrogen / progestin composition, dosage, schedule, and route of administration, did not show significant differences in breast cancer risk.
According to data from epidemiological studies, it is estimated that 32 women per 1,000 women who have never used HRT have breast cancer diagnosed between the ages of 50 and 65. Among 1,000 women who are or have recently been treated with estrogen alone, 5 and 10 years of use from the age of 50, the estimated increase in breast cancer diagnosed by age of 1.5% and 5% respectively. The corresponding figures for estrogen plus progestin therapy were 6% and 19%, respectively. It has been reported that the use of estrogen alone or the use of estrogen plus progesterone leads to an increase in abnormal mammography that requires further evaluation. Therefore, women should have breast examinations performed by medical personnel every year and breast self-examinations every month. In addition, a mammogram should be scheduled based on patient age and risk factors.
c. Ovarian cancer < br In some epidemiological studies, the use of estrogen products alone, especially for 10 years or more, is associated with an increased risk of ovarian cancer. No other epidemiological studies have found such a correlation. Analysis of WHI data suggests that estrogen plus progestin treatment may increase the risk of ovarian cancer.
4. Dementia Women's Health Action Memory Study (MHIMS), a subsidiary study of WHI, a group of 4,532 women aged 65-79 years were randomly assigned to CEE plus MPA (0.625mg / 2.5mg per day) Group or placebo group, the second person group was 2947 65-79-year-old hysterectomy women, randomly assigned to the CEE (0.625mg per day) or placebo group. The relative risk of reported dementia was 2.05 (95% CI 1.21-3.48) compared to the dose group. In the estrogen alone group, after a mean follow-up of 5.2 years, the relative risk of probable dementia compared to placebo was 1.49 (95% CI 0.83-2.66). When the data from the two groups were combined according to the WHIMS plan, the overall relative risk of possible dementia was reported as 1.76 (95% CI 1.19-2.60). Because the study was conducted in women 65-79 years of age, it is unclear whether these results apply to younger postmenopausal women (see [Geriatric Use] ).
5. Effect during pregnancy <br Estrogen should not be used during pregnancy (see [Contraindications] and [Medication for pregnant and lactating women] ).
6. Gallbladder disease < br It has been reported that postmenopausal women undergoing ERT / HRT have a 2-4 times increased risk of gallbladder disease requiring surgery.
7. Hypercalcemia < br Taking estrogen can cause severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, stop using this medicine and take appropriate measures to lower blood calcium levels.
8. Visual abnormalities < br There have been reports of retinal vascular thrombosis in estrogen users. If sudden or partial vision loss occurs, or sudden exophthalmos, diplopia, or migraine occur, medication should be discontinued and carefully treated. Examination. If the examination reveals optic nerve papillary edema or retinal vascular disease, the use of estrogen should be stopped immediately.
B. General Precautions 1. Physical Examination < br Before starting or resuming ERT / HRT, the patient's medical history and family history should be fully collected, and a full physical examination and gynecological examination should be performed. Pay attention to contraindications and warnings and start treatment Pregnancy should be excluded before, and women undergoing ERT / HRT should be checked regularly and the pros and cons carefully evaluated.
2. Women with a uterus should add progestin Studies have shown that in the cycle of estrogen, add progestin for 10 days or more, or take progestin with estrogen every day, and use it alone Compared with estrogen, the incidence of endometrial hyperplasia is reduced. Endometrial hyperplasia may be a precursor to endometrial cancer.
In a group of WHI studies (see [Clinical Trials] ), after an average of 5.2 years of treatment with estrogen / progestin, their endometrial cancer risk did not increase compared to placebo.
However, there may also be risks associated with estrogen / progestin use compared to estrogen alone. These include: may increase the risk of breast cancer; adverse effects on lipoprotein metabolism (eg, lowering high density lipoprotein (HDL), increasing low density lipoprotein (LDL), and impaired glucose tolerance.
