J Am Board Fam Pract: first published as 10.3122/jabfm.10.2.131 on 1 March 1997. Downloaded from Clinical Approaches to Male Infertility With a Case Report of Possible Nifedipine-Induced Sperm Dysfunction
Gary Enders, MD
Background: Male infertility has many causes, and recently it has been suggested that calcium channel blockers might contribute to male infertility. Methods: A case consistent with nifedipine-induced male infertility is described. MEDUNE was searched for articles on the effect of calcium channel blockers and the general causes of infertility, with an emphasis on male infertility, using the key words "nifedipine" "male infertility," "sperm," and "calcium channel blockers." Results and Conclusions: Male infertility induced by calcium channel blockers should be included in the differential diagnosis of infertile couples in appropriate cases. Whether a calcium channel blocker could be developed as a male contraceptive remains to be determined. Further studies are needed to determine the prevalence of infertility among men taking calcium channel blockers. 0 Am Board Fam Pract 1997;10:131-6.)
Recent research indicates that calcium channel adenosine triphosphate (ATP) concentration, as blockers can inhibit human sperm capacitation well as significantly lower egg penetration in and prevent fertilization. Although known to guinea pigs.! Incubation of mouse sperm and those specializing in male infertility, this informa eggs with diltiazem resulted in depressed fertil tion is generally unknown to the general medical ization without affecting sperm motility when community. compared with controls. 2 Human sperm incubated in vitro with dilti Methods azem (1 mmol) had decreased motility, but no ef A case consistent with nifedipine-induced male in fect on motility was found with lower concentra
fertility is described. MEDLINE was searched for tions of diltiazem (1 to 100 pmol).3 Verapamil (5 http://www.jabfm.org/ atides on the effect of calcium channel blockers to 50 pmol) and nifedipine (1 to 100 pmol) caused on male fertility using the key words "nifedipine," disruptive morphologic changes in head and tail "male infertility," "calcium channel blockers," and regions of human spermatozoa, impaired motil "sperm." MEDLINE was also searched for arti ity, lower uptake of extracellular calcium, and de cles on male infertility in general with an emphasis creased calcium-dependent adenosine triphos on drug-induced male infertility. Specialty text phatase (ATPase) activity.4,5 books, along with the medical literature, were When human sperm are ejaculated into the on 27 September 2021 by guest. Protected copyright. used to formulate a discussion of the infertility genital tract, they must undergo complex bio workup with an emphasis on male factors. chemical changes to prepare for attachment to the egg, a process known as capacitation. Evi Effect of Calcium Channel Blockers dence suggests that capacitation involves expres on Male Fertility sion of a mannose lectin receptor on the sperm Calcium channel blockers have been shown to head that can attach to mannose on the egg's zona have several detrimental effects on mammalian pellucida.6 Expression of this mannose lectin re sperm. Verapamil caused decreased sperm den ceptor is inhibited by calcium channel blockers. 7 sity, lowered sperm motility, and decreased After attachment, the sperm head acrosome fuses with the sperm outer plasma membrane, and pro teolytic enzymes are released. This acrosome re Submitted, revised, 28 May 1996. action, which allows egg penetration, is mediated From a private family practice, Corning, NY. Address reprint requests to Gary Enders, MD, Corning Hospital, 176 Dennison by long-acting calcium channels and inhibited by Parkway, Coming, NY 14830. calcium channel blockersJ,8
Nifedipine and Male Infertility 131 J Am Board Fam Pract: first published as 10.3122/jabfm.10.2.131 on 1 March 1997. Downloaded from In 1993 Benoff et aF at North Shore Univer course. She was married to the same man who sity Hospital, Manhasset, NY, investigated a nor had fathered all earlier pregnancies. Thirty mospermic, infertile man whose motile sperm months before this visit, she gave birth to a full failed to fertilize human eggs in vitro. He was tak term normal male infant by spontaneous vaginal ing nifedipine for hypertension. His sperm be delivery. Four years and 2 years earlier she had came fertile after his medication was changed to had spontaneous abortions, but she reported no an angiotensin converting enzyme (ACE) in history of pelvic infection, pelvic operations, or hibitor. Subsequent in vitro investigation of endometriosis. Although