Instructions for use Femoston conti film-coated tablets 1 mg/5 mg blister No. 28
Composition
active ingredients: estradiol; dydrogesterone;
1 tablet contains estradiol hemihydrate, micronized, equivalent to estradiol 1 mg; dydrogesterone, micronized 5 mg;
excipients: lactose monohydrate; hypromellose (HPMC 2910), corn starch, colloidal anhydrous silica, magnesium stearate;
film coating: mixed film coating Orange I (polyethylene glycol 400, hypromellose (HPMC 2910), iron oxide yellow (E 172), iron oxide red (E 172), titanium dioxide (E 171)).
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex, film-coated orange-pink tablet marked "379" on one side. Diameter 7 mm and tablet weight approximately 144 mg.
Pharmacotherapeutic group
Preparations for the treatment of diseases of the genitourinary system and sex hormones. Progestogens in combination with estrogens. Dydrogesterone and estrogen. ATX code G03F A14.
Pharmacological properties
Pharmacodynamics
Estradiol
The active ingredient 17ß-estradiol is chemically and biologically similar to the natural female sex hormone estradiol. It replaces the loss of estrogen production in women during menopause and relieves menopausal symptoms.
Estrogens prevent bone loss after menopause or oophorectomy.
Dydrogesterone
Dydrogesterone is an orally active progestogen whose effects are comparable to those of parenterally administered progesterone.
Because estrogens stimulate endometrial growth, if not used with a progestogen, they increase the risk of endometrial hyperplasia and carcinoma. The addition of a progestogen to therapy significantly reduces the estrogen-induced risk of endometrial hyperplasia in women with an intact uterus.
Clinical trial data
Reducing symptoms of estrogen deficiency and improving the bleeding profile.
A reduction in menopausal symptoms was observed during the first few weeks of treatment.
Amenorrhea (no bleeding or spotting) was observed in 88% of women during months 10-12 of treatment. Irregular bleeding and/or spotting occurred in 15% of women during the first 3 months of treatment and in 12% during months 10-12 of treatment.
Osteoporosis prevention
Estrogen deficiency after menopause is associated with increased bone resorption and decreased bone mass. The effect of estrogens on bone density is dose-dependent. The protective effect of estrogens is only effective during their use. After discontinuation of hormone replacement therapy (HRT), the rate of bone loss is the same as in women who did not receive the therapy.
Data from the Women's Health Initiative (WHI) trial and meta-analyses of other studies suggest that the use of HRT in predominantly healthy women, either as estrogen monotherapy or in combination with a progestogen, reduces the risk of hip, vertebral, and other types of fractures due to osteoporosis. HRT may also prevent fractures in women with low bone density and/or known osteoporosis, but the data on this are limited.
After one year of treatment, bone density in the lumbar spine increased by approximately 4.0% ± 3.4% [mean ± standard deviation (SD)]. In 90% of patients, bone density increased or remained unchanged during treatment.
FEMOSTON®CONTI also affected bone density in the femur. After one year of treatment with FEMOSTON®CONTI, bone density in the femoral neck was 1.5% ± 4.5% (mean ± SD), in the trochanter – 3.7% ± 6.0% (mean ± SD) and in the Ward's triangle – 2.1% ± 7.2% (mean ± SD).
The percentage of women who maintained or increased bone density in these three areas of the femur after treatment with FEMOSTON®CONTI was 71%, 66% and 81%, respectively.
Pharmacokinetics
Estradiol
Absorption
The absorption of estradiol depends on particle size: micronized estradiol is rapidly absorbed from the gastrointestinal tract.
The table presents the average steady-state pharmacokinetic parameters of estradiol (E2), estrone (E1), and estrone sulfate (E1S) for each dose of micronized estradiol.
Data are presented as mean (SD).
Estradiol 1 mg
| E2 | E1 | Parameters | E1S |
| Cmax (pg/mL) | 71 (36) | 310 (99) | Cmax (ng/mL) | 9.3 (3.9) |
| Cmin (pg/mL) | 18.6 (9.4) | 114 (50) | Cmin (ng/mL) | 2,099 (1,340) |
| Cav (pg/mL) | 30.1 (11.0) | 194 (72) | Cav (ng/ml) | 4,695 (2,350) |
| AUC0-24 (pg.h/mL) | 725 (270) | 4767 (1857) | AUC0-24 (ng.h/ml) | 112.7 (55.1) |
Distribution
Estrogens can be found in an unbound or bound state. About 98–99% of an estradiol dose is bound to plasma proteins, of which 30–52% is bound to albumin and about 46–69% to sex hormone binding globulin (SHBG).