3. Elevated blood pressure < br According to a small number of cases, the significant increase in blood pressure during estrogen replacement may be due to a specific response to estrogen. In a large-scale, randomized, placebo-controlled clinical trial, no effect of estrogen therapy on blood pressure was found. During estrogen use, blood pressure should be checked regularly.
4. Hypertriglyceridemia <br Women with hypertriglyceridemia have rare reports of pancreatitis when taking estrogen. Therefore, women who have already suffered from hypertriglyceridemia should pay close attention and follow up.
5. Liver insufficiency and history of cholestatic jaundice <br For patients with liver insufficiency, estrogen metabolism is very poor. It should be used with caution in patients with a history of estrogen-related cholestatic jaundice or pregnancy-related cholestatic jaundice. Patients with relapses should discontinue medication.
6. Hypothyroidism Taking estrogen can cause an increase in thyroid binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increase in TBG by secreting more thyroid hormones, thereby maintaining free T3 and T4 in plasma at normal levels. Patients who rely on thyroxine replacement therapy may need to increase their thyroid hormone if they also take estrogen. These patients need to monitor thyroid function to ensure that their free thyroid hormone levels remain within acceptable limits. (See [Notes]-Drug / Laboratory Interaction )
7.Body fluid retention < br Because estrogen / progestin can cause fluid retention to a certain extent, patients who may be affected by this factor, such as patients with cardiac and renal insufficiency, should be carefully observed if estrogen is prescribed.
8. Hypocalcemia <br Patients with severe hypocalcemia should use estrogen with caution.
9. Endometriosis worsens HRT / ERT may worsen endometriosis.
For patients with known residual ectopic endometrium after hysterectomy, the use of progestin should also be considered. Because there are reports of malignant lesions treated with estrogen alone after hysterectomy.
10. Uterine bleeding < br Some patients may have abnormal uterine bleeding (see Endometrial Cancer).
11. Other exacerbations < br Estrogen causes exacerbations of the following diseases, including asthma, diabetes, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangioma, etc. Patients with the above symptoms Should be used with caution.
C. Laboratory tests < br To alleviate the symptoms of moderate to severe vasoconstriction in postmenopausal women and to alleviate moderate and severe vulvar and vaginal atrophy after menopause, treatment with estrogen should start with the lowest therapeutic dose and then based on clinical response, not Adjust the dose based on serum hormone levels (such as estradiol and follicle stimulating hormone). Laboratory parameters can be used to guide the therapeutic dose required to treat insufficient estrogen secretion due to hypogonadism, ovarian resection, and ovarian failure.
D. Drug / Laboratory Interactions Accelerating prothrombin time, part of prothrombin kinase time and platelet time; increasing platelet count, increasing factor , factor antigen, factor antigen, factor coagulation factor activity, factor , X, , factor -X , --X, and -thromboglobulin; reduced factor anti-Xa antithrombin III levels, reduced antithrombin III activity, increased fibrinogen content and activity, and increased fibrinolysis Zymogen antigen and activity.
2. Elevated TBG results in an increase in total thyroid hormone levels measured by protein-bound iodine (PBI) in the circulation, increasing either T ₄ (by columnar aspiration or radioimmunoassay) or T ₃ (radioimmunoassay). Re-uptake of T ₃ resin was reduced, reflecting an increase in TBG. Free T ₄ and free T ₃ concentrations were unchanged. Patients with thyroxine replacement therapy may require higher doses of thyroid hormone.
3 The increase of other binding proteins in serum, such as corticosteroid-binding globulin (CBG) and gonadal hormone-binding globulin (SHBG), leads to an increase in the total amount of corticosteroids, gonadal circulation, and free hormone concentrations. Other plasma proteins (angiotensinogen / renin substrate, alpha-1-antiinsulin, plasma ceruloplasmin) may increase.
4 HDL and HDL ₂ cholesterol levels increased in plasma, LDL cholesterol levels decreased, and triglyceride levels increased.
5. Impaired glucose tolerance.
6. The response to the mepyridone test decreased.

