Manual of intrauterine insemination and ovulation induction
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Manual of IntrauterineInsemination and OvulationInduction
Manual of IntrauterineInsemination andOvulation InductionEdited byRichard P. DickeyLauisiana State UniversityPeter R. BrinsdenBourn Hall Clinic, CambridgeRoman PyrzakThe Fertility Institute of New Orleans
Contents List of contributors page vi Preface vii1 An overview of intrauterine insemination 10 Insemination technique and insemination and ovulation induction 1 complications 109 Peter R. Brinsden and Richard P. Dickey Richard P. Dickey, Peter R. Brinsden and Roman Pyrzak2 Male causes of infertility: evaluation and treatment 7 11 Cryopreservation 119 Levent Gurkan, Ashley B. Bowen and Roman Pyrzak Wayne J. G. Hellstrom 12 Donor sperm 1303 Female causes of infertility: evaluation Richard P. Dickey and Roman Pyrzak and treatment 19 13 The role of the nurse in intrauterine Richard P. Dickey and Peter R. Brinsden insemination and ovulation induction 1384 Clinic and laboratory design, personnel and Mary M. Macgregor and Lisa T. Lofton, with equipment 31 Gaylyn L. Achary, Wendi S. Dalferes and Roman Pyrzak Wadena M. Saucier5 Semen analysis: semen requirements for 14 Complications of ovulation induction I: intrauterine insemination 37 high-order multiple births, miscarriage, Roman Pyrzak and Richard P. Dickey ectopic pregnancy, congenital anomalies, ovarian cancer 1416 Semen preparation for intrauterine Richard P. Dickey insemination 53 Roman Pyrzak 15 Complications of ovulation induction II: ovarian hyperstimulation syndrome,7 Ovulation induction for intrauterine ovarian torsion 151 insemination I: oral drugs clomiphene, Botros R. M. B. Rizk tamoxifen, letrozole 68 Richard P. Dickey 16 The psychological issues of intrauterine insemination 1608 Ovulation induction for intrauterine Rebecca J. Trimble insemination II: gonadotropins and oral drug–gonadotropin combinations 80 17 Ethical, legal and religious considerations Richard P. Dickey and Peter R. Brinsden of artificial insemination 165 Kathryn Venturatos Lorio9 Ultrasonography in the management of ovulation induction and intrauterine insemination 93 Richard P. Dickey and Sarah C. Romero Index 181 v
Contributors Gaylyn L. Achary RN Kathryn Venturatos Lorio JD The Fertility Institute of New Orleans, Mandeville, Loyola University College of Law, New Orleans, Louisiana, USA Louisiana, USA Ashley B. Bowen MD Mary M. Macgregor RNC Department of Urology, Tulane University School of The Fertility Institute of New Orleans, Metairie, Medicine, New Orleans, Louisiana, USA Louisiana, USA Peter R. Brinsden MB BS FRCOG Roman Pyrzak PhD Assisted Conception Unit, Bourn Hall Clinic, The Fertility Institute of New Orleans, Mandeville, Bourn, Cambridgeshire, UK Louisiana, USA Wendi S. Dalferes RN Botros R. M. B. Rizk MD FACOG FACS The Fertility Institute of New Orleans, Mandeville, FRCOG FRCS Louisiana, USA Department of Obstetrics and Gynecology, College of Medicine, University of South Alabama, Mobile, Richard P. Dickey MD PhD FACOG Alabama, USA Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Sarah C. Romero RT RDMS Gynecology, Louisiana State University, New The Fertility Institute of New Orleans, Mandeville, Orleans, Louisiana, USA; The Fertility Institute of Louisiana, USA New Orleans, Mandeville, Louisiana, USA Wadena M. Saucier RN Levent Gurkan MD The Fertility Institute of New Orleans, Mandeville, Department of Urology, The German Hospital, Louisiana, USA Istanbul, Turkey Rebecca J. Trimble BA MSW LCSW ACSW Wayne J. G. Hellstrom MD FACS Metairie, Louisiana, USA Department of Urology, Tulane University School of The assistance of Renee M. Thibodeaux in the Medicine, New Orleans, Louisiana, USA research for and preparation of this manual is Lisa T. Lofton RN gratefully acknowledged. The Fertility Institute of New Orleans, Mandeville, Louisiana, USAvi
PrefaceThis manual is intended for the general or family explained in the early chapters of this manual. Chapterpractitioner, as well as for gynecologists and special- 2 is written by an excellent team of medical univer-ists in infertility treatment. While treatment by in-vitro sity urologists who explain the causes and treatmentfertilization (IVF) and other advanced techniques of male-factor infertility and erectile dysfunction.attract the most attention and shape the public percep- Chapter 3, by two clinical reproductive endocrinolo-tion of infertility treatment, far more infertile couples gists with many years of experience, describes easy andachieve pregnancies with ovulation induction (OI) or effective methods of diagnosing female-factor infertil-combined ovarian stimulation and intrauterine insem- ity. Chapter 4 describes equipping an office laboratoryination (IUI), the two techniques described in detail in to perform semen analysis and to prepare sperm forthis book, and which form the first line of infertility insemination.treatment. Moreover, they can be performed in almost Chapter 5 reviews those sperm qualities that areany office or clinic, thus allowing patients to be treated necessary for pregnancy when IUI is performed, andby physicians and nurses already familiar with their describes in detail the methods for performing basicgeneral health, without the need to travel to distant and more complex semen analysis. Chapter 6 describesspecialty clinics. Many practitioners believe, from and compares four methods of sperm preparation fortheir time in training, that evaluation of infertile cou- IUI and an additional fifth method for selecting pre-ples is too time-consuming and unrewarding, and that dominantly Y-chromosome-bearing sperm, conclud-treatment is too complex to be part of their general or ing with a section on handling specimens from menobstetric and gynecological practices. Nothing could positive for human immunodeficiency virus (HIV)be further from the truth. Infertility should be viewed, and hepatitis C virus (HCV).not as a diagnosis, but as a symptom of an underlying Chapters 7 and 8 review the pharmacodynamicsmedical problem, affecting either one or both partners, of oral drugs and gonadotropins and describe in detailwhich, if left untreated, will eventually affect their gen- their use for OI. Chapter 9 complements the chapterseral health and emotional well-being. on OI with an atlas of ultrasonographic pictures of fol- The role of IUI and OI in the present era of IVF and licle and endometrial changes throughout the cycle.intracytoplasmic sperm injection (ICSI) is the subject Chapter 10 describes the indications for insemi-of Chapter 1. Although IVF and ICSI have made donor nation, how to time insemination to achieve the bestinsemination unnecessary for many couples with results, insemination techniques including IUI andmale-factor infertility, it is still the method