U.-F. Habenicht

Aromatase inhibitors and benign prostatic hyperplasia

A growing amount of evidence implies that estrogens may play a role together with androgens in the genesis of benign prostatic hyperplasia (BPH) in man. We review here some of this evidence together with advances made in characterizing inhibitors of estrogen biosynthesis (aromatase inhibitors). It is proposed that aromatase inhibitors may find application in non-surgical treatment of BPH.

Effects of estrogen deprivation on human benign prostatic hyperplasia

Sex steroids are thought to play an essential role in the pathogenesis of human benign prostatic hyperplasia (BPH). Since recent studies in animal models and in men have shown that estrogens might be causally linked to the onset and maintenance of BPH, we examined the effect of 1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly developed aromatase inhibitor, in men with BPH. In an open multicenter study 49 men (mean age 70.1 years, range 55 to 84) with obstructive BPH were treated with atamestane (3 x 200 mg/day) for 3 months. Of the 49 patients 44 completed the treatment period; the other patients discontinued the study for reasons unrelated to treatment. With treatment BPH-related symptoms such as daytime voiding frequency, nycturia, peak flow and residual urine improved considerably; however, these parameters did not reach statistical significance. The mean prostatic volume decreased significantly from 74.2 +/- 31.7 to 64.0 +/- 31 ml (mean +/- SD). Serum estrogen levels decreased markedly during treatment. In addition intraprostatic estrogen concentration decreased with treatment as compared to estrogen levels in hyperplastic prostates from untreated patients. The following conclusions can be drawn from this study: first, estrogens appear to have an important supportive role in established BPH, and second, estrogen deprivation improved BPH-related symptoms and reduced significantly prostatic volume.

Estrogens and benign prostatic hyperplasia: The basis for aromatase inhibitor therapy

Benign prostatic hyperplasia is generally regarded as being a hormone-dependent disorder. The inductive action of stromal elements on the glandular epithelium and the demonstrable estrogen sensitivity of the stroma suggest that estrogens may play a role in the etiology of prostatic hyperplasia. This hypothesis forms the theoretical basis for the proposed use of aromatase inhibitors in treatment of this disorder.

Management of benign prostatic hyperplasia with particular emphasis on aromatase inhibitors

The pathogenesis of human benign prostatic hyperplasia (BPH) has not been fully elucidated. There is, however, evidence that estrogens--besides other factors--might play an important role for the growth of the prostate. Consequently, estrogen deprivation might be a new, useful principle for a conservative treatment of BPH. Atamestane, a new, highly selective steroidal aromatase inhibitor has been proven to be successful in antagonizing experimentally-induced estrogen-related stromal overgrowth of the prostate in dogs and monkeys. Double-blind placebo controlled studies are now underway in Europe and the U.S.A. It is anticipated that these studies will give us a definite answer of the clinical validity of this concept in BPH patients in the near future. However, it is very important to take into consideration that for an effective treatment of BPH, a reduction of both the glandular and stromal elements has to be achieved. In other words, both androgens and estrogens seem to be involved in the regulation of (over)growth of the prostate. Therefore, a combination of an androgen and estrogen deprivation might be a more promising approach than any single treatment.

The tumour-inhibiting potential of the progesterone antagonist Onapristone in the human mammary carcinoma T61 in nude mice

SummaryThe progesterone antagonist Onapristone proved to possess strong tumour-inhibiting activity in a panel of experimental mammary carcinomas. Its underlying mechanism of action is due to a progesterone-receptor-mediated induction of terminal differentiation and a specific blockade of the cell cycle and is also present in the absence of progesterone as was shown in the MXT mammary tumour. To prove this further, the tumour-inhibiting activity of Onapristone was investigated in the human postmenopausal T61 mammary tumour implanted in castrated male nude mice. Whereas Onapristone given alone had no effect on growth of established tumours, after stimulation of the relatively low progesterone receptor content of this tumour line with an oestrogen, Onapristone significantly inhibited tumour growth. Thus, we suggest that Onapristone exerts its antitumour action via progesterone receptors. As there is no endogenous progesterone in these mice, the tumour-inhibiting activity of Onapristone is not primarily due to a classical antihormonal effect.