Combination with estrogen tablets for pregnant and lactating women

Premel® should not be used in pregnant women. (See [taboo])
Taking estrogen can reduce the quality and quantity of milk. Estrogen can be detected in the mother's milk. Lactating women should not use estrogen.

Combination estrogen tablets for children

Although estrogen has been used to treat adolescents with adolescent growth retardation to induce pubertal development, safety and effectiveness of medication for children have not been established.
Prolonged high-dose, repeated administration of estrogen will accelerate epiphyseal closure. For normal developing children, if the medication is administered before the completion of physiological puberty, it may lead to short stature. If patients take estrogen before bone development is complete, it is recommended to monitor their effects on bone maturity and epiphyseal center periodically during the medication.
Adolescent girls receiving estrogen treatment can also cause premature breast development and vaginal keratinization, and may cause vaginal bleeding. Boys receiving estrogen therapy can alter the usual puberty process and cause feminization of the boy's breasts. (See [Indications] and [Dosage and Administration])

Combination estrogen tablets for elderly

Of all subjects in the WHI-Estrogen Subgroup Study, 46% (n = 4943) were 65 years of age and older, and 7.1% (n = 767) were 75 and older. Premel® has a relative risk of stroke after medication compared with placebo.
In the WHI estrogen / progestin subgroup study, 44% of the subjects (n = 7320) were aged 65-74 years, and 6.6% (n = 1095) were 75 years and older. Elderly individuals aged 75 years or older observed a higher relative risk of non-fatal stroke and invasive breast cancer after medication than younger subjects. An increase in the risk of non-lethal stroke and invasive breast cancer compared with placebo was observed in women over 75 years of age compared to placebo, with 75 cases versus 24 cases per 10,000 women per year and 52 cases versus Twelve cases per 10,000 women per year.
In the WHI-WHIMS estrogen subgroup study alone, 2947 women with uterine resection (aged 65-79) were randomized to take 0.625 mg of Bemeric® or placebo daily: 81% (n = 2383) was 65 -74 years, 19% (n = 564) were 75 years or older. About 50% of women have not used ERT before. After an average of 5.2 years of follow-up, the absolute risk of probable dementia in the estrogen alone group was 37 cases per 10,000 women per year, compared with 25 cases per 10,000 women in the placebo group (RR 1.49, 95% CI 0.83-2.66). (See [Notes] -Police, Dementia)
In the WHIMS combined estrogen / progestin subgroup study, 4,532 postmenopausal women (aged 65 years) were randomly assigned to take estrogen plus progestin (0.625mg / 2.5mg) or placebo. Among subjects aged 65-74, 82% (n = 3729), and those aged 75 and over accounted for 18% (n = 803). Most women (80%) have never used HRT before. After an average follow-up of 4 years, the absolute risk of developing dementia in the estrogen plus progestin group was 45 cases per 10,000 women per year, compared to 21 cases per 10,000 women in the placebo group (RR 2.05, 95 % CI 1.21-3.48). (See [Notes] -Police, Dementia)
Alzheimer's is a common classification of probable dementia in both treatment and placebo groups. In the CEE group, 79% of cases of dementia occurred in women over 70 years of age. In the CEE plus MPA group, women over 70 years of age developed probable dementia, accounting for 82% of all cases of probable dementia (see [Caution]-Warning, dementia).
Summarizing data from participants in the Premel® or Predominant® group, compared with the placebo group, the absolute risk of dementia using ERT or HRT is 41 cases per 10,000 women per year, corresponding to the placebo group For 23 cases per 10,000 women per year (RR 1.76, 95% CI 1.19-2.60). Given that both sub-studies targeted women aged 65-79, it is unclear whether the above results apply to younger postmenopausal women. (See [Precautions] -Warning, Dementia)
Regarding the effectiveness of the approved indications, a sufficient number of older patients have not been studied to confirm whether older persons over 65 years respond differently to premature compared to younger subjects.

Drug interactions in combination with estrogen tablets

Single-dose drugs (including combinations of estrogen and medroxyprogesterone acetate) -drug interaction studies have shown that pharmacokinetic release does not change when these two drugs are taken simultaneously. No other estrogen-related drugs have been studied clinically.
In vitro and in vivo studies have shown that estrogen is partially metabolized by cytochrome P450 3A4 (CYP3A4). Therefore, both CYP3A4 inducers and inhibitors can affect the metabolism of estrogen drugs. CYP3A4 inducers such as St. John's wort extract (Forsythia suspensa), phenobarbital, carbamazepine, and rifampicin can all reduce estrogen plasma concentrations, which can lead to reduced treatment effects and / or uterine bleeding. Inhibitors of CYP3A4 such as erythromycin, clindamycin, ketoconazole, itramycin, ritonavir, and grapefruit juice can increase estrogen plasma concentrations and cause adverse reactions.

Overdose in combination with estrogen tablets

In adults and children, symptoms of overuse of estrogen-containing drugs include: nausea, vomiting, breast tenderness, dizziness, abdominal pain, lethargy / fatigue; withdrawal bleeding in women. There is no special antidote, and symptomatic treatment should be taken when necessary.