her menstrual cycles sperm from 9 other infertile men taking calcium were slightly irregular, her basal body tempera channel blockers for hypertension showed re ture calendar suggested ovulation and an ade duced capacitation and spontaneous acrosome re quate luteal phase. She was 5 feet 1 inch tall and action compared with fertile sperm. The sperm of weighed 130 pounds, had no evidence of systemic 4 of these men recovered after the drug was disease, and had normal breast development and stopped, and one couple achieved pregnancy. normal hair distribution with no evidence of viril Benoff et al also showed that incubation of fertile ization. Findings on a pelvic examination were sperm in vitro with either nifedipine or verapamil normal: she had no vaginitis, a parous cervix with inhibited spontaneous acrosome reaction. no signs of infection, a normal-sized nontender In 1995 the same group investigated and re uterus, no nodules of the uterine ligaments, and ported a case of another couple with male infertil no adnexal masses. ity secondary to nifedipine.9 The husband's Her 37-year-old husband had a 6-year history sperm recovered after the drug was stopped, and of hypertension. He had been prescribed Procar the couple achieved pregnancy. While he was tak dia (nifedipine) 90 mg/d 10 months prior to con ing nifedipine, the husband's sperm had subnor ception of their first child. He had no history of mal expression of mannose-specific lectin and did cryptorchidism, impotence, loss oflibido, or diffi not exhibit spontaneous acrosome reaction in culty with ejaculation. He did have mumps in vitro. The sperm membranes from this man and volving the parotid glands at the age of 16 years, other men on calcium channel blockers had but no history of orchitis. At his physical exami higher baseline free cholesterol than did sperm nation he weighed 190 pounds, was 6 feet 1 inch membranes from fertile men.9- 11 In vitro experi tall, had normal blood pressure, and had normal ments showed that capacitation involves reduc male hair pattern and secondary sex characteris tion of the cholesterol content of the sperm tics. Both testicles measured 5 cm in greatest http://www.jabfm.org/ plasma membrane. The investigators speculated dimension. No varicocele was observed with Val that calcium channel blockers enter into the salva maneuver. His phallus had a small benign sperm plasma membrane, alter molecular pack appearing nevus near the meatus, and there was ing, and reduce the rate at which cholesterol can no hypospadias. No abnormalities were palpated leave the sperm plasma membrane under capaci in the epididymis or vasa. He also had a history of tating conditions. It is possible that other mild intermittent transaminase elevations and an on 27 September 2021 by guest. Protected copyright. lipophilic drugs might affect sperm by a similar elevated serum ferritin. His liver was of normal mechanism. Investigators from India reported ev size with no stigmata of cirrhosis. He reported no idence that human sperm incubated in vitro with history of alcohol use, and serologic studies for nifedipine are more susceptible to lipid peroxida hepatitis were negative. A liver biopsy showed no tion and have dose-dependent reductions of evidence of hemochromatosis, hepatitis, or cir membrane phospholipid and cholesterol con rhosis. Semen analysis showed total volume 4.5 tent.5 This contrasts with the finding of Benoff mL, complete liquifaction, sperm density et al of higher sperm membrane cholesterol in 31,000,000ImL (normal> 20,000,000ImL, ideal men on calcium channel blockers. > 40,000,000ImL), 72 percent motile (normal > 50 percent), and 87 percent normal morphol Case Report ogy (normal> 50 percent). Early in 1994 a 31-year-old woman, gravida 3, The couple reported having intercourse on a para 1, abortus 2, complained of inability to con regular basis during the fertile period of the cycle. ceive despite 18 months of unprotected inter- Several cycles of clomiphene therapy were at-
