1.1.1. Nomenclature

1.1.2. Structural and molecular formulae and relative molecular mass

Sodium estrone sulfate

Sodium equilin sulfate

1.1.3. Chemical and physical propertie

From Gennaro (2000) and American Hospital Formulary Service (2005)

1. Description: Buff-coloured, odourless or with a slight characteristic odour, amorphous powder (from natural sources); white to light buff, odourless or with a slight odour, crystalline or amorphous powder (synthetic)
2. Solubility: Soluble in water

1.1.4. Technical products and impurities

Conjugated estrogens contain 52.5% min. and 61.5% max. sodium estrone sulfate and 22.5% min. and 30.5% max. sodium equilin sulfate; the total of sodium estrone sulfate and sodium equilin sulfate is 79.5% min. and 88.0% max. of the labelled content of conjugated estrogens. Conjugated estrogens contain as concomitant components (as sodium sulfate conjugates) 13.5% min. and 19.5% max. 17α-dihydroequilin, 0.5% min. and 4.0% max. 17β-dihydroequilin and 2.5% min. and 9.5% max. 17α-estradiol of the labelled content of conjugated estrogens (Pharmacopeial Convention, 2004).

Conjugated estrogens are available as tablets for oral administration, as a liquid for parenteral injection and as a 0.0625% vaginal cream (American Hospital Formulary Service, 2005).

Conjugated estrogens (natural) are a mixture that contains the sodium salts of the water-soluble sulfate esters of estrone and equilin derived wholly or in part from equine urine or prepared synthetically from estrone and equilin. Conjugated estrogens (natural) also contain conjugated estrogenic substances of types that are excreted by pregnant mares and include δ8,9-dehydroestrone, 17α-dihydroequilenin, 17β-dihydroequilenin, 17α-dihydroequilin, 17β-dihydroequilin, equilenin, 17α-estradiol and 17β-estradiol (American Hospital Formulary Service, 2005).

Conjugated estrogens (synthetic) are a mixture of conjugated estrogens that are prepared synthetically from plant sources (i.e. soya and yams). Conjugated estrogens (synthetic) are commercially available as preparations that contain a mixture of nine of the 10 known conjugated estrogenic substances that are present in currently available commercial preparations of conjugated estrogens (natural). However, in contrast to currently available preparations of conjugated estrogens (natural), the conjugated estrogenic substances present in conjugated estrogens (synthetic) are prepared entirely synthetically (American Hospital Formulary Service, 2005).

1.1.5. Use

Conjugated estrogens are used mainly in the treatment of menopausal disorders (e.g. vasomotor symptoms, vulvar and vaginal atrophy) and for the prevention and treatment of osteoporosis. Conjugated estrogens are usually administered orally at a dose of 0.3–1.25 mg/day (American Hospital Formulary Service, 2005).

Table 1 presents comparative global data on sales of conjugated estrogens in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 1

Conjugated estrogens used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

1.2.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 57-63-6
• Deleted CAS Reg. No.: 77538-56-8; 406932-93-2
• Chem. Abstr. Name: (17α)-19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol
• IUPAC Systematic Name: 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol
• Synonyms: Ethinylestradiol; 17-ethinylestradiol; 17-ethinyl-3,17-estradiol; 17α-ethinyl-3,17-dihydroxy-Δ1,3,5-estratriene; 17α-ethinylestradiol; 17α-ethinyl-17β-estradiol; 17α-ethinylestra-1,3,5(10)-triene-3,17β-diol; 17α-ethinyl-1,3,5(10)-estratriene3,17-diol; ethinyloestradiol; 17-ethynyl-3,17-dihydroxy-1,3,5-oestratrione; ethynylestradiol; 17-ethynylestradiol; 17α-ethynylestradiol; 17-ethynylestra-1,3,5(10)-triene3,17β-diol; ethynyloestradiol; 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17β-diol

1.2.2. Structural and molecular formulae and relative molecular mass

1.2.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005), unless otherwise specified

1. Description: White to creamy or slightly yellowish white, odourless, crystalline powder
2. Melting-point: 182–184 °C
3. Solubility: Practically insoluble in water; soluble in acetone (1 part in 5), ethanol (1 part in 6), chloroform (1 part in 20), dioxane (1 part in 4), diethyl ether (1 part in 4) and vegetable oils
4. Optical rotation: [α]²_d°, less than −27° to −30° (Pharmacopeial Convention, 2004; Council of Europe, 2005)

1.2.4. Technical products and impurities

Ethinylestradiol is commercially available as tablets either alone or in combination with progestogens, as described in the monograph on Combined estrogen–progestogen contraceptives.

Reported impurities include: estradiol, 3-hydroxyestra-1,3,5(10)-trien-17-one (estrone), 19-nor-17α-pregna-1,3,5(10),9(11)-tetraen-20-yne-3,17-diol and 19-norpregna-1,3,5(10)trien-20-yne-3,17-diol (17β-ethinylestradiol) (British Pharmacopoeial Commission, 2004).

1.2.5. Use

Ethinylestradiol is a synthetic estrogen that acts similarly to estradiol. It is frequently used as the estrogenic component of combined oral contraceptive preparations; a typical daily dose is 20–50 µg. Ethinylestradiol is also used as an emergency contraceptive combined with levonorgestrel or norgestrel. A combined preparation of ethinylestradiol with the anti-androgen cyproterone is used for the hormonal treatment of acne and hirsutism, particularly when contraception is also required. Ethinylestradiol has also been used for hormonal menopausal therapy; doses of 10–20 µg daily were given (in conjunction with a progestogen in women with a uterus). For the treatment of female hypogonadism, 50 µg has been given up to three times daily for 14 consecutive days in every 4 weeks, followed by a progestogen for the next 14 days (Sweetman, 2005).

Table 2 presents comparative global data on sales of ethinylestradiol in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 2

Ethinylestradiol used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

1.3.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 72-33-3
• Deleted CAS Reg. No.: 43085-54-7; 53445-46-8
• Chem. Abstr. Name: (17α)-3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17-ol
• IUPAC Systematic Name: 3-Methoxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-17-ol
• Synonyms: Ethinylestradiol 3-methyl ether; 17α-ethinylestradiol 3-methyl ether; ethinyloestradiol 3-methyl ether; 17α-ethinyloestradiol 3-methyl ether; ethynylestradiol methyl ether; ethynylestradiol 3-methyl ether; 17-ethynylestradiol 3-methyl ether; 17α-ethynylestradiol 3-methyl ether; 17α-ethynylestradiol methyl ether; ethynyloestradiol methyl ether; ethynyloestradiol 3-methyl ether; 17-ethynyloestradiol 3-methyl ether; 17α-ethynyloestradiol 3-methyl ether; 17α-ethynyloestradiol methyl ether; 3-methoxy17α-ethinylestradiol; 3-methoxy-17α-ethinyloestradiol; 3-methoxy-17α-ethynylestradiol; 3-methoxyethynylestradiol; 3-methoxy-17α-ethynyloestradiol; 3-methoxyethynyloestradiol; 3-methylethynylestradiol; 3-O-methylethynylestradiol; 3-methylethynyloestradiol; 3-O-methylethynyloestradiol; Δ-MVE

