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Methotrexate and reproduction in men: Case report and recommendations
Methotrexate and reproduction in men: Case report and recommendations Laura F. Morris, MD,* Mary 1. Harrod, PhD,a M. Alan Menter, MD,b and Alan K. Silverman, MDb Dallas, Texas Methotrexate has been used in the treatment of recalcitrant psoriasis for more than 35 years. We examined the significance of impaired spermatogenesis in a young man undergoing methotrexate treatment for severe psoriasis with associated arthritis. A medical geneticist was consulted and a review of the literature was performed. Genetic abnormalities that could lead to mutagenesis include chromosomal abnormalities and single-genemutations. These aspects are considered and recommendations are made for counseling men undergoing methotrexate therapy so that risks and options can be considered. (J AM ACAD DERMATOL 1993;29:913-6.) Methotrexate was first used to treat psoriasis in 1953, and by 1977 it was being used by 25,000 patients with psoriasis annually. 1 Methotrexate blocks the S phase of the cell cycle by inhibiting dihydrofolate reductase, an enzyme required for DNA, RNA, and protein synthesis. Specifically, the synthesis of thymidylate is blocked and cell division ceases. Cell populations particularly susceptible to methotrexate suppression include rapidly dividing cells such as bone marrow, gastrointestinal mucosa, and hair roots. Impaired development of new sperm has also been reported. 2-4 We evaluated the significance of impaired spermatogenesis in a man who was receiving methotrexate for treatment of severe psoriasis and arthritis. CASE REPORT
A 26-year-old man who had severe generalized psoriasis and arthritis for 10 years was being treated with methotrexate, 12.5 mg/week. His cumulative dose was 728.0 mg. A previous liver biopsy specimen examined when he had taken a cumulative dosage of 427.5 mg showed no abnormality. Physical examination revealed approximately 25% total body surface area involvement with small-plaque psoriasis.
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas," and the Baylor Psoriasis Center, Baylor University Medical Center. b Supported by a grant from the Simmons Foundation. Reprint requests: M. Alan Menter, MD, Baylor Psoriasis Center, 3600 Gaston Ave., Suite 656 Wadley Tower, Dallas, TX 75246. ·Simmons Clinical Research Fellow at Baylor University Medical Center. Copyright @ 1993 by the American Academy of Dermatology, Inc. 0190-9622/93 $1.00
+ ,10
16/4/47028
Although we began to gradually reduce his methotrexate dosage, the patient expressed concern about discontinuation of methotrexate for a long period of time with inevitable exacerbation ofhis psoriasis and arthritis while he was trying to impregnate his wife. He was referred to a medical geneticist for further counseling. DISCUSSION
The patient's referral for genetic counseling presented two distinct questions: What is the risk of his child inheriting psoriasis? What are the potentially harmful effects of the patient's methotrexate therapy on spermatogenesis?