of choice tubal perfusion, and concludes with a section on man-for many couples when they are confronted with the agement of complications of IUI. Chapter 11 describescost and complexity of IVF and ICSI treatment, or if indications for cryopreservation of patient sperm andthere is a total absence of sperm. Donor insemination methods of cryopreservation and storage. Chapteris easy to perform, requires no special equipment, and 12 is devoted to donor insemination, and includesmay be the only procedure performed by many physi- a detailed description of how to use cryopreservedcians who use this manual. Websites are listed in the specimens.chapter on donor insemination that provide access Chapter 13 is concerned with the many roles thatto United States and European sperm banks that ship nurses play in the treatment of infertile couples, in ainternationally. chapter written by nurse practitioners themselves. The initial step in effective infertility treatment Chapters 14 and 15 describe methods of reduc-is to make a diagnosis. This can be accomplished ing the incidence of multiple births and of prevent- viiwith a few simple and relatively inexpensive tests, as ing and treating ovarian hyperstimulation syndrome
Preface (OHSS) and other complications of OI, and have been in 57 European, Asian, Middle Eastern, North and contributed by physicians who have written extensively South American and African nations. on these subjects. Throughout this manual we have endeavored to Chapter 16, by a clinical psychologist, explains address practical aspects of treatments that will result how counseling helps infertile couples to deal with in optimal results in terms of pregnancy outcome and issues they face, such as feelings of inadequacy, loss safety, but we have tried not to neglect the pharma- and depression, and includes a list of printed and cological and physiological reasons for their use. We internet resources for both medical personnel and believe and hope that both generalists and specialists patients. will find this manual helpful to their practices, and that Chapter 17 deals with some of the legal and reli- it will therefore also benefit their patients. gious issues that confront physicians and couples – and single women – who wish to use donor sperm. Richard P. Dickey The chapter includes a table that describes the laws Peter R. Brinsden relating to husband/partner and donor insemination Roman Pyrzakviii
Chapter 1: An overview of IUI and OI characteristics (see Chapter 12). In countries with Table 1.1. Indications for intrauterine insemination strict regulatory systems, such as the United Kingdom, Effective couples using donor sperm must be made aware of any Male subfertility rules that may affect them when using donor sperm, particularly about parentage, registration of the birth Cervical factor of children and, in some countries, the removal of the Ejaculatory failure right to anonymity of donors and therefore the right of Idiopathic/unexplained infertility a child to discover the identity of his or her true genetic Possibly effective father on reaching the age of 18 (see Chapter 17) . The Immunological infertility attitude of societies in general, certainly in the devel- oped countries, towards the issue of single women and Endometriosis women in same-sex relationships having children has changed dramatically in the past decade or two. The demand for fertility treatment from these women is idiopathic or unexplained infertility. Other indica- increasing, and practitioners are now more willing to tions, for which conclusive evidence of effectiveness provide donor IUI services to them. However, in many is lacking, are immunological causes of infertility and countries, mainly those in which the Roman Catholic endometriosis. or Islamic faiths predominate, donor insemination is The main indications for donor insemination are forbidden. (1) gross male infertility or subfertility (azoospermia The development of oocyte–sperm microman- or severe oligoasthenoteratozoospermia), for couples ipulation procedures, such as intracytoplasmic sperm who cannot afford IVF or reject IVF for other reasons, injection (ICSI) and its introduction into IVF-ET pro- and (2) familial or genetic disease, such as Huntington’s grams , has made it possible to achieve fertilization disease , hemophilia and severe Rhesus incompatibil- and pregnancies when only very few spermatozoa ity . The use of cryopreserved semen in donor insemina- are available. Prior to the development of techniques tion programs is now mandatory in most countries, to such as microsurgical epididymal sperm aspiration minimize the possibility of the transmission of human (MESA) , percutaneous epididymal sperm aspira- immunodeficiency virus (HIV) and other infections to tion (PESA)  and testicular sperm extraction (TESE) the recipients . , men with congenital bilateral absence of vas def- erens (CBAVD), surgically unreconstructable vasa or Intrauterine insemination: natural other causes of vasal obstruction had very little chance of fathering their own children. Now, however, if these and stimulated (OI) cycles Treatment by IUI may be performed either in a natu- techniques are combined with ICSI, these men can be ral or in a stimulated cycle. Many ovarian stimulation offered a very real chance of achieving paternity with protocols have been devised for use with IUI, includ- their own sperm . These methods have reduced the ing: CC alone or in combination with gonadotropins demand for AID; however, the cost of these procedures and human chorionic gonadotropin (hCG); TMX puts them beyond the means of many couples, and alone or combined with gonadotropins; and the use of there is therefore a continuing need for AID, which is a gonadotropin-releasing hormone (GnRH) agonist or most effectively done by IUI using donor sperm. antagonist combined with gonadotropins. hCG is usu- ally used at the end of the stimulation phase to achieve Indications for intrauterine final maturation of the oocyte(s). Full descriptions of the insemination different regimens for OI are given in Chapters 7 and 8. There are a number of indications for IUI using the The rationale for the use of OI with IUI is both husband or partner’s semen; these are summarized to increase the “efficiency” and likelihood of ovula- in Table 1.1. Ejaculatory failure is the classical indica- tion and to increase the number of oocytes available tion, since the male partner is unable to ejaculate into for fertilization, and thus to improve the chance of the vagina, while cervical mucus hostility is a logi- pregnancy. Stimulation also enhances steroid produc- cal indication for IUI, as it bypasses the mucus in the tion, which may improve the chance of fertilization2 cervical canal. The most common indications for IUI and embryo implantation . When considering are the less severe forms of male-factor infertility and whether or not to use ovarian stimulation with IUI, the