Clinical trials with estrogen tablets

Women's Health Action Study < br Women's Health Action (WHI) enrolled approximately 27,000 mostly healthy postmenopausal women into two subgroup studies to evaluate the combination of estrogen (CEE) compared to placebo [Premier Daily 0.625mg] The risks and benefits of using alone or in combination with medroxyprogesterone acetate (MPA) (0.625mg / 2.5mg per day). The primary endpoint was the incidence of coronary heart disease (CHD). Such as non-fatal myocardial infarction (MI), asymptomatic myocardial infarction and coronary heart disease death. The primary safety endpoint was the incidence of invasive breast cancer. This subgroup study did not assess the effect of hormone replacement therapy on menopausal symptoms.
The estrogen monotherapy group was discontinued because an increased risk of stroke was observed, and no further information on the risks and benefits of estrogen alone was obtained at the pre-set primary endpoint. The estrogen alone study included a total of 10,739 women (ages 50-79, average 63 years old: 75.3% were white, 15.1% were black, 6.1% were Hispanic, and 3.6% were others). The average follow-up is 6.8 years. 1.
In the WHI estrogen alone group, the relative risk of CHD (RR 0.95, 95% nominal confidence interval [nCI] 0.79-1.16) overall had no significant effect. A slight increase in the relative risk of CHD was reported early in the follow-up and disappeared over time. No significant effect was reported on the relative risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04) into colorectal cancer (RR 1.08, 95% nCI 0.75-1.55). Estrogen use was associated with a statistically significant increase in the risk of stroke (RR 1.37, 95% nCI, 1.09-1.73) and deep vein thrombosis (DVT) (RR 1.47, 95% nCI 1.06-2.06), and the relative risk of PE (RR 1.37, 95% nCI, 0.90-2.07) without significant increase. Significantly reduced risk of hip fractures (RR 0.61, 95% nCI 0.41-0.91) and spinal fractures (RR 0.62, 95% nCI, 0.42-0.93) with estrogen reported (RR 0.70, 95% nCI 0.63-0.79) . Estrogen alone did not report a significant effect on deaths from other causes (RR 1.08, 95% nCI 0.88-1.32) or a significant effect on overall mortality risk (RR 1.04, 95% nCI 0.88-1.22). No confidence interval was adjusted for multiple observations and comparisons.

a Uncorrected nominal confidence intervals for multiple observations and multiple comparisons.
b Results are based on centrally confirmed data after a mean follow-up of 7.1 years.
c Results are based on data after a mean follow-up of 6.8 years.
d Excludes all deaths from breast or colon or colorectal cancer, definitely / probably CHD, PE, or cerebrovascular disease.
After a mean follow-up of 7.1 years, CHD events from the estrogen-only subgroup were finally confirmed and no results were reported for women with CEE alone compared with the placebo group. There are overall differences.
The estrogen plus progestin study was also terminated early. Following a pre-specified discontinuation principle, the increased risk of breast cancer and cardiovascular events after an average follow-up of 5.2 years outweighed specific benefits (such as a reduction in colorectal cancer and hip fractures). The WHI estrogen plus progestin subgroup study included 16,608 women (ages 50-79, average 63 years; 83.9% were white, 6.8% were black, 5.4% were Hispanic, and 3.9% were others) with an average follow-up of 5.6 years The results are shown in Table 2. These results reflect centrally corroborated data after a mean follow-up of 5.6 years.
In the WHI estrogen plus progestin group study, increased CHD risk was associated with combined hormone therapy (RR 1.24, 95% nCI 1.00-1.54). This increase in risk was most pronounced in the first year of the study (RR 1.81, 95% nCI 1.09-3.01). Increased risk of invasive breast cancer (RR 1.24, 95% nCI 1.01-1.54) in women treated with combination hormones. This subgroup study also reported a significant increase in the relative risk of the disease, all strokes (RR 1.31, 95% nCI 1.02-1.68), ischemic strokes (RR 1.44, 95% nCI 1.09-1.90), and DVT (RR 1.95, 95% nCI 1.43-2.67) and PE (RR 2.13, 95% nCI 1.45-3.11). After 3 years, estrogen plus progestin was found to increase bone density compared to placebo (3.7% vs. 0.14%, P <0.01). The significant reduction in the relative risk of the following diseases is related to the use of estrogen plus progestin, hip fracture (RR 0.67, 95% nCI 0.47-0.96), spine fracture (RR 0.65, 95% nCI 0.46-0.92), and forearm / wrist fracture ( RR 0.71, 95% nCI 0.59-0.85) and total fractures (RR 0.76, 95% nCI 0.69-0.83).
Estrogen plus progesterone was associated with a significantly reduced risk of invasive colorectal cancer (RR 0.56, 95% nCI 0.38-0.81), although colorectal cancer was diagnosed by combined hormone users, and the disease was relatively advanced. Additional analysis showed no significant difference in the relative risks of combined hormone replacement compared to placebo for endometrial cancer (RR 0.81, 95% nCI 0.48-1.36) or cervical cancer (RR 1.44, 95% nCI 0.47-4.42). After an average follow-up of 5.2 years, the estrogen plus progestin subgroup did not report a significant effect on deaths from other causes (RR 0.92, 95% nCI 0.74-1.14) or a significant effect on overall mortality risk (RR 0.98, 95 % nCI 0.82-1.18). Multiple observations and multiple comparisons did not correct the confidence interval.