After oral administration, estradiol is extensively metabolized. The major unconjugated and conjugated metabolites are estrone and estrone sulfate. These metabolites may play a role in estrogenic activity directly or after conversion to estradiol. Estrone sulfate may undergo enterohepatic circulation.
Breeding
In urine, the main compounds are glucuronides of estrone and estradiol. The half-life is from 10 to 16 hours. Estrogens penetrate into breast milk.
Dose and time dependence
With daily oral administration of the drug, estradiol concentrations reach steady state after approximately 5 days. In most cases, steady state concentrations are reached between 8 and 11 days of administration.
Dydrogesterone
Absorption
After oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral dose of 20 mg compared to intravenous infusion of 7.8 mg) is 28%.
The following table presents the mean steady-state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DH) at steady-state. Data are presented as mean (SD).
Dydrogesterone 5 mg
| D | DHD |
| Cmax (ng/mL) | 0.90 (0.59) | 24.68 (10.89 |
| AUC0-t (ng*h/mL) | 1.55 (1.08) | 98.37 (43.21) |
| AUCinf (ng*h/ml) | - | 121.36 (63.63) |
Distribution
After intravenous administration of dydrogesterone, the steady-state volume of distribution is approximately 1400 L. Dydrogesterone and DHD are more than 90% bound to plasma proteins.
Biotransformation
After oral administration, dydrogesterone is rapidly metabolized to DHD. The levels of the main active metabolite 20α-dihydrodydrogesterone (DHD) peak approximately 1.5 hours after administration. DHD plasma levels are generally higher than those of the parent drug. The AUC and Cmax ratios of DHD and dydrogesterone are approximately 40 and 25, respectively. The mean terminal half-lives of dydrogesterone and DHD range from 5–7 and 14–17 hours, respectively.
A common property of all metabolites is the preservation of the 4,6-dien-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the lack of estrogenic and androgenic effects of dydrogesterone.
Breeding
After oral administration of labeled dydrogesterone, an average of 63% of the dose is excreted in the urine. Total plasma clearance is 6.4 l/min. Complete elimination occurs within 72 hours. DHD is present in the urine mainly as a glucuronic acid conjugate.
Dose and time dependence
The pharmacokinetics of single and multiple doses are linear in the oral dose range of 2.5 to 10 mg. Comparison of single and multiple dose kinetics shows that the pharmacokinetics of dydrogesterone and DHD do not change with repeated administration. Steady state was achieved after 3 days of treatment.
Indication
Hormone replacement therapy (HRT) to eliminate symptoms caused by estrogen deficiency in women during menopause, no earlier than 12 months after the last menstruation.
Prevention of osteoporosis in postmenopausal women at high risk of fractures. FEMOSTON® CONTI should be used in patients only in case of intolerance or contraindications to the use of other drugs for the prevention of osteoporosis (see section "Special instructions").
Experience in treating women over 65 years of age is limited.
Contraindication
Known, present or suspected breast cancer; known or suspected estrogen-sensitive tumors (e.g. endometrial cancer); known or suspected progestogen-sensitive tumors (e.g. meningioma); unexplained vaginal bleeding; untreated endometrial hyperplasia; current or history of venous thromboembolism (deep vein thrombosis, pulmonary embolism); presence of thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, see section "Special warnings and precautions for use");
Acute or recent thromboembolic arterial disease (e.g. angina pectoris, myocardial infarction); Acute liver disease or a history of liver disease if liver function tests have not returned to normal; Porphyria; Known hypersensitivity to the active substances or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other types of interactions
Drug interaction studies have not been conducted.
The effectiveness of estrogens and progestogens may be impaired.
The metabolism of estrogens (and progestogens) may be enhanced by concomitant use of substances that can induce enzymes involved in drug metabolism. This applies in particular to the P450 enzymes 2B6, 3A4, 3A5, 3A7. Such substances include anticonvulsants (phenobarbital, carbamazepine, phenytoin) and antibacterial/antiviral agents (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Herbal preparations containing St. John's wort (Hypericum perforatum) may also enhance the metabolism of estrogens (and progestogens) when metabolized by CYP450 3A4.
