(British Approved Name, rINN)
Pharmacopoeias. In China, and US. Europe includes the hemihydrate.
European Pharmacopoeia, 6th ed. (Estradiol Hemihydrate). A white or almost white crystalline powder or colourless crystals. Practically insoluble in water sparingly soluble in alcohol soluble in acetone slightly soluble in dichloromethane.
The United States Pharmacopeia 31, 2008 (Estradiol). White or creamy-white, odourless, hygroscopic small crystals or crystalline powder. Practically insoluble in water soluble 1 in 28 of alcohol, 1 in 435 of chloroform, and 1 in 150 of ether soluble in acetone, in dioxan, and in solutions of fixed alkali hydroxides sparingly soluble in vegetable oils. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.
(British Approved Name Modified, US Adopted Name, rINNM)
(British Approved Name Modified, rINNM)
Pharmacopoeias. In China, Europe, Japan, and US.
European Pharmacopoeia, 6th ed. (Estradiol Benzoate). An almost white crystalline powder or colourless crystals. It exhibits polymorphism. Practically insoluble in water sparingly soluble in acetone freely soluble in dichloromethane slightly soluble in methyl alcohol.
The United States Pharmacopeia 31, 2008 (Estradiol Benzoate). A white to off-white, crystalline powder. Insoluble in water soluble in alcohol and in acetone slightly soluble in ether. Store in airtight containers. Protect from light.
(British Approved Name Modified, rINNM)
Pharmacopoeias. In US.
The United States Pharmacopeia 31, 2008 (Estradiol Cypionate). A white to practically white crystalline powder, odourless or has a slight odour. Insoluble in water soluble 1 in 40 of alcohol, 1 in 7 of chloroform, and 1 in 2800 of ether soluble in acetone and in dioxan sparingly soluble in vegetable oils. Store in airtight containers. Protect from light.
(British Approved Name Modified, rINNM)
(British Approved Name Modified, rINNM)
(British Approved Name Modified, rINNM)
(British Approved Name Modified, rINNM)
(British Approved Name Modified, rINNM)
Pharmacopoeias. In China, Europe, and US.
European Pharmacopoeia, 6th ed. (Estradiol Valerate). A white or almost white, crystalline powder or colourless crystals. Practically insoluble in water soluble in alcohol. Protect from light.
The United States Pharmacopeia 31, 2008 (Estradiol Valerate). A white crystalline powder which is usually odourless or may have a faint fatty odour. Practically insoluble in water soluble in benzyl benzoate, in dioxan, in methyl alcohol, and in castor oil sparingly soluble in arachis oil and in sesame oil. Store in airtight containers. Protect from light.
The adverse effects of estradiol and other oestrogens are related, in part, to dose and duration of therapy, and to the gender and age of the recipient. In addition, adverse effects may be modified by a progestogen in combined oral contraceptives or menopausal HRT. Whether adverse effects of natural and synthetic oestrogens differ, and whether the dosage route has an effect, is less clear.
The adverse effects of oestrogens used in hormonal contraceptives are considered in detail starting. Those of oestrogens used in HRT are considered in detail starting. The use of oestrogens in children may cause premature closure of the epiphyses resulting in decreased final adult height.
Large doses of oestrogens used in palliation of cancers have also been associated with nausea, fluid retention, venous and arterial thrombosis, and cholestatic jaundice. In men, they cause impotence and feminising effects such as gynaecomastia. In women, they may cause withdrawal bleeding, and, when used for breast cancer, they have caused hypercalcaemia and bone pain.
Effects on the skin
Transdermal patches in which estradiol is dissolved in the adhesive matrix may cause fewer skin reactions than those releasing estradiol from an alcoholic reservoir.
The precautions for the use of estradiol and other oestrogens used as menopausal HRT are considered in detail starting. Those for oestrogens used in hormonal contraceptives are considered in detail starting.
High doses of oestrogen used in treating malignant disease should be used cautiously in patients with cere-brovascular disorders, coronary artery disease, or venous thromboembolism. They may exacerbate hypercalcaemia of malignancy. Oestrogens should be used with caution in children because premature closure of the epiphyses may occur resulting in inhibited linear growth and small stature. Oestrogens have been reported to interfere with some diagnostic tests such as those for thyroid function and glucose tolerance.
Estradiol has been detected in breast milk after the use of pessaries containing 50 or 100 mg of estradiol. The American Academy of Pediatrics considers that estradiol is usually compatible with breast feeding.
Use of cosmetic products containing oestrogens has led to adverse effects such as precocious puberty in children and gynaecomastia or postmenopausal bleeding in adults. Such products have been used by a greater proportion of African Americans than any other ethnic group in the USA, and it has been hypothesised that this may have contributed to the observations of earlier onset of puberty in girls’ and increased risk of breast cancer in young women
Oestrogens are considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrfnogenicity.
Although gross abnormalities of the genito-urinary tract have been reported in the male offspring of women who took diethylstilbestrol during pregnancy there is conflicting evidence as to whether the oestrogen produced an increased risk of abnormalities, infertility, or testicular cancer in such offspring. The male fetus is normally protected from the feminising effects of the natural oestrogens in the uterine environment by the early development of the testes and the secretion of male hormones.
However, there has been considerable concern about a rising incidence of disorders of the male reproductive tract, and a reduction in sperm counts, which has been noted in the last 20 to 30 years. It has been hypothesised that overexpo-sure of male fetuses to environmental oestrogens derived from pollutants such as pesticides and plastics may be responsible for this decline, although some dispute this A systematic review of epidemiological data found no strong evidence to link fetal exposure to oestrogens (as pharmaceuticals or pollutants) with reduced sperm count, cryptorchidism, or hypospadias, although there was some evidence to support a possible link with testicular cancer.