Chapter 1: An overview of IUI and OIbenefit of a potential increase in success rates that may disadvantages. Sperm preparation using the densitybe achieved, compared with natural cycle IUI, must be gradient technique yields the highest number of motilebalanced against the increased cost of the medication spermatozoa when compared with simple washing orand monitoring, as well as the potential complications swim-up or swim-down methods, and significantlyof these medications, including ovarian hyperstimula- reduces bacterial contamination , but it should nottion syndrome (OHSS) and the increased incidence be used when the initial specimen contains fewer thanof multiple pregnancies , with their associated mater- 15 × 106 motile sperm (see Chapter 6). Equipment andnal and neonatal complications  (see Chapters 14 materials necessary for semen analysis and prepara-and 15). tion of husband/partner sperm for IUI are described There are several methods available to time ovu- in Chapters 4 and 6 .lation in both natural and stimulated cycles. Theseinclude simple methods such as the measurement of Results of treatment by IUI and OI withbasal body temperature (BBT) , which has been foundto be the least accurate, and assessment of the cycli- husband/partner spermcal changes that occur in cervical mucus . Templeton The results of IUI with husband/partner sperm inet al. showed that in 35% of cycles the optimum mucus terms of pregnancy rates per treatment cycle vary con-score was observed on the day before the luteinizing siderably between clinics, and the evaluation of resultshormone (LH) surge, in 44% of cycles it was optimum is difficult because of the heterogeneity of the patienton the day of the LH surge and in 18% of cycles on the populations and the different ovarian stimulation pro-day after the LH surge, while in 3% it occurred two days tocols, if any, used in the studies. Although there areafter the LH surge . However, the detection of the a large number of published studies on IUI, most ofserum or urinary LH surge and ultrasound assessment these are retrospective and/or on small numbers; onlyof follicular growth and rupture have proved to be the a few are prospective and randomized trials. There ismost accurate methods of monitoring IUI and OI/IUI an undoubted need for more large prospective rand-cycles. Vermesh et al. showed that use of a “dipstick” LH omized studies to evaluate the real effectiveness of IUItest kit predicted ovulation in 84% of cycles in his series and to elicit which group of patients will benefit most. In a stimulated cycle, if hCG is administered when from this treatment. Results of IUI and OI at Bournthe average diameter of the leading follicle is 18–20 mm, Hall and the Fertility Institute of New Orleans areovulation may be expected to occur 34–40 hours later . shown in Table 1.2. Two European Society of Human Reproduction and Embryology (ESHRE) multicenter prospectiveSperm preparation studies compared ovulation induction alone with ovu-The ideal sperm preparation technique is the one lation induction in conjunction with IUI, intraperito-which will achieve the largest number of morphologi- neal insemination (IPI) , gamete intrafallopian transfercally normal motile spermatozoa in a small volume of (GIFT) and IVF [18,19]. In the treatment of unexplainedphysiological culture media, free from seminal plasma, infertility, the pregnancy rate achieved from superovu-leukocytes and bacteria . There is more informa- lation alone was less than when combined with IUI,tion than formerly about sperm quality and quantity IPI, GIFT or IVF . In the treatment of male sub-necessary in an initial specimen for IUI to be suc- fertility, ovulation induction with IUI, GIFT and IVFcessful, so that an informed decision can be made on gave better results than IPI and ovulation inductionwhether to perform IUI or, instead, to recommend IVF alone . Martinez et al., in an extensive review of thewith intracytoplasmic sperm injection (ICSI) or donor English-language literature from 1980 to 1991, showedsperm . Although there is no threshold of sperm that there was marked variation in the results of IUIconcentration below which pregnancy is impossible, between different clinics . Retrospective analysesmost conceptions occur when the number of insemi- of IUI data using life-table analysis showed a relativelynated motile sperm is 4 × 106 or greater (see Chapter 6). constant probability of becoming pregnant after eachThe degree of motility and percentage of morphologi- IUI treatment through four gonadotropin IUI cyclescally normal spermatozoa are other important vari-  or six IUI cycles without OI [22,23], and that there-ables in fertility prognosis. after it is hardly increased at all by continuing for longer. There are several different sperm preparation tech- Most clinicians are now agreed that further evaluation 3niques for IUI, and each has its own advantages and and discussion of the other treatment options available
Chapter 1: An overview of IUI and OI Table 1.2. Pregnancy success rates related to cause of infertility Bourn Hall Clinic Fertility Institute of New Fertility Institute of New (1989–93) a Orleans (1983–98)  Orleans (1983–98)  Medication Mixed Clomiphene hMG/FSH IUI cycles > 1400 3381 4062 Indication Pregnancies per cycle (%) Pregnancies per cycle (%) Pregnancies per cycle (%) Ovulatory dysfunction – 14.6 19.5 Cervical, unexplained – 10.4 19.2 Idiopathic 12.3 – – Cervical 16.4 – – Endometriosis – 8.1 16.1 Immunological 10.0 – – Male subfertility 21.0 11.4 16.9 Donor sperm – 16.5 22.2 Ejaculatory failure 13.3 – – a Unpublished data FSH, follicle-stimulating hormone; hMG, human menopausal gonadotropin. to couples should be carried out after 4–6 cycles of IUI Guzick et al. looked at the cost-effectiveness of no treat- without OI. In IUI with OI, the probability of preg- ment, CC alone, CC+IUI, hMG alone, hMG+IUI, IVF, nancy per cycle and the number of cycles in which and GIFT . Analysis of the data showed that pregnancy rates remain constant, in patients treated CC+IUI was the most cost-effective treatment for idi- at the Fertility Institute of New Orleans , depended on opathic infertility (US$10,000 per pregnancy), com- diagnosis, age, sperm source and the number of pre- pared to hMG+IUI (US$17,000 per pregnancy) and ovulatory follicles that developed in response to CC IVF (US$50,000 per pregnancy). In their conclusions, (see Chapter 7, Table 7.1)  and human menopausal they state that “on the highest level of evidence found in gonadotropin (hMG) or follicle-stimulating hormone the data,” their recommendations for the cost-effective (FSH) (see Chapter 8, Table 8.4) . management of idiopathic infertility are: IUI does not The United Kingdom