Clinically, increased metabolism of estrogens and progestogens may be expressed in reduced efficacy and altered bleeding profiles.
Estrogens may interfere with the metabolism of other drugs
Estrogens may inhibit CYP450 enzymes involved in drug metabolism by competitive inhibition. This should be considered especially for drugs with a narrow therapeutic index, such as:
tacrolimus and cyclosporine A (CYP450 3A4, 3A3); fentanyl (CYP450 3A4); theophylline (CYP450 1A2).
Clinically, this may result in increased plasma levels of such substances to toxic concentrations. Thus, careful monitoring of drug levels over a long period of time may be required, as well as dose reduction of tacrolimus, fentanyl, cyclosporine A, and theophylline.
Application features
For the treatment of symptoms of estrogen deficiency in postmenopausal women, HRT should only be initiated if these symptoms significantly adversely affect quality of life. The benefits and risks of HRT should be carefully assessed regularly, at least annually, and treatment should only be continued if the benefits outweigh the risks.
Data on the risks associated with HRT in the treatment of premature menopause are limited. However, due to the low absolute risk in younger women, the benefit-risk ratio is more favourable in these women than in older women.
Medical examination/follow-up
Before starting HRT or when restarting HRT after a break, a complete medical history (including family history) should be taken. A physical examination (including gynaecological and breast examination) should be performed, taking into account the medical history, contraindications and precautions for use. Regular check-ups are recommended during treatment, the frequency and extent of which should be determined individually. Women should be advised of any changes in their breasts that they should report to their doctor or nurse (see section below on Breast Cancer). Examination, including appropriate imaging techniques such as mammography, should be carried out in accordance with current screening practice, modified according to individual clinical needs.
Diseases in which it is necessary to monitor the condition of patients
Patients with any of the following conditions, present or past, and/or aggravated during pregnancy or previous hormonal therapy, should be closely monitored. It should be borne in mind that these conditions may recur or worsen during treatment with FEMOSTON® CONTI. These include:
leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic diseases (see below); risk factors for estrogen-sensitive tumors, such as a first-degree hereditary predisposition to breast cancer; arterial hypertension; liver disease (e.g., hepatic adenoma); diabetes mellitus with or without vascular complications; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; history of endometrial hyperplasia (see below); epilepsy; bronchial asthma; otosclerosis; meningioma.
Reasons for immediate discontinuation of therapy
Hormone replacement therapy should be discontinued immediately if a contraindication is identified, as well as in the following situations:
the appearance of jaundice or impaired liver function; a significant increase in blood pressure; the appearance of a migraine-like headache for the first time; pregnancy.
Endometrial hyperplasia and carcinoma
In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased with prolonged use of estrogen-only HRT. The observed increased risk of endometrial cancer in women taking estrogen-only HRT ranges from 2- to 12-fold compared with those not taking estrogen, depending on the duration of treatment and the dose of estrogen (see section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years.
Cyclical combination of estrogen with progestogen for at least 12 days per month/per 28-day cycle or continuous combined estrogen-progestogen therapy in women with a preserved uterus avoids the excess risk associated with estrogen alone.
Breakthrough uterine bleeding or spotting may occur during the first months of treatment. If this occurs some time after starting treatment or persists after stopping therapy, the cause should be investigated. This may include endometrial biopsy to exclude malignancy.
Breast cancer
All available evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestogen HRT or oestrogen-only HRT. This risk depends on the duration of use.
Both the randomised placebo-controlled Women's Health Initiative Study (WHI) and a meta-analysis of prospective epidemiological studies have consistently shown an increased risk of breast cancer in women using combined oestrogen-progestagen HRT. The increased risk becomes apparent after approximately 3 (1-4) years (see section 4.8).
Estrogen monotherapy
The WHI trial did not find an increased risk of breast cancer in hysterectomised women taking oestrogen-only HRT. Pilot studies have mostly reported a small increased risk of breast cancer, which is significantly lower than in patients taking combinations of oestrogens and progestogens (see section 4.8).