For discussion of the lack of effects of hormonal contraceptives on the fetus, including evidence that they are unlikely to increase the risk of hypospadia in the male fetus, see Pregnancy, under Precautions of Hormonal Contraceptives.
An FAO/WHO expert committee examining the risks from residues of veterinary drugs in foodstuffs established an acceptable daily intake for estradiol, but concluded that there would be no need to specify a numerical maximum residue limit for estradiol in the edible tissues of cattle when products are used as growth promotors according to good practice.l However, it should be noted that in the EU the use of steroidal hormones such as oestrogens in veterinary practice is restricted, and their use as growth promotors is banned.
There is concern about the effect of environmental oestrogens on male fertility and development, see Pregnancy, above.
Interactions involving estradiol and other oestrogens used in menopausal HRT are covered. Interactions for oestrogens used in hormonal contraceptives are covered.
In general, estradiol and other oestrogens are readily absorbed from the gastrointestinal tract and through the skin or mucous membranes. However, the natural unconjugated oestrogens such as estradiol undergo extensive first-pass metabolism in the gastrointestinal tract and liver after oral doses. They are, therefore, generally not orally active, although a micronised preparation of estradiol has sufficient bioavailability (3 to 5%) to be orally active. Estradiol is metabolised in part to less active oestrogens such as estriol and estrone.
Synthetic oestrogens produced by alkylation of the C17 position, such as ethinylestradiol, are more slowly metabolised and are therefore orally active. Conjugated oestrogens, which are essentially oestrogen metabolites, are also orally active because they are hydrolysed by enzymes in the lower gastrointestinal tract allowing absorption of the active oestrogen. Vaginal, transdermal, intranasal, or parenteral use of oestrogens also avoids first-pass hepatic metabolism. Plasma-estradiol concentrations are reported to reach a peak 1.5 to 2 hours after an oral dose, and again at about 8 hours due to enterohepatic recycling. Estradiol esters are rapidly hydrolysed to free estradiol when given orally. After intramuscular injection of the esters, absorption is prolonged.
Oestrogens are extensively bound to plasma proteins. Naturally occurring oestrogens such as estradiol are principally bound to sex-hormone binding globulin. Conversely, ethinylestradiol is mostly bound to albumin.
Oestrogens are metabolised in the liver. A variety of sulfate and glucuronide conjugates are formed, and these are excreted in the urine and the bile. Those excreted in the bile undergo enterohepatic recycling or are excreted in the faeces.
Uses and Administration
Estradiol is the most active of the naturally occurring oestrogens (for further details). Estradiol and its semisynthetic esters and other natural oestrogens are primarily used as menopausal HRT whereas synthetic derivatives such as ethinylestradiol and mestranol have a major role as components of combined oral contraceptives (see Hormonal Contraceptives). Estradiol may also be used as replacement therapy for female hypogonadism or primary ovarian failure. Replacement therapy (‘add-back’ therapy) may also be given to women in whom the pituitary-ovarian axis is suppressed by therapy with gonadorelin or its analogues.
Estradiol hemihydrate 1.03 mg is equivalent to about 1 mg of the anhydrous substance.
For menopausal HRT oral preparations or transdermal patches of estradiol are commonly used. Other transdermal formulations, subcutaneous implants, and a nasal spray are also available. Intramuscular injections were formerly used. In women with a uterus, a progestogen is also required, given cyclically or continuously, usually by mouth although some combined transdermal preparations are available. Local vaginal estradiol preparations are used specifically for the treatment of menopausal atrophic vaginitis these are generally recommended for short-term use only, if given without a progestogen in women with a uterus, although specific recommendations vary between products.
For use by mouth estradiol or estradiol valerate are normally given doses are 1 or 2 mg daily cyclically or more often continuously. Estradiol acetate may be given in an initial dose of 450 micrograms daily, increasing if necessary to 0.9 or 1.8 mg once daily.
Estradiol may be used topically as transdermal skin patches to provide a systemic effect a variety of patch-es are available which release between 25 and 100 micrograms of estradiol every 24 hours. A low-dose patch supplying 14 micrograms daily is also available specifically for the prevention of postmenopausal osteoporosis in women at significant risk with this low dose, the addition of a 14-day course of progestogen in women with a uterus is only required once every 6 to 12 months. Depending on the preparation, patches are replaced once or twice weekly. Each new patch is applied to a different area of skin in rotation, usually below the waistline patches should not be applied on or near the breasts.
Topical gel preparations are also used for systemic effect. The usual applied dose is 0.25 to 1.5 mg of estradiol daily, depending on the preparation, but up to 3 mg daily may be required for control of menopausal symptoms in some women. The gel should not be applied on the face or on or near the breasts, vagina, or vulval region. A topical emulsion is also available estradiol hemihydrate 8.7 mg is applied daily to provide a systemic estradiol dose of about 50 micrograms. A transdermal spray has also been developed, delivering a single dose of estradiol 1.53 mg onto the skin. It should be applied to the skin of the inner surface of the forearm, and the dose may be increased up to 3 sprays once daily in the morning, at separate sites on the forearm, according to response.
A nasal spray is available, delivering 150 micrograms of estradiol hemihydrate per spray. The usual initial dose is 150 micrograms daily (1 spray in 1 nostril). After 2 or 3 cycles the dose may be adjusted according to response the usual maintenance dose is 300 micrograms daily (1 spray in each nostril once daily) but may range from 150 micrograms once daily up to 450 to 600 micrograms daily in 2 divided doses.
