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Clinical Investigations: CYSTIC FIBROSIS |

Fertility in Men With Cystic Fibrosis*: An Update on Current Surgical Practices and Outcomes FREE TO VIEW

Theresa J. McCallum, MD; Jeff M. Milunsky, MD; Donna L. Cunningham, BS, MT; Doria H. Harris, PhD; Thomas A. Maher, BS; Robert D. Oates, MD
Author and Funding Information

*From the Department of Urology (Drs. McCallum and Oates), and the Center for Human Genetics (Dr. Milunsky and Mr. Maher), Boston University School of Medicine, Boston; Reproductive Science Center of Boston (Ms. Cunningham), Waltham, MA; and Boston IVF (Dr. Harris), Brookline, MA.

Correspondence to: Robert D. Oates, MD, DOB Suite 606, 720 Harrison Ave, Boston, MA 02118-2334; e-mail: robert.oates@BMC.org



Chest. 2000;118(4):1059-1062. doi:10.1378/chest.118.4.1059
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Published online

Background: Men with cystic fibrosis (CF) have bilateral absence of the vas deferens causing an obstructive azoospermia that is not amenable to surgical correction. Advances in the field of reproductive medicine allow for the procurement of viable sperm and facilitate fertilization and pregnancy in couples where the man has CF.

Objectives: To describe patient anatomy and semen characteristics and to determine the pregnancy rates of couples in whom the male partner has CF and who have undergone microsurgical epididymal sperm aspiration coupled with in vitro technology, specifically intracytoplasmic sperm injection (ICSI).

Design: Retrospective analysis.

Setting: Clinical department of urology and two reproductive medicine units.

Patients: Thirteen married men with CF who were referred for infertility.

Interventions: History, physical examination, semen analysis, transrectal and renal ultrasonography, CF mutation analysis, and microsurgical sperm aspiration coupled with ICSI.

Results: All 13 men had low-volume azoospermia, absent vasa, and aplasia/hypoplasia of the seminal vesicles. CF mutation analysis was carried out in 11 of 13 men, and 9 of 11 were ΔF508 homozygous. Eight men underwent microsurgical sperm aspiration, and their partners underwent one or more cycles of ICSI. Five couples (62.5%) achieved a pregnancy, with four couples delivering (three sets of twins and one singleton).

Conclusions: CF in men is accompanied by bilateral vasal aplasia. The resultant obstructive azoospermia can be treated quite successfully with a combination of sperm aspiration and ICSI. It is important for physicians involved in the care of men with CF to convey the message that prospects for fatherhood are excellent with current technology.

Figures in this Article

Cystic fibrosis (CF) is one of the most common single-gene disorders in North America. With the combination of aggressive treatment strategies, effective antibiotic regimens, refined pancreatic enzyme replacement, and a diversity of other interventions, deterioration in pulmonary function and nutritional status has slowed while survival has improved. Marriage and the possibility of reproduction are now options to be considered. However, nearly all men with CF have absent vasa deferentia, resulting in an obstructive azoospermia that cannot be surgically corrected and precludes natural conception.1In the last few years, techniques to harvest sperm and to combine them with retrieved oocytes in an in vitro system have allowed these men to achieve biological paternity.2 Surgical collection techniques include microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration, and testicular sperm extraction. The most common method to assist in fertilization of the oocyte is intracytoplasmic sperm injection (ICSI). Since 1991, 13 men with CF have been evaluated for obstructive azoospermia at Boston Medical Center. Described below are their clinical findings and therapeutic results, including pregnancy in five of eight couples (62.5%) who underwent sperm retrieval and ICSI. The primary intent of this study is to update the pulmonologist on the latest advances in the field of reproduction as it applies to the man with CF. With this knowledge at hand, pulmonologists will be able to inform their patients about the options for parenthood and to encourage referral to a center involved in reproductive medicine (ie, to a urologist or reproductive endocrinologist). In addition, the parents of boys who have recently received a diagnosis of CF may ask about their sons’ future reproductive capability. They can be told that, at present, the chances for reproduction are excellent.