The results of a large meta-analysis showed that after stopping treatment, the increased risk will decrease over time, and the time taken to return to baseline depends on the duration of previous HRT use. In cases where HRT has been used for more than 5 years, the risk may persist for 10 years or longer. Treatment with HRT, especially combined estrogen-progestagen therapy, increases the density of mammographic images, which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much less common than breast cancer. Epidemiological data from a large meta-analysis have shown a slightly increased risk in women using oestrogen-only or combined oestrogen-progestagen hormone replacement therapy; this risk becomes apparent within 5 years of use and decreases over time after discontinuation of therapy. Some other studies, including the WHI study, suggest that the use of combined HRT may be associated with the same or a slightly lower risk (see section 4.8).
Venous thromboembolism
HRT is associated with a 1.3- to 3-fold increased risk of venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. This is most likely to occur during the first year of HRT use rather than later (see section 4.8).
Patients with known thrombophilic conditions are at increased risk of VTE, and HRT may further increase this risk. Therefore, hormone replacement therapy is contraindicated in this group of patients (see section 4.3).
The generally accepted risk factors for VTE are: estrogen use, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus on the role of varicose veins in the development of VTE. As for all post-operative patients, precautions should be taken to prevent VTE after surgery. If prolonged immobilisation is expected after elective surgery, it is recommended that HRT be temporarily discontinued 4-6 weeks before surgery. Treatment should only be resumed when the woman has regained full mobility.
Women without a history of VTE but with a first-degree relative who has had thrombosis at a young age may be offered screening after careful discussion of its limitations (screening only detects a subset of thrombophilic disorders).
If a congenital thrombophilic disorder is identified, accompanied by a family history of thrombosis, or if the disorder is severe (e.g., antithrombin, protein S, or protein C deficiency, or a combination of disorders), HRT is contraindicated.
In women already taking regular anticoagulant therapy, the benefits and risks of HRT should be carefully weighed.
If VTE develops after initiation of therapy, the drug should be discontinued immediately. Patients should be advised to seek immediate medical attention if they develop potential symptoms of thromboembolism (e.g., painful swelling of a leg, sudden chest pain, shortness of breath).
Coronary heart disease (CHD)
There is no evidence from randomized controlled trials of protection against myocardial infarction in women with or without coronary heart disease who took combined estrogen-progestogen HRT or estrogen-only HRT.
Combined estrogen-progestogen therapy
The relative risk of CHD with combined estrogen-progestogen HRT is slightly increased. Since the baseline absolute risk of CHD is largely age-dependent, the number of additional cases of CHD due to estrogen and progestogen use is very small in healthy women close to menopause, but will increase with older age.
Estrogen monotherapy
Data from randomized controlled trials have not shown an increased risk of CHD in hysterectomized women taking estrogen monotherapy.
Combined estrogen-progestogen therapy and estrogen monotherapy are associated with an increased risk of ischemic stroke of up to 1.5 times. The relative risk does not change with age or time since menopause. However, as the baseline absolute risk of stroke is largely age-dependent, the overall risk of stroke in women taking HRT will increase with age (see section 4.8).
Other states
Estrogens may cause fluid retention, and patients with impaired cardiac or renal function should be carefully monitored. Women with pre-existing hypertriglyceridemia should be closely monitored during estrogen replacement therapy or hormone replacement therapy, as rarely in women with this condition, plasma triglyceride levels have increased significantly during estrogen treatment, resulting in pancreatitis. Estrogens increase thyroxine-binding globulin (TBG), leading to increased circulating thyroid hormones as measured by protein-bound iodine (PBI), T4 levels (by column assay or radioimmunoassay), or T3 levels (by radioimmunoassay). Triiodothyronine (T3) uptake is reduced as a result of elevated TGB levels. Free triiodothyronine (T3) and thyroxine (T4) concentrations are unchanged. Serum levels of other binding proteins, corticoid-binding globulin (CBG) and sex hormone-binding globulin (SHBG), may increase, leading to increased blood concentrations of corticosteroids and sex hormones. Free or biologically active hormone concentrations are unchanged. Other plasma proteins (angiotensin-renin substrate, alpha-I-antitrypsin, ceruloplasmin) may increase. HRT does not improve cognitive function. There has been some evidence of an increased risk of possible dementia in women who start long-term combined or oestrogen-only HRT after the age of 65.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
FEMOSTON® CONTI is not a contraceptive.
Ability to influence reaction speed when driving vehicles or other mechanisms
FEMOSTON® CONTI has no or negligible influence on the ability to drive or use machines.
