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Hormonal Control of Spermatogenesis, 1997

This Satellite Symposium for the VIth International Congress of Andrology "Hormonal Control of Spermatogenesis: Basic and Clinical Aspects" was held on May 21-22, 1997 in Cracow, Poland.

The Presidential Address from ISA was given by Geoffrey Waites. During the Opening Ceremony, the first Honorary Memberships of the Polish Andrology Society were given to Emil Steinberger (USA) for his contribution to research in reproductive medicine and to Anna Steinberger (USA) for her contribution to research in reproductive biology. In this way PAS would like to acknowledge their fruitful co-operation with Polish andrologists during the difficult time of our recent history.

The program consisted of 15 plenary lectures grouped in the following sessions: I. Molecular Andrology, II. Physiology of Spermatogenesis, III. Hormonal Manipulations and Spermatogenesis, IV. Environmental Effects on Male Reproductive Functions.

The first session of the Symposium started with the presentation of Ilpo Huhtaniemi (Finland) entitled "Gonadal tumorigenesis directed by the inhibin a-subunit promoter in transgenic mice". He and his co-workers created a mouse model for tumors of gonadal somatic cells by expressing in transgenic mice the powerful viral oncogen, SV40 virus T-antigen, under regulation of the mouse inhibin a-subunit promoter. Ovarian granulosa and theca cells tumors were formed in the female, and testicular Leydig cells tumors in the male transgenic mice. They attempted to relate these findings to human beings assuming that the incidence of ovarian cancer in women was increased by elevated concentration of circulating gonadotropins during perimenopause. Using their animal model they were able to suppress but not totally inhibit gonadal tumorigenesis by the reduction of gonadotropin secretion by long term GnRH antagonist treatment in transgenic mice. However, low gonadotropin levels throughout life totally eliminated gonadal tumorigenesis in mice. Later experiments of this group showed that inhibin was the first secreted tumor suppressor in mouse gonads and adrenal glands.

The next presentation was by Andrzej Bartke (USA). who discussed the unexpected effects of overexpression of different growth hormone (GH) genes on male reproductive functions in transgenic mice. His results indicate that chronic excess of GH produced decreased breeding performance as indicated by increased time intervals from mating to conception, shorter reproductive life span and increased incidence of male infertility. Age-related decline in copulatory behavior and fertility develop earlier in GH-excessive than in normal males. The GH-excessive mice have shorter lives.

A new era of testicular physiology was indicated by Searge Carreau (France). He presented a paper about the molecular identification of functional cytochrome P450 aromatase in male germ cells. He reported that estrogen (E) can be formed not only in Leydig and Sertoli cells but also in pachytene spermatocytes, round spermatids and testicular spermatozoa. These data correspond very well with the results presented by K. Kula et al (Poland) entitled: "Hormones and premeiotic spermatogenesis in men and rats. A possible involvement of estradiol and prolactin". They published the first evidence of possible positive effect of E on premeiotic spermatogenesis in immature rats in 1988 (Endocrinology, 122: 34-39). In the following years they produced other evidence including the demonstration that testicular growth and first spermatogenesis could be stimulated by simultaneous administration of testosterone (T) and E and inhibited by experimentally induced imbalances in circulating hormones, favoring only one of them (E over T or T over E). Finally they showed that although E seemed to be an effective mitogenic factor for spermatogonia, it needed the presence of FSH for differentiation of spermatogonia and induction of spermatogenesis, while FSH, T or E when given alone were not effective in inducing first spermatogenesis.

For some years research on the influence of thyroid hormones on testicular development has caught the attention of both basic scientists and clinicians. This was discussed by Paul S. Cooke (USA). Besides his classic discoveries demonstrating that transient neonatal hypothyroidism resulted in increased testicular mass and sperm production in adulthood, he demonstrated the newest data indicating that while thyroid hormones inhibited Sertoli cells proliferation, they stimulated the proliferation of Leydig cells. Also, he presented data that peritubular myoid cells have receptors for thyroid hormones. He cited data indicating a similar effect of hypothyroidism in prepubertal boys (isolated precocious gonadarche and final testicular overgrowth). In conclusion, it appears evident that triiodothyronine acts as a unique hormone that switches developmental multiplication of immature Sertoli cells into numerically stable, functionally active, adult Sertoli cells.

Marvin L. Meistrich (USA) showed that recovery of spermatogenesis after irradiation in rats could be stimulated by hormone treatment not only during irradiation but also when T or GnRH treatment were initiated at different intervals after cessation of irradiation. The very interesting point was that recovery of spermatogenesis was more effective in those animals where intratesticular T was critically reduced by the treatments with T or GnRH agonist.

Robert I. McLachlan (Australia) emphasized the importance of precise stereological methods for studies of the hormonal control of spermatogenesis. He concluded that T supported meiosis and spermatid maturation while FSH promoted spermatogonial division and/or survival. He noted that it was difficult to separate FSH and T actions in intact animals because administration of T stimulated the secretion of FSH.