In order to prolong the duration of action subcutaneous implants of estradiol may be used. The dose of estradiol is generally 25 to 100 mg with a new implant being given after about 4 to 8 months according to oestrogen concentrations.
Estradiol may be used locally either as 25-microgram vaginal tablets, at an initial dose of one tablet daily for 2 weeks followed by a maintenance dose of one tablet twice a week, or as a 0.01% vaginal cream, in initial amounts of 2 to 4 g of cream daily for 1 to 2 weeks followed by half the initial dose for a similar period, then a maintenance dose of 1 g up to 3 times weekly. A local delivery system using a 3-month vaginal ring contains 2 mg of estradiol hemihydrate, and delivers about 7.5 micrograms of estradiol per 24 hours.
Another 3-month vaginal ring system, which contains estradiol acetate, releases either 50 or 100 micrograms of estradiol daily, and is used for the relief of both local and systemic postmenopausal symptoms. Intramuscular injections of estradiol benzoate or valer-ate esters have been used as oily depot solutions, usually given once every 3 to 4 weeks. The cipionate, di-propionate, enantate, hexahydrobenzoate, phenylpropionate, and undecylate esters have been used similarly. The enantate and cipionate esters are used as the oestrogen component of combined injectable contraceptives.
Estradiol and other oestrogens have sometimes been used in higher doses for palliative treatment in prostate cancer and breast cancer in men and postmenopausal women.
Administration, buccal and sublingual administration.
Estradiol is absorbed through the buccal route, and has been reported to improve postmenopausal vasomotor symptoms. A pharmacokinetic study of micronised estradiol found the sublingual route resulted in more rapid absorption, a higher peak concentration, and more rapid elimination, than oral dosage. Sublingual micronised estradiol has been studied for the management of postpartum depression.
There may be a striking interpatient variation in blood-estradiol concentrations in women receiving estradiol implants, and symptoms of oestrogen deficiency have re-appeared in some patients even though serum-estradiol concentrations were within or above the physiological range. After debate on the appropriateness of using serum concentrations of estradiol as a guide to implant use, rather than symptoms, it is now recommended that estradiol concentration should be monitored during therapy.
Cyclical progestogen may be required for a prolonged period after removal of estradiol implants in women with a uterus.
The intranasal route for estradiol HRT has been reviewed. It appears to be comparable in efficacy to oral or transdermal use in the treatment of meno-pausal symptoms. As with transdermal application, the intranasal route avoids intestinal and hepatic first-pass metabolism.
Transdermal estradiol given via patches applied to the skin has been reviewed. This method of delivery has certain advantages over the oral route in that gastrointestinal and hepatic first-pass metabolism is avoided, liver enzymes are not stimulated (although this may also mean that beneficial effects on serum lipids are absent), and the prolonged drug release from the patch means less frequent application is necessary and hence patient compliance may be improved.
For oestrogen replacement in menopausal and postmenopausal women estradiol patches are used continuously or in a cyclical manner, with added progestogen for part of the cycle in those women with an intact uterus. This does not lead to drug accumulation and produces blood-estradiol concentrations and estradiol to estrone ratios similar to those normally observed in premenopausal women. The patch is well tolerated with skin irritation being the main problem. Patches are as effective as oral oestrogens in treating menopausal and postmenopausal symptoms such as flushing and vaginal atrophy and in preventing osteoporosis. Combined HRT patches, providing both estradiol and a progestogen, have also been developed.
Estradiol is also effective when applied topically to the skin as a gel or emulsion.
The use of oestrogen therapy in the treatment of premenopausal women with postnatal depression has been shown to be effective. However, although such therapy could be a useful adjunct to conventional treatment (see Depression), the risk of serious adverse effects including thrombosis may limit its value.
Whether oestrogens are of benefit in older women, typically with depression associated with the menopause, is less clear. Some studies of transdermal estradiol have reported benefit, whereas other studies of transdermal or oral dosage have not found it to be effective. Whether the presence of a progestogen in combination HRT would reduce any purported benefit is also unclear. Antidepressants remain the standard of care in perimen-opausal or postmenopausal women with clinical depression.
Oestrogens are used in male-to-female transsexuals to develop and maintain secondary sexual characteristics. Although ethinylestradiol and conjugated oestrogens have been used for this purpose, and there is some evidence that such use can improve vascular function, others consider ethinylestradiol too thrombogenic at the doses required [typically 50 to 100 micrograms daily or more] and suggest that estradiol, as the valerate in oral doses of 2 to 4 mg daily, or transdermally as a patch supplying 100 micrograms daily, is the oestrogen of choice. Cyproterone acetate is usually also given for its anti-androgenic effect.
Supraphysiological doses of oestrogens inhibit somatic growth and have been used, with a cyclical progestogen, to reduce final height in girls with constitutional tall stature, although such treatment has declined markedly with changing social norms. In early reports, diethylstilbestrol was used, but this is an unsuitable choice because of the increased risk of cancer. Ethinylestradiol has been given in the past in doses of up to 500 micrograms daily, but doses of 50 to 100 micrograms daily came to be preferred, although lower doses may be equally effective. Conjugated oestrogens have also been used, and a study reported that doses of 7.5 to 11.25 mg daily resulted in an average decrease of about 5 cm from final predicted height.
