Gonadal and sexual function in men treated for childhood cancer.

BACKGROUND: Insofar as a majority of children with malignant diseases are cured, the late effects of treatment are of major importance. PROCEDURE: A retrospective study was conducted of gonadal and sexual function of 77 adult male survivors of childhood malignancies treated and cured at a single center from 1970 to 1989 and followed for a median of 13 years. The study included an interview, physical examination, sperm test, and hormonal analyses. RESULTS: One-third of the patients were treated for hematological malignancies, one-third for CNS tumors, and one-third for other malignancies. Eleven patients required androgen substitution after treatment for tumors of the pituitary-hypothalamic region or acute lymphoblastic leukemia including testicular irradiation and/or orchiectomy. In three patients the testicles were removed. The other eight had small testicles, and those providing sperm samples had azoospermia, and sexual function was disturbed in most of them. Most of the remaining 66 patients had small testicles. Normozoospermia was found in 63%, oligozoospermia in 20%, and azoospermia in 17%. Although there was a highly significant correlation between testicular volume and sperm test, 25% of patients with testicles of <10 ml had normozoospermia. Sexual function was normal in 46 patients, and they were married at a frequency comparable to the normal population. Twenty-one patients had no signs of gonadal dysfunction. CONCLUSIONS: Patients treated for tumors in the hypothalamic-pituitary region or treated with testicular irradiation or with high doses of alkylating agents had severe gonadal and sexual dysfunction. Most of the other patients had good prospects for preserved gonadal and sexual function.

Recovery of sperm production following radiation therapy for Hodgkin's disease after induction chemotherapy with mitoxantrone, vincristine, vinblastine, and prednisone (NOVP).

PURPOSE: The effect on human male fertility of radiotherapy following chemotherapy for the treatment of Hodgkin's disease (HD) is unknown. The impact of radiation therapy, given after mitoxantrone, vincristine, vinblastine, and prednisone (NOVP) chemotherapy, on sperm production is the focus of this study. PATIENTS: Serial semen analyses were performed on 34 patients with HD Stages I-III before NOVP chemotherapy, after chemotherapy prior to radiation, and after radiation therapy. The most inferior radiation portals for patients were: mantle, 1 patient; paraaortic-spleen, 3 patients; upper abdomen, 24 patients; abdominal spade, 4 patients; and pelvic, 2 patients. Testicular radiation dose measurements were available for 20 of these patients. RESULTS: Before the start of radiation, 90% of patients were normospermic. The magnitude of the decline in sperm counts was related to the measured testicular dose and/or radiation fields employed. The minimum postradiotherapy counts, expressed as a fraction of pretreatment counts, for the various treatment groups are as follows: paraaortic-spleen, 20%; upper abdomen, testicular dose < 30 cGy, 4%; upper abdomen, testicular dose 30-39 cGy, 0.9%; abdominal spade, 0.02%; and pelvis, 0%. The time to nadir of sperm counts averaged 4.5 months. Recovery to normospermic levels occurred in 96% of patients, with most recovering to that level within 18 months. CONCLUSION: The effect of radiation following NOVP chemotherapy on sperm counts was no greater than would be expected with radiation therapy alone. In most patients, sperm counts recovered to levels compatible with normal fertility.

Inhibin B is a more sensitive marker of spermatogenetic damage than FSH in the irradiated non-human primate model.

This study evaluated the effect of bilateral testicular irradiation (2 Gy) on reproductive hormones, testicular volume (TV) and sperm parameters in six adult cynomolgus monkeys. Hormone levels (FSH, inhibin B and testosterone (T)) were determined to find the most valuable endocrine marker of irradiation-induced damage. All parameters were analysed at weekly intervals for 14 weeks. Histological evaluation of both testes was performed at week 14 after irradiation when one monkey was castrated and at week 27 when the remaining five monkeys were bilaterally biopsied. A decrease in body weight, TV (30% of the pre-treatment size) and sperm count was observed after irradiation. Severe oligozoospermia was achieved throughout the study but azoospermia was recorded only occasionally. Histological evaluation revealed a heterogeneous picture with patchy arrangement of seminiferous tubules containing advanced germ cell types. An increase (P<0.05) in FSH levels and, to a lesser degree also in T levels, occurred several weeks after irradiation. Inhibin B levels showed a sharp decline (P<0.001) as soon as 1 week after irradiation. FSH and inhibin B did not return to baseline levels during the observation period. A negative correlation was found between FSH and inhibin B values (r=-0.35, P<0.001). Inhibin B correlated positively with testis volume (r=0.73, P<0.001) and sperm counts (r=0.55, P<0.01). In conclusion, this study shows that inhibin B represents an early and more sensitive marker of testicular damage than FSH. Furthermore, the rapid fall of inhibin B after irradiation suggests that this hormone is a direct parameter of premeiotic germ cell proliferation.

