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BRIEF SUMMARY OF THE INVENTION
U.S. Pat. Nos. 5,880,117 and 5,578,588 both relate novel methods of using direct precursor hormones to testosterone as a means of replacing androgen levels in men. Although the suggested practice of using a precursor to an active hormone seems quite sound, the target hormone of replacement in both patents (testosterone), however, may be less than idea in many cases due to its high rate of conversion to estrogen. The problem of the present invention is therefore to provide other naturally occurring androgenic hormone precursors that can be used to replace androgen action in humans but are devoid of undesirable estrogenic activity. According to the invention this problem is solved by the use of at least one precursor of dihydrotestosterone and which is preferably 5alpha-androstanediol or 5alpha-androstanedione. The mentioned precursors of dihydrotestosterone are ideal because they are natural, non-toxic, quickly metabolized to active form after oral administration and unable to be aromatized into estrogens due to their structure.
DETAILED DESCRIPTION OF THE INVENTION
The chemical term 5alpha-androstanediol refers to two isomers: 5alpha-androstane 3beta, 17beta diol and 5alpha-androstane 3alpha, 17beta diol. This invention concerns both isomer forms of 5alpha-androstanediol. 5alpha-androstanediol and 5alpha androstanedione are naturally occurring compounds. They have been identified as direct metabolites of dihydrotestosterone in placental, uterine, testicular, adrenal and nervous system tissues. They act as efficient precursors to dihydrotestosterone, converting to DHT via the 3-hydroxysteroid dehydrogenase (3alpha and 3beta HSD depending on isomer) and 17beta-hydroxysteroid dehydrogenase enzymes respectively.
Human tests carried out by Horst H J, Dennis M, Kaufmann J and Voigt K D (Acta Endocrinol (Copenh) June; 1975 79(2):394-402) have fundamentally proved the rapid transformation of tritiated 5alpha-androstanediol into dihydrotestosterone in vivo. In this study it was demonstrated that 30 minutes after intravenous injection of the 3alpha isomer, recovery of dihydrotestosterone was measured to be 54%, 23% and 43% in prostate, muscle and plasma respectively. After injection of the 3beta isomer, the recovery was measured to be 29%, 8% and 9% in prostate, muscle and plasma. With both compounds the principle metabolite produced was dihydrotestosterone. Studies by Stanczyk F, et al. (J. Steroid Biochem. Molec. Biol., 1990, 37(1):129-132) have fundamentally proved that 5-alpha androstanedione is also an important and direct precursor to dihydrotestosterone in the human body, converting to active form through a similar, yet distinct, metabolic pathway.
The idea of focusing on dihydrotestosterone as an androgen for replacement with men noticing declining androgen levels is also well supported in medical literature. A review by Bruno De Lignieres (Annals of Medicine (1993) 25:235-241), for example, covers successful studies in which transdermal DHT has been utilized with great success. The men undergoing such trails reaped the expected benefits of androgen replacement on mood, sexual functioning, without significant clinical or metabolic side effects. The risk for developing benign prostatic hypertrophy (BPH) may also be reduced with DHT (a non-aromatizable steroid) therapy compared to testosterone (the primary substrate for the synthesis of estradiol in men), as both androgenic and estrogenic stimulation is needed to induce this condition.
After discovering the efficiency in which both isomers of 5-alpha androstanediol, as well as 5-alpha androstanedione, convert to dihydrotestosterone in the human body, plus the suitability of dihydrotestosterone as a target for androgen replacement, it became the focus of this invention that one of the mentioned DHT precursors can be administered perorally as an effective means of raising dihydrotestosterone levels in humans. The oral daily dosage used should be 25 mg to 500 mg. Due to the rapidity in which the discussed compounds are metabolized in the body, the total daily dosage can be further subdivided for a more sustained blood hormone concentration, with 3-5 applications per day being most preferred. In addition to peroral use, 5-alpha androstanediol and 5-alpha androstanedione can be effectively administered by several other routes including transdermal, sublingual or intranasal. In order to increase bioavailability during sublingual or intranasal administration, the target hormone can additionally be complexed with a cyclodextrin, such as beta-hydroxypropyl-beta-cyclodextrin. ##STR1##