A series of 13 men with CF who were referred for evaluation of infertility between 1991 and 1998 constitute the study group. The mean age at presentation was 31 years, while the mean age of their partners was 28 years. Three men (23%) had a family member with CF. Physical examination, semen analysis, renal and transrectal ultrasonography, and CF mutation analysis were requested of all men. All partners had appropriate investigations performed to assess their individual fertility status. If the couple was going to proceed with attempts to achieve pregnancy, the partners had CF mutation analysis to fully assess their risk as a couple for conceiving a child with CF. All couples were educated about the in vitro processes and sperm harvesting techniques that would be employed. Following these initial determinations, 8 of 13 couples elected to pursue microsurgical sperm aspiration coupled with in vitro technology.

Prior to the ability to use cryopreserved surgically harvested sperm with ICSI, sperm retrieval was undertaken on the day that the oocytes would be harvested to maximize the ability of these sperm to fertilize. Presently, sperm retrieval is performed on a day remote from an ICSI cycle, and the sample is subdivided into 8 to 10 vials that are cryopreserved. Each vial serves as the source of sperm for an ICSI cycle that will take place at a later date. Microsurgical sperm aspiration was accomplished under local bupivacaine anesthesia with a small amount of IV sedation. The testis and epididymal remnant were delivered, and a single epididymal tubule was microsurgically isolated (Fig 1 , 2 ). The anterior presenting surface was incised gently, and the fluid that exuded was aspirated and placed into media that supports sperm survival. If the spermatozoa showed no motility, a new tubule closer to the testis was selected, and the process was repeated. After determining that enough motile sperm had been retrieved, the sample was sent for final processing and cryopreservation. More recently, a piece of testis tissue might also be obtained and cryopreserved as an additional sperm source. Recovery at home was generally quick, and patients were able to return to their work in a few days and to other normal activities within a week of surgery.

The female partner underwent ovulation induction receiving a combination of human menopausal gonadotropins and human chorionic gonadotropin, the intent being to produce multiple oocytes that could be harvested under transvaginal ultrasound guidance. This increases any pregnancy rate simply by providing for an increased number of embryos that can be transferred to the uterus several days later. Individual sperm (either freshly obtained or thawed) were delivered by micropipette into the cytoplasm of the oocyte. Fertilization was assessed 24 h later, and an appropriate number of embryos (two or three depending on their morphology) were transferred to the uterus 3 to 5 days after initial harvesting. Pregnancy was determined 10 to 12 days after transfer, and obstetric ultrasounds were accomplished at 6 weeks and thereafter as needed.

All patients had normal testes size, complete absence of vasa, and at least the caput epididymis present. Semen analysis demonstrated azoospermia with a low volume (ie, < 1 mL) and acidic pH (ie, < 7.0). Eleven men had severely hypoplastic or absent seminal vesicles and aplastic vasal ampullae as shown on transrectal ultrasonography, while renal anatomy was normal in all 13 men. CF mutation analysis was requested of each of the men, the results of which are shown in Table 1 . The results of the analysis for two of the partners are not known (they did not proceed with attempts at pregnancy achievement), but the remainder were noninformative, using the assay protocol being employed at that time.

The harvested sperm parameters at the embryology laboratory before cryopreservation are listed in Table 2 . The fertilization rate (ie, the number of viable embryos per the number of oocytes injected) was 75 ± 24% (Table 2). A pregnancy rate of 62.5% reflects five of the eight couples becoming pregnant. Pregnancy occurred with the first ICSI cycle in three of five couples, and with the second cycle in two of five couples. There have been seven babies born to date within four couples: three sets of twins and one singleton.

In 1968, Denning and colleagues3hypothesized that spermatogenic compromise secondary to nutritional deficiency led to the azoospermia found in the adult man with CF. However, the exact etiology only became clear in subsequent investigations and turned out to be a defect in the reproductive ductal system.4 Numerous authors documented that the vasa deferentia were nearly always absent, the seminal vesicles were typically atrophic or aplastic, and the epididymis often was malformed and not of full length.1,57 Subsequent series have confirmed that at least 97% of men with CF have palpably absent vasa bilaterally.810 Physical examination reveals descended testicles of a normal size and consistency and variable lengths of the epididymal remnants. The caput epididymis (the most proximal portion) derives from a different embryologic precursor than the distal two thirds of the epididymis, the entire vas deferens, and the seminal vesicles and is spared the pathophysiologic insult that affects the development of these other structures.11 Consequently, the caput is invariably present, is firm on palpation, and serves as a reservoir of sperm. Semen analysis demonstrates azoospermia with a low volume (ie, < 1 mL), thin, watery, acidic ejaculate due to the absence/dysfunction of the seminal vesicles, the secretions of which provide most of the volume and alkalinity to the normal ejaculate. The seminal fluid in these men consists only of the prostatic contribution. This information helps patients understand why their ejaculate is so different from what they might expect to see. Serum follicle stimulating hormone, luteinizing hormone, and testosterone levels are within adequate limits as spermatogenesis is inherently normal.