results for donor insemina- appear to be effective without some form of superovu- tion are reported yearly by the Human Fertilisation lation; CC+IUI appears to be more cost-effective than and Embryology Authority (HFEA) on their website hMG+IUI or IVF; IVF and GIFT are effective for cou- (www.hfea.gov.uk). The data from all clinics show live ples who have not conceived after superovulation + IUI. birth rates for 2006 of 14.5% per donor insemination In a study from the Netherlands by Goverde et al., treatment cycle for women below the age of 35, reduc- 258 couples with a diagnosis of idiopathic or mild male- ing to 9.9% for women aged 35–39, 5.4% for ages 40–42 factor infertility were divided into three equal groups: and just 1.2% for women aged 43–44, with no live (1) IUI alone, (2) IUI with mild ovarian stimulation births for women over the age of 44. Data from Bourn using low-dose FSH, and (3) IVF . Their conclu- Hall Clinic for 2007, for all age groups combined, show sion was that stimulated IUI was as effective as IVF in a 22% clinical pregnancy rate per cycle started for IUI achieving a pregnancy (31% vs. 33%), and was more with husband/partner sperm and a 26% clinical preg- cost-effective than IVF – cost per pregnancy resulting nancy rate per cycle started for IUI with donor sperm in a single live birth was US$4,511–5,710 for stimu- (www.bourn-hall-clinic.co.uk). The majority of cycles lated IUI versus US$14,679 for IVF. They concluded are stimulated with CC or gonadotropins . that patients should be counseled that IUI for these two diagnostic groups offers as good a chance of achieving Cost-effectiveness of IUI and OI a pregnancy as IVF and is more cost-effective. More4 In a large retrospective analysis of 45 published reports controversially, they suggested that non-stimulated on the treatment of couples with unexplained infertility, IUI should be the first-choice treatment, as it carries
Chapter 1: An overview of IUI and OIfewer health risks, even though it is not as effective as techniques such as IVF, if there are adequate facilitiesstimulated IUI. Cohlen reviewed the literature look- for semen preparation and cycle monitoring and theing at the evidence of the efficacy of IUI with “mild clinic is staffed by adequately trained physicians andovarian hyperstimulation” (MOH) as a treatment for laboratory scientists. However, careful selection ofcervical mucus hostility, moderate male-factor infer- patients suitable for IUI is important. Those who willtility and unexplained infertility . His conclusion benefit most are young women with patent fallopianon the treatment of these three groups of patients was tubes, with no ovulatory disorder, no endometriosisthat “When multiple pregnancies are kept to a mini- of more than moderate or severe degree and no severemum, MOH/IUI is more cost-effective compared with degree of male-factor infertility in their partners. Allin-vitro fertilization and embryo transfer .” couples require in-depth advice and counseling about the method, the effectiveness and the potential compli-Complications of treatment cations of treatment.There are few complications to treatment by IUI. Failure The main advantages of IUI over IVF are its sim-of the treatment could be said to be the most frequent, plicity and relative inexpensiveness. However, theresince pregnancy rates per cycle are reported at any- are many advantages of IVF over IUI – principallywhere between 5% and 25%. The complication which those of a higher pregnancy rate, the ability to avoidcauses couples the most concern, but which is almost multiple pregnancies by transferring a single embryocertainly very rare, is the possibility that the patient and cryopreserving any spare embryos generated inmight be inseminated with the wrong semen sample. the IVF cycle, and the knowledge gained about theOther complications include the possibility of transmis- ability of the sperm to fertilize the oocytes. IVF or ICSIsion of venereal disease , HIV or hepatitis B or C. Proper are the only realistic treatments for couples with severeadherence to protocols and the establishment of clinical male-factor infertility , as well as for severe endome-and laboratory quality systems should almost eliminate triosis and infertility due to severe tubal damage.these possibilities. Painful uterine contractions which Although IUI can be performed outside of specialistmay occur during insemination can usually be mini- units, a clinic with IVF facilities offers the best settingmized by inseminating slowly. Intrauterine infection in which to perform IUI in case complications, such asand anaphylaxis rarely may also occur, especially if neat an excessive follicular response or ovarian hyperstim-semen is used – which it should never be. ulation, occur. If they do, then patients can be offered The two most serious complications of OI are mul- the chance to convert to IVF, with the chance to freezetiple pregnancy and ovarian hyperstimulation . There any surplus embryos.is increased awareness of the dangers of multiple preg- Finally, in an interesting paper on “Patients’ pref-nancy, including twins. Singleton birth is now the “gold erences for intrauterine insemination or in-vitro fer-standard” of IVF, and many countries in Europe now tilization,” van Weert et al.  concluded that, whenmandate single embryo transfer for most IVF patients. couples knew their cumulative chances of pregnancy atTwins occur in 10% of CC and 20% of gonadotropin each stage, both at the start of treatment and after threeOI cycles with or without IUI, and triplet and higher- cycles of IUI, the majority of couples wished to continueorder multiple pregnancies occur in as many as 20% of with IUI, but their preference changed to IVF after sixhMG/FSH IUI pregnancies in women younger than 32 cycles of IUI, in the knowledge that their chances ofwho develop seven or more follicles . Occurrence success were very much less at this stage  .of multiple pregnancy and OHSS can be minimizedby careful management and monitoring of treatment Referencescycles and, if necessary, abandoning the cycle or con- 1. Yovich JL, Matson PL. The treatment of infertilityverting it to an IVF cycle (see Chapters 14 and 15) . by the high intrauterine insemination of the husbands washed spermatozoa. Hum Reprod 1988; 3:Conclusion 939–43. 2. Palermo G, Joris H, Devroey P, Van Steirteghem AC.IUI is an effective, non-invasive, relatively simple and Pregnancies after intracytoplasmic injection ofcost-effective method of treatment for certain diag- single spermatozoon into an oocyte. Lancet 1992; 340:nostic groups of infertile couples. It can be provided 17–18.more easily to more infertile couples in office practices 3. Shields FE. Artificial insemination as related to females. 5and general hospitals than can the more specialized Fertil Steril 1950; 1: 271–80.