[Evaluation of radioprotective properties of a lipocarotenoid extract from mycelium of basidiomycetes during external irradiation]. / Otsenka radiozashchitnykh svoistv lipokarotinoidnogo ékstrakta iz mitseliia bazodial'nogo griba v usloviiakh vneshnego oblucheniia.

Radioprotective properties of LPC extract from mycelium of Basidiomycetes fungus at doses 12.0; 3.0 and 1.0 Gy of external irradiation were investigated. The extract of LPC at 2.5 mkg/ml concentration promoted the survival of animals (to 40%) and increased the average life at the lethal dose. At 1.0 Gy dose the use of extract resulted in restoration of radiosensitive organs weights, the number of blood leucocytes and some indexes of lipid peroxidation in blood plasma. The extract has produced some effect on the amount of spermatogenic cells in the testis.

A non-parametric method of reconstructing single-dose survival curves from multi-fraction experiments.

PURPOSE: A method of estimating the single-dose curve from designed multifraction experiments is described and applied to three datasets. MATERIALS AND METHODS: The method, which is non-parametric and based on standard statistical regression techniques, can be used for functional endpoints which are either continuous or binary. The datasets are concerned with wound healing on mice, myelopathy in guinea pigs and spermatogenesis in mice. The results are compared with the results from fitting the linear quadratic model. The statistical methods of Bootstrapping and residual plots are illustrated. RESULTS: The method is based in part on an assumed statistical model, however, exact knowledge of the correct statistical model is not necessary to obtain an estimate of the shape of the single-dose survival curve. We find no good evidence from the reconstructed single-dose survival curve of an "induced repair" phenomena at low doses for the wound healing and spermatogenesis experiments. For the myelopathy experiment the data are consistent with the LQ model with a low alpha-beta ratio down to doses of at least 1.5 Gy per fraction. CONCLUSIONS: A robust statistical method of estimating the shape of the single-dose survival curve is demonstrated using standard statistical software on three datasets.

Exposure to different spectra of light, continuous light and treatment with melatonin affect reproduction in the Indian desert gerbil Meriones hurrianae (Jerdon).

In two separate experiments, the gonadal response to melatonin treatment and exposure to continuous white light (LL) and different spectra of light (blue, green, yellow and red) was investigated in the Indian desert gerbil Meriones hurrianae. In experiment 1, exposure to green light for 8 weeks increased (p < 0.01) the gonadosomatic index (GSI) and sperm count, whereas exposure to red light decreased (p < 0.01) the GSI and sperm count. The response of accessory organs to the treatment varied. In experiment 2, exposure to LL for 5 weeks decreased the GSI and sperm count, and treatment with melatonin (in the late-light period) not only increased the GSI and sperm count, but also counteracted the inhibitory action of LL and red light. Melatonin treatment stimulated accessory sex organs and the scent gland surface area. The inhibition or stimulation of the reproductive parameters correlated with an increase or decrease in pinealocytes and pinealocyte nuclear diameters. Therefore, the influence of light and its spectra on reproduction may be mediated by the pineal gland, though extrapineal mechanisms cannot be ruled out.

A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group.

PURPOSE: The results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy. METHODS AND MATERIALS: Of a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed. RESULTS: A fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy. CONCLUSION: Our data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle.

[The interaction of the thyroid-adrenal system with testicular function in mice subjected to gamma irradiation]. / Vzaimodeistvie tireoid-adrenalovoi sistemy s testikuliarnoi funktsiei u myshei, podvergnutykh gamma-oblucheniiu.

Single whole-body gamma-irradiation of BALB/c mice at a dose of 6.0 Gy results in an immediate response of the hypothalamus and hypophysis system: an increased generation of gonadotropin, adrenocorticotropin, and thyreotropin. The response of other organs manifests itself in an increase in testosterone, corticosterone and thyroxine in the organism. The above disturbances result in depression of the testicular activity and in fertility. The deficiency of testosterone is partly compensated by the enhancement of the adrenal secretion of adrogens.

[Radiation reactions in the gonads: importance in patient counseling]. / Strahlenreaktionen an den Gonaden. Konsequenzen für die Patientenberatung.