In practice, doses as low as 625 micrograms daily have been used. Reported height reductions have ranged from 2 to 10 cm but studies are difficult to compare. Treatment has generally been continued until closure of the epiphyses, but the effects of oestrogen therapy may be influenced by both chronological and bone age at the onset of treatment, duration of treatment, the oestrogen used and its dose, and the point of final height assessment. High-dose oestrogen therapy is also associated with adverse effects such as weight gain, headache, nausea, and pigmentation of the areolae or nipples, and there can be adverse changes to haemostatic and lipid measures. A retrospective cohort review has also reported that girls who had been treated with high-dose oestrogens were more likely to report fertility problems in later life than similar girls who had not been treated.
Oestrogen therapy has occasionally been used to help promote growth in girls with constitutional delayed puberty.
Limited evidence supports the use of oestrogens in various bleeding disorders. There have been mixed results from small studies of oestrogens, given alone or with a progestogen, in patients with hereditary haemorrhagic telangiectasia the use of a combined oral contraceptive has been suggested as a suitable option for fertile women with symptomatic epistaxis. There are also some reports of bleeding being reduced in patients with gastrointestinal vascular malformations from other causes. Conjugated oestrogens have been used in haemorrhagic disorders associated with chronic renal failure and haemorrhagic cystitis.
Synthetic oestrogens (e.g. quinestrol) and nonsteroidal oestrogens (e.g. diethylstilbestrol) were historically used to suppress lactation. However, this use is now considered inappropriate because of an increased risk of puerperal thromboembolism.
Premenstrual syndrome (PMS) presents as a variable combination of psychological and somatic symptoms occurring during the luteal phase of the menstrual cycle, which resolve during, and immediately after, menstruation. Another term, premenstrual dysphoric disorder, has been proposed to cover severe cyclical mood disorder that is functionally incapacitating. Whereas about 20 to 40% of women have complaints that may be classified as PMS, only 3 to 8% meet criteria for premenstrual dysphoric disorder.
The term premenstrual tension (PMT) has sometimes been applied to the psychological symptoms. Many symptoms of PMS are the same as normal premenstrual symptoms, but are more severe. The aetiology of PMS is not fully understood, although it is thought that affected women may be more sensitive to the effects of normal hormonal fluctuations on CNS neurotransmitter function.
Initial management includes non-medical interventions such as education and support, counselling, stress management, relaxation techniques, and exercise caffeine and salt restriction are of unproven benefit. The herbal remedy agnus castus has been found to be of benefit For patients with moderate to severe symptoms, a number of drugs have been tried with varying degrees of success objective assessment of efficacy has been hampered by varying diagnostic criteria, a marked placebo response, and difficulties in obtaining reproducible responses. Treatment may be aimed at modifying the menstrual cycle or treating specific symptoms.
In women with mainly psychological symptoms, SSRIs can be helpful. Fluoxetine and sertraline have been shown in controlled studies to alleviate both psychological and somatic symptoms in women with PMS, and may be given intermittently (only in the luteal phase) or continuously. If treatment with one SSRI is ineffective or not tolerated, another SSRI or venlafaxine may be substituted. ‘e There is limited information on the use of S S-RIs for PMS in adolescents, and precautions regarding suicidal ideation in young adults should be considered. Clomipramine, a nonselective serotonin reuptake inhibitor, has been tried for PMS with some success. The anxiolytic alprazolam has also been used, but use of this and other benzodiazepines should be restricted to the luteal phase of the cycle in selected patients to minimise the risk of dependence and tolerance.
Abdominal bloating and swelling associated with PMS has traditionally been thought to be due to sodium and water retention. However, in most women with these symptoms there is no evidence of an increase in body-weight or in body sodium or total water, and use of diuretics is therefore not justified. Nevertheless, in women with appreciable weight gain and abdominal bloating in the luteal phase, the aldosterone antagonist spironol-actone may be useful. Another symptom of PMS, cyclical mastalgia, is discussed.
Pyridoxine has been tried on the basis that it is a cofactor in neu-rotransmitter (specifically serotonin) synthesis, and has been found to relieve depression induced by oral contraceptives in selected patients. However, its efficacy in PMS is equivocal, and high daily doses have been associated with neurotoxicity. Calcium supplementation may relieve symptoms of PMS.
Treatments that modify the menstrual cycle have often been used in women with PMS. In general, drugs with proven efficacy such as danazol, oestrogen implants, and gonadorelin analogues are reserved for women with severe PMS unresponsive to other treatments, because of their adverse effects. Progestogen therapy was once popular, but beneficial responses have not been universally achieved and the theory that progesterone was necessary to correct a hormone imbalance is now losing ground. In addition, a systematic review of clinical trials found no evidence to support the use of progesterone or progestogens for PMS. Combined oral contraceptives have met with limited success.
They may be useful in some women for the control of somatic symptoms, but in others, PMS is caused or exacerbated by them. There is some suggestion that combined contraceptives containing dros-pirenone may be more effective in managing PMS than those containing progestogens such as levonorgestrel or norethister-one. Consideration should be given to continuous rather than cyclical use. Perimenopausal women may benefit from oestrogen delivered from transdermal patches. In women with a uterus, use with a cyclical progestogen is required to avoid endometrial hyperplasia unfortunately, the progestogen may be associated with the return of symptoms.