1.3.2. Structural and molecular formulae and relative molecular mass

1.3.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White to creamy white, odourless, crystalline powder
2. Melting-point: 150–154 °C
3. Solubility: Practically insoluble in water; sparingly soluble in ethanol; slightly soluble in methanol; soluble in acetone, dioxane and diethyl ether; freely soluble in chloroform
4. Optical rotation:[α]²_D°, −20° to −24° (British Pharmacopoeial Commission, 2004; Council of Europe, 2005); +2° to +8° (Society of Japanese Pharmacopoeia, 2001; Pharmacopeial Convention, 2004)

1.3.4. Technical products and impurities

Mestranol is commercially available as a component of combination tablets with chlormadinone acetate, ethynodiol diacetate, levonorgestrel, lynoestrenol or norethisterone and formerly with norethynodrel (IPPF, 2002; Sweetman, 2005; see the monograph on Combined estrogen–progestogen contraceptives and Annex 2).

1.3.5. Use

Mestranol is a synthetic estrogen pro-drug that is rapidly metabolized to ethinylestradiol; it therefore acts similarly to estradiol. It is used as the estrogen component of combined oral contraceptive preparations at a usual daily dose of 50 µg. The progestogen component is frequently norethisterone. Mestranol has also been used as the estrogen component of some preparations for hormonal menopausal therapy. Administration has usually been in a sequential regimen with doses ranging from 12.5 to 50 µg daily, in combination with a cyclical progestogen (Sweetman, 2005).

Table 3 presents comparative global data on sales of mestranol in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 3

Mestranol used in combined estrogen–progestogen contraceptives and combined estrogen-progestogen menopausal therapy (thousands of standard units).

1.4.1. Estradiol

(b) Structural and molecular formulae and relative molecular mass

1.4.2. Estradiol benzoate

(b) Structural and molecular formulae and relative molecular mass

1.4.3. Estradiol cypionate

(b) Structural and molecular formulae and relative molecular mass

1.4.4. Estradiol valerate

(b) Structural and molecular formulae and relative molecular mass

1.4.5. Use of estradiols

Estradiol is the most active of the naturally occurring estrogens. Estradiol and its semi-synthetic esters and other natural estrogens are primarily used in hormonal menopausal therapy, whereas synthetic derivatives such as ethinylestradiol and mestranol have a major role as components of combined oral contraceptives. Estradiol may also be used in hormonal therapy for female hypogonadism or primary ovarian failure (Sweetman, 2005).

For hormonal menopausal therapy, oral preparations of estradiol are commonly used, as are transdermal patches. Transdermal gels, subcutaneous implants and a nasal spray are also available. Intramuscular injections were used formerly. In women with a uterus, a progestogen is also required, given cyclically or continuously, and is usually taken orally, although some transdermal preparations are available. 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 (Sweetman, 2005).

For oral use, estradiol or estradiol valerate are normally given; doses are 1–2 mg daily cyclically or, more usually, continuously (Sweetman, 2005).

Estradiol may be used topically as transdermal skin patches to provide a systemic effect; a variety of patches are available that release between 25 and 100 µg estradiol every 24 h. Depending on the preparation, patches are replaced once or twice weekly. Topical gel preparations are also applied for systemic effect: the usual dose is 0.5–1.5 mg estradiol daily. A nasal spray is available that delivers 150 µg estradiol hemihydrate per spray. The usual initial dose is 300 µg daily; maintenance doses are 150–600 µg daily (Sweetman, 2005).

In order to prolong the duration of action, subcutaneous implants of estradiol may be used. The dose of estradiol is generally 25–100 mg and a new implant is given after about 4–8 months according to the concentrations of estrogen (Sweetman, 2005).

Estradiol may be used locally as vaginal tablets, as a 0.01% vaginal cream or as a 3month vaginal ring (Sweetman, 2005).

Intramuscular injections of estradiol benzoate or valerate esters have been used as oily depot solutions, usually given once every 3–4 weeks. The cypionate, dipropionate, enanthate, hexahydrobenzoate, phenylpropionate and undecylate esters of estradiol have been used similarly. The enanthate and cypionate esters are used as the estrogen component of combined injectable contraceptives (Sweetman, 2005).

Tables 4 and 5 present comparative global data on sales of estradiol and methylestradiol, respectively, in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 4

Estradiol used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

Table 5

Methylestradiol used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

1.5.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 50-27-1
• Chem. Abstr. Name: (16α,17β)-Estra-1,3,5(10)-triene-3,16,17-triol
• IUPAC Systematic Name: Estriol
• Synonyms: Estra-1,3,5(10)-triene-3,16α,17β-triol; estratriol; 16α-estriol; 16α,17β-estriol; 3,16α,17β-estriol; follicular hormone hydrate; 16α-hydroxyestradiol; 3,16α,17β-trihydroxyestra-1,3,5(10)-triene; trihydroxyestrin

1.5.2. Structural and molecular formulae and relative molecular mass

1.5.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White, odourless, crystalline powder
2. Melting-point: 282 °C
3. Solubility: Practically insoluble in water; sparingly soluble in ethanol; soluble in acetone, chloroform, dioxane, diethyl ether and vegetable oils; freely soluble in pyridine
4. Specific rotation: [α]²⁵_d, +58° (in dioxane)

1.5.4. Technical products and impurities

Estriol is commercially available as tablets, pessaries and a cream. Sodium succinate and succinate salts of estriol are also available (Sweetman, 2005).

Reported impurities include: estradiol, estra-1,3,5(10),9(11)-tetraene-3,16α,17β-triol (9,11-didehydroestriol), estra-1,3,5(10)-triene-3,16α,17α-triol (17-epi-estriol), estra1,3,5(10)-triene-3,16β,17β-triol (16-epi-estriol), estra-1,3,5(10)-triene-3,16β,17α-triol (16,17-epi-estriol), 3-hydroxyestra-1,3,5(10)-trien-17-one (estrone); 3,16α-dihydroxyestra-1,3,5(10)-trien-17-one, 3-hydroxy-17-oxa-D-homoestra-1,3,5(10)-trien-17a-one and 3-methoxyestra-1,3,5(10)-triene-16α,17β-diol (estriol 3-methyl ether) (British Pharmacopoeial Commission, 2004).