PURPOSE: The intention of this article is to summarize the effects of radiation therapy on the female and male gonadal function. RESULTS: In woman a decreasing tolerance to radiation is observed with increasing age, due to the decreasing number of follicles. The mean tolerance dose for sterilization is between 5 and 10 Gy. If both ovaries receive only scattered doses-radiation effects on the ovaries are dependent on the age of the women at the time of treatment. However, if both ovaries are included in the treatment volume of a tumor radiation therapy, sterilisation is unavoidable. In man even scattered doses are able to decrease the sperm cell counts in the range of 2 to 3 Gy in conventional fractionation regimes. Complete restoration of spermatogenesis is possible during the first 2 years after treatment, but is unlikely after 3 years. In contrast to the situation in female, impairment of male endocrine gonadal functions are observed only after testicular doses higher than 20 to 30 Gy. In female children the tolerance dose of the ovaries is higher than in the adult woman, while the gonadal endocrine function in boys is more sensitive than in adult men. In contrast, spermatogenesis is not initiated in young boys, and hence less radiation effects are induced. CONCLUSIONS: In all treatment situations-in adults as well as in children-an additive effect of the combination of chemotherapy with radiation on gonadal function has been shown. However, the severity of damage by radio-chemotherapy is highly dependent on the drugs used.

Testicular toxicity of the transferrin binding radionuclide 114mIn in adult and neonatal rats.

Adult (70 d) and neonatal (7 d) male rats were dosed (i.p.) with 37 MBq/kg (1 mCi/kg; approximately 1 microgram elemental indium/kg) 114mIn, a transferrin-binding radionuclide. In adults, approximately 0.25% of the injected activity localised within the testis by 48 h postinjection and remained constant for up to 63 d. In neonates, 0.06% of the activity was in the testis by 48 h, and this declined such that by 63 d only 0.03% remained. At 63 d, treated rats had reduced sperm head counts and abnormal testicular histology that was more marked in animals dosed as adults than as neonates. In vitro, uptake of 114mIn into seminiferous tubules isolated from 7-, 20-, or 70-d-old rats was compared with that of 125I. Both radionuclides were readily accumulated by the tubules. Whilst 114In uptake into 20- and 70-d tubules was inhibited by excess transferrin, uptake into 7-d tubules was unchanged. 125I uptake was not affected by excess transferrin. These data support the contention that some radionuclides may cross the blood-testis barrier by utilisation of the physiologic iron-transferrin pathway, which may lead to greater testicular damage in adult compared to neonatal animals.

Effect of low-dose testicular irradiation on sperm count and fertility in patients with testicular seminoma.

The treatment of seminoma with radiation therapy risks transient infertility. We have prospectively followed eight patients with stage I seminoma of the testicle. All patients underwent radical orchiectomy of the affected testis. The mean age of the patients was 32.9 years (range 24-40). Each patient was treated with megavoltage radiation with a 10- or 18-MV linear accelerator. The remaining testicle was shielded using a standard lead enclosure, and the mean testicular dose was 44 cGy (range 20.8-78.2). Semen specimens were delivered to the lab within 30 minutes of ejaculation. All specimens were analyzed using a computer-assisted sperm analyzer. Pretreatment parameters were within normal limits for all but one patient; one patient presented with a borderline normal sperm count at 18 and 22 x 10(6)/ml. Following treatment, there was a decrease in sperm count, detected at 3 months, to < 10 x 10(6)/ml (range 4.4- 8.6 x 10(6)) in all patients except one, who presented with an initial pretreatment count of 189 x 10(6)/ml, which decreased to 58 x 10(6)/ml at 3 months, 32 x 10(6)/ml at 6 months, and rose to 325 x 10(6)/ml by 12 months following treatment. Although the sperm count for this patient (D.L.) was within the normal range, the post-radiation sperm count was less than 20% of the pretreatment count. There was no difference in the motility at 3 months, the mean of which was 51.3%. One patient's (F.C.) wife conceived at 9 months following treatment, one at 12 months (J.R.), and one (J.S.) at 14 months, and all have delivered normal infants.(ABSTRACT TRUNCATED AT 250 WORDS)

[The reproductive function of male rats in the late periods after x-ray irradiation]. / Reproduktivnaia funktsiia samtsov krys v otdalennye sroki posle rentgenovskogo oblucheniia.

Reproductive function in male rats was studied in 1, 3 and 6 months after X-ray irradiation of doses of 2 and 3 Gy. It has been established that long-term effects of irradiation at a dose of 3 Gy are manifested through decrease in spermatozoa content in the epididymis and reduction of nucleic acid and protein content in the testes. Fertility of male rats under study significantly lowered shortly after irradiation and full recovery of fecundating ability was observed 6 months later. The effect of irradiation with a dose of 2 Gy was less pronounced.

