INTRODUCTION
Hodgkin's lymphoma is a neoplastic disorder arising from the lymphoid cells and diagnosed on the basis of a pathological study of the tissue suspected of the disease, by observing the Reed-Sternberg cells and connective tissue in a study of tissue sections. The classical Hodgkin's disease has four histopathological subtypes, which are as follows:[1,2]
Lymphocyte-predominant Hodgkin's lymphoma (LPHL)
Nodular sclerosis Hodgkin's lymphoma (NSHL)
Mixed cellularity Hodgkin's lymphoma (MCHL)
Lymphocyte depletion Hodgkin's lymphoma (LDHL)
Each pathological subtype of Hodgkin's lymphoma has its own manifestations and symptoms. The histological subtype has a partial effect on the treatment and prognosis of the disease. Male patients show worse prognosis than female patients.
Hodgkin's lymphoma is a neoplastic disease that threatens a patient's life if it grows rapidly. Late diagnosis of the disease can have serious outcomes, which may be irreparable. A delayed diagnosis results in progress of the disease, and consequently, more invasive methods will be needed to control it.[2,3]
Infertility refers to the inability of a couple to reproduce over one year of sexual intercourse, without using contraceptive means.
Male infertility is caused by different factors including endocrine abnormalities, epigenetic changes, and genetic mutations. In many cases, identifying the cause of infertility and treating it results in the continuation of marriage and mental relief for the couple.
Sterility may exist in patients several years before appearance of the clinical symptoms of Hodgkin's lymphoma. Primary hypogonadism is usually distinguished from secondary hypogonadism by measuring the serum levels of LH and FSH. In case of primary hypogonadism, the serum levels of LH and FSH increase and the serum level of testosterone and the sperm count decrease.[4] The present study examines patients with Hodgkin's lymphoma in terms of azoospermia before any medical intervention [Table 1].
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Table 1: Duration of sterility by month, before diagnosis of Hodgkin's Lymphoma
MATERIALS AND METHODS
In this study, the infertility of 238 patients with Hodgkin's lymphoma was examined. They did not receive any chemotherapy, or radiotherapy, and were being examined to discover the stage of the disease. Female patients were excluded from the study due to lack of certain facilities to prove their sterility. Sterility of male patients was confirmed using the spermogram test. The serum levels of LH, FSH, and testosterone were checked. The present study was performed from 1999 to 2009, in Isfahan's Hazrat-e-Seyedoshohada Center, affiliated to the School of Medicine, in the Isfahan University of Medical Sciences. The patients were asked about their experiences of the disease and probable infertility symptoms, including the state of the testes when touched, status of the secondary sexual characteristics, hair growth, patient's sexual behavior in the past, any history of radiation, previous surgical operations and medication, family history, and secondary disorders of infertility. If there was any doubt about the patients’ experiences of the disease and clinical symptoms, they were examined through a pelvic and testes ultrasound examination or urology consultation. Subsequently, a fasting blood sample was taken and delivered to the laboratory of the same center, to measure the serum levels of LH, FBS, and testosterone. Almost 10 weeks after medical intervention and complete remission of the disease, the patients underwent a spermogram again and the results were recorded and examined.
All the spermograms were carried out by one person in one laboratory. The spermogram examined the following factors: Volume of the sperm and seminal fluid, sperm count in a cubic centimeter, percentage of motile sperm in a microscopic field, percentage of deformed, abnormal, dead, and tailless sperms and sperm components, white blood cell and red blood cell count in the blood sample, and abnormal cell infiltration.[5,6] All the patients were examined in periodical follow-ups for five years, after complete remission.
RESULTS
In this study, 238 patients with Hodgkin's lymphoma in the age range of 18-52 years were examined. Among these patients, 24 patients (10.08%) were affected with azoospermia before receiving any chemotherapy or radiotherapy. An analysis of the number of patients with azoospermia, based on the histopathological subtypes, revealed that LDHL was more common than the other subtypes [Table 2].
