Testosterone and derivatives

Fig. 1 Fluorescence scan of a blank track (A) and of the testosterone derivative (B, 2 jig). Start (1), testosterone-INH derivative hRf 39) (2), unknown substances (3, 4).

The testosterone ester derivative (10 mmol) is dissolved in ca. 100 ml of a solution of hydrazoic acid in chloroform (0.15 and treated with stirring... 

Testosterone (T.) derivatives for clinical use. T. esters for im. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

Testosterone and its derivatives can be administered in several ways. Fluoxymesterone and methyl-testosterone are 17-alpha-alkylated derivatives which are active when administered orally. 

Higashi and coworkers [28] used 2-hydrazino-l-methylpyridine (HMP) derivatization to introduce a positively charged moiety in testosterone and dihydrotestosterone (DHT) to achieve a sensitivity improvement of 70- to 1600-fold compared to underivatized molecules in ESI. However, they found the derivative was unsuitable for di-keto steroids such as androstenedione and progesterone, so this form of derivatization is unlikely to be widely accepted. Separable syn- and anti- (E and Z) stereoisomers are formed using this derivative. Preparation is as follows a solution of 10 pg HMP in 50 pi ethanol containing 25 pg TFA was added to the steroid dissolved in 30 pi ethanol. After heating for 1 h at 60 C, the solvents can be removed and sample injected. 

In their studies, Kushnir and co-workers [44, 45] found an increase in sensitivity of ESI detection of testosterone and adrenal steroids when they convert carbonyl groups to oximes. The steroid mixture is dissolved in 300 pi of an aqueous hydroxylamine solution (1.5 mol, pH 10), and following heating for 30 min at 90 C the derivatives are extracted with methyl t-butyl ether (2 ml). 

Photochemically reactive molecules have often been used as labels for specific sites in proteins and nucleic acids. Psoralen derivatives serve as relatively nonspecific photochemically activated crosslinking agents for DNA and double-stranded RNA.195 Aryl azides are converted by light to aryl nitrenes, which react in a variety of ways including insertion into C-H bonds (Eq. 23-27).200 201 In some cases UV irradiation can be used to join natural substrates to enzymes or hormones to receptors. For example, progesterone, testosterone, and other steroids have been used for direct photoaffinity labeling of their receptors.202 Synthetic benzophenones have also been used widely as photoactivated probes.203... 

The testosterone ester derivative (10 mmol) is dissolved in ca. 100 ml of a solution of hydrazoic acid in chloroform (0.15 M)138 and treated with stirring with a solution of 20 ml of f-butyl alcohol and N-chlorosuccinimide (2 g, 15 mmol). The reaction mixture is stirred for 8-10 hr and then added with stirring to a saturated solution of sodium bisulfite. The mixture is diluted with 200 ml of chloroform and washed with water. The chloroform layer is further washed with dilute sodium bicarbonate solution and water, dried (Na2S04) and the solvent removed in vacuo. The residual /-butyl alcohol is removed by repeatedly adding methanol to the product and concentrating to dryness in vacuo. The residue is triturated four times with Skellysolve F to separate the two isomeric adducts, (103) and (104). 

For therapeutic purposes and under the control of a responsible veterinarian, the administration to farm animals of 17/3-estradiol, testosterone, and progesterone and derivatives that readily yield the parent compound on hydrolysis after absorption at the site of application may be authorized by the individual EU member states. Also, for therapeutic purposes, the administration of authorized veterinary medicinal products containing (i) allyl trenbolone, administered orally, or beta-agonists to equidae and pets, provided they are used in accordance with the manufacturer s instructions, (ii) beta-agonists, in the form of an injection to induce tocolysis in cows when calving may be authorized. Again, these veterinary medicinal products must be administered by a veterinarian under his direct responsibility. 

Both men and women produce androgens and estrogens. Women s dominant production is estrogens, and men s dominant production is androgens. Reverse this and each will take on their counter-parts characteristic to quite some extent. Our main focus for the following chapters is the male androgen testosterone and its almost endless derivatives and esters. 

Anabolic steroids, antidepressants and drugs of abuse affect libido, potency, and ejaculatory function. Anabolic steroids are derivatives of testosterone, and have strong genitotropic effects. There is published evidence indicating that anabolic steroids increases sexual desire however, the frequency of erectile dysfunction is also increased. Treatment with the antidepressant fluoxetine has been associated with sexual side effects including delayed or nonexistent ejaculation and hyposexuality. Mice treated in utero with the anideukemic agent 5-aza-2/-deoxycytidine exhibit abnormal reproductive behavior and low reproductive capacity. 

Testosterone and its derivatives are used in the treatment of hypogonadism (eunuchoidism), hypopituitarism, accelerated growth, aging in men, osteoporosis, anemia, endometriosis, promotion of anabolism, suppression of lactation, and breast carcinoma. 

In spite of all the successes of this structural work, the extraordinary discriminatory potential that chiroptical methods would obviously have if applied to the rather mundane task of preliminary routine screening for drugs has never been exploited. One reason for this may be that the sensitivity to stereochemistry has not been fully explained in theoretical terms. The utter inadequacy of the aforementioned theoretical models is easier to understand and appreciate when one realizes that the spatial redirection of just one bond in a molecule, while not affecting the absorption spectra for the structural analogs, will produce changes in the CD spectra that are so dramatic that their individual distinction is elementary. Outstanding illustrations are plentiful in the CD literature of the steroids, for example testosterone and its dihydro-derivative, Figure 1. 

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