1.5.5. Use

Estriol is a naturally occurring estrogen that has actions and uses similar to those described for estradiol. It is used for hormonal menopausal therapy. For short-term treatment, oral doses of estriol have been 0.5–3 mg daily given for 1 month, followed by 0.5–1 mg daily. Estriol has also been given in combination with other natural estrogens, such as estradiol and estrone; usual doses of estriol have ranged from about 250 µg to 2 mg daily. It is also administered intravaginally for the short-term treatment of menopausal atrophic vaginitis as a 0.01% or 0.1% cream or as pessaries containing 500 µg (Sweetman, 2005).

Table 6 presents comparative global data on sales of estriol in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 6

Estriol used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

1.6.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 53-16-7
• Deleted CAS Reg. No.: 37242-41-4
• Chem. Abstr. Name: 3-Hydroxyestra-1,3,5(10)-trien-17-one IUPAC Systematic Name: 3-Hydroxyestra-1,2,5(10)-triene-17-one
• Synonyms: d-Estrone; d-oestrone

1.6.2. Structural and molecular formulae and relative molecular mass

1.6.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White to creamy white, odourless, crystalline powder (exists in three crystalline phases: one monoclinic, the other two orthorhombic)
2. Melting-point: 254.5–256 °C
3. Solubility: Practically insoluble in water (0.003 g/100 mL at 25 °C); soluble in ethanol (1 in 250), chloroform (1 in 110 at 15 °C), acetone (1 in 50 at 50 °C), dioxane and vegetable oils; slightly soluble in diethyl ether and solutions of alkali hydroxides
4. Specific rotation: [α]²⁵_d, +152° (in chloroform)

1.6.4. Technical products and impurities

Estrone is available commercially as pessaries and as a sterile suspension in water or 0.9% sodium chloride for injection. It is also available as a multicomponent tablet, cream and injectable solution (American Hospital Formulary Service, 2005; APPCo, 2005; Editions du Vidal, 2005).

1.6.5. Use

Estrone is a naturally occurring estrogen that has actions and uses similar to those described for estradiol. For hormonal menopausal therapy, estrone has been given orally at a dose of 1.4–2.8 mg daily, in a cyclical or continuous regimen, as a combination product with estradiol and estriol. Estrone has also been administered by intramuscular injection in oily solutions and aqueous suspensions. When used specifically for menopausal atrophic vaginitis, estrone has been administered vaginally (Sweetman, 2005).

Table 7 presents comparative global data on sales of estrone in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 7

Estrone used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

1.7.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 7280-37-7
• Deleted CAS No.: 29080-16-8
• Chem. Abstr. Name: 3-(Sulfooxy)-estra-1,3,5(10)-trien-17-one, compd. with piperazine (1:1)
• IUPAC Systematic Name: Estrone, hydrogen sulfate, compd. with piperazine (1:1) Synonyms: Piperazine estrone sulfate; piperazine oestrone sulfate; 3-sulfatoxyestra1,3,5(10)-trien-17-one piperazine salt; 3-sulfatoxyoestra-1,3,5(10)-trien-17-one piperazine salt

1.7.2. Structural and molecular formulae and relative molecular mass

1.7.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

• Description: White to yellowish white, odourless, fine crystalline powder
• Melting-point: 190 °C; solidifies on further heating and decomposes at 245 °C
• Solubility: Very slightly soluble in water, ethanol, chloroform and diethyl ether; soluble in warm water and warm ethanol (1 part in 500)
• Optical rotation: [α]²⁵_d, +87.8° (in sodium hydroxide)

1.7.4. Technical products and impurities

Estropipate is available as tablets and as a vaginal cream (American Hospital Formulary Service, 2005). Reported impurities include: estrone (British Pharmacopoeial Commission, 2004).

1.7.5. Use

Estropipate is a semi-synthetic conjugate of estrone with piperazine that is used for hormonal menopausal therapy. Its action is due to estrone to which it is hydrolysed in the body. Estropipate is given orally for the short-term treatment of menopausal symptoms; suggested doses have ranged from 0.75 to 6 mg daily, given cyclically or continuously. When used for longer periods for the prevention of postmenopausal osteoporosis, a daily dose of 0.75 or 1.5 mg is given cyclically or continuously. In women with a uterus, estropipate should be used in conjunction with a progestogen. Estropipate has also been used in the short-term treatment of menopausal atrophic vaginitis as a vaginal cream that contains 0.15%; 2–4 g of cream is applied daily (Sweetman, 2005).

Table 8 presents comparative global data on sales of estropipate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 8

Estropipate used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.1.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 302-22-7
• Chem. Abstr. Name: 17-(Acetyloxy)-6-chloropregna-4,6-diene-3,20-dione
• IUPAC Systematic Name: 6-Chloro-17-hydroxypregna-4,6-diene-3,20-dione, acetate
• Synonyms: 17α-Acetoxy-6-chloro-4,6-pregnadiene-3,20-dione; 6-chloro-Δ⁶-17-acetoxyprogesterone; 6-chloro-Δ⁶-[17α]acetoxyprogesterone

2.1.2. Structural and molecular formulae and relative molecular mass

2.1.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Society of Japanese Pharmacopoeia (2001)

1. Description: White to light-yellow, odourless crystals
2. Melting-point: 212–214 °C
3. Solubility: Practically insoluble in water; very soluble in chloroform; soluble in acetonitrile; slightly soluble in ethanol and diethyl ether
4. Optical rotation: [α]²⁰_d, −10.0° to −14.0° (in acetonitrile) (Society of Japanese Pharmacopoeia, 2001); [α]d, +6° (in chloroform) (O'Neil, 2001)

2.1.4. Technical products and impurities

Chlormadinone acetate is available commercially as tablets, either alone or in combination with ethinylestradiol or mestranol (IPPF, 2002).

2.1.5. Use

Chlormadinone acetate is a progestogen that is structurally related to progesterone and that may have some anti-androgenic activity. It is given orally either alone or in combination with an estrogen in the treatment of menstrual disorders such as menorrhagia and endometriosis at doses of 2–10 mg daily either cyclically or continuously. It may also be used as the progestogen component of combined oral contraceptives at a dose of 1–2 mg daily, particularly in women with androgen-dependent conditions such as acne and hirsutism (Sweetman, 2005).