In 1978, Steptoe and Edwards12facilitated the first successful birth following fertilization of an oocyte in a petri dish using ejaculated sperm and then transferring the resultant embryo to the uterus of the woman (ie, in vitro fertilization). In 1985, Temple-Smith et al13 described a pregnancy in which the sperm source used for in vitro fertilization was harvested surgically from a man with an unreconstructable vasal blockage. Silber et al14 extended this novel concept to those with congenital bilateral absence of the vas deferens (a phenotypically mild disorder secondary to abnormalities in the CF alleles). This technique15was then applied by Oates et al1617 to a man with CF as others began exploring various and diverse obstructive circumstances. However, the success rate in terms of both how many eggs were fertilized and the ultimate birth rate was exceedingly low using standard in vitro technology. In 1992, Palermo and coworkers18 detailed the technique of ICSI in which a single sperm is injected into an oocyte using an extremely fine micropipette. As for many other sperm-deficiency syndromes, success rates with surgically retrieved sperm increased dramatically.1920

Sperm is now harvested and cryopreserved prior to an ICSI cycle.2 This allows male sperm and female oocyte retrievals to be performed at different times and at different facilities. Cryopreservation also permits the use of the aliquot of sperm obtained from one procedure to be subdivided for multiple future attempts at ICSI. The efficacy of ICSI using intentionally cryopreserved epididymal spermatozoa or testicular tissue gives excellent results, with fertilization rates from 37 to 48% and pregnancy rates of about 30% per ICSI attempt.2,1920 Alternatives to microsurgical sperm retrieval include percutaneous epididymal sperm aspiration and testicular sperm extraction with individual sperm recovered from the testis parenchyma.

Prior to the initiation of any therapy in a man with CF, an assessment for CFTR mutations and polymorphisms should be performed in both the man and his partner. This provides a full assessment of their risks as a couple for potentially conceiving a child with CF.21 Each child conceived by this process will inherit one abnormal CF allele making them at least a carrier. If the partner is noninformative using the usual mutation analysis, the risk of this couple having a child with CF is approximately 1:400.

In summary, CF is now a disease of the adult population due to dedicated health-care professionals and advances in multimodal therapies for the control of pulmonary disease and pancreatic insufficiency. Men with CF now can be offered the opportunity to be biological fathers as improvements in reproductive medicine continue to make conception easier as well as more successful. It cannot be overemphasized that genetic testing and counseling are an integral part of these reproductive therapies, permitting couples to make informed decisions in their pursuit of parenthood. The strategy for accomplishing this is an intensive one for both partners compared to natural conception, but it is one that is ultimately quite successful and rewarding.

Abbreviations: CF = cystic fibrosis; ICSI = intracytoplasmic sperm injection; MESA = microsurgical epididymal sperm aspiration

Figure Jump LinkFigure 1. The caput (head) of the epididymis is always present in men with CF. The tubules within the caput connect to the ductal system within the testis, and sperm can be harvested from the caput. Occasionally, the corpus (body) of the epididymis is also present.Grahic Jump Location
Figure Jump LinkFigure 2. MESA. Individual tubules within the caput epididymis are opened, and the sperm-rich fluid that exudes is gently aspirated and placed into media (eg, human tubal fluid) prior to cryopreservation.Grahic Jump Location
Table Graphic Jump Location
Table 1. CFTR Genotype in 13 Male Patients With CF
* 

From outside laboratory.

Table Graphic Jump Location
Table 2. Results of Eight Couples Following MESA and ICSI
* 

Values given as No. × 106 sperm per mL.