a Results are based on centrally validated data. Mortality data are not conclusive; however, for all causes of death in each group, the data at 5.2 years of follow-up did not differ (RR 0.98, 95% nCI 0.82-1.18).
b Nominal confidence intervals are not adjusted for multiple observations and multiple comparisons.
c Includes metastatic and non-metastatic breast cancers (except breast cancer in situ)
Women 's Healthy Action Memory Study <br Women's Healthy Action Memory Study (WHIMS), a subsidiary study of WHI, a group of 4532 women aged 65-79 years were randomly assigned to CEE plus MPA (0.625mg / 2.5mg per day) Or the placebo group. The second cohort of WHIMS was 2947 women 65-79 years of hysterectomy who were randomly assigned to receive CEE (0.625 mg per day) or placebo. After an average follow-up of 4 years, the reported relative risk of possible dementia was 2.05 (95% CI 1.21-3.48) compared to placebo in the estrogen plus progestin group. In the estrogen alone group, after a mean follow-up of 5.2 years, the relative risk of probable dementia compared to placebo was 1.49 (95% CI 0.83-2.66). Aggregating data from the two populations as planned in the WHIMS programme, the total reported relative risk of possible dementia was 1.76 (95% CI 1.19-2.60). Because the study was conducted in women aged 65-79, it is unclear whether these results apply to younger postmenopausal women. (See [Precautions] -Warning, Dementia )
Effect on vasomotor symptoms Health and osteoporosis, progesterone and estrogen (HOPE) study in the first year, a total of 2805 postmenopausal women (average age 53.3, ± 4.9 years) were randomly divided into eight treatment groups, Receive placebo or estrogen combined with medroxyprogesterone acetate or estrogen alone. A subgroup of symptomatic women (n = 241) was evaluated for their effect on vasomotor symptoms during the first 12 weeks of treatment. This group of women had at least 7 moderate to severe hot flashes or There were at least 50 moderate to severe hot flashes per week.
At 4 and 12 weeks, Premel (0.3mg and 0.625mg tablets) was better than placebo in the frequency and extent of relieving the symptoms of moderate to severe vasomotor symptoms, and the difference was statistically significant. Table 3 lists the average number of adjusted hot flashes for Premel 0.3mg and 0.625mg and placebo-treated groups during the first 12 weeks.
table 3. Summary list of hot flashes per day-average and comparison of active drug treatment group and placebo group:
Patients have at least 7 times a day at baseline or at least 50 times a week with moderate to severe hot flashes, carryover (LOCF)