The results of investigation of gonadotropins action on spermatogenesis in primates were presented by Gerhard Weinbauer (Germany). His conclusion was that germ cell yields per testicular unit or mass volume were comparatively low in primates and germ cell loss during meiosis was the suspected cause. The stimulatory action of gonadotropins is mediated via an increase in numbers of spermatogonia. It is not known, however, whether this effect is related to altered proliferative or apoptotic activity or both.

Emil Steinberger (USA) reviewed the 7 historical phases of the studies on the role of FSH in spermatogenesis since the first purification of human urinary gonadotropins. The most interesting part was the last phase appearing in 1990s when genetically modified FSH receptors were created, synthesis of "pure" human recombinant FSH was available and creation of "knock-out" genes allowed development of animals lacking the genetic mechanism to synthesize FSH. The use of the last technique in mice indicated that FSH might not be essential for the initiation and completion of the initial wave of spermatogenesis and for the maintenance of spermatogenesis in the special strain of mice. The only role FSH may play is related to the quantitative aspect of the spermatogenic process. Concerning man "an activating mutation" of the FSH receptors was described and the conclusion was reached that FSH might not be essential for initiation of spermatogenesis. The results were considered, however, by the reviewer as not conclusive because spermatogenic activity was not precisely described . It is important to note that from the clinical point of view both purified urinary FSH and recombinant FSH (Gonal F) are very effective in inducing spermatogenesis and fertility in hypogonadotropic hypogandism with azoospermia.

Practical (clinical) important modification of spermatogenesis include the use of hormones to suppress spermatogenesis for male contraceptive purposes. Frederic C.W. Wu (England) proposed that both contraceptive efficacy and the reduction of side effects was possible when androgen contraception therapy would be modified by the decrease of the androgen dose, with the simultaneous addition of progestin that did not influence negatively the lipid profile. He stated that in that way sperm number could be maintained at the level of 3 million/ml which was sufficient to obtain infertility.

The molecular basis of androgen insensitivity was reviewed by Olli A. Jänne (Finland). He concluded that the molecular basis of androgen insensitivity in human patients was usually a single-point mutation in the androgen receptor gene. They are, however, other mechanisms by which attenuated androgen responsiveness can be generated, such as through altered interaction with auxiliary proteins (co-activators) or other signaling systems, or via the presence of dominant negative receptor forms.

The environmental session was initiated by the lecture of A. Giwercman (Denmark). He reviewed results of a meta-analysis that compared semen data in different centers during the period 1940-1990 suggesting that male reproductive function decreased during this time. He reviewed other recent papers supporting the results of this classic meta-analysis. He also quoted data that such phenomenon could not be demonstrated in USA and Finland.

Difficulties in estimating the work place risk factors for male reproductive function were analyzed by Jens P. Bonde (Denmark). He emphasized that human spermatogenesis was susceptible to xenobiotics even at low-level exposure. He quoted studies that have failed to establish harmful effects of anaesthetic gases, formaldehyde and trichloroethylene. Also it is not clear whether reduced semen quality is related to welding of mild steel. In contrast, radiant heat and high frequency electromagnetic fields appear to be noxious to the male reproductive system. The role of endocrine disruptors in male reproductive function was summarized by Jorma Toppari (Finland). A highly informative presentation was given by Bernard Jegou (France) on an experimental approach in studies of decline in semen quality.

The final part of the environmental session was a Round Table Discussion entitled "Need and Proposals for Collaborative East-West Studies on Environmental Effects on Male Reproductive Function" under the initiative of N. Skakkebaek (Denmark) and A. Giwercman. The involvement of Polish scientists in research on the influence of area pollution on male fertility potential was discussed. It has been postulated that army recruits would be the most important source for screening of semen defects in different areas of the country. However, this seems to be difficult to perform in Poland because of religion, cultural traditions and restrictive army law. One of the solutions would be comparison of semen quality in the donor sperm banks collecting semen samples in highly polluted (Silesia) and unpolluted areas (northeastern part of Poland). Considering that only the best semen samples are stored there, the greatest value would have samples of all men that apply to be a donor as suggested by K. Kula.

Jorma Toppari (Finland) demonstrated a project of screening for disturbances in intrauterine exposure to androgens in male infants. His project involves simple anthropometric measurements of external genitalia in newborn boys.

The Symposium concluded with a Poster Discussion which consisted of 3 minute oral presentations of 30 posters. The abstracts had been published for all participants in the issue of the Polish Journal of Endocrinology preceding the Symposium. The posters were grouped as follows: I. Developmental Aspects and Testis Cancer in Men, II. Hormones in Clinical Diagnostics, III. Hormones in Experimental Investigations, IV. Miscellaneous. A special supplement of this journal was edited by Krzysztof Kula, and Jolanta Sowikowska-Hilczer in the 152-page Proceedings of the Symposium. In the Proceedings the authors presented broader reviews of their scientific achievements. Some copies are still available through the Clinical Andrology Unit, Institute of Endocrinology, University Medical School of Lodz, 91-425 Lodz, 5 Sterling str., Poland, the organizer of the Symposium.

The Symposium was accompanied by social events that included a welcome reception at Jagiellonian University, which is the second oldest university in Europe (after Padua, Italy), and the official dinner in the old castle with the panorama view of the Vistula river and Cracow.

Krzysztof Kula, Poland