Table 9 presents comparative global data on sales of chlormadinone acetate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 9

Chlormadinone acetate used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.2.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 427-51-0
• Chem. Abstr. Name: (1β,2β)-17-(Acetyloxy)-6-chloro-1,2-dihydro-3′H-cyclopropa-[1,2]pregna-1,4,6-triene-3,20-dione
• IUPAC Systematic Name: 6-Chloro-1β,2β-dihydro-17-hydroxy-3′H-cyclopropa[1,2]-pregna-1,4,6-triene-3,20-dione acetate
• Synonyms: Cyproterone 17-O-acetate; cyproterone 17α-acetate; 1,2α-methylene-6-chloro-17α-acetoxy-4,6-pregnadiene-3,20-dione; 1,2α-methylene-6-chloro-Δ^4,6-pregnadien-17α-ol-3,20-dione acetate; 1,2α-methylene-6-chloro-pregna-4,6-diene-3,20dione 17α-acetate; methylene-6-chloro-17-hydroxy-1α,2α-pregna-4,6-diene-3,20-dione acetate

2.2.2. Structural and molecular formulae and relative molecular mass

2.2.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Council of Europe (2005)

1. Description: White, crystalline powder
2. Melting-point: 200–201 °C
3. Solubility: Practically insoluble in water; very soluble in dichloromethane and acetone; soluble in methanol; sparingly soluble in ethanol
4. Specific rotation: [α]²⁰_d, +152° to +157°

2.2.4. Technical products and impurities

Cyproterone acetate is commercially available as tablets and an injectable solution (IPPF, 2002; British Medical Association/Royal Pharmaceutical Society of Great Britain, 2004; APPCo, 2005).

Reported impurities include: 3,20-dioxo-1β,2β-dihydro-3′H-cyclopropa[1,2]pregna-1,4,6-trien-17-yl acetate and 6-methoxy-3,20-dioxo-1β,2β-dihydro-3′H-cyclopropa[1,2]-pregna-1,4,6-trien-17-yl acetate (British Pharmacopoeial Commission, 2004).

2.2.5. Use

Cyproterone acetate is a progestogen that has anti-androgenic properties. It is typically used in conjunction with ethinylestradiol for the control of acne and hirsutism in women, and also provides contraception in these women. The usual oral doses are 2 mg cyproterone acetate with 35 µg ethinylestradiol given daily for 21 days of each menstrual cycle (Sweetman, 2005).

Table 10 presents comparative global data on sales of cyproterone acetate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 10

Cyproterone acetate used in combined estrogen–progestogen contraceptives, combined estrogen–progestogen menopausal therapy and other uses (thousands of standard units).

2.3.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 54024-22-5
• Chem. Abstr. Name: (17α)-13-Ethyl-11-methylene-18,19-dinorpregn-4-en-20-yn-17-ol
• IUPAC Systematic Name: 13-Ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol
• Synonyms: 13-Ethyl-11-methylene-18,19-dinor-17α-4-pregnen-20-yn-17-ol; 17α-ethynyl-18-methyl-11-methylene-Δ⁴-oestren-17β-ol

2.3.2. Structural and molecular formulae and relative molecular mass

2.3.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White, crystalline powder
2. Melting-point: 109–110 °C
3. Solubility: Practically insoluble in water; slightly soluble in ethanol and ethyl acetate; sparingly soluble in n-hexane
4. Optical rotation: [α]²⁰_d, +53° to +57° (in chloroform)

2.3.4. Technical products and impurities

Desogestrel is available commercially only in combination with ethinylestradiol in tablets for monophasic and triphasic regimens (IPPF, 2002; British Medical Association/Royal Pharmaceutical Society of Great Britain, 2004; American Hospital Formulary Service, 2005; Editions du Vidal, 2005; Sweetman, 2005).

Reported impurities include: 13-ethyl-16-[13-ethyl-17β-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-16-ylidene]-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17β-ol, 13-ethyl-11-methylene-18,19-dinor-5α,17α-pregn-3-en-20-yn-17-ol (desogestrel D³-isomer) and 11-methylene-19-nor-17α-pregn-4-en-20-yn-17-ol; 13-ethyl-11-methylenegon-4-en-17-one (British Pharmacopoeial Commission, 2004).

2.3.5. Use

Desogestrel is a synthetic progestene that is structurally related to levonorgestrel, has actions and uses similar to those of progestogens in general and has little or no androgenic activity. It is used as the progestogenic component of combined mono- and multiphasic oral contraceptive preparations and as a subdermal implantable ‘progestogen-only’ contraceptive. A typical daily oral dose of 150 µg is used as the progestogenic component of combined oral contraceptive preparations. An oral dose of 75 µg daily is used as a progestogenonly contraceptive (Editions du Vidal, 2005; Sweetman, 2005).

Table 11 presents comparative global data on sales of desogestrel in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 11

Desogestrel used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.4.1. Nomenclature

• Chem. Abst. Services Reg. No.: 67392-87-4
• Chem. Abstr. Name: (2′S,6R,7R,8R,9S,10R,13S,14S,15S,16S)-1,3′,4′,6,7,8,9,10,11,12, 13,14,15,16,20,21-Hexadecahydro-10,13-dimethyl-spiro[17H-dicyclopropa-[6,7:15,16]cyclopenta[a]phenanthrene-17,2′ (5′H)-furan]-3,5′ (2H)-dione
• Synonyms: Dihydrospirorenone; 1,2-dihydrospirorenone; drospirenona; spiro[17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene-17,2′ (5′H)-furan]-3,5′ (2H)-dione, 1,3′,4′,6,7,8,9,10,11,12,13,14,15,16,20,21-hexadecahydro-10,13-dimethyl-, [6R-(6α, 7α,8β,9α,10β,13β,14α,15α,16α,17β)]

2.4.2. Structural and molecular formulae and relative molecular mass

2.4.3. Chemical and physical properties

From O'Neil (2001)

1. Melting-point: 201.3 °C
2. Optical rotation: [α]²²_d, −182° (in chloroform)

2.4.4. Technical products and impurities

Drospirenone is available as capsules that contain 3.0 mg drospirenone and 0.030 mg ethinylestradiol as part of an oral contraceptive regimen (IPPF, 2002).

2.4.5. Use

Drospirenone is a progestogen with anti-mineralo-corticoid and anti-androgenic activities; it is used as the progestogenic component of a combined oral contraceptive at doses of 3 mg daily (Sweetman, 2005). Its use in hormonal menopausal therapy has also been reported very recently (IMS Health, 2005).

Table 12 presents comparative global data on sales of drospirenone in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 12

Drospirenone used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.5.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 152-62-5
• Chem. Abstr. Name: (9β,10α)-Pregna-4,6-diene-3,20-dione
• IUPAC Systematic Name: 10α-Pregna-4,6-diene-3,20-dione
• Synonyms: 10α-Isopregnenone; dehydro-retroprogesterone; dehydroprogesterone

2.5.2. Structural and molecular formulae and relative molecular mass

2.5.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White to pale yellow, odourless, crystalline powder
2. Melting-point: 169–170 °C
3. Solubility: Practically insoluble in water; soluble in acetone, chloroform (1 in 2), ethanol (1 in 40) and diethyl ether (1 in 200); slightly soluble in fixed oils; sparingly soluble in methanol
4. Specific rotation: [α]²⁵_d, −484.5° (in chloroform)

2.5.4. Technical products and impurities

Dydrogesterone is available commercially as tablets and capsules, either alone or in combination with estradiol (British National Formulary, 2004; APPCo, 2005; Editions du Vidal, 2005).