Inheritance Inheritance of psoriasis is probably multifactorial. 5-8 The patient was informed that there is approximately a 10% risk that he would have a child with psoriasis and that there was no way to predict how serious the condition might be in an affected child. Oligospermia The second question is not as straightforward. Sussman and Leonard 2 reported oligospermia in a young man with severe psoriasis who was treated intermittently with MTX. During the first 3 months after discontinuation of MTX the oligospermia disappeared but recurred within 1 month after resuming MTX. Van Scott and Reinertson) noted a decreased sperm count in two patients 12 to 14 days after a single intravenous injection of methotrexate for treatment of psoriasis, but no follow-up was available to determine if this was a reversible event. SchOning 4 investigated semen samples from one patient several times and found that the number of ab-
913
914 Morris et al. normal and immobile spermatozoa increased during treatment. These values normalized 2 months after the medication was stopped. In 1968 Frank et at. 9 warned against giving methotrexate to childbearing women or to men with a fertile partner. In contrast, Gunther lO reported no important change in sperm concentration, motility, or morphologic features in semen samples obtained from 11 male patients with psoriasis before and during long-term methotrexate administration. Grunnet et al. II studied human semen in patients with psoriasis who were treated with topical corticosteroids and in patients with psoriasis who were treated with methotrexate but was unable to demonstrate any unfavorable effect on the semen quality during methotrexate therapy. In fact, he found that the semen analysis was more frequently normal in the methotrexate-treated group. He proposed that oligospermia in some patients with psoriasis was caused by the severity of the disease or possibly by lesions of the genital tract. This idea was supported by the demonstration of excess leukocytes in several semen samples. EI- Beheiry et al. 12 examined semen quality, testicular histologic features, and spermatogenic activity and found no abnormalities either before methotrexate treatment or 70 days after treatment. They did not evaluate the semen during methotrexate administration. Because spermatogenesis takes 74 days to complete, it is difficult to explain the rapid decrease in sperm count that has been reported within 2 to 3 weeks after initiation of methotrexate therapy. To explain this decrease, methotrexate must interfere with some of the late events in the spermatogenic cycle, namely, spermiogenesis 2 (the transformation of spermatids into mature sperm). The exact nature of this interference is not known. Fox and Fox 13 suggested that inhibition of late spermatids and earlier germ cell precursors occurred in mice given methotrexate. Russell and Russell 14 reported spermatogonial death and failure of sperm release by Sertoli cells in rat testis after treatment with methotrexate. Grunnet et al. 11 found that a group of patients treated with steroids had substantially decreased sperm counts but that the patients treated with methotrexate had no decrease. However, they claimed that the group treated with steroids had more extensive psoriasis. Some investigators have pointed out that other events such as an intervening illness can cause a decrease in sperm count and that normally wide day-to-day fluctuations in semen analysis are found when a single or a few samples are examined. IS, 16
Journal of the American Academy of Dermatology November 1993
Another question is whether methotrexate causes seminiferous tubule fibrosis and permanent oligospermia when given in doses used to treat psoriasis. Freeman-Narrod and N arrod 17 found moderate tubular atrophy and decreased spermatogenesis in the testes of mice treated with methotrexate. This was associated with fewer litters. When the methotrexate was discontinued, the litter number increased. In contrast to the situation in the pregnant woman for whom direct teratogenic effects of methotrexate on the developing embryo and fetus represent a significant risk,18 exposure of a man to methotrexate would result in an increased risk of birth defects only if the drug acts as a mutagen during spermatogenesis. There are two types of genetic abnormalities that must be considered when discussing the potential mutagenic effect of any agent, that is, chromosomal abnormalities and single-gene mutations. Chromosomal abnormalities Structural chromosomal rearrangements such as translocations that may result from chromosome breakage can have serious genetic consequences and have been attributed to many drugs, possibly including methotrexate. Chromosomal abnormalities that can be identified by variations in the number or structure of specific chromosomes can be identified by studying prometaphase or metaphase chromosomes in any dividing tissue, such as lymphocytes, skin fibroblasts, or bone marrow cells. Several studies have been performed on lymphocytes in patients with psoriasis. Melnyk et al. 19 found mitotic chromosome damage in bone marrow cells but not in cultured lymphocytes or fibroblasts from a patient treated with methotrexate. No meiotic chromosome damage was detected in testicular biopsy specimens taken at the same time. Krogh Jensen and Nyfors 20 also found chromosomal damage in bone marrow cells in patients treated with methotrexate, but they found no damage in peripheral lymphocytes. Voorhees et a1. 21 examined the metaphase chromosomes in leukocytes from nine patients with psoriasis who were treated with methotrexate, nine untreated patients with psoriasis, and 10 healthy adults. No biologically or statistically significant increase in chromosomal abnormalities could be detected at the various methotrexate dosages used in these patients. The few aberrations that were found could not be correlated with the peak plasma concentration. Rees et al. 22 found a slight increase in the number of gaps and breaks in lymphocyte chromosomes of patients with psoriasis compared with normal subjects.