Possible strategies to minimise this include the use of a less androgenic progestogen, reducing the frequency with which it is given, or using an intra-uterine device to deliver the progestogen locally. Danazol can be useful, but there is concern over its adverse effects on lipids during long-term use and over the risk of masculinisation of a female fetus should pregnancy occur. For patients with severe symptoms not amenable to other treatments, gonadorelin analogues such as goserelin can be used to eliminate ovarian function, ‘add-back’ treatment with oestrogen plus progestogen being given to protect against the adverse effects of oestrogen deficiency including osteoporosis. This treatment is very effective for both physical and psychological symptoms. Short-term use (3 months) of a gonadorelin analogue alone has been used to confirm the diagnosis of PMS, or to predict the response to bilateral oophorectomy.
British Pharmacopoeia 2008: Estradiol and Norethisterone Acetate Tablets; Estradiol and Norethisterone Tablets; Estradiol Injection; Estradiol Transdermal Patches
The United States Pharmacopeia 31, 2008: Estradiol and Norethindrone Acetate Tablets; Estradiol Cypionate Injection; Estradiol Injectable Suspension; Estradiol Pellets; Estradiol Tablets; Estradiol Transdermal System; Estradiol Vaginal Cream; Estradiol Valerate Injection.
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Aerodiol; Climaderm¤; Disequens; Estraderm; Estradot; Estreva; Estring¤; Estrofem; Etrosteron; Eutocol; Evorel; Fem 7; Ginatex; Hormodiol; Lindisc; Oestro Gel; Progynon; Progynova; Replasyn; Ronfase; Rontagel; Transdiol¤; Trial Gel; Trial Sat; Australia: Aerodiol; Climara; Dermestril; Estraderm; Estradot; Estring¤; Estrofem; Femtran; Menorest; Primogyn Depot; Progynova; Sandrena; Vagifem; Zumenon;
Austria: Aerodiol; Climara; Cycloderm; Dermestril; Duokliman; Estracutan; Estraderm; Estradot; Estramon; Estring¤; Estrofem; Estrogel; FemSeven; FemSieben; Klimapur; Klimareduct; Linoladiol; Menorest; Merimono; Oesclim¤; Progynon; Progynova; Sandrena¤; Sterigin; Substitol¤; Systen; Vagifem; Zerella; Zumenon;
Belgium: Aerodiol; Climara; Dermestril; Estraderm; Estreva; Estrofem; Feminova; Meno-Implant; Oestrogel; Progynova; Systen; Vagifem; Vivelle; Zumenon;
Brazil: Aerodiol; Avicis; Benzo-Ginoestril; Climaderm; Estradelle; Estraderm; Estradot; Estreva; Estrofem; Fem 7; Ginedisc¤; Hormodose; Lindisc; Menorest¤; Merimono; Natifa; Oesclim¤; Oestrogel¤; Primogyna; Reglovar¤; Riselle; Sandrena; Systen;
Canada: Climara; Delestrogen; Estrace; Estraderm; Estradot; Estring; Estrogel; Femogex¤; Oesclim; Vagifem; Vivelle¤; Chile: Climaderm; Cyclobiol; Dermatrans; Enadiol; Epiestrol; Estranova E; Estreva; Farlutes; Fem 7; Femalon; Femiderm; Femidott; Ginoderm; Mirion; Oesclim¤; Primaquin; Primofol Depot¤; Primogyna¤; Progynova; Sandrena; Transvital; Vagifem;
Czech Republic: Agofollin; Climara; Dermestril; Divigel; Elleste; Estrace; Estraderm; Estrahexal; Estreva; Estrimax; Estring; Estrofem; Fem 7; Linoladiol N; Menorest; Neofollin; Octodiol; Oesclim; Oestrogel; Riselle; Systen; Vagifem;
Denmark: Aerodiol; Climara; Divigel; Estraderm; Estring; Estrofem; Estrogel; Evorel; Femanest; FemSeven¤; Menorest¤; Progynon; Sandrena; Vagifem; Vivelle Dot;
Finland: Climara; Dermestril; Divigel; Estraderm; Estradot; Estrena; Estring; Estrofem; Estrogel; Evorel; FemSeven; Menorest¤; Merimono; Progynova; Vagifem; Zumenon;
France: Aerodiol; Benzo-Gynoestryl¤; Climara; Delidose; Dermestril; Estraderm; Estrapatch; Estrofem; Evafilm¤; Femsept; Menorest; Oesclim; Oestrodose; Oestrogel; Oromone; Progynova; Provames; Systen; Thais; Vivelledot;
Germany: Aerodiol; Cerella¤; Cutanum; Dermestril; Ephelia; Estrabeta; Estraderm; Estradot; Estramon; Estreva; Estrifam; Estring; Estronorm; Evorel; Fem 7; Femoston mono; Gynokadin; GynPolar; Linoladiol N; Menorest; Merimono; Pantostin; Progynon B¤; Progynon Depot 100¤; Progynon Depot 10; Progynon Depot 40¤; Progynova; Sandrena; Sisare mono; Tradelia; Vagifem;