Chapter 1: An overview of IUI and OI 4. Sims JM. Clinical Notes on Uterine Surgery, with Special 17. Punjabi U, Gerris J, Van Bijlen J, et al. Comparison Reference to the Management of the Sterile Condition. between different pre-treatment techniques for sperm London: Hardwicke, 1866. recovery prior to intrauterine insemination, GIFT 5. Hard AD. Artificial impregnation. Medical World 1909; or IVF. Hum Reprod 1990; 5: 75–83. 27: 253. 18. Crosignani PG, Walters DE. Clinical pregnancy and male 6. Allen MC, Herbert CM, Maxson WS, et al. Intrauterine subfertility: the ESHRE multicentre trial on the treatment insemination: a critical review. Fertil Steril 1985; 44: of male subfertility. Hum Reprod 1994; 9: 1112–18. 569–80. 19. Crosignani PG, Walters DE, Soliani A. The ESHRE 7. Tournaye H, Devroey P, Liu P, et al. Microsurgical multicentre trial on the treatment of unexplained epididymal sperm aspiration and intraycytoplasmic infertility: a preliminary report. Hum Reprod 1991; 6: sperm injection: a new effective approach to infertility 953–8. as a result of congenital bilateral absence of the vas 20. Martinez AR, Bernardus RE, Vermeiden JPW. deferens. Fertil Steril 1994; 62: 644–7. Factors affecting pregnancy results after intrauterine 8. Craft IL, Khalifa Y, Boulos A, et al. Factors insemination. Hum Reprod 1988; Abstract 35. influencing the outcome of in-vitro fertilization with 21. Remohi J, Gastaldi C, Patrizio P, et al. percutaneous aspirated epididymal spermatozoa and Intrauterine insemination and controlled ovarian intracytoplasmic sperm injection in azoospermic men. hyperstimulation in cycles before GIFT. Hum Reprod Hum Reprod 1995; 10: 1791–4. 1989; 4: 918–20. 9. Silber SJ, Van Steirteghem AC, Liu J, et al. 22. Lalich RA, Marut EL, Prins GS, Scommegna A. Life High fertilization and pregnancy rates after table analysis of intrauterine insemination pregnancy intracytoplasmic sperm injection with spermatozoa rates. Am J Obstet Gynecol 1988; 158: 980–4. obtained from testicle biopsy. Hum Reprod 1995; 10: 23. Martinez AR, Bernardus RE, Vermeiden JPW, 148–52. Schoemaker J. Basic questions on intrauterine 10. Devroey P, Nagy Z, Goossens A, et al. Pregnancies after insemination: an update. Obstet Gynecol Surv 1993; 48: testicular sperm extraction and intracytoplasmic sperm 811–28. injection in non-obstructive azoospermia. Hum Reprod 24. Dickey RP, Taylor SN, Lu PY, et al. Effect of diagnosis, 1995; 10: 1457–60. age, sperm quality, and number of preovulatory follicles 11. Wallach EE. Gonadotropin treatment of the ovulatory on the outcome of multiple cycles of clomiphene citrate- patient: the pros and cons of empiric therapy for intrauterine insemination. Fertil Steril 2002; 78; 1088–95. infertility. Fertil Steril 1991; 55: 478–80. 25. Dickey RP, Taylor SN, Lu PY, et al. Risk factors for 12. Levene MI, Wild J, Steer P. Higher multiple births and high-order multiple pregnancy and multiple birth after the modern management of infertility in Britain. The controlled ovarian hyperstimulation: results of 4,062 British Association of Perinatal Medicine. Br J Obstet intrauterine insemination cycles. Fertil Steril 2005; 83: Gynaecol 1992; 99: 607–13. 671–83. 13. Templeton AA, Penney GC, Lees MM. Relation between 26. Guzick DS, Sullivan MW, Adamson GD, et al. Efficacy of the luteinizing hormone peak, the nadir of basal body treatment for unexplained infertility. Fertil Steril 1998; temperature and the cervical mucus score. Br J Obstet 70: 207–13. Gynaecol 1982; 89: 985–8. 27. Goverde AJ, McDonnell J, Vermeiden JPW, et al. 14. Vermesh M, Kletzky OA, Davajan V, Israel R. Intrauterine insemination or in vitro fertilisation Monitoring techniques to predict and detect ovulation. in idiopathic subfertility and male subfertility: a Fertil Steril 1987; 47: 259–64. randomized trial and cost-effectiveness analysis. Lancet 15. Pardo M, Bancells N. Artificial insemination with 2000; 355: 13–18. husbands’ sperm (AIH): techniques for sperm selection. 28. Cohlen BJ. Should we continue performing intrauterine Arch Androl 1989; 22: 15–27. inseminations in the year 2004? Gyn Obst Invest 2005; 16. Dickey RP, Pyrzak R, Lu PY, Taylor SN, Rye PH. 59: 3–13. Comparison of the sperm quality necessary for 29. van Weert JM, van den Broek J, van der Steeg J, et al. successful intrauterine insemination with World Health Patients’ preferences for intrauterine insemination or Organization threshold values for normal sperm. Fertil in-vitro fertilization. Reprod Biomed Online 2007; 15: Steril 1999; 71: 684–9. 422–7.6
Chapter 2: Male causes of infertility They are reserved for special cases of unexplained a flagellar tail containing tightly packed mitochondria infertility . in the proximal portion. Spermatogenesis is heavily Men with non-obstructive azoospermia or severe dependent on FSH and testosterone for initiation and oligospermia must be counseled for potential genetic maintenance [7,8]. abnormalities that may be transmitted to their off- spring, and offered formal genetic screening prior to The epididymis ART . After release into the lumen, spermatids continue to mature. They are moved to the epididymis by active Normal spermatogenesis and peristalsis by the peritubular myoid cells. When enter- ing the epididymis, sperm are non-motile and unable ejaculation to fertilize the oocyte via IUI. The maturation of sper- The sperm cycle is a complex series of events that matids within the epididymis largely occurs as a result requires approximately three months from the begin- of micro-environmental influence, and hence there is ning of spermatogenesis to the antegrade ejaculation negligible protein synthesis within the spermatid itself. of semen. The physiology of sperm production and Most of the changes occur on the cell membrane by delivery is paramount to the diagnosis and treatment altering protein content, immunoexpression, net sur- of male-factor infertility. face charge, integrity and fatty acid content . These changes prepare the sperm for fertilization and are Spermatogenesis and the testicle androgen-dependent. The epididymis also serves as a Spermatogenesis occurs in the seminiferous tubules , favorable storage environment for mature sperm. which are the microscopic ducts made up primarily by Sertoli cells , germ cells and peritubular myoid cells . The vas deferens The seminiferous tubules make up the bulk of the tes- After leaving the tail (or cauda) of the epididymis, sperm ticular cortex. Sertoli cells form the walls of the tubules enter the thick, muscular, vas deferens. The vas is the and are connected by tight junctions; these form the major storage location of mature sperm prior to ejacu- blood–testis barrier that prevents macromolecules lation, although it is not capable of preserving viability from entering the tubules from the lymph system, thus to the same degree as the epididymis. The physiology allowing spermatogenesis to occur in an immunologi- of the vas results in the recommended two-day optimal cally privileged site . Sertoli cells also play an impor- interval for intercourse, because more frequent inter- tant role in supporting the germ cells with nourishment course produces less than optimal sperm counts and and supplying high levels of androgens (20–50 × serum less frequent intercourse produces decreased sperm levels) in the seminiferous tubule lumen . viability . Germ cells lie within the tubule in an ordered fash- ion, beginning with the spermatogonia at the base- Seminal vesicles and prostate ment membrane, progressing to the mature spermatid The seminal vesicles and prostate are the sexual