Journal of the American Academy of Dermatology Volume 29, Number 5, Part 2
Cytogenetic studies on human sperm are difficult to perform and require techniques such as fusion with hamster egg nuclei to visualize the tightly condensed sperm chromosomes. The action of a mutagen on the dividing genetic material of a male stem cell could lead to the production of multiple chromosomally abnormal sperm. If viable, such a sperm cell could result in a zygote with a cytogenetic abnormality. If the chromosomal defect were compatible with continued development, this could lead to the birth of an infant with multiple anomalies. If methotrexate alters testicular stem cell chromosomes, this change would be permanent unless counteracted by another event or corrected by DNA repair mechanisms. Whether or not a change in the genetic material would result in a problem for the offspring of that cell would depend on the nature of the chromosomal change. The actual risk of this occurrence appears to be low, probably because chromosomally abnormal sperm are at a disadvantage biologically and are unlikely to fertilize the egg or because abnormal zygotes may fail to implant or cease development at an early stage. This type of chromosomal damage might therefore be associated with decreased fertility or an increased risk of spontaneous abortion but represents a relatively small risk for producing a chromosomally abnormal offspring. Prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis could be performed to rule out a chromosomal abnormality in any viable pregnancy, and this option was discussed with the patient. Single-gene mutations
The other type of mutagenic event that might occur in spermatogenesis, a single-gene mutation, presents a more difficult counseling situation. A single base-pair change in DNA can result in a deleterious mutation. Although many such mutations would not be expressed in the offspring because of their recessive nature, a mutation for an autosomal dominant trait could be expressed. An increased frequency of such new mutations has been shown to correlate with increasing paternal age for several genetic conditions. This increased age-related risk for new mutations may be related to the accumulation of environmentally-induced genetic changes in the DNA of stem cells in the testes. A single mutational hit in a spermatogonium could therefore lead to the production of several sperm carrying the new mutation and an increased risk for an affected offspring. Similar risks for new paternal mutations presumably exist for exposure to mutagenic agents such as
Morris et al.
915
methotrexate. It is this concern that has led to recommendations ofvarious waiting periods after medication exposure before attempting conception. Although this is a reasonable precaution for reducing the risk caused by mutations sustained during meiotic divisions of the spermatocyte, no period of waiting, short of avoidance of conception altogether, can completely eliminate the risk that a spermatogonial mutation could result in the appearance of a new mutation in the offspring of the exposed father. New dominant mutations are unlikely to be detected by the available methods of prenatal diagnosis. CVS and amniocentesis provide information regarding chromosomal number and structural alterations, but specific testing for DNA alterations is possible for only a limited number of single-gene disorders, and then only when the family history indicates an increased risk and per-pregnancy DNA studies have confirmed that the mutation can be identified prenatally. Anecdotal reports exist of apparently normal children born to fathers who were being treated with methotrexate. I, 9. 23 Certainly this is a poor representation of the actual number. These reports do not include children of fathers treated previously with methotrexate. The best evidence that men treated with methotrexate can father normal offspring involves patients who received chemotherapy for various types of cancer. 24-28 The clinical data available do not provide any evidence of an increased incidence of congenital abnormalities in the children of male patients exposed to methotrexate or several other chemotherapeutic agents. This observation may reflect the repair ability of the exposed cells, the rare occurrence of viable mutations, or simply an effect of small numbers of reported cases. N onetheless, it is a reassuring finding that can be incorporated in the counseling of concerned patients. Recommendations
We agree with the recommendation to wait at least 3 months, or longer than one spermatogenic cycle, to conceive. 1 Of course, no guarantee of normal offspring is possible, but few question the prudence of avoiding conception during the 74 days needed for sperm development. Whether waiting more than 90 days would decrease the chance of an affected offspring is unknown. One method for avoiding the risk of psoriasis in an offspring and the risk of congenital abnormalities would involve the use of donor insemination or adoption. Other options include sperm storage before commencing methotrexate therapy and post-
Journal of the American Academy of Dermatology November 1993
916 Morris et al. ponement of methotrexate treatment until after a patient's family is complete. Pretreatment semen cryopreservation has made possible the retention of reproductive capacity for cancer patients treated with chemotherapeutic agents. 29-34 However, the success of this technique is dependent on favorable pretreatment semen analysis. If conception occurs while a man is receiving methotrexate, the obstetricianshould be made aware of the exposure of the paternal gamete to methotrexate so that the appropriate screening studies can be carried out on the fetus. The use of CVS or amniocentesis to rule out the occurrence of a chromosomal abnormality and the use of ultrasonography to attempt to visualize structural malformations in the fetus are possible. These procedures could provide reassurance, but their limitations should be recognized.