132 ]ABFP March-April1997 Vol. 10 No.2 J Am Board Fam Pract: first published as 10.3122/jabfm.10.2.131 on 1 March 1997. Downloaded from tempted in the wife, but pregnancy was not trimoxazole), preventing erection (diuretics, ~ achieved. Because of a newly reported (but gener blockers, etc), preventing ejaculation (ganglionic ally known only to fertility specialists) association blockers), promoting retrograde ejaculation (a of nifedipine with male infertility, the husband's adrenergic blockers) or by interfering with sperm nifedipine was stopped, and his blood pressure capacitation or the acrosome reaction (calcium was monitored. Six weeks later his wife became channel blockers).7,9-15 Libido can be diminished pregnant and subsequently gave birth to a normal by dopamine blockers, such as thorazine, or by male infant. The husband's hypertension re drugs that interfere with testosterone. Anabolic curred. Diuretic therapy was instituted, but it was steroid use causes suppression of the hypothala ineffective and not well tolerated, so nifedipine mic-pituitary axis with decreased follicle-stimu was again prescribed. lating hormones and leutinizing hormones, re sulting in lowered sperm counts. Spironolactone, Discussion colchicine, allopurinol, cimetadine, and cy This and previous case reports suggest that closporine have been associated with male infer nifedipine could interfere with male fertility, but tility. Alcohol, drug abuse, and central nervous there are few cases reported. Unfortunately, no in system depressants can decrease male sexual de vitro studies were done to determine whether this sire and performance. man's sperm had reduced capacitation and spon The workplace environment is a potential taneous acrosome reaction, as was reported with source of male infertility. The nematode pesticide other men on calcium channel blockers. The dibromochloropropane has been associated with findings in this case suggest that nifedipine has lowered sperm count in California pesticide man only a partial contraceptive effect, as the patient ufacturing workers and banana workers.16,17 Eth initially was able to father a child while taking ylene glycol (antifreeze) metabolites are toxic to nifedipine, but later he was unable to father an sperm. IS In smelter and battery factory workers, other child until nifedipine was stopped. His increases in serum lead correlate with decreased sperm count of 31 ,OOO,OOO/mL is on the low side sperm count, lowered motility, and abnormal of normal, which might be a separate cause of de morphology. 19 creased fertili ty. There are no large studies available to deter Infertility Workup With Emphasis
mine the prevalence of infertility among men tak on Male Factors http://www.jabfm.org/ ing nifedipine. The product information on Pro Physicians need to take a complete history of both cardia was revised in September 1994 (and partners when evaluating infertility (Table 1).20 appeared first in the 1996 edition of the Physi Physical examination in the male patient should cians' Desk Reference)12 to include the following focus on hair pattern, penile meatus size and loca statement of association with male infertility in tion, prostate, seminal vesicles, testicular size humans: (normal long axis > 4 em), any epididymal indura tion suggesting obstruction, presence or absence on 27 September 2021 by guest. Protected copyright. Nifedipine was administered orally to rats for of the vasa, presence of varicocele when standing two years and was not shown to be carcinogenic. with Valsalva maneuver, anosmia, and visual fields. \Vhen given to rats prior to mating, nifedipine Routine laboratory testing in the man includes caused reduced fertility at a dose approximately 30 times the maximum human dose. There is a litera complete blood count, semen analysis, urinalysis, ture report of reversible reduction in the ability of and VDRL. Testosterone, follicle-stimulating human sperm obtained from a limited number of hormone (FSH), and prolactin levels, chromo infertile men taking recommended doses of some analysis, vasogram, and testicular biopsy can nifedipine to bind to and fertilize an ovum in be indicated as secondary tests. vitro. In vitro mutagenicity studies were negative. The routine workup for the woman includes an examination focusing on secondary sex character Drugs and Male Infertility istics, presence of galactorrhea, evidence of viril Drugs can interfere with male fertility by affect ization (hair pattern), complete and thorough ing spermatogenesis (cytotoxic agents, nitro pelvic examination, complete blood count, Papan furantoin, aminoglycosides, sulfasalazine, co- icolaou smear, urinalysis, VD RL, and basal body