Holsclaw, DS, Perlmutter, AD, Jockin, H, et al (1971) Genital abnormalities in male patients with cystic fibrosis.J Urol106,568-574. [PubMed]
 
Oates, RD, Lobel, SM, Harris, D, et al Efficacy of intracytoplasmic sperm injection using intentionally cryopreserved epididymal sperm.Hum Reprod1996;11,133-138
 
Denning, CR, Sommers, SC, Quigley, HJ Infertility in male patients with cystic fibrosis.Pediatrics1968;41,7-17. [PubMed]
 
Kaplan, E, Shwachman, H, Perlmutter, AD, et al Reproductive failure in males with cystic fibrosis.N Engl J Med1968;279,65-69. [CrossRef] [PubMed]
 
Landing, BH, Wells, TR, Wang, C-I Abnormality of the epididymis and vas deferens in cystic fibrosis.Arch Pathol1969;88,569-580. [PubMed]
 
Olson, JR, Weaver, DK Congenital mesonephric defects in male infants with mucoviscidosis.J Clin Pathol1969;22,725-730. [CrossRef] [PubMed]
 
Valman, HB, France, NE The vas deferens in cystic fibrosis.Lancet1969;2,566-567. [PubMed]
 
Gaillard, DA, Carre-Pigeon, F, Lallemand, A Normal vas deferens in fetuses with cystic fibrosis.J Urol1997;158,1549-1552. [CrossRef] [PubMed]
 
Phillipson, G Cystic fibrosis and reproduction.Reprod Fertil Dev1998;10,113-119. [CrossRef] [PubMed]
 
Heaton, ND, Pryor, JP Vasa aplasia and cystic fibrosis.Br J Urol1990;66,538-540. [CrossRef] [PubMed]
 
Cooper, TG In defense of a function for the human epididymis.Fertil Steril1990;54,965-975. [PubMed]
 
Steptoe, PC, Edwards, RG Birth after reimplantation of human embryo.Lancet1978;2,366-370
 
Temple-Smith, PD, Southwick, GJ, Yates, CA, et al Human pregnancy byin vitrofertilization (IVF) using sperm aspirated from the epididymis.J In Vitro Fert Embryo Transf1985;2,119-122. [CrossRef] [PubMed]
 
Silber, SJ, Ord, T, Balmaceda, J, et al Absence of the vas deferens: the fertilizing capacity of human epididymal sperm.N Engl J Med1990;323,1785-1792
 
Silber, SJ, Balmaceda, J, Borrero, C, et al Pregnancy with sperm aspiration from the proximal head of the epididymis: a new treatment for congenital absence of the vas deferens.Fertil Steril1988;50,525-528. [PubMed]
 
Oates, RD, Honig, S, Berger, MJ, et al Microscopic epididymal sperm aspiration (MESA): a new option for the treatment of the obstuctive azoospermia associated with cystic fibrosis.J Assist Reprod Genet1992;9,36-40. [CrossRef] [PubMed]
 
Oates, RD Microscopic epididymal sperm aspiration (MESA) in conjunction with advanced reproductive techniques.Rep Urol Techniques1992;2,88-90
 
Palermo, G, Joris, H, Devroey, P, et al Pregnancies after intracytoplasmic injection of single spermatozoa into an oocyte.Lancet1992;340,17-18. [CrossRef] [PubMed]
 
Okada, H, Yoshimura, K, Fujioka, H, et al Assisted reproduction technology for patients with congenital bilateral absence of vas deferens.J Urol1999;161,1157-1162. [CrossRef] [PubMed]
 
Dohle, GR, Ramos, L, Pieters, MH, et al Surgical sperm retrieval and intracytoplasmic sperm injection as treatment of obstructive azoospermia.Hum Reprod1998;13,620-623. [CrossRef] [PubMed]
 
Oates, RD The genetics of male reproduction.Infertil Reprod Med Clin North Am1999;3,411-427
 

Figures

Figure Jump LinkFigure 1. The caput (head) of the epididymis is always present in men with CF. The tubules within the caput connect to the ductal system within the testis, and sperm can be harvested from the caput. Occasionally, the corpus (body) of the epididymis is also present.Grahic Jump Location
Figure Jump LinkFigure 2. MESA. Individual tubules within the caput epididymis are opened, and the sperm-rich fluid that exudes is gently aspirated and placed into media (eg, human tubal fluid) prior to cryopreservation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. CFTR Genotype in 13 Male Patients With CF
* 

From outside laboratory.