16.
17. 18.
19.
20.
21.
22. 23.
REFERENCES 1. Weinstein GD. Methotrexate. Ann Intern Med 1977;86: 199-204. 2. Sussman A, Leonard JM. Psoriasis, methotrexate and oligospermia. Arch DermatolI980;116:215-7. 3. Van Scott EJ, Reinertson RD. Morphologic and physiologic effects of chemotherapeutic agents in psoriasis. J Invest Dermatol 1959;33:357-69. 4. SchOning FW. Teratospermie nach Verabreichung von Methotrexat. Z Haut-Geschlkrankh 1967;42:271-5. 5. McKusick VA. Mendelian inheritance in man. 9th ed. Baltimore; Johns Hopkins University Press, 1990:818-9. 6. Watson W, Cann HM, Farber EM, et al. The genetics of psoriasis. Arch DermatoI1972;105:197-207. 7. Russell TJ, Schultes LM, Kuban DJ. Histocompatibility (HL-A) antigens associated with psoriasis. N Engl J Med 1972;287:738-40. 8. Berini RY, Kahn E, eds. Clinical genetics handbook. Oradell, N.J.: Medical Economics Company, 1987: 196. 9. Frank L, Lichtman H, Petrou P. Experiences with methotrexate in psoriasis. Dermatologica 1968;1937:87-96. 10. Gunther VE. Andrologische untersuchungen bei der antimetabolite therapie der psoriasis. Dermatol Monatsschr 1970;156:498-502. 11. Grunnet E, Nyfors A, Hansen KB. Studies on human semen in topical corticosteroid-treated and in methotrexatetreated psoriatics. Dermatologica 1977;154:78-87. 12. EI-Beheiry A, El-Mansy E, Kamel N, et al. Methotrexate and fertility in men. Arch Androl 1979;3:177-9. 13. Fox BW, Fox M. Biochemical aspects of the actions of drugs on spermatogenesis. Pharmacol Rev 1967;19: 21-57. 14. Russell LD, Russell JA. Short-term morphological response of the rat testis to administration of five chemotherapeutic agents. Am J Anat 1991;192:142-68. 15. Lipsett MB, Sherins R. The testis. In: Bondy PK, Rosen-
24.
25.
26.
27.
28. 29. 30.
31.
32. 33.
34.
