Hormonal Manipulation

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The belief that prepubertal boys have a lower rate of permanent chemotherapy-induced gonadal damage (5) has led many investigators to propose that suppression of testicular function in adult men (i.e., inducing a prepubertal state) will provide a degree of protection against cytotoxic therapy. Irrespective of the validity of the hypothesis, data derived from animal models have been encouraging, but there is presently no convincing evidence of similar success in humans. Ward et al. (51) demonstrated enhanced spermatogenesis recovery in procarbazine-treated rats by the administration of the gonadotropin-releasing hormone (GnRH) analog Zoladex for 2 wk before chemotherapy and during chemotherapy. Increased stem cell survival was evident by 50 d, and, at 90 d, sperm count was close to normal values and significantly higher than procar-bazine-only treated rats. Similar protective effects have been described with the use of testosterone (52), testosterone and estradiol (53), GnRH and testosterone (54), and GnRH and the antiandrogen flutamide (55,56) after testicular insult with procarbazine, cyclophosphamide, or radiotherapy. Pogach et al. (54) suggested that testosterone administered after treatment with procarbazine enhanced spermatogenesis recovery. More recently, Meistrich et al. (57) confirmed that treatment with either testosterone or Zoladex after irradiation with 3.5 Gy markedly improved the recovery of spermatogenesis, even if treatment was delayed for 10 wk after irradiation. The same group had previously shown that spermatogenesis did not occur after a similar dose of irradiation. Despite the presence of A spermatogonia in the seminiferous tubules (58), they postulated that the role of hormonal treatments in the "protection" of germinal epithelial function, possibly to enhance recovery of surviving A spermatogonia and to facilitate their differentiation to more mature cells, rather than to protect them from damage during cytotoxic therapy or radiotherapy. They suggested that a reduction of the level of intratesticular testosterone or one of its metabolites is the mechanism by which hormone therapy stimulates spermatogenesis recovery.

In humans, attempts to reproduce the protective effects seen in animals have been unsuccessful. Several groups have used GnRH analogs, with and without testosterone replacement, to suppress testicular function during MOPP (59) or MVPP (60) chemotherapy for lymphoma, cisplatin-based chemotherapy for teratoma (61), and testicular irradiation for seminoma (62). None has demonstrated any significant protective effect of these therapies in spermatogenesis maintenance or increasing the rate of recovery. However, none of the studies involved the continuation of gonadal-suppressive therapy for a significant period of time after the completion of chemotherapy or radiotherapy. The most recent animal data suggest that hormonal treatment may enhance recovery of spermatogenesis from surviving stem cells rather than protect them from damage during cytotoxic or radiation insult. Thus, suppression of gonadal function with a GnRH agonist or testosterone for a fixed time after the completion of irradiation or chemotherapy may prove more successful in reducing the effect of these treatments on fertility.

This approach relies on enhancing recovery of sperm production, and, therefore, a prerequisite for its success is the survival of stem cells during the gonadotoxic insult. However, there are few data regarding testicular histology after chemotherapy or radiotherapy. After cisplatin-based chemotherapy and low-dose radiation, spontaneous sper-matogenesis recovery occurs in most patients, although there is often a latent period of azoospermia, which may last several years. However, the eventual spermatogenesis recovery implies the survival of A spermatogonia. After chemotherapy for Hodgkin's disease with procarbazine-containing regimens, and high-dose radiotherapy, recovery to oligospermia or normospermia is much less common. Testicular biopsies taken after standard chemotherapy (MVPP and COPP) for Hodgkin's disease have shown complete germinal aplasia with a Sertoli cell-only pattern (9,16,21,63-64), and this is also the case in men treated with 20-Gy radiotherapy (41). There have been some recent reports of the isolation of mature sperm in the testicular parenchyma of some men with biopsy evidence of Sertoli cell only, suggesting that even in this situation, there may be small foci of spermatogenesis (65). In addition, spermatogenesis recovery occurs in a minority of these patients, indicating that some germ cells survive in some patients. However, the absence of histological evidence of any spermatogenesis at biopsy in many men suggests that all spermatogonia may be eradicated during chemotherapy.

Hormonal manipulation after treatment to enhance the recovery of spermatogenesis is, therefore, likely to be of most benefit in those patients in whom the testicular insult is less severe, because it is these patients in whom there is significant preservation of A spermatogonia. The success of this approach in those patients who have undergone more intense gonadotoxic therapy will depend on whether any stem cells remain. Complete ablation of the germinal epithelium may occur in many men after treatment with procarbazine-based chemotherapy regimens for Hodgkin's disease, and this will clearly be irreversible.

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