Persistent Azoospermia Research Articles

Testicular sperm extraction in patients with persistent azoospermia after chemotherapy for testicular germ cell tumor

Sperm cryopreservation before chemotherapy in young males is recommended because of chemotherapy's gonadotoxic effects. However, many patients miss sperm banking, and consequently are often sterile. Two azoospermic patients presented to us after chemotherapy, and we obtained sperm from them by testicular sperm extraction (TESE). One patient was 32 years old and had been treated with six cycles of cisplatin, etoposide and bleomycin (BEP) chemotherapy and one cycle of high-dose chemotherapy for stage III non-seminoma. Histopathology of the testicular specimen showed germinal aplasia with focal islands of full spermatogenesis. Although two intracytoplasmic sperm injection (ICSI) cycles were performed, pregnancy was not achieved. The other patient was 33 years old who was treated with four cycles of BEP chemotherapy for stage II seminoma. Histopathology of the testicular specimen showed Sertoli-cell-only syndrome. Ongoing pregnancy was achieved after one ICSI cycle. TESE should be considered in patients with persistent azoospermia after chemotherapy if frozen sperm samples are not available.

Gonadal dysfunction and fertility problems in cancer survivors

Gonadal dysfunction and fertility problems are adverse effects of cancer treatment or may be associated with specific malignancies. This review focuses on these problems in the young cancer survivors, where methods of protecting or restoring endocrine function and fertility need to be considered. In females, treatment adverse effects can result in infertility, but premature ovarian failure (POF) is probably relevant for more female cancer survivors, affecting also those who do not wish post-treatment parenthood. POF affects present and future health, especially through oestrogen deficiency symptoms and an increased risk of developing osteoporosis. A lower risk of developing POF has been considered in young females than in older due to a larger pool of oocytes. However, a recent long-term follow-up study reported a prevalence of POF in young females with Hodgkin's lymphoma of 37% showing that young age at time of treatment only delays the development of POF. In male gonads, germ cells are much more sensitive to irradiation and chemotherapy than Leydig cells. Thus, infertility is a more common adverse effect than hypogonadism. Some malignancies are particular relevant. Persistent azoospermia was formerly common after treatment for Hodgkin's lymphoma, but currently, most patients recover spermatogenesis. Modern treatment of childhood acute lymphoblastic leukemia is also unlikely to cause infertility. Norwegian testicular cancer survivors diagnosed in 1980–1994 who attempted conception had an overall 15-year actuarial post-treatment paternity rate of 71% (range 48–92% depending on the treatment). However, the rate was significantly higher among men diagnosed in1989–1994 (over 80%) than in 1980–1988 (about 63%). Patients at risk for hypogonadism and infertility should be defined prior to treatment, and available methods for gonadal preservation should maximally be utilised. During follow-up, oncologists should routinely address these issues.

Strategies for Preventing Chemotherapy- and Radiotherapy-Induced Gonadal Damage

Gonadal toxicity is an important adverse effect of curative chemotherapy and radiotherapy. However, the individual risk of infertility or gonadal failure is not predictable. Therefore, knowledge of preventive strategies to improve post-treatment fertility is important. In this article we have assessed data from the literature related to this problem. Principally, male germinal epithelium is very sensitive to chemotherapy and radiation. If restoration of spermatogenesis occurs, it will occur within 2 years. Patients have to be counseled that persistent azoospermia is likely, if azoospermia is still present after 3 years. Besides reproductive function, hormonal deficits can also occur and have to be treated. A radiation dose of 2Gy (fractionated irradiation) causes persistent azoospermia and changes in spermatogonia can also be expected with 0.1Gy (fractionated irradiation). Women are less likely to show persistent damage to the ovaries. The sterilization dose is about 20Gy. With 4Gy half the follicles will be lost. These effects are very age dependent, with more sensitive ovaries in the older woman (>40 years). Regarding chemotherapy, those agents with severe effects on germinal function (e.g. chlorambucil, procarbazine, cisplatin) have to be distinguished from those with less severe effects (e.g. methotrexate, mercaptopurine, vincristine). Rates for the likelihood of permanent reproductive failure are listed in the main text. Preventive strategies are either operative (transposition of ovaries out of the radiation field) or hormonal (suppression of gonadotropin-releasing hormone [GnRH] and the pituitary-gonadal-axis by GnRH analogs or oral contraceptive pills). For both strategies, prospective, randomized studies are not available. Only case series have been published; however, both strategies of prevention seem to allow some hope for permanent success. In cases where there is no permanent sterility as a result of childhood cancer there does not seem to be an increased risk for the subsequent generation to experience genetic problems as a result of spontaneous mutations in germ cells. Overall, the new assisted reproductive techniques such as intracytoplasmic sperm injection, maybe using testicular sperms (testicular sperm extraction), offer new hope for those men who have long-term infertility with severely reduced semen concentrations. However, for women, no treatment can be offered in the case of primary ovarian insufficiency. New hope may come from techniques such as germ cell transplantation; these techniques have not yet been evaluated in a clinical setting.

Testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) results in secondary azoospermic patients after chemotherapy

Objective: Anti tumoral treatments have increased the chance of remission or cure of many cancer types, also increasing life expectancies. Unfortunately, these treatments are often aggressive and can cause detrimental effects on fertility. Persistent azoospermia is frequently found in these men. This status can be treated by testicular sperm extraction (TESE) with the aim to recover some spermatozoa to be used in assisted reproduction techniques (ART). Our objectives in this study were: 1) to determine the probability of finding spermatozoa after cytotoxic treatments in those patients with long-term azoospermia caused by therapies against cancer, and 2) assessment of fertilization, embryo development and pregnancy rates, to describe the expectative that ART can offer to these men. Design: During five years, 12 men, mean age of 34 (range: 30–44) were evaluated for azoospermia secondary to chemotherapy alone (n=7) or combined with radiotherapy (n=5) after testicular cancer (n=6), Hodgkin’s lymphoma (n=3) or other malignancies. Some of them were unilaterally orchidectomized (n=3) or suffered retroperitoneal lymph node resection (n=3). The period within the treatment and TESE ranged 4–24 years (mean 10.8 years). Follicle-stimulating hormone concentrations were within the normal range except for two patients. All of them had repeated spermiograms showing azoospermia either in ejaculates (if possible) or urine. Females were normal except for one severe endometriosis. Materials/Methods: From the TESE, two parts were embedded within Bouin’s solution and were sent for histopathological examination. The remaining parts were checked for the presence of sperm cells. If the search resulted positive, samples were immediately frozen until future use for ICSI. Results: Five out of twelve patients (41.6%) had spermatozoa available for ICSI. All of them had testicular cancer. The pathology found in the testicular biopsy comprised discrete spermatogenesis in one patient, and Sertoli-cell only syndrome alone or with mixed causes in the remaining individuals. Mixed causes included hyalinisation, tubular sclerosis and spermatogenesis arrest at various stages. Of these five samples, four were frozen to be employed in next infertility treatments, because one of them yielded only few spermatozoa that were just enough to be injected, and then used in the moment. Twelve cycles were performed, divided in 8 with fresh and 4 with frozen/thawed embryos. Total fertilization failure was one case, and the average fertilisation rate in those patients was 52.4%, ranging between 33.3% and 83.3%. Only one pregnancy was achieved which resulted in a normal newborn. Conclusions: To our knowledge, this is the second extensive study available that comprises TESE and ICSI in long term azoospermic patients after treatments against cancer. Our results indicate that is possible to achieve pregnancy in these cases, although fertilization rates, number of cycles with no transfer, clinical pregnancies and take home baby rates seem to be worse than those expected for the pre-vasectomized men previously reported by our group. Testicular cancer patients have better chances for sperm recovery. A correct management should include the offer the cryopreservation of sperm samples prior to any treatment prescribed by their oncologists. Supported by: None provided.

Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy.

Men who remain azoospermic long after undergoing chemotherapy have generally been considered sterile. The authors report their experience with testicular sperm extraction (TESE) combined with intracytoplasmic sperm injection (ICSI) applied to azoospermic men who previously received chemotherapy for a variety of indications. Among 231 cycles in 198 patients who underwent TESE-ICSI for nonobstructive azoospermia from 1995 to 2000, 20 TESE procedures in 17 patients who previously received chemotherapy were identified. All TESE procedures were performed with microsurgical control under local anesthesia with sedation or general anesthesia. The pretreatment hormonal profile, histology of testicular biopsies, and outcomes of TESE-ICSI in this subgroup of patients were analyzed. The mean patient age was 37.4 years (range, 28-54 years), and the mean follicle-stimulating hormone level was 21.8 mIU/mL (range, 7.1-43.1 mIU/mL). The mean age for female partners was 33.5 years (range, 22-43 years). Six patients had received chemotherapy for Hodgkin lymphoma (34%), four patients had received chemotherapy for testicular neoplasm (24%), two patients had received chemotherapy for non-Hodgkin lymphoma (12%), two patients had received chemotherapy for leukemia (12%), one patient had received chemotherapy for Wilms tumor (6%), one patient had received chemotherapy for mediastinal germ cell tumor (6%), and one patient had received chemotherapy for nephrotic syndrome (6%). Three patients (18%) received additional radiation therapy. The mean interval from chemotherapy to TESE was 16.3 years (range, 6-34 years). All patients had at least two semen analyses to confirm azoospermia. A total of 20 attempts of TESE-ICSI were performed (mean, 1.2 attempts per patient). Testicular histology revealed Sertoli cell-only pattern in 76% of patients. The remaining 24% of patients had hypospermatogenesis as their most advanced spermatogenic pattern. Among the men with Sertoli cell-only pattern, 23% had sperm retrieved by TESE. Sperm retrieval was accomplished in 9 of 20 attempts (45%), with biochemical pregnancy after sperm retrieval in 4 of 9 couples (45%) and clinical pregnancy in 3 of 9 couples (33%). Live deliveries were achieved in 2 of 9 couples (22%). Two healthy boys and one girl were delivered. No correlation was noted between the outcome of TESE-ICSI and the underlying conditions that were treated with chemotherapy nor with the chemotherapeutic agents used. Using TESE-ICSI, sperm retrieval leading to pregnancy and the delivery of healthy children is possible for men with long-standing azoospermia after chemotherapy. The prognosis for sperm retrieval was not influenced clearly by the chemotherapy regimen or the disease treated. Diagnostic biopsy also was of limited value in predicting the outcome of sperm retrieval. Despite prolonged nonobstructive azoospermia after undergoing chemotherapy, men no longer should be considered sterile in the era of advanced assisted reproductive techniques.