berg, eds. Duncan's disease of metabolism. 7th ed. Philadelphia: W B Saunders, 1974:1553-84. Sherins RJ, Brightwell D, Stenthal PM. Longitudinal analysis of semen of fertile and infertile men. In: Troen P, Nankin HY, eds. The testis in normal and infertile man. New York: Raven Press, 1977:473-88. Freeman-Narrod M, Narrod SA. Chronic toxicity of methotrexate in mice. J Nat! Cancer Inst 1977;58:735-41. Jones KL, ed. Smith's recognizable patterns of human malformation. 4th ed. Philadelphia: W B Saunders, 1988: 506-7. Melnyk J, Duffy OM, Sparkes RS. Human mitotic and meiotic chromosome damage following in vivo exposure to methotrexate. Clin Genet 1971;11:28-31. Krogh Jensen M, Nyfors A. Cytogenetic effect of methotrexate on human cells in vivo: comparison between results obtained by chromosome studies on bone-marrow cells and blood 1ymphocytes and by the micronucleus test. MutatRes 1979;64:339-43. Voorhees JJ, Janzen MK, Harrell ER, et aL Cytogenetic evaluation of methotrexate treated psoriatic patients. Arch DermatoI1969;100:269-74. Rees RB, Bennett JH, Maibach HI, et al. Methotrexate for psoriasis. Arch Dermatol 1967;95:2-10. Perry WHo Methotrexate and teratogenesis. Arch Dermatol 1983;119:874-5. Shamberger RC, Rosenberg SA, Seipp CA, et al. Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. Cancer Treat Rep 1981/65:739-45. Sher ns RJ, De Vita VT. Effect of drug treatment for lymphoma on male reproductive capacity. Ann Intern Med 1973;79:216-20. Eyenson DP, Arlin Z, Welt S, et al. Malereproductivecapacity may recover following drug treatment with the L-l 0 protocol for acute lymphocytic leukemia. Cancer 1984; 53:30-6. Kroner TH, TschumiA Conception of normal child during chemotherapy of acute lymphoblastic leukemia in the father. Br Med J 1977;1:1322-3. Hinkes E, Plotkin D. Reversible drug-induced sterility in a patient with acute leukemia. JAMA 1973;223:1490-1. Averette HE, Boike GM, Jarrell MA. Effects of cancer chemotherapy on gonadal function and reproductive capacity. CA Cancer J Clin 1990;40:199-206. Sanger WG, Armitage JO, Schmidt MA. Feasibility of semen cryopreservationin patients with malignant disease. JAMA 1980;244:789-90. Reed E, Sanger WG, Armitage JO. Results of semen cryopreservation in young men with testicular carcinoma and lymphoma. J Clin OncoI1986;4:537-9. Redman JR, Bajorunas DR, Goldstein MC, et al. Semen cryopreservation and artificial insemination for Hodgkin's disease. J Clin Oncol 1987;5:233-8. Rhodes EA, Hoffman DJ, Kaempfer SH. Ten years of experience with semen cryopreservation by cancer patients: follow-up and clinical considerations. Fertil Steril 1985; 44:512-6. Scammell GE, White N, Stedronska J, et al. Cryopreservation ofsemen in men with testicular tumour or Hodgkin's disease: results of artificial insemination of their partners. Lancet 1985;2:31-2.
A 26-year-old man who had severe generalized psoriasis and arthritis for 10 years was being treated with methotrexate, 12.5 mg/week. His cumulative dose was 728.0 mg. A previous liver biopsy specimen examined when he had taken a cumulative dosage of 427.5 mg showed no abnormality. Physical examination revealed approximately 25% total body surface area involvement with small-plaque psoriasis.
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas," and the Baylor Psoriasis Center, Baylor University Medical Center. b Supported by a grant from the Simmons Foundation. Reprint requests: M. Alan Menter, MD, Baylor Psoriasis Center, 3600 Gaston Ave., Suite 656 Wadley Tower, Dallas, TX 75246. ·Simmons Clinical Research Fellow at Baylor University Medical Center. Copyright @ 1993 by the American Academy of Dermatology, Inc. 0190-9622/93 $1.00
+ ,10
16/4/47028
Although we began to gradually reduce his methotrexate dosage, the patient expressed concern about discontinuation of methotrexate for a long period of time with inevitable exacerbation ofhis psoriasis and arthritis while he was trying to impregnate his wife. He was referred to a medical geneticist for further counseling. DISCUSSION
The patient's referral for genetic counseling presented two distinct questions: What is the risk of his child inheriting psoriasis? What are the potentially harmful effects of the patient's methotrexate therapy on spermatogenesis?
