Intratesticular testosterone level and spermatogenesis; implications into the development of hormonal male contraception

Condoms and male sterilization (vasectomy) are the only modern contraceptive methods available for men. However, men and women around the world would use more advanced methods if they were available. Because the world population overgrowth is a major threat of mankind, new contraceptive methods are desperately needed. In developed countries, respectively, male contraception is an important gender equality issue. The lack of novel male methods is thus a real missed opportunity. The currently tested methods are based on use of the male sex hormone, testosterone, in somewhat similar fashion as female sex hormones in the female pill. They suppress testicular testosterone production, thereby blocking sperm formation. The drawback of these methods is that only 2 out of 3 men become infertile. New concepts to improve the efficacy are therefore needed, which is the goal of the proposed research. New principles must first be tested in experimental animals. We will test therefore in normal and genetically modified mice how to enhance the contraceptive efficacy by suppressing intratesticular hormone levels more profoundly than with testosterone, inhibiting the function of a key testicular enzyme involved in testosterone production. If the mouse experiments are successful, the same principle can be tested in men.

The world population explosion calls for introduction of novel contraceptive methods. The lack of modern reversible methods for men is a real missed opportunity, besides being a gender equality issue. Investigations have demonstrated that male contraceptive methods, if available, would be welcomed by men and women alike in different societies. The most promising lead to a novel male contraceptive method is testosterone (T) treatment. Its principle is to suppress the gonadotrophin secretion supporting testicular T production; high intratesticular (IT) T is considered essential for spermatogenesis. T treatment has a dual role: (i) to suppresses gonadotrophin secretion with consequent drop of ITT, and (ii) to maintain the extragonadal potency, libido and anabolic effects of T. A combination of T with another antigonadotrophic agent (e.g. progestin) appears currently most promising.
A major problem with the current hormonal regimens is that complete cessation of spermatogenesis (azoospermia) occurs only in about 2/3 of men. The reason remains unknown, but it is not incomplete gonadotrophin suppression. Improved efficacy requires more profound ITT suppression, and the reasons why it is not reached by gonadotrohin suppression are: (i) a residual gonadotrophin independent component of ITT production may maintain spermatogenesis, (ii) the exogenously administered T + the residual ITT exceed the threshold to stimulate spermatogenesis, and (iii) in some men spermatogenesis is less dependent on T. In fact, the extent of ITT suppression needed for azoospermia and the concept that maintenance of peripheral T is possible without simultaneously activating spermatogenesis have not been experimentally tested.
Although ITT decreases upon contraceptive trials by about 98% it still remains about 2-fold higher than normal peripheral T. It is therefore feasible that it should be further decreased to achieve consistent azoospermia. The purpose of this research is to demonstrate experimentally, using wild-type and knockout mice, that this is necessary, theoretically possible and achievable practically by pharmacological means. The specific aims of the project are therefore: (1) To determine the threshold of T replacement dose that maintains in mice with genetically disrupted gonadotrophin action the peripheral androgen actions without stimulating spermatogenesis, (2) To study whether genetic or pharmacological inhibition of the key enzyme in testicular T biosynthesis, 17beta-hydroxysteroid dehydrogenase III, will induce complete suppression of ITT, and (3) To study whether complete suppression of ITT increases the safety margin of the T replacement needed for peripheral effects without activating spermatogenesis. The results obtained provide improved concepts for clinical trials on hormonal male contraception.