Nifedipine and Male Infertility 133 J Am Board Fam Pract: first published as 10.3122/jabfm.10.2.131 on 1 March 1997. Downloaded from Table 1. Infertility History. to 30 percent of couples have more than one.20 Relationship Frequent causes include male factors (in 18 to 31 Duration of infertility percent of infertile couples), ovulatory dysfunc Fertility in previous relationships tion (16 to 30 percent), tubal damage (12 to 16 Frequency of intercourse percent), endometriosis (5 to 25 percent), cervical Coital techniques Use oflubricants mucus abnormalities (3 to 5 percent), and unex Impotence plained factors (13 to 28 percent). Twenty percent Adult illnesses of couples will have both a male and female factor Acute viral or febrile illness in past 3 months contributing to infertility. Mumps orchitis Renal disease Male factors include varicocele, oligospermia or Radiation therapy azoospermia, obstruction of sperm flow, erection Sexually transmitted disease or ejaculation problems, improper coital tech Stress and fatigue Tuberculosis niques, semen antisperm antibodies, disorders of Other chronic disease sperm function or motility (asthenospermia), and Occupation and habits disorders of sperm morphology (teratospermia). Exposure to radiation, chemicals (lead, ethylene glycol, Varicocele is a dilatation of the venous plexus of dibromochloropropane, etc), or excessive heat (saunas, hot tubs, etc) the scrotum and spermatic cord. Varicocele is Childhood illnesses very common, occurring in 15 to 20 percent of Cryptorchidism the male population. Most varicoceles are left Timing of puberty sided resulting from incompetent venous valves Surgery Hemiorraphy of the left internal spermatic vein, which allows Retroperitoneal surgery gravity-dependent retrograde blood flow from Tubal ligation the left renal vein into the scrotal venous plexus. Vasectomy Most men with varicoceles have normal fertility. Drug use Drugs affecting spermatogenesis: alkylating agents, nitrofu Varicoceles are found in about 35 percent of men rantoin, sulfasalazine, co-trimoxawle with primary infertility and 81 percent of men Drugs affecting erection: diuretics, ~-blockers, others with secondary infertility. 21 Varicoceles, particu Drugs causing retrograde ejaculation: «-adrenergic blockers larly large varicoceles, can cause a progressive in Drugs inhibiting capacitation: calcium channel blockers jury to the seminiferous epithelium. Correction Drugs suppressing hypothalamic pituitary axis: anabolic of varicocele is associated with improved sperm steroids 22 Drugs decreasing libido: dopamine blockers, drugs that count in 60 to 80 percent of cases. Reported http://www.jabfm.org/ interfere with testosterone, alcohol, drug abuse, pregnancy rates after varicocelectomy vary from central nervous system depressants 21 Miscellaneous drugs: spironolactone, colchicine, allopuri- 20 to 60 percent. nol, cimetadine, cyciosporine Congenital obstruction of sperm flow is sug Review of systems gested by azoospermia, normal FSH and testos Focus on endocrine systems (diabetes, thyroid disorders) terone levels, and a testicular biopsy showing nor Gynecology mal spermatogenesis. Sometimes pregnancy can
Contraceptive use on 27 September 2021 by guest. Protected copyright. Diethylstilbestrol use by mother be achieved with microsurgical techniques. Douches Vasectomy reversal, or microsurgical vasovasos Menstrual history tomy, results in sperm in the ejaculate in about 85 Pelvic inflammatory disease (history, recent, or past symptoms, might be asymptomatic) percent of cases, and a pregnancy rate of 50 to 55 Previous pregnancies percent according to the results of the Vasovasos tomy Study Group.23 The procedure can be done Modified from Frey20 under local anesthesia with conscious sedation. In temperature recording. Specialized tests might in certain cases the distal vas will need to be anasto clude the postcoital test, hysterosalpingogram, la mosed to the epididymis because of epididymal paroscopy, endometrial biopsy, and serum proges obstruction. Vasoepididymostomy is a technically terone measurements. Detailed explanations of demanding procedure and usually requires gen specialized workup and treatment of female infer eral or spinal anesthesia.21 Causes of epididy tility is beyond the scope of this article. mal obstruction include infection, long-standing There are multiple causes of infertility, and 10 previous vasectomy, trauma, congenital anom-
134 ]ABFP March-April1997 Vol. 10 No.2 J Am Board Fam Pract: first published as 10.3122/jabfm.10.2.131 on 1 March 1997. Downloaded from aly, and perhaps a mild variant of cystic fibrosis. retroperitoneal lymph node dissection). Retro Sperm flow can be obstructed at the level of the grade ejaculation is diagnosed by examination of ejaculatory ducts, which can be visualized with postorgasmic urine for sperm. Retrograde ejacula transrectal sonography. The obstruction can be tion can be treated medically with a 2-week trial of anatomic and amenable to transurethral resec sympathomimetic agents, such as pseudoephe tion.24 Functional obstruction might result from drine 60 mg four times a day, or by collection of various neurologic disorders discussed later in postejaculation urine with sperm concentration this article. and