Inheritance Inheritance of psoriasis is probably multifactorial. 5-8 The patient was informed that there is approximately a 10% risk that he would have a child with psoriasis and that there was no way to predict how serious the condition might be in an affected child. Oligospermia The second question is not as straightforward. Sussman and Leonard 2 reported oligospermia in a young man with severe psoriasis who was treated intermittently with MTX. During the first 3 months after discontinuation of MTX the oligospermia disappeared but recurred within 1 month after resuming MTX. Van Scott and Reinertson) noted a decreased sperm count in two patients 12 to 14 days after a single intravenous injection of methotrexate for treatment of psoriasis, but no follow-up was available to determine if this was a reversible event. SchOning 4 investigated semen samples from one patient several times and found that the number of ab-
913
914 Morris et al. normal and immobile spermatozoa increased during treatment. These values normalized 2 months after the medication was stopped. In 1968 Frank et at. 9 warned against giving methotrexate to childbearing women or to men with a fertile partner. In contrast, Gunther lO reported no important change in sperm concentration, motility, or morphologic features in semen samples obtained from 11 male patients with psoriasis before and during long-term methotrexate administration. Grunnet et al. II studied human semen in patients with psoriasis who were treated with topical corticosteroids and in patients with psoriasis who were treated with methotrexate but was unable to demonstrate any unfavorable effect on the semen quality during methotrexate therapy. In fact, he found that the semen analysis was more frequently normal in the methotrexate-treated group. He proposed that oligospermia in some patients with psoriasis was caused by the severity of the disease or possibly by lesions of the genital tract. This idea was supported by the demonstration of excess leukocytes in several semen samples. EI- Beheiry et al. 12 examined semen quality, testicular histologic features, and spermatogenic activity and found no abnormalities either before methotrexate treatment or 70 days after treatment. They did not evaluate the semen during methotrexate administration. Because spermatogenesis takes 74 days to complete, it is difficult to explain the rapid decrease in sperm count that has been reported within 2 to 3 weeks after initiation of methotrexate therapy. To explain this decrease, methotrexate must interfere with some of the late events in the spermatogenic cycle, namely, spermiogenesis 2 (the transformation of spermatids into mature sperm). The exact nature of this interference is not known. Fox and Fox 13 suggested that inhibition of late spermatids and earlier germ cell precursors occurred in mice given methotrexate. Russell and Russell 14 reported spermatogonial death and failure of sperm release by Sertoli cells in rat testis after treatment with methotrexate. Grunnet et al. 11 found that a group of patients treated with steroids had substantially decreased sperm counts but that the patients treated with methotrexate had no decrease. However, they claimed that the group treated with steroids had more extensive psoriasis. Some investigators have pointed out that other events such as an intervening illness can cause a decrease in sperm count and that normally wide day-to-day fluctuations in semen analysis are found when a single or a few samples are examined. IS, 16
Journal of the American Academy of Dermatology November 1993
Another question is whether methotrexate causes seminiferous tubule fibrosis and permanent oligospermia when given in doses used to treat psoriasis. Freeman-Narrod and N arrod 17 found moderate tubular atrophy and decreased spermatogenesis in the testes of mice treated with methotrexate. This was associated with fewer litters. When the methotrexate was discontinued, the litter number increased. In contrast to the situation in the pregnant woman for whom direct teratogenic effects of methotrexate on the developing embryo and fetus represent a significant risk,18 exposure of a man to methotrexate would result in an increased risk of birth defects only if the drug acts as a mutagen during spermatogenesis. There are two types of genetic abnormalities that must be considered when discussing the potential mutagenic effect of any agent, that is, chromosomal abnormalities and single-gene mutations. Chromosomal abnormalities Structural chromosomal rearrangements such as translocations that may result from chromosome breakage can have serious genetic consequences and have been attributed to many drugs, possibly including methotrexate. Chromosomal abnormalities that can be identified by variations in the number or structure of specific chromosomes can be identified by studying prometaphase or metaphase chromosomes in any dividing tissue, such as lymphocytes, skin fibroblasts, or bone marrow cells. Several studies have been performed on lymphocytes in patients with psoriasis. Melnyk et al. 19 found mitotic chromosome damage in bone marrow cells but not in cultured lymphocytes or fibroblasts from a patient treated with methotrexate. No meiotic chromosome damage was detected in testicular biopsy specimens taken at the same time. Krogh Jensen and Nyfors 20 also found chromosomal damage in bone marrow cells in patients treated with methotrexate, but they found no damage in peripheral lymphocytes. Voorhees et a1. 21 examined the metaphase chromosomes in leukocytes from nine patients with psoriasis who were treated with methotrexate, nine untreated patients with psoriasis, and 10 healthy adults. No biologically or statistically significant increase in chromosomal abnormalities could be detected at the various methotrexate dosages used in these patients. The few aberrations that were found could not be correlated with the peak plasma concentration. Rees et al. 22 found a slight increase in the number of gaps and breaks in lymphocyte chromosomes of patients with psoriasis compared with normal subjects.