Note: CE is combined with estrogen a: covariance analysis was performed with treatment as the influencing factor and baseline as the covariate.
The effects of vulvar and vaginal atrophy were in the 6th and 13th week. All vaginal maturity indices of all treatment groups (the combination of estrogen alone and the combination of estrogen and medroxyprogesterone acetate) were compared with placebo There were statistically significant differences (P <0.001).
Impact on Bone Mineral Density HOPE Study The HOPE Study is a double-blind, randomized, placebo / active drug controlled, multicenter study of healthy postmenopausal women with intact uterus. Subjects (mean age 53.3 ± 4.9 years) had an average menopausal age of 2.3 ± 0.9 years, taking one calcium tablet (calcic) containing 600mg of calcium per day. Subjects were not supplemented with vitamin D. They received premature 0.625mg, 0.45mg, 0.3mg or placebo, respectively. The prevention of bone loss is evaluated by measuring bone mineral density (8MD), mainly by measuring the lumbar spine (L2 to L4) from the anterior and posterior positions. Secondly, the BMD of the whole body is also tested, and the BMD of the femoral neck and femoral trochanter is also analyzed. In cycles 6, 13, 19, and 26, serum osteocalcin, urinary calcium, and N-terminal peptides were used as indicators of bone turnover (BTM).
At 6, 13, 19, and 26 cycles in intent-to-treat subjects, all active drug treatment groups had significant differences compared to the placebo group at all four BMD endpoints. In the final treatment evaluation (the 26th cycle of the completer and the last evaluation provided by the early exiter), the average percentage increase in the primary efficacy index (L2-L4BMD) was 2.46% in the 0.625mg group and 0.46% in the 0.45mg group. 2.26% and 0.33% in the 0.3mg group. At the end of the assessment, the placebo group had an average percentage decrease of 2.45% from baseline. These results indicate that low-dose Premeril is effective in increasing B2 to L4 BMO compared to placebo and therefore supports the effectiveness of low-dose.
Analysis of the endpoints of the other three BMDs showed that the changes in the average percentage of the femoral trochanter relative to baseline were greater than those in L2-L4, while the changes in the average percentage of the femoral neck and body were smaller than those in L2-L4. Significant differences between the groups suggested that each dose of Premel® was more effective than placebo for the other three BMD endpoints. In femoral neck and systemic BMD, the active drug-treated group showed an increase in average percentages, while the placebo group decreased. In the femoral trochanter, the average percentage increase in each Predominant dose group was significantly greater than the small increase in the placebo group. The percentage change of the final assessment from the baseline is shown in Table 4.
Table 4. Percentile change in bone mineral density (BMD) between active drug-treated and placebo groups in intent-to-treat populations, carried forward (LOCF)

a: Differentiated according to the dose (mg) of predominant or placebo. Figure 1 shows the cumulative percentage of subjects whose change from baseline is equal to or greater than the X-axis value.
figure 1. Cumulative percentage of subjects with predominantly BMI and placebo changes in vertebral BMD compared to baseline

The average percentage change and standard error line of L2 to L4BMD from baseline in women who completed the BMD study in each treatment group are shown in Figure 2. At 6, 13, 19, and 26 cycles, there were significant differences between each of the prednisone dose and placebo groups.
figure 2. For subjects who have completed Premarin and placebo, the mean percentage change in BMD of the vertebral body after each cycle relative to baseline correction (SE)

At 6, 13, 19, and 26 cycles, compared with the placebo group, all doses of the Premel® treatment group had significantly reduced serum osteocalcin and urine N-terminal peptides (p <0.001). The mean decrease in osteocalcin and urine N-terminal peptides from baseline was greater in the Premel® group than in the placebo group. Significant differences in urinary calcium were rare compared to the placebo group.

Pharmacology and toxicology with estrogen tablets

Pharmacological effects Endogenous estrogen mainly contributes to the development and maintenance of female reproductive system and secondary sexual characteristics. Try to circulate estrogen in a dynamic equilibrium of metabolic conversion, but estradiol is the main estrogen in human cells and is more effective at the receptor level than its metabolites estrone and estriol.
In adult women with normal menstrual cycles, follicles are the main source of estrogen, and 70 to 500 mcg of estradiol is secreted every day, depending on the menstrual cycle they are in. After menopause, endogenous estrogens are mainly produced by conversion of androstenedione, which is secreted by the adrenal cortex. Androstenyl glycol is converted to estrone in peripheral tissues. Therefore, in postmenopausal women, estrone and its combined sulfate form, estrone sulfate, are the most important circulating estrogen.
In tissues that respond to estrogen, estrogen works by binding to nuclear receptors. At present, two types of estrogen receptors have been identified. These receptors are distributed differently in different tissues.
Circulating estrogen regulates the secretion of pituitary gonadotropin-luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. In postmenopausal women, estrogen can reduce these elevated gonadotropin levels.
 ,

®52×0.3mg2×0.625mg

SHBG

Store at room temperature (10-30 ° C).

142

36 months.

JX20050051 ^[1]