Table Graphic Jump Location
Table 2. Results of Eight Couples Following MESA and ICSI
* 

Values given as No. × 106 sperm per mL.

References

Holsclaw, DS, Perlmutter, AD, Jockin, H, et al (1971) Genital abnormalities in male patients with cystic fibrosis.J Urol106,568-574. [PubMed]
 
Oates, RD, Lobel, SM, Harris, D, et al Efficacy of intracytoplasmic sperm injection using intentionally cryopreserved epididymal sperm.Hum Reprod1996;11,133-138
 
Denning, CR, Sommers, SC, Quigley, HJ Infertility in male patients with cystic fibrosis.Pediatrics1968;41,7-17. [PubMed]
 
Kaplan, E, Shwachman, H, Perlmutter, AD, et al Reproductive failure in males with cystic fibrosis.N Engl J Med1968;279,65-69. [CrossRef] [PubMed]
 
Landing, BH, Wells, TR, Wang, C-I Abnormality of the epididymis and vas deferens in cystic fibrosis.Arch Pathol1969;88,569-580. [PubMed]
 
Olson, JR, Weaver, DK Congenital mesonephric defects in male infants with mucoviscidosis.J Clin Pathol1969;22,725-730. [CrossRef] [PubMed]
 
Valman, HB, France, NE The vas deferens in cystic fibrosis.Lancet1969;2,566-567. [PubMed]
 
Gaillard, DA, Carre-Pigeon, F, Lallemand, A Normal vas deferens in fetuses with cystic fibrosis.J Urol1997;158,1549-1552. [CrossRef] [PubMed]
 
Phillipson, G Cystic fibrosis and reproduction.Reprod Fertil Dev1998;10,113-119. [CrossRef] [PubMed]
 
Heaton, ND, Pryor, JP Vasa aplasia and cystic fibrosis.Br J Urol1990;66,538-540. [CrossRef] [PubMed]
 
Cooper, TG In defense of a function for the human epididymis.Fertil Steril1990;54,965-975. [PubMed]
 
Steptoe, PC, Edwards, RG Birth after reimplantation of human embryo.Lancet1978;2,366-370
 
Temple-Smith, PD, Southwick, GJ, Yates, CA, et al Human pregnancy byin vitrofertilization (IVF) using sperm aspirated from the epididymis.J In Vitro Fert Embryo Transf1985;2,119-122. [CrossRef] [PubMed]
 
Silber, SJ, Ord, T, Balmaceda, J, et al Absence of the vas deferens: the fertilizing capacity of human epididymal sperm.N Engl J Med1990;323,1785-1792
 
Silber, SJ, Balmaceda, J, Borrero, C, et al Pregnancy with sperm aspiration from the proximal head of the epididymis: a new treatment for congenital absence of the vas deferens.Fertil Steril1988;50,525-528. [PubMed]
 
Oates, RD, Honig, S, Berger, MJ, et al Microscopic epididymal sperm aspiration (MESA): a new option for the treatment of the obstuctive azoospermia associated with cystic fibrosis.J Assist Reprod Genet1992;9,36-40. [CrossRef] [PubMed]
 
Oates, RD Microscopic epididymal sperm aspiration (MESA) in conjunction with advanced reproductive techniques.Rep Urol Techniques1992;2,88-90
 
Palermo, G, Joris, H, Devroey, P, et al Pregnancies after intracytoplasmic injection of single spermatozoa into an oocyte.Lancet1992;340,17-18. [CrossRef] [PubMed]
 
Okada, H, Yoshimura, K, Fujioka, H, et al Assisted reproduction technology for patients with congenital bilateral absence of vas deferens.J Urol1999;161,1157-1162. [CrossRef] [PubMed]
 
Dohle, GR, Ramos, L, Pieters, MH, et al Surgical sperm retrieval and intracytoplasmic sperm injection as treatment of obstructive azoospermia.Hum Reprod1998;13,620-623. [CrossRef] [PubMed]
 
Oates, RD The genetics of male reproduction.Infertil Reprod Med Clin North Am1999;3,411-427
 
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