intrauterine in~emination. Disruption of the hypothalamic-pituitary-go Spinal cord injury patients usually are unable to nadal axis leads to understimulation of the testis, ejaculate, and some may be treated with artificial impotence, and infertility. One third of chromo electrical stimulation of ejaculation. Some spinal phobe pituitary tumors make prolactin, suppress cord injury patients are able to lead productive ing the hypothalamic gonadotropin pulse genera lives; they marry and some desire children. Al tor.22 Abuse of anabolic steroids will suppress though sperm obtained from electrical stimula FSH, and spermatogenesis will not be stimulated. tion of ejaculation from spinal cord injury pa Klinefelter syndrome results from two X and tients is generally of poor quality, an overall one Y chromosomes. These men have small tes pregnancy rate of 37 percent has been reported tes, sometimes gynecomastia, and variable testos with an average of 3.5 electrical stimulations of terone levels. The patients vary in appearance ejaculation per patient.25 A special probe is in from severely eunuchoid to fully masculinized serted into the rectum of the patient with spinal with small testes. Buccal smear is positive for sex cord injury, and a rhythmic current is applied to chromatin, chromosomal analysis reveals the ex cause erection and ejaculation. Often retrograde tra X chromosome, testosterone is usually low, ejaculation occurs, and this sperm is collected and FSH is high. with urethral catheterization. Complications in The Sertoli-cell-only syndrome results from clude rectal burns (rare), muscular contractions, the absence of germ cells in the testis, which can and autonomic dysreflexia. be found by testicular biopsy. The testis might be The most common cause of male infertility is smaller, and there might be a defect on the long idiopathic oligospermia « 50,000,000 sperm per arm of the Y chromosome. In the germ-cell ejaculate) and asthenospermia « 50 percent arrest syndrome, testicular biopsy shows that motile sperm). Various treatments have been re spermatogenesis is arrested at a given stage. viewed by Howards.26 Unproved but possibly http://www.jabfm.org/ Kartagener syndrome (immotile cilia syndrome) helpful medical treatments include pulsatile go is the triad of infertility, bronchiectasis, and situs nadotropin-releasing hormone, human chorionic inversus. The sperm tail is immotile, as are the gonadotropin, clomiphene citrate, tamoxifen, respiratory cilia, secondary to a defect in the pro testolactone, and mesterolone. tein dynein. This protein is part of the micro Another approach to male infertility is sperm tubular assembly that gives the sperm tail and res processing and intrauterine insemination. These on 27 September 2021 by guest. Protected copyright. piratory cilia mobility. procedures can be used when antisperm antibod Various neurologic disorders can affect erectile ies are present or when there are abnormalities of function and ejaculation. Antegrade ejaculation semen volume, liquifaction, or viscosity. requires coordination of emission of semen, con Assisted reproduction techniques include in traction of the bladder neck, and contraction of vitro fertilization, gamete intrafallopian transfer, the bulbocavernosus, ischiocavernosus, and pelvic zygote intrafallopian transfer, and intracytoplas floor muscles. Emission and bladder neck contrac mic sperm injection (lCSI). ICSI involves inject ture are controlled by the sympathetic ganglia ing a single selected sperm through the oocyte from T-lO to L-2. Subsequent contraction of the zona pellucida and cytoplasmic membrane with a other muscles of ejaculation is mediated by the micropipette under microscopic visualization. A parasympathetic nervous system. Retrograde ejac preliminary pregnancy rate of 46 percent was re ulation and anejaculation can result from diabetic ported by Palermo et alP It is possible that ICSI autonomic neuropathy, multiple sclerosis, or sur will become the most effective treatment for idio gical interruption of sympathetic nerves (eg, pathic oligospermia and asthenospermia.