2.5.5. Use

Dydrogesterone is a progestogen that is structurally related to progesterone, but does not have estrogenic or androgenic properties. Together with cyclic or continuous estrogen, dydrogesterone is also given cyclically in oral doses of 10 mg once or twice daily, or continuously in doses of 5 mg daily, for endometrial protection during hormonal menopausal therapy. It is also given orally in the treatment of menstrual disorders such as menorrhagia, usually in a dose of 10 mg twice daily in a cyclical regimen, and for the treatment of endometriosis at a dose of 10 mg two or three times daily cyclically or continuously (British Medical Association, 2004; Sweetman, 2005).

Table 13 presents comparative global data on sales of dydrogesterone in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 13

Dydrogesterone used in a combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.6.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 297-76-7
• Chem. Abstr. Name: (3β,17α)-19-Norpregn-4-en-20-yne-3,17-diol, diacetate
• IUPAC Systematic Name: 19-Nor-17α-pregn-4-en-20-yne-3β,17β-diol, diacetate
• Synonyms: Ethinodiol diacetate; ethynodiol acetate; β-ethynodiol diacetate

2.6.2. Structural and molecular formulae and relative molecular mass

2.6.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005), unless otherwise noted

1. Description: White, odourless, crystalline powder
2. Melting-point: ∼126–127 °C
3. Solubility: Very slightly soluble to practically insoluble in water; soluble in ethanol; freely to very soluble in chloroform; freely soluble in diethyl ether
4. Optical rotation: [α]²⁰_d, −70° to −76° (in chloroform) (Pharmacopeial Commission, 2004)

2.6.4. Technical products and impurities

Ethynodiol diacetate is available commercially alone or as a component of a combination tablet that contains ethynodiol diacetate plus ethinylestradiol or mestranol (Sweetman, 2005).

2.6.5. Use

Ethynodiol diacetate is a progestogen that is used as the progestogenic component of combined oral contraceptives and also alone as an oral progestogen-only contraceptive. Typical daily doses are 1–2 mg in combination products and 500 µg for progestogen-only contraceptives (Sweetman, 2005).

Table 14 presents comparative global data on sales of ethynodiol diacetate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 14

Ethynodiol diacetate used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.7.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 60282-87-3
• Deleted CAS Reg. No.: 110541-55-4
• Chem. Abstr. Name: (17α)-13-Ethyl-17-hydroxy-18,19-dinorpregna-4,15-dien-20-yn-3-one
• IUPAC Systematic Name: 13-Ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,15-dien-20-yn-3-one

2.7.2. Structural and molecular formulae and relative molecular mass

2.7.3. Chemical and physical properties of the pure substance

From O'Neil (2001)

1. Description: Crystals
2. Melting-point: 197.9 °C

2.7.4. Technical products and impurities

Gestodene is available commercially as a component of combination tablets with ethinylestradiol (IPPF, 2002; Editions du Vidal, 2005).

2.7.5. Use

Gestodene is used as the progestogenic component of combined oral contraceptives; a typical daily dose is 75 µg in monophasic preparations and 50–100 µg in triphasic preparations (Sweetman, 2005).

Table 15 presents comparative global data on sales of gestodene in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 15

Gestodene used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.8.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 797-63-7
• Deleted CAS Reg. No.: 797-62-6; 4222-79-1; 121714-72-5
• Chem. Abstr. Name: (17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one
• IUPAC Systematic Name: 13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn3-one
• Synonyms: 13-Ethyl-17-ethynyl-17β-hydroxy-4-gonen-3-one; 13-ethyl-17α-ethynyl-17-hydroxygon-4-en-3-one; 13-ethyl-17α-ethynylgon-4-en-17β-ol-3-one; 13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one; 13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one; 17-ethynyl-18-methyl-19-nortestosterone; 18-methylnorethindrone; l-norgestrel; D-l-norgestrel; D-norgestrel

2.8.2. Structural and molecular formulae and relative molecular mass

2.8.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White or almost white, odourless, crystalline powder
2. Melting-point: 235–237 °C
3. Solubility: Practically insoluble in water; slightly soluble in ethanol; sparingly soluble in dichloromethane; soluble in chloroform
4. Specific rotation: [α]²⁰_d, −32.4° (in chloroform)

2.8.4. Technical products and impurities

Levonorgestrel is available commercially as a single-ingredient tablet and in combined tablets with estradiol, estradiol valerate, estriol and ethinylestradiol for hormonal therapy (British Pharmacopaeial Commission, 2004). It is also available as an intrauterine system and as a flexible, closed-capsule implant made of silicone rubber tubing (Sweetman, 2005).

Reported impurities include: 13-ethyl-3,4-diethynyl-18,19-dinor-17α-pregn-5-en-20-yn-3β,4α,17-triol, 13-ethyl-3,4-diethynyl-18,19-dinor-17α-pregn-5-en-20-yn-3α,4α,17-triol 13-ethyl-18,19-dinor-17α-pregn-4-en-20-yn-17-ol, 13-ethyl-3-ethynyl-18,19-dinor-17α-pregna-3,5-dien-20-yn-17-ol, 13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,8(14)-dien-20-yn-3-one and 13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-5(10)-en-20-yn-3-one (British Pharmacopoeial Commission, 2004).

2.8.5. Use

Levonorgestrel is D-(–)-norgestrel, the active levorotatory form of norgestrel.

Levonorgestrel is more commonly used as a hormonal contraceptive than norgestrel (and is twice as potent) and has androgenic activity. The typical daily dose of levonorgestrel is 30 or 37.5 µg when used as an oral progestogen-only contraceptive, 150–250 µg when used as a combined oral contraceptive in monophasic preparations, and 50–125 µg when used as a combined oral contraceptive in triphasic preparations. Levonorgestrel is also used as a long-acting (up to 5 years) progestogen-only contraceptive administered by subcutaneous implantation. A long-acting intrauterine device is also available for contraception or menorrhagia (Sweetman, 2005).

Levonorgestrel is used as the progestogenic component of hormonal menopausal therapy. A typical oral regimen is 75–250 µg levonorgestrel for 10–12 days of a 28-day cycle. Levonorgestrel may also be given via a combined transdermal patch, applied once weekly for 2 weeks of a 4-week cycle, that releases 10 µg per 24 h together with an estrogen. Alternatively, a patch that releases 7 µg per 24 h together with an estrogen is applied once weekly for continuous hormonal therapy (Sweetman, 2005).