Greece: Aerodiol; Dermestril; Estraderm TTS¤; Estradot; Estramon; Estring¤; Estrofem; Estrogel; Menorest; Oesclim¤; Oestrogel; Vagifem;
Hong Kong: Aerodiol¤; Bisteron¤; Dermestril; Estraderm; Estreva; Estrofem; Fem 7¤; Oestrogel; Progynova;
Hungary: Calidiol; Dermestril; Divigel; Estraderm; Estradot; Estramon; Estrimax; Estrofem; Linoladiol N; Oesclim; Oestrogel; Systen; Triaklim; Vagifem;
Ireland: Aerodiol; Climara; Dermestril; Divigel; Epiestrol¤; Estraderm; Estradot; Estramon¤; Estrofem; Evorel; Fematab; Fematrix¤; Menorest¤; Oestrogel; Progynova¤; Vagifem;
Israel: Climara¤; Dermestril; Estraderm; Estrofem; Evorel; Meno-Patch¤; Oestrodose; Oestrogel; Progynova; Vagifem;
Italy: Aerodiol; Armonil; Benztrone¤; Climara; Dermestril; Ephelia; Epiestrol; Esclima; Estraderm; Estroclim; Estrodose; Estrofem; FemSeven; Gelestra; Ginaikos; Menorest; Progynon B¤; Progynon Depot¤; Progynova; Sandrena; Sprediol; Systen; Vagifem; Zerella;
Malaysia: Divigel; Estrofem; Oestrogel; Progynova; Trisequens; Mexico: Armistor; Benzo-Ginestryl; Climaderm; Essventia; Estraderm; Estramon; Estreva; Evorel; Fem 7; Ginedisc; Oestrogel; Primogyn; Sandrena; Systen;
Monaco: Estreva; Netherlands: Aerodiol; Climara; Dermestril; Dimenformon¤; Estraderm; Estradot; Estring¤; Estrofem; Fem 7; Femring; Meno-Implant; Menorest; Progynon Depot 100¤; Progynon Depot 10¤; Progynova; Sandrena; Systen; Vagifem; Zumenon;
Norway: Climara; Estraderm; Estradot; Estring; Evorel; Menorest¤; Progynova; Vagifem;
New Zealand: Aerodiol; Climara; Estraderm; Estring¤; Estrofem; Femtran; Progynova; Sandrena¤; Vagifem¤;
Portugal: Climara; Dermestril; Estraderm; Estradot; Estrofem; Estronar¤; Menorest; Vagifem; Zumenon;
Russia: Climara (Климара); Divigel (Дивигель); Estrimax (Естримакс); Estrofem (Естрофем); Oestrogel (Естрожель);
South Africa: Climara; Estraderm; Estring; Estro-Pause; Estrofem; Evorel; Femigel; Menorest¤; Primogyn Depot; Progynova; Vagifem; Singapore: Divigel; Estraderm; Estreva; Estrofem; Fem 7¤; Oestrogel; Progynova; Vagifem;
Spain: Absorlent; Alcis; Cliogan; Dermestril; Endomina; Esotran¤; Esprasone; Estraderm; Estradot; Estroffik; Evopad; Menorest¤; Meriestra; Oestraclin; Oestrodose¤; Progynon Depot¤; Progynova; Vagifem;
Sweden: Climara; Divigel; Estraderm; Estradot; Evorel; Femanest; FemSeven; Menorest¤; Oesclim; Oestring; Progynon; Vagifem;
Switzerland: Aerodiol; Cerina; Climara; Dermestril; Divigel; Epiestrol¤; Estraderm; Estradot; Estramon; Estreva; Estring; Estrofem N; Fem 7; FemSeven¤; Menorest; Oestrogel; Progynon Depot 100¤; Progynon Depot 10¤; Progynova; Sandrena; Systen; Vagifem; Zumenon; Thailand: Climara; Divigel; Estrofem; Oestrogel; Progynon; Progynova; Vagifem;
United Kingdom: Adgyn Estro¤; Aerodiol; Bedol; Benztrone¤; Climaval; Dermestril¤; Elleste-Solo; Estraderm; Estradot; Estring; Evorel; Fematrix; FemSeven; FemTab; Menorest¤; Menoring¤; Oestrogel; Progynova; Sandrena; Vagifem; Zumenon;
United States: Alora; Climara; Deladiol¤; Delestrogen; depGynogen; Depogen; Dioval¤; Dura-Estrin¤; Duragen¤; E-Cypionate¤; Esclim; Estra-D¤; Estra-L¤; Estrace; Estraderm; Estrasorb; Estring; Estro-Cyp¤; Estrogel; Estroject¤; FemPatch; Femring; Femtrace; Gynodiol; Gynogen¤; Menaval¤; Menostar; Vagifem; Valergen; Vivelle;
Venezuela: Aerodiol; Climaderm; Estraderm; FemSeven
Argentina: Activelle; Angeliq; Atrimon; Ciclocur; Climene; Cristerona; Dilena; Dos Dias N; Estalis Sequi; Estalis; Estracomb; Estragest; Evorel Conti; Evorel Sequi; Farludiol Ciclo; Farludiol; Fem 7 Combi; Fempack; Gynodian Depot; Hosterona; Kliogest; Lubriderm; Menstrogen; Mesigyna; Perlutal; Plenifem¤; Prefest; Primosiston; Supligol NF; Supligol¤; Totelle Ciclico; Totelle Continuo; Trial Combi; Trial Gest; Trial Pack¤; Trisequens;
Australia: Angeliq; Climen; Divina¤; Estalis Continuous; Estalis Sequi; Estracombi; Estrapak¤; Femoston; Kliogest; Kliovance; Primodian Depot¤; Trisequens;