Journal of the American Academy of Dermatology Volume 29, Number 5, Part 2
Cytogenetic studies on human sperm are difficult to perform and require techniques such as fusion with hamster egg nuclei to visualize the tightly condensed sperm chromosomes. The action of a mutagen on the dividing genetic material of a male stem cell could lead to the production of multiple chromosomally abnormal sperm. If viable, such a sperm cell could result in a zygote with a cytogenetic abnormality. If the chromosomal defect were compatible with continued development, this could lead to the birth of an infant with multiple anomalies. If methotrexate alters testicular stem cell chromosomes, this change would be permanent unless counteracted by another event or corrected by DNA repair mechanisms. Whether or not a change in the genetic material would result in a problem for the offspring of that cell would depend on the nature of the chromosomal change. The actual risk of this occurrence appears to be low, probably because chromosomally abnormal sperm are at a disadvantage biologically and are unlikely to fertilize the egg or because abnormal zygotes may fail to implant or cease development at an early stage. This type of chromosomal damage might therefore be associated with decreased fertility or an increased risk of spontaneous abortion but represents a relatively small risk for producing a chromosomally abnormal offspring. Prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis could be performed to rule out a chromosomal abnormality in any viable pregnancy, and this option was discussed with the patient. Single-gene mutations
The other type of mutagenic event that might occur in spermatogenesis, a single-gene mutation, presents a more difficult counseling situation. A single base-pair change in DNA can result in a deleterious mutation. Although many such mutations would not be expressed in the offspring because of their recessive nature, a mutation for an autosomal dominant trait could be expressed. An increased frequency of such new mutations has been shown to correlate with increasing paternal age for several genetic conditions. This increased age-related risk for new mutations may be related to the accumulation of environmentally-induced genetic changes in the DNA of stem cells in the testes. A single mutational hit in a spermatogonium could therefore lead to the production of several sperm carrying the new mutation and an increased risk for an affected offspring. Similar risks for new paternal mutations presumably exist for exposure to mutagenic agents such as
Morris et al.