Table 16 presents comparative global data on sales of levonorgestrel in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 16

Levonorgestrel used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.9.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 52-76-6
• Deleted CAS Reg. No.: 60416-16-2
• Chem. Abstr. Name: (17α)-19-Norpregn-4-en-20-yn-17-ol
• IUPAC Systematic Name: 19-Nor-17α-pregn-4-en-20-yn-17-ol Synonyms: 3-Desoxynorlutin; Δ⁴-17α-ethinylestren-17β-ol; Δ⁴-17α-ethinyloestren17β-ol; ethynylestrenol; ethynyloestrenol; 17α-ethynylestrenol; 17α-ethynyloestrenol; 17α-ethynyl-17β-hydroxy-Δ⁴-estrene; 17α-ethynyl-17β-hydroxy-Δ⁴-oestrene

2.9.2. Structural and molecular formulae and relative molecular mass

2.9.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White, crystalline powder
2. Melting-point: 158–160 °C
3. Solubility: Practically insoluble in water; soluble in ethanol, acetone and diethyl ether; freely soluble in chloroform
4. Specific rotation: [α]_D, −13° (in chloroform)

2.9.4. Technical products and impurities

Lynestrenol is available commercially as a single-ingredient tablet and as a component of combination tablets that contain ethinylestradiol or mestranol (Reynolds, 1996; IPPF, 2002; Editions du Vidal, 2005).

2.9.5. Use

Lynestrenol is used alone or as the progestogenic component of oral contraceptives. Typical oral daily doses for contraception are 0.5 mg when used as a progestogen-only preparation and 0.75–2.5 mg when combined with an estrogen. When used alone for menstrual disorders, doses of 5 to 10 mg daily are given, frequently as cyclical regimens (Sweetman, 2005).

Table 17 presents comparative global data on sales of lynestrenol in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 17

Lynoestrenol used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.10.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 71-58-9
• Chem. Abstr. Name: (6α)-17-(Acetyloxy)-6-methylpregn-4-ene-3,20-dione
• IUPAC Systematic Name: 17-Hydroxy-6α-methylpregn-4-ene-3,20-dione, acetate
• Synonyms: 17α-Acetoxy-6α-methylprogesterone; depomedroxyprogesterone acetate; depo-progestin; depot-medroxyprogesterone acetate; DMPA; 17-hydroxy-6α-methylprogesterone, acetate; 17α-hydroxy-6α-methylprogesterone acetate; MAP; medroxyprogesterone 17-acetate; 6α-methyl-17-acetoxyprogesterone; 6α-methyl-17α-hydroxyprogesterone acetate

2.10.2. Structural and molecular formulae and relative molecular mass

2.10.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White to off-white, odourless, crystalline powder
2. Melting-point: 207–209 °C
3. Solubility: Practically insoluble in water; slightly soluble in diethyl ether; sparingly soluble in ethanol and methanol; soluble in acetone and dioxane; freely soluble in chloroform and dichloromethane
4. Specific rotation: [α]²⁵_d, +61° (in chloroform)

2.10.4. Technical products and impurities

Medroxyprogesterone acetate is available commercially as single-ingredient tablets, as combination tablets with conjugated estrogens, estradiol or estradiol cypionate and as sterile suspensions (IPPF, 2002; American Hospital Formulary Service, 2005; Editions du Vidal, 2005).

Reported impurities include: 6α,17a-dimethyl-3,17-dioxo-D-homoandrost-4-en-17aα-yl acetate, 6β-hydroxy-6-methyl-3,20-dioxopregn-4-en-17-yl acetate (6β-hydroxymedroxyprogesterone acetate), 17-hydroxy-6α-methylpregn-4-ene-3,20-dione (medroxyprogesterone), 6-methyl-3,20-dioxopregna-4,6-dien-17-yl acetate, 6α-methyl-3,20-dioxo-5β-pregnan-17-yl acetate (4,5β-dihydromedroxyprogesterone acetate), 6β-methyl-3,20-dioxopregn-4-en-17-yl acetate (6-epimedroxyprogesterone acetate) and 6-methylene-3,20-dioxopregn-4-en-17-yl acetate (6-methylenehydroxyprogesterone acetate) (British Pharmacopoeial Commission, 2004).

2.10.5. Use

Medroxyprogesterone acetate is given by intramuscular injection as a contraceptive. A combined contraceptive injection that contains 25 mg medroxyprogesterone acetate with 5 mg estradiol cypionate is given monthly. As a progestogen-only contraceptive, a dose of 150 mg is given every 12 weeks.

When used as the progestogen component of hormonal menopausal therapy, medroxyprogesterone acetate is administered orally in a variety of regimens that include 2.5 or 5 mg daily continuously, 5 or 10 mg daily for 12–14 days of a 28-day cycle and 20 mg daily for 14 days of a 91-day cycle (Sweetman, 2005).

It is also used for the treatment of menorrhagia and secondary amenorrhoea and in the palliative treatment of some hormone-dependent malignant neoplasms (Sweetman, 2005).

Table 18 presents comparative global data on sales of medroxyprogesterone acetate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 18

Medroxyprogesterone acetate used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.11.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 595-33-5
• Chem. Abstr. Name: 17-(Acetyloxy)-6-methylpregna-4,6-diene-3,20-dione
• IUPAC Systematic Name: 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione, acetate
• Synonyms: DMAP; megestryl acetate; MGA

2.11.2. Structural and molecular formulae and relative molecular mass

2.11.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White to creamy white, odourless, crystalline powder
2. Melting-point: 214–216 °C
3. Solubility: Practically insoluble in water (2 µg/mL at 37 °C); very soluble in chloroform; soluble in acetone; slightly soluble in diethyl ether and fixed oils; sparingly soluble in ethanol
4. Specific rotation: [α]²⁴_d, +5° (in chloroform)

2.11.4. Technical products and impurities

Megestrol acetate is available commercially as tablets and as an oral suspension (IPPF, 2002; Editions du Vidal, 2005).

Reported impurities include: 6,17a-dimethyl-3,17-dioxo-D-homoandrosta-4,6-dien17aα-yl acetate (D-homo megestrol acetate), 6α-methyl-3,20-dioxopregn-4-en-17-yl acetate (medroxyprogesterone acetate), 6-methyl-3,20-dioxopregna-1,4,6-trien-17-yl acetate, 6-methylene-3,20-dioxopregn-4-en-17-yl acetate (6-methylene hydroxyprogesterone acetate) and 6-methyl-17-hydroxypregna-4,6-diene-3,20-dione (megestrol) (British Pharmacopoeial Commission, 2004).

2.11.5. Use

Megestrol acetate has been used in a few countries as an oral contraceptive, usually in combination with ethinylestradiol, although it is believed that such usage has been discontinued. It is used for the palliative treatment of carcinoma of the breast or endometrium, in the treatment of acne, hirsutism and sexual infantilism in women and in the treatment of anorexia and cachexia in patients with acquired immunodeficiency syndrome or cancer (Reynolds, 1996; Sweetman, 2005).

Table 19 presents comparative global data on sales of megestrol acetate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 19

Megestrol acetate used in combined oestrogen–progestogen contraceptives (thousands of standard units).

