17-Ethinyl steroids

Due to the lack of suitable functional groups in steroid hormones, titrimetry has never played an important role in steroid hormone analysis. Of the several indirect methods, however, one is still widely used all pharmacopoeias contain methods for the determination of ethinyl steroids on the basis of the exchange of the acetylenic hydrogen for silver ions and the titration of the liberated acid with standard sodium hydroxide. 

The two synthetic steroidal estrogens which have attained the greatest degree of therapeutic use are ethinyl estradiol [57-63-6] (EE) (5) and its 3-methyl ether, mestranol [72-33-3]((5). In contrast to the naturally occurring estrone derivatives, these acetylenic analogues are orally active and are the main estrogenic components of combination oral contraceptives (see Contraceptives) and certain estrogen replacement products. 

If homolytic reaction conditions (heat and nonpolar solvents) can be avoided and if the reaction is conducted in the presence of a weak base, lead tetraacetate is an efficient oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The yield of product is in many cases better than that obtained by oxidation with chromium trioxide. The reaction in pyridine is moderately slow the intial red pyridine complex turns to a yellow solution as the reaction progresses, the color change thus serving as an indicator. The method is surprisingly mild and free of side reactions. Thus 17a-ethinyl-17jS-hydroxy steroids are not attacked and 5a-hydroxy-3-ket-ones are not dehydrated. 

Combined oral contraceptives contain a combination of a synthetic estrogen and one of several steroids with progestational activity. Most oral contraceptives contain one of two types of estrogen ethinyl estradiol, which is pharmacologically... 

Luzardo OP, Machln RP, Dlaz-Chico BN, Fernandez L (2000) Photoaffinity labeling identification of a specific binding protein for the anabolic steroids stanozolol and danazol an oligomeric protein regulated by age, pituitary hormones, and ethinyl estradiol. Endocrinology 141 3377... 

Synthetic steroid hormones retain the common steroid nucleus, but they may contain novel substituents that affect their pharmacological activity. The two most widely used synthetic steroid estrogens are ethinyl estradiol (Estinyl) and mestranol, found in oral contraceptives. Synthetic steroids containing an ethinyl substitution are metabolized more slowly. Thus, these synthetic steroid hormones have better oral absorption properties and extended biological half-lives than the natural estrogens. 

Approximately 50% of a dose of mestranol is de-methylated to form ethinyl estradiol. Ethinyl estradiol also can be deethinylated. Subsequently, the metabolism of these two synthetic estrogens proceeds by means of the same pathways as the natural steroid hormones. The principal metabolites of mestranol and ethinyl estradiol are hydroxylated derivatives that are conjugated with either glucuronic acid or sulfate. The synthetic steroid estrogens, in contrast to the natural estrogens, are excreted primarily in the feces. 

ALESSE 28 (levonorgestrel and ethinyl estradiol tablets) Wyeth April 2004 labeling Precautions. Drug Interactions Herbal products containing St. John s wort H. perforatum) may induce hepatic enzymes (CYP) and P-gp transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding ... 

Huang NH, Li C, Goldzieher JW. Absence of antibodies to ethinyl estradiol in users of oral contraceptive steroids. Fertil Steril 1984 41(4) 587-92. 

One rarely used but powerful means of maximizing both content uniformity (as mentioned above) and stability aspects of low-dose pharmaceuticals is the formation of inclusion complexes to increase both the drug load in the formulation as well as the stability of the API. One specific example is the complexation of ethinyl estradiol in the form of its /3-cyclodextrin clathrate for use in pharmaceutical formulations.23 This inclusion complex has been successfully applied in the development of an ultralow-dose formulation of this steroid.24... 

UGT activity is modulated by various hormones. Excess thyroid hormone and ethinyl oestradiol (but not other oral contraceptives) inhibit bilirubin glucuronidation. In contrast, the combination of progestational and oestrogenic steroids results in increased enzyme activity. Bihrubin glucuronidation can also be inhibited by certain antibiotics (e.g. novobiocin or gentamicin, at serum concentrations exceeding therapeutic levels) and by chronic hepatitis, advanced cirrhosis and Wilson s disease. 

Steroids, hormones, and related compounds betamethasone, dexamethasone, dienoeshol, ethinyl-oestradiol, ethynodiol diacetate, fludrocortisone, liothyronine, lynoestrenol, mestranol, norethister-one, stilboestrol, thyroxine. 

The steroids as a group tend to be poorly soluble in water. Their complex stmcture makes prediction of solubility somewhat difficult, but one can generally rationalise, post hoc, the solubility values of related steroids. Table 5.6 gives solubility data for 14 steroids. As examples, the substitution of an ethinyl group has conferred increased solubility on the estradiol molecule, as would be expected. Estradiol benzoate with its 3-OH substituent is much less soluble than the parent estradiol because of the loss of the hydroxyl and its substitution with a hydrophobic group. The same relationships are seen in testosterone and testosterone propionate. As both estradiol benzoate and testosterone propionate are oil soluble, they are used as solutions in castor oil and sesame oil for intramuscular and subcutaneous injection (see Chapter 9). 

---