Austria: Activelle; Climabelle; Climen; Climodien; Cyclacur; Estalis Sequens; Estalis; Estandron¤; Estracomb; Estragest¤; Femipak; Femoston Conti; Femoston; Femphascyl conti; Femphascyl; FemSeven Combi; Filena; Gravibinon¤; Gynodian Depot; Ichth-Oestren¤; Kliogest; Lafamme; Liseta; Mericomb; Merigest; Minique; Novofem; Ostrolut¤; Perikliman; Primodian Depot¤; Totelle cyclo¤; Tri-Filena¤; Trisequens;
Belgium: Activelle; Climen; Climodien; Cyclocur; Dimenformon; Diviplus¤; Diviva¤; Estracombi; Feminova Plus; Femoston Conti; Femoston; Kliogest; Novofem; Totelle Cycle; Trisequens; Trivina¤;
Brazil: Activelle; Cicloprimogyna; Ciclovular¤; Cliane; Climene; Cyclofemina; Dilena; Elamax; Estalis SQ; Estalis; Estandron P; Estracomb; Estragest; Evitas¤; Femineo; Femoston Conti; Femoston; Gestadinona; Ginecoside¤; Ginedisc 50 Plus¤; Hormoginase¤; Kliogest; Lindisc Duo¤; Mericomb; Merigest; Mesigyna; Natifa Pro; Normomensil¤; Perlutan; Postoval; Prefest; Preg-Less; Progest¤; Suprema; Systen Conti; Systen Sequi; Trinestril; Trisequens; Unalmes; Uno-Ciclo;
Canada: Climacteron; Duogex LA¤; Estalis Sequi; Estalis; Estracomb; Estrand¤; Neo-Pause¤;
Chile: Activelle; Agurin; Avaden; Cliane; Climene; Cyclofem; Enadiol CC; Enadiol MP; Enadiol Neta; Estandron Prolongado; Estracomb; Estragest; Estranova 30 Simple; Estranova CC; Farlupost; Fem 7 Combi; Femoston Conti; Femoston; Ginefolin; Gravidinona¤; Gynodian Depot; Kilios; Kliogest; Mesigyna; Novafem; Postoval; Primaquin MP Continuo; Primaquin MP; Progyluton; Totelle Continuo; Totelle; Trisequens; Unalmes¤;
Czech Republic: Activelle; Aknefug; Alpicort F; Avaden; Climara Duo; Climen; Convaden; Cyclo-Menorette; CycloOstrogynal; Divina; Diviseq; Estalis Sequi; Estalis; Estrace Plus; Estrace-C; Estracomb; Estragest; Femoston; Folivirin; Gynodian Depot; Indivina; Kliane; Klimodien; Klimonorm; Kliogest; Linoladiol-H N; Pausogest; Systen Conti; Systen Sequi; Triaklim; Trisequens;
Denmark: Activelle; Climen; Climodien; Cyclo-Progynon; Divina Plus; Divina; Estracomb; Evo-Conti; Evo-Sequi; Femanor; Femasekvens; Indivina; Klimalet; Klimaxil¤; Kliogest; Novofem; Nuvelle; Ostranorm¤; Totelle; Trevina; Trinorm¤; Trisekvens;
Finland: Activelle; Climara Duo¤; Cyclabil; Divina; Divitren; Estalis Sekvens; Estalis; Estracomb¤; Evorel Conti; Evorel Sequi; Femilar; Femoston Conti; Femoston; FemSeven Combi; Indivina; Kliogest; Mericomb; Merigest; Novofem; Senikolp¤; Totelle Sekvens; Trisekvens;
France: Activelle; Avadene; Climaston; Climaston; Climene; Climodiene; Divina; Diviseq; Duova; FemseptCombi; Gravibinan¤; Gynodian Depot¤; Kliogest; Naemis; Novofemme; Successia¤; TOM¤; Trisequens;
Germany: Acetonal Vaginale¤; Activelle; Aknefug-Emulsion¤; Alpicort F; Androfemon¤; Climen; Climodien; Clionara; Crinohermal fem; Cyclo-Menorette; Cyclo-Progynova; CycloOstrogynal; CycloPolar¤; Ell-Cranell¤; Estalis Sequi; Estracomb; Estrafemol; Estragest; Fem 7 Combi; Femoston Conti; Femoston; Fissan-Brustwarzensalbe¤; Gianda; Gravibinon¤; Gynamon; Gynodian Depot; Ichth-Oestren¤; Indivina; Jephagynon¤; Klimonorm; Kliogest N; Lafamme; Linoladiol-H N; Lynandron¤; Malun¤; Mericomb; Merigest; NeoOstrogynal; NeyNormin N (Revitorgan-Dilutionen N Nr 65); Novofem; Osmil; Ostronara; Ovatest¤; Primodian Depot¤; Primosiston¤; Procyclo; Sebohermal¤; Sisare 28; Sisare; Syngynon¤; Trisequens; Vitrena;
Greece: Activelle; Angeliq; Climodien; Cyclacur; Divina; Estalis; Estopause; Estracomb TTS; Femaston; Kliogest; Nuvelle¤; Systen Conti; Systen Sequi; Trisequens; Hong Kong: Activelle; Climen 28; Dilena; Estracomb; Femoston; Hormonin; Klimonorm¤; Kliogest; Progestrol¤; Trisequens;
Hungary: Activelle; Alpicort F; Climen; Cyclo-Menorette; Divina; Divitren; Estracomb; Estragest; Femoston; Klimodien; Klimonorm; Kliogest; Linoladiol-H N; Pausogest; Trisequens;
India: Kemicetine Antiozena; Mixogen;
Ireland: Activelle; Cyclo-Progynova¤; Diviseq¤; Estalis Sequi; Estalis; Estracombi; Estrapak¤; Evorel Conti; Femoston Conti; Femoston; Femplan-MA¤; Indivina; Kliogest; Novofem; Nuvelle; Tridestra¤; Trisequens;