Vasectomy reversal.

Vasectomy reversal.

Persistence of infertility in GnRH immunized male rats treated with subdermal implants of dihydrotestosterone (DHT)

Male hormonal contraception has been limited to date because two fundamental requirements have not been concurrently satisfied, these are, consistent and dependable azoospermia and infertility coupled with maintenance of libido. The objective of this study was to determine the extent to which implants of potent androgen (DHT) will restore androgenization and spermatogenesis in hypogonadotropic infertile male rats. Twenty-five sexually mature male rats of proven fertility were actively immunized against gonadotropin releasing hormone (GnRH) to induce azoospermia. After azoospermia was achieved, GnRH immunized rats received subdermal DHT-filled Silastic implants of 2, 4, 6, or 8 cm, or empty implants (n=5/group). Five untreated control rats received empty capsules. Eight weeks later, fertility was evaluated, sperm number was obtained from the testis, and weights of androgen-dependent organs were measured. The results indicate that immunoneutralization of GnRH induced complete azoospermia, and subsequent treatment with DHT implants of 2 or 4 cm for 8 wk restored accessory organ weights, but did not restore spermatogenesis or fertility. In addition, DHT implants of 6 to 8 cm partially restored spermatogenesis, but not fertility. We conclude that low-dose DHT supplementation of GnRH-immunized rats may be a suitable alternate therapy able to maintain androgenization in the face of persistent azoospermia in the rat. This may be an effective model for development of a male contraceptive.

Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections.

We studied 29 men with Young's syndrome, a combination of obstructive azoospermia and chronic sinopulmonary infections. Men with this syndrome have only mildly impaired respiratory function and normal spermatogenesis; the azoospermia is due to obstruction of the epididymis by inspissated secretions. The diagnosis is based on the occurrence of chronic sinopulmonary infections, persistent azoospermia, normal spermatogenesis, and characteristic epididymal findings, as well as exclusion of cystic fibrosis and the immotile-cilia syndrome. The sperm themselves appear to be normal in Young's syndrome. Pregnancies had occurred in five couples; in three paternity was documented by genotyping. Thus, improved microsurgical and medical therapy might restore fertility. We suggest that Young's syndrome has a prevalence comparable to that of Klinefelter's syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia.

Epididymal Extravasation following Vasectomy as a cause for failure of Vasectomy Reversal

Twenty-eight men undergoing vasectomy reversal who were found to have no sperm in the proximal vas fluid on one or both sides underwent microscopic epididymal exploration. In 33 of 39 cases so explored, normal sperm were found in the epididymal fluid of the corpus, despite absence of sperm in the vas fluid. Epididymal histology distal to this site revealed extensive interstitial sperm granulomas resulting from rupture of the epididymal duct. Testicular biopsy revealed normal spermatogenesis. Secondary epididymal obstructions were noted when there was copious fluid in the vas deferens proximal to the vasectomy site as well as when there was scanty fluid. It is concluded that persistent azoospermia after an accurate microscopic vasovasostomy results from the secondary epididymal obstruction induced by rupture of the epididymal duct related to the pressure increase after vasectomy.

Testosterone Rebound Therapy: A Neglected Modality

A summary of the literature and a 20-year review of our own experience with testosterone rebound therapy is presented. Of 225 patients followed, 52% rebounded to fertile levels followed by pregnancy in the wives of 25%. Pregnancy occurred in 3 wives (8%) of the 38 initially azoospermic patients. There was only a 4% incidence of failure to return to at least the pretreatment sperm count following therapy, and no persistent azoospermia was observed. These results are consistent with other recent reports of several large series of patients. Proper screening and selection of patients is mandatory. Testosterone rebound is a neglected form of therapy meriting consideration in selected patients.