[Occupational medical research of male reproductive capacity]. / Arbejdsmedicinsk forskning i maends forplantningsevne.

During the past 15 years, approximately 50 occupational medical sperm quality investigations have been carried out in the world as a whole. The discovery of reduced testicular function among workers exposed to the chemical agent dibromochloropropane (DBCP) was an important incitment for the conduct of these investigations. These have not demonstrated new occupational medical influences with as dramatic an effect as DBCP but moderately reduced sperm quality has, however, been proved or suspected after occupational exposure to a series of other agents: certain cell poisons (ethylene dibromide, carbaryl, chlordecone), certain glycoethers (in paint, glue, printing inks, antifreeze solutions), certain organic solvents e.g. styrene (plastic casting), choroprene (plastic production), low exposure to lead, metal welding, thermal influences and high frequent electromagnetic fields (300 kHz-300 mHz). Only a few investigations illustrate the significance of the male factors for infertility and delay before deliberate pregnancy and there are still no well-proved examples of human paternal teratogenic agents or carcinogens. Our present knowledge only serves to prevent a limited proportion of reproductory failure in men. Reports of decreased sperm quality in the population and the influence of the environment on reproduction in domestic animals indicate that further investigations are necessary. Longitudinal investigations of sperm quality together with investigations of fertility or delay till deliberate pregnancy are proposed subjects for future strategy.

Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas.

PURPOSE: Treatment of lymphomas with combination chemotherapy with or without radiation therapy (XRT) can result in long-term or permanent azoospermia. PATIENTS AND METHODS: Semen analyses of lymphoma patients were performed before, during, and after treatment with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo) chemotherapy. Some of the patients also received other drugs or radiation therapy. RESULTS: Although no patients were azoospermic before treatment, all were rendered azoospermic during treatment. Following the completion of treatment, the fraction of patients whose sperm counts recovered increased gradually over 5 years and plateaued by 7 years, with two thirds of the men achieving normospermic levels. Scattered gonadal radiation dose and cumulative cyclophosphamide dose were found to be independently significant determinants of recovery: the fraction of patients whose sperm counts recovered to 10 x 10(6)/mL were 83%, 47%, and 20% for those who received less than 9.5 g/m2 of cyclophosphamide, greater than 9.5 g/m2 of cyclophosphamide, and pelvic XRT, respectively. The inclusion of additional drugs and interferon alfa did not significantly affect the long-term recovery of spermatogenesis. CONCLUSION: Pelvic XRT and cumulative cyclophosphamide dosages greater than 9.5 g/m2 are associated with a high risk of permanent sterility in lymphoma patients treated with the CHOP-Bleo regimen.

Effects of chemotherapy and radiotherapy on spermatogenesis.

Radiation and chemotherapy reduce sperm count and cause infertility in males. In the mouse, rat, and human, the differentiating spermatogonia are the most sensitive to killing by cytotoxic agents, resulting in short-term azoospermia. Stem spermatogonia are also killed by some agents. In the mouse, sperm production gradually recovers from surviving stem cells without a lag period. In the rat, however, surviving stem cells may remain as A spermatogonia for long times without initiating differentiation. In humans, there may be a long period of azoospermia; the time at which recovery or sperm production is initiated appears to be related to the degree of stem cell killing. Knowledge of the mechanisms regulating spermatogonial proliferation and differentiation could lead to ways to minimize the duration of azoospermia following treatment.

Semen quality after treatment for testicular cancer.

During the last 14 years repeated sperm cell analyses and serum hormone analysis were done regularly in patients with testicular cancer before and after treatment. The summarized results are hereby reported. The sperm cell count was highly impaired in 60-70% of testicular cancer patients evaluated 1-4 weeks after unilateral orchidectomy before further treatment. However, improvement of the exocrine gonadal function was regularly observed during the following 2-3 years, provided there were normal or only slightly elevated pre-treatment FSH levels. Standard irradiation and cytotoxic treatment (abdominal radiotherapy 30-40 Gy; < or = 4 cycles of cisplatin-based chemotherapy) delayed this recovery by about one year. Higher doses of chemotherapy or combined irradiation/chemotherapy reduced the chances of rapid improvement of the exocrine gonadal function. Unilateral retroperitoneal lymph node dissection resulted in a slight reduction of the post-treatment ejaculatory volume, even in patients with preserved antegrade ejaculation.