הקפאת זרע - דחוף

השפעת ההידרוקסי אוריאה על הזרע עלולה להשפיע לרעה על כל מדדי הזרע,ולכן טוב היו עושים אם ההקפאה היתה נעשין בטרם הוחל בטיפול,בכל מקרה יש לבצע הקפאת זרע לשם שימור הפוריות ולעקוב אחרי המדדים בטווחי זמן ובהתאם לבצע הקפאות נוספות להלן מאמר הדן ב-4 מקרים שטופלו עם החומר: BRIEF COMMUNICATION Effect of hydroxyurea on sperm count, motility and morphology in adult men with sickle cell or myeloproliferative disease A. Grigg Department of Clinical Haematology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia Key words hydroxyurea, spermatogenesis, sickle cell. Correspondence Andrew Grigg, The Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3050, Australia. Email: [email protected] Received 1 March 2006; accepted 19 June 2006. doi:10.1111/j.1445-5994.2006.01290.x Abstract Hydroxyurea (HU) is not infrequently used in patients with sickle cell disease and myeloproliferative disorders. Despite murine data showing adverse effects on sperm counts, motility and morphology, there is little information on the effect of HU on human spermatogenesis. A retrospective review of four adult men who had semen analysis during HU therapy and in three cases after its cessation suggests that HU generally reduces sperm counts and motility and results in abnormal morphology. Cessation of HU in one case with azoospermia resulted in recovery of spermatogenesis; in two of the three cases, however, sperm morphology and mobility remained impaired. Recommendations for fertility management in adult men receiving long-term HU therapy are proposed. Hydroxyurea (HU) is a cytotoxic and mitotic agent that impairs DNA synthesis by inhibiting ribonucleotide reductase and reducing the pool of deoxynucleotide triphospates, particularly dATP. It is predominantly used for the treatment of myeloproliferative disorders and more recently for sickle cell disease. HU causes an increase in HbF, which interferes with the polymerization of HbS and at a dosage of 20 mg/kg per day reduces the frequency and severity of painful crises.1,2 There is extensive published work describing the adverse effects ofHUonfertilityinmurinemodels.HUgiventomale rats at a dose
60 mg/kg per day (at the higher end of the range generally used in myeloproliferative disease and three times the recommended sickle cell dose) produces testicular atrophy, decreases spermatogenesis, reduces sperm motility and induces abnormalities in sperm morphologyandchromatinstructure, 3–5 although experiments suggest that the germ cell toxicity may be reversible.6 Despite these observations and the increased use of long-term HU therapy in young patients with sickle cell disease, there are few data on the effect of HU on human spermatogenesis. The medium to long-term follow-up studies of chronic HU used predominantly relate to prepubertal children;7 those including young adults do not, to my knowledge, address the issues of fertility.8 There is one case report in which azoospermia was documented after 6 months of HU treatment in a 27-year-old man.9 HU was then ceased and 10 months later the sperm count recovered, albeit to lower levels (35 vs 92  109/L) and reduced mobility (40 vs 75% compared with pre-HU analysis. Table 1 details a retrospective review of our experience at the Royal Melbourne Hospital on the effect of HU on spermatogenesis in four adult men, three with sickle cell disease, who were encouraged to have semen analysis during and after HU and consented to presentation of the results. Only one patient (2) was married and had fathered children before commencement of HU. All patients were not clinically hypogonadic, that is, they had normal testes size and virilization. No patient was tested during an episode of fever or general illness. Patient 1 was azoospermic when first tested after more than 10 years on HU, but 3 months after ceasing the drug the patient had recovered a normal sperm count, although with a high percentage of abnormal forms and impaired motility. HU was recommenced after sperm cryopreservation and he became azoospermic again when retested 6 months later. Patient 2 maintained a count at the lower limit of the normal range with reduced motility when Funding: None Potential conflicts of interest: None Internal Medicine Journal 37 (2007) 190–192 190 ª 2007 The Author Journal compilation ª 2007 Royal Australasian College of Physicians tested during ongoing HU therapy for 17 months. HU was then ceased with repeat sperm analysis 32 months later showing persistently subnormal count, motility and morphology. Patient 3 had a modestly low count but normal motility and morphology when checked 12 months after ceasing 4 years of HU therapy. Patient 4 had substantially low levels with normal motility but abnormal morphology after 8 months and again at 2 and 4 years ofHUtherapy. In patients 1, 2 and 4, the abnormal morphology consisted of small or absent acrosomes, which may reduce the chances of successful fertilization; acrosomes contain lytic enzymes that digest the outer membrane of the ovum, allowing penetration of the sperm. Of note, however, is that patient 4 reported that his partner became pregnant during the third year of HU therapy; the pregnancy was terminated at the partner’s choice. Interpretation of these results is limited by the retrospective nature of the analysis and the absence of baseline data before HU, noting that sperm counts may be low in sickle cell patients before cytotoxic therapy.10,11 Nevertheless, they suggest that: (i) low levels of spermatogenesis may be retained at least within the first few years of HU therapy, but that prolonged therapy may result in azoospermia; some patients, however, may rapidly become azoospermic, (ii) the inhibitory effect of HU is generally at least partly reversible but more data are required to evaluate whether counts ultimately return to pretherapy levels, the kinetics of this recovery and the effects of duration of HU therapy and patient age on these parameters and (iii) HU may alter sperm morphology and abnormal morphology may persist, at least in the short to medium terms, after its cessation.9 There are no data to my knowledge that describe the effect of HU on fertility or on the incidence of abnormal pregnancies fathered by men on HU resulting in first trimester miscarriage. The rates of fertilization may be low because of oligospermia from HU and/or underlying sickle cell disease or clinically invisible genetic damage impairing sperm fertilizing capacity. However, once HU is ceased for more than 3 months and new spermatozoa are formed without exposure to the drug, any fertilized ovum carried to term is unlikely to produce an abnormal infant as a result of paternal exposure to HU. Reassuringly, sperm from men previously treated for childhood cancer does not contain more damaged DNA when compared with age-matched controls and their offspring do not appear to be at greater risk of congenital malformations.12,13 As a result of these observations, our current recommendations for men in whom fertility is relevant and who are planned to receive long therapy with HU are to (i) sperm bank before commencing treatment, (ii) monitor sperm counts annually and (iii) use contraception if not azoospermic and sexually active with a potentially fertile partner duringHUtherapyandfor at least3 monthsafter cessation.