acces- at the lumen. Spermatogonia undergo several mitotic sory glands responsible for contributing to the fluid divisions to produce a large supply of stem cells, allow- environment for sperm, with their secretions making ing for indefinite production of spermatozoa. The dip- up 95% of the normal ejaculate volume . The semi- loid spermatogonia undergo further mitotic division nal vesicles produce phosphorylcholine, ascorbic acid, to produce the primary spermatocytes. After the first flavin, prostaglandins, fructose and clotting factors. meiotic division the spermatocytes cross the blood– Prostaglandins relax the myometrium of the uterus testis barrier into the adluminal compartment , becom- and cervix; fructose is an energy source for sperm . The ing diploid secondary spermatocytes. Next, within the prostate is under regulation by androgens, specifically adluminal compartment, the secondary spermatocytes the potent dihydrotestosterone. undergo the second meiotic division, each producing two round spermatids that mature by spermiogenesis Penis physiology into elongated flagellar cells before entering the semi- The penis is responsible for effective transportation of niferous tubule lumen. Each primary spermatocyte sperm and semen from the vas in an antegrade fash-8 produces four mature spermatids, which have com- ion to the cervical os, a process requiring erection and pressed chromatin and acrosome in the head, with ejaculation. Erections occur from genital or central
Chapter 2: Male causes of infertilitystimulation. Genital stimulatory erections may be the prostate cells to stimulate growth and secretion.preserved in lesions above T10, although erections Within the testicle, testosterone drives spermatogen-in spinal cord injury patients are usually short and esis. FSH binds to Sertoli cells , initiating seminif-uncontrolled . Central-originating erections erous tubule development during puberty , and isinvolve contributions from many different areas of the essential for continued spermatogenesis duringbrain, involving memories, fantasy, visual and auditory adulthood. FSH is negatively inhibited by the Sertoli-stimuli. The flaccid penis is under constant sympa- cell-produced protein inhibin and, to a lesser extent,thetic stimulation, causing constricted sinusoidal by testosterone . Physiologic levels of testosterone arespaces within the corpora cavernosa. When parasym- required for adequate libido and spontaneous erec-pathetic stimulation increases from the pelvic plexus tions .(nervi ergentes) these sinusoids relax under the influ-ence of nitric oxide, causing an increase in the flow ofblood into the penis, while simultaneously compress- Pathophysiology of male infertilitying the emissary veins (activation of the veno-occlusive Semen quality can deteriorate with any of the rec-mechanism) and decreasing blood outflow . These ognized pathologies that may interfere with normalprocesses produce a physiologic erection. spermatogenesis. This section will focus on these pathologies and the treatment options for couples withEjaculation such problems.Ejaculation is a very quick and complex series of eventsthat is crucial in the ability to deposit sperm in the vag- Failure to produce adequate-qualityinal canal. Ejaculation is the result of a combination spermatozoaof central and genital nervous stimulation. Penile Production of spermatozoa is complicated by severalsensory information is passed through the dorsal mechanisms which are discussed below. Endocrine,nerve to the spinal column, where it is integrated and testicular failure, anatomical, infectious, genetic andsympathetic efferent signals are generated to initiate immunologic defects can impair the maturation ofthe ejaculatory reflex . The threshold for this proc- spermatogonia to produce quality sperm.ess can be lowered or raised by central modulation.Activation of the sympathetic ejaculatory pathway Endocrine/hormonal causesresults in contraction of the vas deferens, bladder The most common endocrine causes of male infertilityneck, seminal vesicles and prostate. Concurrent with are summarized in Table 2.1 .seminal emission is a sense of general and localizedpleasure, or orgasm . After emission of sperm into the Testicular causesposterior urethra, rhythmic contractions of the peri- The most common testicular causes of male infertilityurethral muscles result in an involuntary projectile are summarized in Table 2.2 .ejaculation of the seminal fluid. VaricoceleHypothalamo–pituitary–testicular axis in Varicoceles are dilated tortuous testicular veins, classi-the adult male cally described as “a bag of worms,” within the spermaticThe hypothalamo–pituitary–testicular axis is cord. They do not transilluminate when a pen light isessential for human reproduction, especially sper- held against the scrotal skin and usually do not collapsematogenesis and erectile function. Gonadotropin- in the supine position. Subclinical varicoceles can bereleasing hormone (GnRH), synthesized in the detected with scrotal ultrasound . Varicocele ishypothalamus, is released into the portal system in a the most common correctable cause of male infertility,pulsatile fashion, stimulating the pituitary to synthe- and 90% occur on the left side owing to the anatomy ofsize and release FSH and luteinizing hormone (LH). entering the renal vein rather than the vena cava on theLH stimulates the Leydig cells of the testicle to pro- right side. The prevalence of varicocele in infertile menduce testosterone. The anterior pituitary production is 20–40% . Authorities theorize that increasedof LH is negatively inhibited by serum testosterone . temperature, hypoxia and reflux of adrenal and renalTestosterone increases secretory production in the metabolites may impair spermatogenesis in patients 9seminal vesicles and is converted by 5α-reductase in with varicocele.
Chapter 2: Male causes of infertility Table 2.1. Endocrine causes of male infertility Disease process Characteristics Pituitary disease Tumors, infarcts, surgery, radiation, infiltrative or granulomatous disease. Isolated hypogonadotropic Absence of gonadotropin-releasing hormone, associated with anosmia. Fertility can be hypogonadism (Kallmann syndrome) achieved with LH and FSH replacement. Fertile eunuch syndrome LH is normal, but testosterone deficient. Patients have incomplete virilization, gynecomastia and reduced number of sperm. Isolated FSH deficiency Normal testes and virilization, does not respond to GnRH stimulation, azoospermic or oligospermic. Androgen excess Anabolic steroid abuse: 15% of high-school, 30% of college, and 70% of professional athletes. Temporary subfertility can result. Discontinue steroid use and re-evaluate in 3–6 months. Rarely caused by 21-hydroxylase deficiency characterized by precocious puberty. Estrogen excess Usually related to cirrhosis or obesity, which augment aromatase activity resulting in secondary pituitary suppression. Prolactin excess Secondary to pituitary adenoma, diagnosed by serum prolactin and CT/MRI of sella turcica. Check prolactin in end-stage renal disease or chronic renal insufficiency. Thyroid abnormalities Results in hypothalamic–pituitary dysfunction and alters sex hormone-binding globulin (SHBG) levels; < 0.5% of male infertility. Glucocorticoid excess Cushing’s syndrome features, decreases spermatogenesis, suppresses LH, fertility improves with correction. Table 2.2. Testicular causes of male infertility Disease process Characteristics Bilateral anorchia Secondary to torsion, trauma, infection or vascular injury. No effective ART. Cryptorchidism 0.8% of boys