2.12.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 68-22-4
• Chem. Abstr. Name: (17α)-17-Hydroxy-19-norpregn-4-en-20-yn-3-one
• IUPAC Systematic Name: 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one
• Synonyms: Ethinylnortestosterone; 17α-ethinyl-19-nortestosterone; ethynylnortestosterone; 17-ethynyl-19-nortestosterone; 17α-ethynyl-19-nortestosterone; norethindrone; norethisteron; norethynodrone; 19-nor-17α-ethynyltestosterone; norpregneninolone

2.12.2. Structural and molecular formulae and relative molecular mass

2.12.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White or yellowish white, odourless, crystalline powder
2. Melting-point: 203–204 °C
3. Solubility: Practically insoluble in water; slightly to sparingly soluble in ethanol; slightly soluble in diethyl ether; soluble in chloroform and dioxane
4. Specific rotation: [α]²⁰_d, −31.7° (in chloroform)

2.12.4. Technical products and impurities

Norethisterone is available commercially as single-ingredient tablets or as a component of combination tablets with ethinylestradiol or mestranol (IPPF, 2002).

2.12.5. Use (norethisterone and its acetate and enanthate esters)

Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties. They are commonly used as hormonal contraceptives in monophasic, biphasic and triphasic regimens (Sweetman, 2005).

Norethisterone and norethisterone acetate are both given orally. Typical daily doses are 0.35 mg for norethisterone and 0.6 mg for norethisterone acetate when used alone, or 0.5–1 mg for norethisterone and 1–1.5 mg for norethisterone acetate when used with an estrogen. Norethisterone enanthate is given by intramuscular injection; a dose of 200 mg provides contraception for 8 weeks (Sweetman, 2005).

Norethisterone and norethisterone acetate are used as the progestogen component of hormonal menopausal therapy. Typical regimens have included either continuous daily doses of 0.7 mg norethisterone or 0.5–1 mg norethisterone acetate, or cyclical regimens of 1 mg norethisterone or norethisterone acetate daily for 10–12 days of a 28-day cycle. Norethisterone acetate is also available as transdermal patches that supply 170 or 250 µg in 24 h and are applied twice weekly for 2 weeks of a 4-week cycle; the lower dose may also be applied twice weekly on a continuous basis (Sweetman, 2005).

Table 20 presents comparative global data on sales of norethisterone in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 20

Norethisterone used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.13.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 51-98-9
• Chem. Abstr. Name: (17α)-17-(Acetyloxy)-19-norpregn-4-en-20-yn-3-one
• IUPAC Systematic Name: 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, acetate
• Synonyms: 17α-Ethinyl-19-nortestosterone 17β-acetate; 17α-ethinyl-19-nortestosterone acetate; 17α-ethynyl-19-nortestosterone acetate; norethindrone acetate; norethindrone 17-acetate; norethisteron acetate; norethisterone 17-acetate; 19-norethisterone acetate; norethynyltestosterone acetate; 19-norethynyltestosterone acetate; norethysterone acetate

2.13.2. Structural and molecular formulae and relative molecular mass

2.13.3. Chemical and physical properties of the pure substance

1. Description: White or creamy white, odourless, crystalline powder (Sweetman, 2005)
2. Melting-point: 161–162 °C (O'Neil, 2001)
3. Solubility: Practically insoluble in water (1 g in > 10 L); soluble in ethanol (1 part in 10), chloroform (1 part in < 1), dioxane (1 part in 2) and diethyl ether (1 part in 18) (Sweetman, 2005)
4. Specific rotation: [α]²⁵_d, −32° to −38° (Pharmacopeial Convention, 2004)

2.13.4. Technical products and impurities

Norethisterone acetate is available commercially as single-ingredient tablets or as a component of combination tablets with ethinylestradiol. For hormonal postmenopausal therapy, norethisterone acetate is used in combination with estradiol or estradiol hemihydrate. It is also available as a percutaneous patch with estradiol (IPPF, 2002; British Medical Association, 2004; Editions du Vidal, 2005).

Reported impurities include: 6β-acetyl-3-oxo-19-nor-17α-pregn-4-en-20-yn-17-yl acetate, 3,20-dioxo-19-nor-17α-pregn-4-en-17-yl acetate, 6β-hydroxy-3-oxo-19-nor-17α-pregn-4-en-20-yn-17-yl acetate, 3,6-dioxo-19-nor-17α-pregn-4-en-20-yn-17-yl acetate, norethisterone, 3-oxo-19-nor-17α-pregn-5(10)-en-20-yn-17-yl acetate and 3-oxo-19-nor17α-pregn-5-en-20-yn-17-yl acetate (British Pharmacopoeial Commission, 2004).

2.13.5. Use

See norethisterone.

2.14.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 3836-23-5
• Chem. Abstr. Name: (17α)-17-(Heptanoyl)-19-nor-pregn-4-en-20-yn-3-one
• IUPAC Systematic Name: 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, heptanoate
• Synonyms: Norethindrone enanthate; norethindrone oenanthate; norethisterone enanthate; norethisterone heptanoate; 17β-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one heptanoate

2.14.2. Structural and molecular formulae and relative molecular mass

2.14.3. Chemical and physical properties of the pure substance

No information was available to the Working Group.

2.14.4. Technical products and impurities

Norethisterone enanthate is available commercially in an oily solution for depot injection (IPPF, 2002).

2.14.5. Use See norethisterone.

2.15.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 68-23-5
• Chem. Abstr. Name: (17α)-17-Hydroxy-19-norpregn-5(10)-en-20-yn-3-one
• IUPAC Systematic Name: 17-Hydroxy-19-nor-17α-pregn-5(10)-en-20-yn-3-one
• Synonyms: Enidrel; noretynodrel

2.15.2. Structural and molecular formulae and relative molecular mass

2.15.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005)

1. Description: White, odourless, crystalline powder
2. Melting-point: 169–170 °C
3. Solubility: Very slightly soluble in water; freely soluble in chloroform; soluble in acetone; sparingly soluble in ethanol
4. Optical rotation: [α]²⁵_d, +108° (in 1% chloroform)

2.15.4. Technical products and impurities

Norethynodrel was available commercially as a component of a combination tablet with mestranol. Information available in 2005 indicated that there is no usage of norethynodrel at any dose in any form of drug (Sweetman, 2005).

2.15.5. Use

Norethynodrel is a progestogen that is structurally related to norethisterone, which has been given orally in conjunction with an estrogen such as mestranol for the treatment of various menstrual disorders and endometriosis (Sweetman, 2005). Available information indicates that it is no longer produced or used.