Israel: Activelle; Evorel Conti; Evorel Sequi; Kliogest; Meno-MPA¤; Meno-Net¤; Novofem; Progyluton; Trisequens;
Italy: Ablacton¤; Activelle; Biormon¤; Climen; Clym-Depositum¤; Combiseven; Cyclacur¤; Duo-Ormogyn¤; Estalis Sequi; Estandron¤; Estiamen B¤; Estiamen¤; Estracomb; Femoston Conti; Femoston; Filena; Gravibinan; Gynodian Depot; Kliogest; Menovis; Nuvelle TS¤; Nuvelle; Pausene; Primodian Depot¤; Tesor-C¤; Totelle; Trisequens; Malaysia: Activelle; Climen; Femoston; Klimonorm; Kliogest; Progyluton;
Mexico: Anafertin; Binodian; Cliane; Climene; Cyclofemina; Damax; Despamen; Dilena; Estracomb; Estrapak¤; Evorel Conti; Ginoplan¤; Gravidinona; Lutalmin; Lutoginestryl F; Mesigyna; Metrigen Fuerte; Ominol¤; Patector; Perludil; Perlutal; Prefest; Primosiston; Primoson-F; Progediol; Proger-F; Progyluton; Totelle Continuo; Totelle Secuencial; Yectames;
Monaco: Trioestrine-Retard¤; Netherlands: Activelle; Angeliq; Avaden; Climene; Cyclocur; Dimenformon Prolongatum¤; Divina¤; Estandron Prolongatum; Estracomb; Fem 7 Sequi; Femoston; Kliogest; Naemis; Novofem; Trisequens; Zumeston¤;
Norway: Activelle; Climen; Climodien; Cyclabil; Diviseq¤; Estalis Sekvens; Estalis; Estracomb¤; Indivina; Kliogest; Novofem; Totelle Sekvens; Trisekvens;
New Zealand: Cliane; Estrapak¤; Kliogest; Kliovance; Nuvelle; Trisequens; Portugal: Activelle; Cicnor; Climara Duo; Climen; Climodien; Dilena; Emmenovis; Estalis Sequi; Estalis; Estracomb; Femoston 1/5; Femoston 2/10; Kliogest; Nuvelle; Progyluton; Trisequens;
Russia: Climen (Климен); Climodien (Климодиен); Cyclo-Progynova (Цикло-прогинова); Divina (Дивина); Diviseq (Дивисек); Divitren (Дивитрен); Femoston (Фемостон); Femoston 1/5 (Фемостон 1/5); Gynodian Depot (Гинодиан Депо); Indivina (Индивина); Klimonorm (Климонорм); Pausogest (Паузогест); Triaklim (Триаклим); Trisequens (Трисеквенс);
South Africa: Activelle; Angeliq; Climen; Divina; Estracombi; Estro-Pause N; Evorel Conti; Evorel Sequi; Femoston; Kliogest; Mixogen; Postoval; Prefesta; Primodian Depot; Trisequens; Trivina;
Singapore: Activelle; Climen; Estracomb; Femoston; Kliogest; Progyluton; Trisequens;
Spain: Ablacton¤; Absorlent Plus; Activelle; Auroclim; Climen; Climodien; Clisin; Dinatrofon¤; Duofemme; Emenovister¤; Endomina Plus; Estalis Sequi; Estalis; Estandron Prolongado¤; Estracomb; Gynodian Depot¤; Merigest Sequi; Merigest; Mevaren; Nuvelle; Perifem; Primodian Depot¤; Primosiston Fuerte¤; Progyluton; Topasel; Trisequens;
Sweden: Activelle; Climodien; Cyclabil; Divina Plus; Divina; Estalis Sekvens; Estalis; Estracomb¤; Evorel Micronor; Femanor; Femasekvens; Indivina; Kliogest; Novofem; Totelle Sekvens; Totelle; Trisekvens; Trivina;
Switzerland: Activelle; Alpicort F; Climen; Cyclacur; Diviseq; Estalis Sequi; Estalis; Estandron Prolongatum¤; Estracomb; Estragest; Fem 7 Combi; Femoston Conti; Femoston; Gravibinon¤; Gynodian Depot; Indivina; Kliogest N; Linoladiol¤; Mericomb; Merigest; Novofem; OestroTabs Plus Cyclic¤; Primodian Depot¤; Primosiston¤; Systen Conti; Systen Sequi; Triaval; Trisequens; Tyliculine¤;
Thailand: Activelle; Climen; Cyclo-Progynova; Duoton; Indivina; Klimonorm; Kliogest¤; Primodian Depot; Trisequens¤; United Kingdom: Adgyn Combi¤; Angeliq; Climagest; Climesse; Clinorette; Cyclo-Progynova 1 mg; Cyclo-Progynova 2 mg; Elleste Duet Conti; Elleste-Duet; Estracombi; Estrapak¤; Evorel Conti; Evorel Pak¤; Evorel Sequi; Femapak; Femoston Conti; Femoston; FemSeven Conti; FemSeven Sequi; FemTab Continuous¤; FemTab Sequi; Hormonin; Indivina; Kliofem; Kliovance; Novofem; Nuvelle Continuous; Nuvelle TS¤; Nuvelle; Tridestra; Trisequens;
United States: Activella; Andro/Fem¤; ClimaraPro; CombiPatch; Deladumone¤; depAndrogyn¤; Depo-Testadiol; Depotestogen; Duo-Cyp¤; Duratestrin¤; Estra-Testrin¤; Lunelle¤; Prefest; T-E Cypionate¤; Test-Estro¤; Testaval 90/4¤; Valertest¤;
Venezuela: Cliane; Climene; Estracomb; Estragest; Ginecosid; Gynodian Depot; Mesigyna; Primosiston; Progyluton