at 1 year of age; germ-cell abnormalities begin to appear at 2 years of age. Increased risk for infertility and malignancy. Testicular torsion If testicle saved, predisposed to immunologic infertility. Contralateral testis is at risk for abnormalities. Sertoli-cell-only syndrome Germ-cell aplasia, azoospermia, normal virilization, small testes, elevated FSH. Extensive sampling and biopsy may find sperm suitable for ART. Myotonic dystrophy Adult-onset muscular dystrophy, cataracts, muscle atrophy, various endocrinopathies, elevated FSH and LH. Fertility has been reported. Chemotherapy/ radiation Dose-dependent, inverse relationship between radiation and sperm counts, primarily affecting spermatogonia; sperm counts rebound after therapy, no increased incidence in congenital defects. Alkylating agents are the most gonadotoxic chemotherapy agents, cytotoxic to spermatogonia, but no increased incidence of congenital defects. Patients should be advised to avoid conception until 6 months after the end of treatment. Consider sperm cryopreservation prior to treatment. Medications Discontinue all unnecessary medications: ketoconazole, spironolactone and alcohol inhibit testosterone synthesis, cimetidine is an androgen antagonist and some pesticides have estrogen-like activity. Semen analysis in patients with varicocele demon- all of which increase the overall success rate of intrauter- strate decreased motility, decreased sperm concentra- ine insemination (IUI) . Conception rates following tion and increased amorphic cells . The majority of varicocele repair average 40–50% when female factors men who have varicoceles are fertile, but any subfertile are not present or have been appropriately treated . man with varicocele should be considered for repair, as 70% of men receiving surgical repair have significant Infection improvement in semen parameters. Motility improve- Infection of the male reproductive tract may be present10 ments are most common (70%), followed by improved in up to 23% of men seeking infertility evaluation . sperm densities (51%) and improved morphology (44%), Pyospermia is defined as > 1 × 106 leukocytes/mL of
Chapter 2: Male causes of infertility Table 2.3. Genetic causes of male infertility Disease process Characteristics Klinefelter’s syndrome (XXY) Most common genetic defect with azoospermia, 1/500 males, small firm testes, gynecomastia. Virilization and fertility may respond to testosterone. XX male Absent spermatogenesis and azoospermic. XYY syndrome Oligospermia or azoospermia with increased FSH and LH; biopsy demonstrates arrest of maturation of Sertoli cells. Noonan’s syndrome Also known as male Turner’s syndrome, fertility possible if descended testes, but cryptorchidism present in 75%. Y-chromosome microdeletions 7% of men with low sperm counts have Y microdeletions, usually the long arm. Often these men are fertile with ART, but will likely pass on DNA to their male offspring. Cystic fibrosis Azoospermia secondary to congenital bilateral absence of the vas deferens (CBAVD); 80% of men with CBAVD have mutations in the cystic fibrosis transmembrane regulator (CFTR) gene.semen. Although no specific bacterial organisms areclearly related to infertility, leukocytes produce reac- Failure to deposit ejaculate into thetive oxygen species, which are harmful to sperm cells. prostatic urethraOrchitis, specifically mumps orchitis , can be a specific In 7–14% of cases of azoospermia or severe oligosper-etiology, and occurs in 30% of postpubertal males who mia, despite normal spermatogenesis, the cause iscontract mumps parotitis . obstruction of the seminal ducts . While epididy- mal obstruction is the most common etiology, occur-Genetic ring in 30–67% of cases of azoospermia in men withThe most common genetic causes of male infertility are normal FSH levels, intratesticular obstruction hassummarized in Table 2.3 . been reported in up to 15% of cases. Ejaculatory duct obstruction is rare, found inImmunologic infertility 1–3% of cases of obstructive azoospermia. PatientsImmunologic infertility is present in 10% of infertile suffering from obstructive infertility may present withcouples . Sperm are highly antigenic cells, but coex- less conventional histories, such as a hematospermia,ist in the male body because of the blood–testis barrier. post-ejaculatory pain, recurrent urethritis or prostati-Tight junctions in the seminal tracts provide the immu- tis, obstructive or irritative urinary symptoms, scrotalnoprotective environment for haploid sperm cells. swelling, infection or pain, prior genitourinary proce-Antisperm antibodies (ASA) form when the barrier is dures, inguinal herniorrhapy, trauma and chronic pul-compromised, commonly through trauma, testicular monary infections.biopsy, vasectomy or infection. ASA can be detected Diagnostic steps in these patients include meas-in semen, serum and cervical mucus, usually using the urement of fructose levels in semen, ultrasonographicimmunobead test, which is available at most special- imaging and a standard infertility evaluation, to deter-ized andrology laboratories. ASA interfere with sperm mine the presence and level of obstruction. Scrotaltransport in the female reproductive tract, and with ultrasound evaluates the testis and epididymis, whereasthe egg–sperm interaction. They are found in 3–12% of transrectal ultrasound (TRUS) images the distal com-men presenting for infertility evaluation. Specifically ponents of the ejaculatory ducts.relating to IUI, in theory sperm can be washed to pre-vent clumping and agglutination, but fertility rates Ejaculatory duct obstructionare similar to matched controls . Treatment with Ejaculatory duct obstruction can be caused by inflam-steroids for both partners has been attempted, with mation or prostatic cysts. Calculi obstructing bothmild improvement in pregnancy rates and high rates ejaculatory ducts have been reported . Althoughof side effects (60%) . Intracytoplasmic sperm controversial, prostatic cysts are usually classified intoinjection (ICSI ) provides fertilization rates in ASA- the following two groups: (1) urogenital sinus cysts ,positive couples comparable to those in ASA-negative in which one or both ejaculatory ducts drain into the 11couples . cyst; (2) Müllerian cysts , in which ejaculatory ducts
Chapter 2: Male causes of infertility are displaced and compressed by an external cyst. suitable for patients undergoing concurrent TRUS- Post-inflammatory obstructions are usually a result guided aspiration of a midline cyst . of prostatitis or urethritis . Functional obstruction or mega-seminal vesicles are rarer causes of ejaculatory Epididymal and vasal obstruction duct obstruction that can occur in men with diabetic Vasectomy is the most common cause of acquired neuropathy or polycystic kidney disease , where the obstructive azoospermia, with 2–6% of vasectomized seminal vesicles are dilated without any demonstrable men requesting vasectomy reversal later in life. obstruction . Unfortunately, 5–10% of such patients will have a con- Partial obstruction of the ejaculatory duct is also a comitant epididymal obstruction secondary to epidi- controversial topic. Although there are signs suggestive dymal blow-out, necessitating epididymovasostomy of ejaculatory duct obstruction, such as dilated semi- . Vasovasostomy can be performed with loupes or nal vesicles, low-volume ejaculate, seminal vesicle sta- microscopically, though high-power operating micro- sis, medial prostatic cyst or intraprostatic hyperechoic scopic procedures have better pregnancy outcomes. foci, no definitive