Use during pregnancy or breastfeeding
Pregnancy
FEMOSTON®CONTI is not indicated for use during pregnancy. If pregnancy occurs during treatment with FEMOSTON®CONTI, the drug should be discontinued immediately.
There are no adequate data on the use of estradiol/dydrogesterone in women during pregnancy.
The literature has reported that the use of some progestogens has been associated with an increased risk of hypospadias. However, due to confounding factors during pregnancy, it is not possible to definitively determine whether progestogens contribute to the development of hypospadias.
Currently, the results of most epidemiological studies on accidental fetal exposure to combinations of estrogens and progestogens indicate no teratogenic risk or toxic risk to the fetus.
Breast-feeding
FEMOSTON® CONTI is not indicated for use during breastfeeding.
Impact on the ability to get pregnant.
FEMOSTON® CONTI is not indicated for use in women of reproductive age.
Method of administration and doses
FEMOSTON® CONTI should be administered orally daily according to a continuous combined regimen as described below.
Take 1 tablet daily for each 28-day cycle. Each blister is intended for treatment for 28 days. After that, a new cycle should be started immediately. Such consecutive treatment cycles are continuous.
For the treatment of estrogen deficiency in postmenopausal women, the lowest effective dose should be used as the initial and maintenance dose, and the duration of treatment should be as short as possible (see also section "Special warnings and precautions for use").
Continuous combined treatment can be started with FEMOSTON® CONTI depending on the time since menopause and the severity of symptoms. Women who have had a natural menopause can start treatment 12 months after their last menstrual period. Women who have had a surgical menopause can start treatment immediately.
The dose should be individualized based on clinical response.
If a dose is missed, it should be taken as soon as possible. If more than 12 hours have passed, treatment is recommended to continue with the next tablet, without taking the missed tablet. In such cases, the missed tablet may increase the likelihood of breakthrough bleeding or spotting.
FEMOSTON® CONTI can be taken regardless of meals.
Children
The medicine is not intended for use in children.
Overdose
Both estradiol and dydrogesterone are substances of low toxicity. Symptoms of overdose may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue and withdrawal bleeding. It is unlikely that any specific or symptomatic treatment will be required in case of overdose. The information described above also applies to cases of overdose in children.
Adverse reactions
The most common adverse reactions in patients treated with estradiol/dydrogesterone during clinical trials were headache, abdominal pain, breast pain/tenderness, and back pain.
During clinical trials (n = 4929), the following adverse reactions were observed with the following frequencies:
Table 1
| MedDRA system organ classes | Very common, ≥ 1/10 | Common, ≥ 1/100, < 1/10 | Uncommon, ≥ 1/1000, <1/100 | Rare, ≥ 1/10,000 to <1/1,000 |
| Infections and parasitic diseases | | Vaginal candidiasis | Cystitis-like syndrome | |
| Neoplasms benign, malignant and unspecified | | | Increase in the size of the fibroid | |
| Blood and lymphatic system disorders | | | | Hemolytic anemia* |
| On the part of the immune system | | | Hypersensitivity | |
| From the psyche | | Depression, nervousness | Effect on libido | |
| Central nervous system | Headache | Migraine, dizziness | | Meningioma* |
| From the organs of vision | | | | Increased corneal curvature*, contact lens intolerance* |
| From the heart | | | | Myocardial infarction |
| Vascular disorders | | | Venous thromboembolism**, arterial hypertension, peripheral vascular disease, varicose veins | Stroke* |
| Gastrointestinal tract | Abdominal pain | Nausea, vomiting, flatulence | Dyspepsia | |
| Hepatobiliary system | | | Liver dysfunction (in some cases in combination with jaundice, asthenia or malaise and abdominal pain), gallbladder disease | |
| Skin and subcutaneous tissue disorders | | Allergic skin reactions (e.g. rash, hives, itching) | | Angioedema, erythema nodosum*, vascular purpura; chloasma or melasma, which may persist after discontinuation of treatment* |
| Musculoskeletal and connective tissue disorders | Back pain | | | Cramps of the lower extremities* |
| Reproductive system and breast disorders | Breast pain/tenderness | Menstrual disorders (including postmenopausal spotting, metrorrhagia, menorrhagia, oligo/amenorrhea, irregular menstruation, dysmenorrhea) pelvic pain, cervical discharge | Breast enlargement, premenstrual syndrome (PMS) | |
| General disorders and administration site conditions | | Asthenic conditions (asthenia, fatigue, malaise), peripheral edema | | |
| Abnormalities detected during the examination | | Weight gain | Weight loss | |
*Adverse reactions reported from spontaneous reports that were not observed during clinical trials are included in the frequency category "rare".