915
methotrexate. It is this concern that has led to recommendations ofvarious waiting periods after medication exposure before attempting conception. Although this is a reasonable precaution for reducing the risk caused by mutations sustained during meiotic divisions of the spermatocyte, no period of waiting, short of avoidance of conception altogether, can completely eliminate the risk that a spermatogonial mutation could result in the appearance of a new mutation in the offspring of the exposed father. New dominant mutations are unlikely to be detected by the available methods of prenatal diagnosis. CVS and amniocentesis provide information regarding chromosomal number and structural alterations, but specific testing for DNA alterations is possible for only a limited number of single-gene disorders, and then only when the family history indicates an increased risk and per-pregnancy DNA studies have confirmed that the mutation can be identified prenatally. Anecdotal reports exist of apparently normal children born to fathers who were being treated with methotrexate. I, 9. 23 Certainly this is a poor representation of the actual number. These reports do not include children of fathers treated previously with methotrexate. The best evidence that men treated with methotrexate can father normal offspring involves patients who received chemotherapy for various types of cancer. 24-28 The clinical data available do not provide any evidence of an increased incidence of congenital abnormalities in the children of male patients exposed to methotrexate or several other chemotherapeutic agents. This observation may reflect the repair ability of the exposed cells, the rare occurrence of viable mutations, or simply an effect of small numbers of reported cases. N onetheless, it is a reassuring finding that can be incorporated in the counseling of concerned patients. Recommendations
We agree with the recommendation to wait at least 3 months, or longer than one spermatogenic cycle, to conceive. 1 Of course, no guarantee of normal offspring is possible, but few question the prudence of avoiding conception during the 74 days needed for sperm development. Whether waiting more than 90 days would decrease the chance of an affected offspring is unknown. One method for avoiding the risk of psoriasis in an offspring and the risk of congenital abnormalities would involve the use of donor insemination or adoption. Other options include sperm storage before commencing methotrexate therapy and post-
Journal of the American Academy of Dermatology November 1993
916 Morris et al. ponement of methotrexate treatment until after a patient's family is complete. Pretreatment semen cryopreservation has made possible the retention of reproductive capacity for cancer patients treated with chemotherapeutic agents. 29-34 However, the success of this technique is dependent on favorable pretreatment semen analysis. If conception occurs while a man is receiving methotrexate, the obstetricianshould be made aware of the exposure of the paternal gamete to methotrexate so that the appropriate screening studies can be carried out on the fetus. The use of CVS or amniocentesis to rule out the occurrence of a chromosomal abnormality and the use of ultrasonography to attempt to visualize structural malformations in the fetus are possible. These procedures could provide reassurance, but their limitations should be recognized.
16.
17. 18.
19.
20.
21.
22. 23.
REFERENCES 1. Weinstein GD. Methotrexate. Ann Intern Med 1977;86: 199-204. 2. Sussman A, Leonard JM. Psoriasis, methotrexate and oligospermia. Arch DermatolI980;116:215-7. 3. Van Scott EJ, Reinertson RD. Morphologic and physiologic effects of chemotherapeutic agents in psoriasis. J Invest Dermatol 1959;33:357-69. 4. SchOning FW. Teratospermie nach Verabreichung von Methotrexat. Z Haut-Geschlkrankh 1967;42:271-5. 5. McKusick VA. Mendelian inheritance in man. 9th ed. Baltimore; Johns Hopkins University Press, 1990:818-9. 6. Watson W, Cann HM, Farber EM, et al. The genetics of psoriasis. Arch DermatoI1972;105:197-207. 7. Russell TJ, Schultes LM, Kuban DJ. Histocompatibility (HL-A) antigens associated with psoriasis. N Engl J Med 1972;287:738-40. 8. Berini RY, Kahn E, eds. Clinical genetics handbook. Oradell, N.J.: Medical Economics Company, 1987: 196. 9. Frank L, Lichtman H, Petrou P. Experiences with methotrexate in psoriasis. Dermatologica 1968;1937:87-96. 10. Gunther VE. Andrologische untersuchungen bei der antimetabolite therapie der psoriasis. Dermatol Monatsschr 1970;156:498-502. 11. Grunnet E, Nyfors A, Hansen KB. Studies on human semen in topical corticosteroid-treated and in methotrexatetreated psoriatics. Dermatologica 1977;154:78-87. 12. EI-Beheiry A, El-Mansy E, Kamel N, et al. Methotrexate and fertility in men. Arch Androl 1979;3:177-9. 13. Fox BW, Fox M. Biochemical aspects of the actions of drugs on spermatogenesis. Pharmacol Rev 1967;19: 21-57. 14. Russell LD, Russell JA. Short-term morphological response of the rat testis to administration of five chemotherapeutic agents. Am J Anat 1991;192:142-68. 15. Lipsett MB, Sherins R. The testis. In: Bondy PK, Rosen-
24.
25.
26.
27.
28. 29. 30.
31.
32. 33.
34.
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