Nifedipine and Male Infertility 135 J Am Board Fam Pract: first published as 10.3122/jabfm.10.2.131 on 1 March 1997. Downloaded from Conclusion ligand receptor expression, acrosome status and There are many causes of infertility, and there membrane cholesterol content. Hum Reprod 1993; 8:2155-66. can be multiple causes in one or both partners. 11. Benoff S, Hurley I, Cooper Gw, Mandel FS, This case study suggests but does not prove that Rosenfeld DL, Hershlag A. Head-specific mannose nifedipine might contribute to male factor infer ligand receptor expression in human spermatozoa is tility. If the male partner of an infertile couple is dependent on capacitation-associated membrane taking nifedipine, verapamil, or diltiazem, an cholesterol loss. Hum Reprod 1993;8:2141-54. other drug should be substituted that would not 12. Procardia package insert, revised September 1994. interfere with fertility. ACE inhibitors are an ap In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company, 1996. propriate alternative for hypertension. 13. WIlson B. The effect of drugs on male sexual func Perhaps in the future a calcium channel blocker tion and fertility. Nurse Pract 1991;16:12-7,21-4. or other drug will be developed that reversibly 14. Schlegel PN, Chang TS, Marshall FF. Antibiotics: and reliably inhibits sperm function with accept potential hazards to male fertility. Fertil Steril able side effects. Further studies are needed to 1991;55:235-42. know the prevalence of infertility among men 15. Thompson ST. Preventable causes of male infertil taking calcium channel blockers. ity. WorldJ UroI1993;11:111-9. 16. Lamb EJ, Bennett S. Epidemiologic studies of male factors in infertility. Ann NY Acad Sci 1994;709: References 165-78. 1. Juneja R, Gupta I, Wali A, Sanyal SN, Chakravarti 17. Levine RJ, Symons MJ, Balogh SA, Milby TH, RN, Majumdar S. Effect of verapamil on different Whorton MD. A method of monitoring the fertility spermatozoal functions in guinea pigs-a prelimi of workers. 2. Validation for the method among nary study. Contraception 1990;41: 179-87. workers exposed to dibromochloropropane. J Occup 2. BlancatoJK, Seyler DE. Effect of calcium-modify Med 1981;23:183-8. ing drugs on mouse in vitro fertilization and preim 18. Veulemans H, Steeno 0, Masschelein R, Groe plantation development. IntJ FertiI1990;35:171-6. seneken D. Exposure to ethylene glycol ethers and 3. Aaberg RA, Sauer MY, Sikka S, Rajfer]. Effects of spermatogenic disorders in man: a case-control extracellular ionized calcium, diltiazem and cAMP study. Br J Ind Med 1993;50:71-8. on motility of human spermatozoa. J U rol 1989; 141: 19. Gennart JP, Buchet JP, Roels H, Ghyselen P, Ceule 1221-4. mans E, Lauwerys R. Fertility of male workers ex 4. Anand RJ, Kanwar U, Sanyal SN. Calcium channel posed to cadmium, lead, or manganese. Am J Epi antagonist verapamil modulates human spermato demioI1992;135:1208-19. zoal functions. Res Exp Med BerlI994;194:165-78. 20. Frey KA. Infertility. In Rakel RE, editor. Saunders 5. Kanwar U, Anand RJ, Sanyal SN. The effect ofni manual of medical practice. Philadelphia: WB Saun http://www.jabfm.org/ fedipine, a calcium channel blocker, on human sper ders,1996. matozoal functions. Contraception 1993;48:453-70. 21. Goldstein M, editor. Surgery of male infertility. 6. Benoff S, Cooper GW, Hurley I, Napolitano B, Philadelphia: WB Saunders, 1995. Rosenfeld DL, Scholl GM, et al. Human sperm fer 22. Federman DD. The testis. In: Dale D, Federman D, tilizing potential in vitro is correlated with differen editors. Scientific American medicine. New York: tial expression of a head-specific mannose-ligand re Scientific American, 1995.
ceptor. Fertil SterilI993;59:854-62. 23. Belker AM, Thomas AJ Jr, Fuchs EF, Sharlip ID. on 27 September 2021 by guest. Protected copyright. 7. Benoff S, Cooper GW, Hurley I, Mandel FS, Ros Results of 1,469 microsurgical vasectomy reversals enfeld DL, Scholl GM, et al. The effect of calcium by the Vasovasostomy Study Group. J U rol 1991; ion channel blockers on sperm fertilization poten 145:505-11. tial. F ertil Steril 1994;62 :606-17. 24. Gilbert BR. Transurethral resection for ejaculatory 8. Florman HM, Corron ME, Kim TD, Babcock DF. duct obstruction. In Goldstein M, editor. Surgery of Activation of voltage-dependent calcium channels of male infertility. Philadelphia: WB Saunders, 1995. mammalian sperm is required for zona pellucida 25. EidJF. Electroejaculation. In Goldstein M, editor. induced acrosomal exocytosis. Dev Bioi 1992; 152: Surgery of male infertility. Philadelphia: WB Saun 304-14. ders,1995. 9. Hershlag A, Cooper GW, Benoff S. Pregnancy fol 26. Howards SS. Treatment of male infertility. N Engl J lowing discontinuation of a calcium channel blocker Med 1995;332:312-7. in the male partner. Hum Reprod 1995;10:599-606. 27. Palermo GD, Alikani M, Adler A, Rosenwaks Z, Co 10. Benoff S, Hurley I, Cooper Gw, Mandel FS, Her hen]. Gamete micromanipulation to facilitate fertil shlag A, Scholl GM, et al. Fertilization potential in ization. In Goldstein M, editor. Surgery of male in vitro is correlated with head-specific mannose- fertility. Philadelphia: WB Saunders, 1995.
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