Table 21 presents comparative global data on sales of norethynodrel in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 21

Norethynodrel used in combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.16.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 35189-28-7
• Chem. Abstr. Name: (17α)-17-(Acetyloxy)-13-ethyl-18,19-dinorpregn-4-en-20-yn-3-one, 3-oxime
• IUPAC Systematic Name: 13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one oxime acetate (ester)
• Synonyms: 17α-Acetoxy-13-ethyl-17-ethynylgon-4-en-3-one oxime; dexnorgestrel ace-time

2.16.2. Structural and molecular formulae and relative molecular mass

2.16.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005), unless otherwise noted

1. Description: White to pale yellow powder (a mixture of (E)- and (Z)-isomers that has a ratio of (E)- to (Z)-isomer of between 1.27 and 1.78)
2. Melting-point: 214–218 °C
3. Solubility: Insoluble in water; sparingly soluble in acetonitrile; freely to very soluble in dichloromethane
4. Specific rotation: [α]²⁵_d, +110°; [α]_D, +40° to +46° (in chloroform) (Pharmacopeial Commission, 2004)

2.16.4. Technical products and impurities

Norgestimate is available commercially as a component of a combination tablet with ethinylestradiol (British Medical Association, 2004; IPPF, 2004; Editions du Vidal, 2005).

2.16.5. Use

Norgestimate is structurally related to levonorgestrel (to which it is partly metabolized) and is used as the progestogenic component of combined oral contraceptives and in hormonal menopausal therapy. A typical daily dose is 250 µg in monophasic contraceptive preparations and 180–250 µg in triphasic preparations. For hormonal menopausal therapy, a regimen of estradiol daily for 3 days followed by estradiol combined with 90 µg norgestimate daily for 3 days is used; this 6-day cycle is repeated continuously without interruption (Sweetman, 2005).

Table 22 presents comparative global data on sales of norgestimate in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 22

Norgestimate used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.17.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 6533-00-2
• Chem. Abstr. Name: (17α)-dl-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one
• IUPAC Systematic Name: dl-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one
• Synonyms: (17α)-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one; methylnorethindrone; α-norgestrel; dl-norgestrel; DL-norgestrel

2.17.2. Structural and molecular formulae and relative molecular mass

2.17.3. Chemical and physical properties of the pure substance

From O'Neil (2001) and Sweetman (2005), unless otherwise noted

1. Description: White, practically odourless, crystalline powder
2. Boiling-point: 205–207 °C
3. Solubility: Practically insoluble in water; slightly to sparingly soluble in ethanol; sparingly soluble in dichloromethane; freely soluble in chloroform
4. Optical rotation: [α]²⁵_d, −0.1° to +0.1° (in chloroform) (Pharmacopeial Convention, 2004)

2.17.4. Technical products and impurities

Norgestrel is available commercially as a single-ingredient tablet and as a component of combination tablets with ethinylestradiol, estradiol valerate or as combined injectable solution with ethinylestradiol (IPPF, 2002; Editions du Vidal, 2005).

2.17.5. Use

Uses of norgestrel in oral contraception and menopausal hormonal therapy are similar to those of levonorgestrel, with the exception of applications of the levo-enantiomer in subcutaneous implants and intrauterine devices (Sweetman, 2005).

Table 23 presents comparative global data on sales of norgestrel in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 23

Norgestrel used in combined estrogen–progestogen contraceptives and combined estrogen–progestogen menopausal therapy (thousands of standard units).

2.18.1. Nomenclature

• Chem. Abst. Services Reg. No.: 57-83-0
• Chem. Abstr. Name: Pregn-4-ene-3,20-dione
• Synonyms: Corpus luteum hormone; luteal hormone; luteine; luteohormone; Δ⁴-pregnene-3,20-dione

2.18.2. Structural and molecular formulae and relative molecular mass

2.18.3. Chemical and physical properties

From O'Neil (2001) and Sweetman (2005), unless otherwise noted

1. Description: Exists in two readily interconvertible crystalline forms: the α form, in white orthorhombic prisms, and the β form, in white orthorhombic needles
2. Melting-point: α form, 128.5–131 °C; β form, 121–122 °C
3. Solubility: Practically insoluble in water; soluble in ethanol (1 in 8), arachis oil (1 in 60), chloroform (1 in < 1), diethyl ether (1 in 16), ethyl oleate (1 in 60) and light petroleum (1 in 100) (Wade, 1977); soluble in acetone, dioxane and concentrated sulfuric acid; sparingly soluble in vegetable oils
4. Optical rotation: α form — [α]²⁰_d, +192°; β form — [α]²⁰_d, +172° to +182° (in dioxane)

2.18.4. Technical products and impurities

Progesterone is available in an oily solution for injection, as pessaries or suppositories and as an intrauterine device (IPPF, 2002; British Medical Association, 2004; Editions du Vidal, 2005).

Reported impurities include: 21-(cyclohex-1-enyl)pregn-4-ene-3,20-dione, 21-(cyclohexylidene)pregn-4-ene-3,20-dione, (20R)-20-hydroxypregn-4-en-3-one, (20S)-20-hydroxypregn-4-en-3-one, (20R)-3-oxopregn-4-en-20-yl acetate, (20S)-3-oxopregn-4-en-20-yl acetate and pregna-4,14-diene-3,20-dione (British Pharmacopoeial Commission, 2004).

2.18.5. Use

Progesterone is a naturally occurring steroidal hormone found in a wide variety of tissues and biological fluids, including cow's milk. It has also been found in certain plant species (IARC, 1979).

Progesterone is used in human medicine for the treatment of secondary amenorrhoea and dysfunctional uterine bleeding, although progestational agents that are active orally are generally preferred to progesterone (Reynolds, 1996). Progesterone is usually administered as an oily intramuscular injection, a vaginal gel or pessaries or as suppositories. An oral micronized preparation of progesterone is also available. In dysfunctional uterine bleeding or amenorrhoea, 5–10 mg progesterone daily may be given by intramuscular injection for about 5–10 days until 2 days before the anticipated onset of menstruation. Alternatively, progesterone may be administered as a vaginal gel at a usual dose of 45 mg on alternate days from day 15 to 25 of the cycle or orally at a dose of 400 mg daily for 10 days (Sweetman, 2005).

Progesterone gel may be administered intravaginally at a dose of 45 mg on alternate days for 12 days of a 28-day cycle as the progestogen component of menopausal hormonal therapy. A progesterone-releasing intrauterine device has also been used as a hormonal contraceptive; the device contains 38 mg of progesterone and is effective for up to 12 months (Sweetman, 2005).

In women with a history of recurrent miscarriage and proven progesterone deficiency, twice-weekly intramuscular injections (increased to daily if necessary) of 25–100 mg progesterone, from approximately day 15 of the pregnancy until 8–16 weeks, has been used. A similar schedule has been used in in-vitro fertilization or gamete intra-fallopian transfer techniques (Sweetman, 2005).

Table 24 presents comparative global data on sales of progesterone in 1994, 1999 and 2004 (IMS Health, 2005). The regions are broadly as those defined by WHO.

Table 24

Progesterone used for combined estrogen–progestogen menopausal therapy (thousands of standard units).