Possible vascular effects of an LH-RH agonist on the peripheral circulation of the rat testes

Summary:  The single injection of an LH‐RH agonist caused severe damage to the rat testis within 24 hours. Especially the seminiferous tubules appear to be affected whereby these effects are thought to be secondary to vascular effects of LH‐RH agonists.

The AMPPA network as a successful model for public–private or private–private partnership

In 1997, the Rockefeller Foundation and the Ernst Schering Research Foundation (a subsidiary of Schering AG, Germany, on a non-profit basis) mounted a multi-year global collaborative effort, involving a network of top-level research institutions to intensify research on the regulation of the male reproductive system with special emphasis on post-testicular activity, utilizing new approaches in molecular pharmacology (application of molecular pharmacology for post-testicular activity (AMPPA) network). The new venture proved a success as a public-private sector partnership, as a collaborative scientific program, and as an approach to identify new targets applicable and suitable for drug finding for male fertility regulation.

Disturbance of Peripheral Microcirculation by LHRH-Agonists. II

Summary: It could be demonstrated with the aid of a cheek pouch model of the hamster that the LHRH‐agonist lutrelin (Wyeth, WY 40972) caused disturbances of microcirculation within minutes, for example constriction of the arterioles and venules, reduction in capillary density and increased permeability, effects which were not reversible within the observation period (1 h) and could not be antagonized by the cyclooxygenase inhibitor indomethacin. Likewise, the lutrelin‐induced accumulation of leucocytes in the capillaries of the testes of the rat could not be prevented within 6 hours after administration of indomethacin, whereas the harmful effect of lutrelin on the germinal epithelium could be antagonized by indomethacin within 24 hours. A biphasal course is assumed, characterised by an acute non‐prostaglandin‐dependent phase and a second prostaglandin‐dependent phase, which causes the definitive damage to the testis of the rat.

Development of New Immunocontraceptives-Industrial Perspective

Contraception has been practiced for thousands of years. Nevertheless, it took until the late 1950s and early 1960s before a major breakthrough in contraceptive technology was achieved by the introduction of oral hormonal contraceptives. However, we have not succeeded in the development of a non‐hormonal contraceptive that is comparable to the pill regarding its efficacy, safety, and acceptance. The immunological interference with the complex fertilization process is a very attractive target in this respect, whereby the zona pellucida, a non‐cellular surrounding of all mammalian eggs, represents a potentially ideal target. Another interesting target are sperm: either for the development of a female contraceptive or for a male contraceptive, although the latter approach does not look very promising so far. In conclusion, given the enormous impact on mankind of a growing world population and given the very individual needs for contraceptive methods of different women in one and the same country and in different cultures we should make widely available a whole set of suitable, adjusted methods of fertility control and this includes the search for an effective method of male fertility control.

Short-term effects of an LHRH-agonist alone or in combination with testosterone propionate or indomethacin on rat testes. Evidence of testosterone independent effects. I.

Summary:  The treatment of adult male Wistar rats with a LHRH‐agonist (lutrelin Wyeth/WY 40972) resulted in severe damage of the seminiferous tubules as well as in remarkable changes of the blood vessels within 24 hours. First striking signs of alterations within the blood vessels were already found 6 hours after the injection of lutrelin: the blood vessels were almost totally filled with leucocytes. Neither the effects on the germinal epithelium nor the effects on the blood vessels were prevented by the simultaneous treatment with 3 mg testosterone propionate (TP). The treatment with indomethacin, however, clearly antagonized both events. The complete inefficiency of TP to overcome the inhibitory effects of lutrelin on the testes does argue against an androgen deficiency as the primary cause. The results obtained with indomethacin strengthen the hypothesis, that the early deleterious effects of LHRH‐agonists on the germinal epithelium of the rat are primarily caused by circulatory disturbances in the testes and that prostaglandins may act as mediators.