Table 2: Percentage of azoospermia based on the pathological subtypes of Hodgkin's Lymphoma
The percentage of azoospermia in advanced stages (III and IVB) was more than that in the moderate stages (I and IIA) of the disease [Table 3]. Moreover, oligospermia, obvious reduced sperm motility, and teratospermia were observed frequently. However, there was no hypospermia and aspermia.
Table 3: Percentage of azoospermia based on Hodgkin's Lymphoma stages
Specifications of the spermogram
The sperm volume of 14 samples was less than 1 cc and 10 samples had a sperm volume of 1-2 cc. The percentage of motile sperm in 20 samples was less than 10%, and four and three samples comprised of 20 and 30%, respectively.[5,6]
There were 10-15 motile sperms in each microscopic field. The number of spermatozoa in all the patients was less than 40 million per cubic centimeter, and the deformed and dead spermatozoa increased noticeably.
The results of the hormone analysis of LH, FSH, and testosterone were in the normal range in all patients. On the basis of the above-mentioned results, the azoospermia of the patients could not be attributed to primary and secondary testicular failure; however, it could be attributed to immune and autoimmune disorders like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
DISCUSSIONS
According to the clinical observations and experiences and also global publications, hypogonadism and sperm disorders were observed in certain cancers.[7] In the present study, 10.08% of the patients with Hodgkin's lymphoma suffered from gonadal failure, before medical intervention. The results showed that Hodgkin's lymphoma could cause infertility. The mechanisms by which Hodgkin's lymphoma caused gonadal failure were not clear.[8,9] Although the initial gonadal damage was not important and could be due to hypothalamus–pituitary axis failure, it was more likely due to the humoral and cellular immune system, and consequently, incidence of an autoimmune disorder against the spermatozoa; however, it could be reduced by controlling the disease and by complete remission.[10] The type of medications used by the patients was of special importance, as some chemotherapy drugs could result in sterility.
After chemotherapy, especially along with an MOPP (Mustin, Oncovine, Procarbazine and Prednisone) diet or similar diets, testicular dysfunction is seen in almost all patients (more than 90%) and spermatogenetic recovery is seen only in 20% of the patients (9b). The rate of testicular damage depends on the number and dosage of the drug and frequency of chemotherapy. If the three-course therapeutic protocol of MOPP is restricted, the azoospermia will be moderate and spermatogenetic recovery will be possible after some months. However, in most cases, more chemotherapeutic courses are needed to control the disease completely. Azoospermia is considerably reduced when no combined treatment with alkylating agents or procarbazine is applied.[9,10] When using an ABVD (Adriamycine, bleomycine, Vinblastine and Decarbazine) diet, azoospermia is seen in 36% of the cases and spermatogenetic recovery is seen in all patients (100%).[10,11] The gonadal toxicity reaches a minimum when using the VMB (vinblastine, Bleomycin, and methotrexate) diet.
Secondary sterility, which occurs following chemotherapy, is the result of initial testicular damage. Although FSH increases, spermatogenetic recovery may not happen. Therefore, determining the level of FSH alone is not enough to prove recovery.[12,13] In general, young men with Hodgkin's Lymphoma suffer an underlying gonadal dysfunction.
The study of 15 patients with azoospermia, 10 weeks after termination of chemotherapy (along with an ABVD diet), showed that three patients recovered, one patient recovered six months after treatment, and another patient who was unsatisfied with undergoing the spermogram test after chemotherapy, gained his fertility after 14 months (based on the pregnancy of his wife). Going by the above-mentioned results, it can be concluded that azoospermia underlies Hodgkin's Lymphoma, and this may be due to autoimmune reasons, and may be treated or reduced after a while using an appropriate treatment. Azoospermia is mostly seen in the advanced stages of Hodgkin's Lymphoma and can be used as a prognostic factor to detect the progress of the disease and deterioration of the patient's status.[14,15]
Among the studied patients, 24 patients with azoospermia underwent chemotherapy or radiotherapy or both. Ten weeks after termination of the treatment, a spermogram and measurement of the LH, FSH, and testosterone serum levels were carried out again, and it was revealed that 15 patients had recovered from azoospermia.[16]
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Source of Support: Isfahan University of Medical Sciences
Conflict of Interest: No.