** See below for details.
Breast cancer risk
An increased risk of breast cancer diagnosis of up to 2 times has been reported in women taking combined estrogen-progestogen HRT for more than 5 years.
The increased risk in women taking estrogen monotherapy is lower than in those women taking combined estrogen-progestogen therapy.
The level of risk depends on the duration of use (see section "Special precautions for use").
Below is an estimate of the absolute risk based on the results of the largest randomized placebo-controlled trial, the Women's Health Initiative (WHI), and the largest meta-analysis of prospective epidemiological studies.
Largest meta-analysis of prospective epidemiological studies
Estimated additional risk of breast cancer after 5 years of use in women with a body mass index of 27 (kg/m2)
| Age at start of HRT (years) | Number of cases per 1000 women who have never used HRT, over a 5-year period (50–54 years)1 | Risk ratio | Number of additional cases per 1000 women using HRT after 5 years |
| HRT with estrogen only | | | |
| 50 | 13.3 | 1.2 | 2.7 |
HRT using a combination of estrogen and progestogen | | | | | 50 | 13.3 | 1.6 | 8.0 |
Note: As the incidence of breast cancer varies in each EU country, the number of additional breast cancer cases will also vary proportionally. 1 Taken from baseline incidence rates in England in 2015 in women with a body mass index of 27 (kg/m2). | | | |
Estimated additional risk of breast cancer after 10 years of use in women with a body mass index of 27 (kg/m2)
| Age at start of HRT (years) | Number of cases per 1000 women who have never used HRT, over a 10-year period (50–59 years)1 | Risk ratio | Number of additional cases per 1000 women using HRT after 10 years |
| HRT with estrogen only | | | |
| 50 | 26.6 | 1.3 | 7.1 |
| HRT using a combination of estrogen and progestogen | | | |
| 50 | 26.6 | 1.8 | 20.8 |
1 Taken from baseline incidence rates in England in 2015 in women with a body mass index of 27 (kg/m2). Note: As the incidence of breast cancer varies in each EU country, the number of additional breast cancer cases will also vary proportionally. | | | |
WHI study in the US – additional risk of breast cancer after 5 years of use
| Age at onset (years) | Number of cases per 1000 women in the placebo group over 5 years | Hazard ratio and 95% confidence interval (CI) | Number of additional cases per 1000 women using HRT for 5 years (95% CI) |
| Hormone replacement therapy with estrogen monotherapy (CTE) | | | |
| 50-79 | 21 | 0.8 (0.7 - 1.0) | -4 (-6-0)2 |
| CCE + MPA combined estrogen-progestogen HRT ‡ | | | |
| 50 - 79 | 17 | 1.2 (1.0-1.5) | +4 (0–9) |
‡ When the analysis was restricted to women who had not used HRT at baseline, there was no clear risk during the first 5 years of treatment: after 5 years the risk was higher than in those who had not taken HRT. 2 WHI studies in women with an absent uterus that did not show an increased risk of breast cancer. CCE – conjugated equine estrogen, MPA – medroxyprogesterone acetate | | | |
Endometrial cancer risk
Postmenopausal women with a retained uterus
The risk of endometrial cancer is about 5 cases for every 1000 women with an intact uterus who are not taking HRT.
Estrogen-only HRT is not recommended for women with an intact uterus, as it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of estrogen monotherapy and the dose of estrogen, the increased risk of endometrial cancer in epidemiological studies has ranged from 5 to 55 additional cases diagnosed in every 1000 women aged 50 to 65 years.
Adding a progestogen to estrogen monotherapy for at least 12 days per cycle may prevent this increased risk. In the Million Women Study, 5 years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer [hazard ratio 1.0 (0.8–1.2)].
Ovarian cancer
Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of ovarian cancer (see section 4.4).
A meta-analysis of 52 epidemiological studies reported an increased risk of ovarian cancer in women who used HRT compared with women who had never used HRT (hazard ratio 1.43, 95% confidence interval (CI) 1.31–1.56). In women aged 50 to 54 years who had used HRT for 5 years, this was