obstruction can be identified. The success of vasovasostomy is inversely correlated If TRUS evaluation reveals obstruction of the with the obstruction interval. Important prognostic ejaculatory ducts secondary to fibrosis, calcification factors for pregnancy following the vasovasostomy or compression by a superficial midline cyst, the pre- include sperm quality, partner’s age and presence of ferred therapy is transurethral resection (TURED) antisperm antibodies (ASA) . Approximately 20% or unroofing of the ejaculatory duct region [22,23]. of the patients who undergo successful vasovasos- Relief of the obstruction is confirmed by efflux of copi- tomy experience a deterioration of semen parameters ous cloudy material or dye from the ejaculatory ducts. within a year. Patients with low sperm quality or ASA Complications can arise on occasion due to reflux of are candidates for IUI or ICSI, depending on sperm urine back into the ejaculatory ducts and genital tract, quality. Epididymovasostomy is a challenging opera- leading to a possible infection and deterioration of tion that demands advanced training in microsur- sperm function from exposure to urine. Transurethral gery. The ultimate pregnancy rate is lower (20–30%), resection also carries a 4% risk of scarring severe and it is reasonable to perform MESA/TESE concur- enough to cause azoospermia. Overall, TURED results rently for cryopreservation of gametes as a back-up for reveal an improvement of 55% for semen parameters ICSI in case of failure of the reversal. When perform- and 27% for pregnancy rates. Patients with partial or ing epididymovasostomy for congenital obstructions, congenital obstructions, or those secondary to mid- spermatogenesis may be demonstrated by testicular line cysts, tend to have better outcomes after TURED. biopsy . Even in cases where natural pregnancy is not achieved, Although reconstructive reversal procedures are improvement in semen parameters may allow the the more cost-effective treatment options, ART can be reproductive endocrinologist improved IUI results. used with sperm retrieval techniques in selected cases, Alternative treatment options proposed for distal e.g. the presence of ASAs or advanced age of the part- ejaculatory duct obstruction include decompression ner . Testicular sperm extraction (TESE) , testicular of the ejaculatory ducts via aspiration of a midline cyst sperm aspiration (TESA) , microsurgical epididymal under TRUS guidance, transurethral balloon dila- sperm aspiration (MESA) , percutaneous epididymal tion of the strictured area, antegrade seminal vesicle sperm aspiration (PESA) and vasal sperm aspiration lavage or laser drilling of the ejaculatory duct region. (VSA) are routinely used sperm retrieval techniques. However, because of low success rates, none of these Pregnancies using vasal sperm aspiration in combina- procedures has become the standard of care. tion with IUI have been reported, but the success rate TRUS may also be employed in azoospermic men (14.3%) is lower than with ICSI . with obstruction distal to the seminal vesicles for sperm retrieval by seminal vesicle aspiration for use in ICSI. Ejaculatory dysfunction Although well described as successful in the literature, Although erectile dysfunction (ED) occupies a this is not a commonly performed procedure, as testic- prominent position in public awareness and interest, ular extraction (TESE) and/or epididymal aspiration ejaculatory dysfunction (EjD) is the most common (MESA) are the preferred methods for sperm retrieval. sexual dysfunction. Forty-six percent of men aged12 TRUS-guided aspiration of the seminal vesicles is often between 50 and 80 years have some type of ejaculatory
Chapter 2: Male causes of infertilitydisturbance . Encompassing a broad spectrum of carries the greatest potential consequences. Surgeriesconditions, EjD includes premature ejaculation (PE) , that damage the outlet of the ejaculatory ducts can alsoanejaculation (AE) and retrograde ejaculation (RE) . cause anejaculation (as well as retrograde ejaculationDespite the large proportion of affected men, EjD – see below). Transurethral resection of the prostateremains poorly studied or understood and its treat- (TURP), bladder neck reconstructions and ablation ofment does not share the same level of success as that of posterior urethral valves are all potential causes of AE.ED. Although PE is the most prevalent form (30–40%) Disease processes or lesions affecting either theof EjD, this section will focus on AE and RE, as they are peripheral nerves or the central nervous system canmore likely to interfere with fertility. cause ejaculatory delay or absence. Diabetes mellitus, a common metabolic condition that causes autonomicInhibited ejaculation / anejaculation neuropathy, inhibits neural outflow via the sym-According to guidelines published by the European pathetic tracts to the bladder neck. Lack of a closedAssociation of Urology (EAU) in 2001, anejacula- bladder neck during ejaculation may lead to anejacu-tion (AE) is defined as the failure of expulsion of semen lation or retrograde ejaculation. Spinal cord lesions,that is usually associated with normal orgasmic func- whether congenital, acquired or traumatic, commonlytion, whereas inhibited ejaculation (IE) is defined as induce ejaculatory dysfunction. Lesions above T10–the persistent or recurrent difficulty, delay, or absence of T11 cause anejaculation, whereas lower lesions mayattaining orgasm following sufficient sexual stimulation merely inhibit the expulsion phase of ejaculation, leav-. Retarded ejaculation, delayed ejaculation, as well ing emission intact. Partial spinal cord injuries mayas psychogenic AE, are often used synonymously with only cause IE. In spinal cord injury (SCI) patients, theinhibited ejaculation. This can be a lifelong condition, reported incidence of the ability to ejaculate duringoccurring in all sexual encounters, or acquired, occur- sexual intercourse or masturbation is 0–55% (medianring only in specific situations. Some men with IE are 15%) . Multiple sclerosis commonly causes aable to achieve orgasm via masturbation or, alterna- number of sexual dysfunctions, including an inabil-tively, nocturnal emission into a condom may provide ity to achieve orgasm or ejaculation in up to 61% ofa potential source of semen for IUI . patients. Anejaculation occurs in 0.14% of the general popu- A wide array of medications can induce ejaculatorylation, while in patients seeking infertility treatments dysfunction, through a variety of mechanisms. Anti-it is at 0.39%. Anejaculation is more common in older hypertensive medications, including α-methyldopa ,men , likely due to altered sensation and diminished thiazide diuretics and clonidine , have been implicated.erectile capacity. Numerous psychiatric medications from psychotrop- Although the etiology of IE has not been eluci- ics to antidepressants , including haloperidol , tricyclicdated, it has been attributed to psychosocial issues , antidepressants , selective serotonin reuptake inhibitorsincluding cultural and religious beliefs, concurrent (SSRIs) and monoamine oxidase inhibitors , have rec-psychopathologies such as unconscious aggression ognized ejaculatory side effects. When possible, discon-and unexpressed anger, insufficient sexual arousal, tinuation of the offending pharmaceutical agent is thepreconditioning for inhibited ejaculation due to pref- optimal option . Prolonged alcohol abuse may also leaderence for masturbation over partnered sex, and fear of to AE or IE. Alpha-adrenergic blockers such as tamsu-pregnancy or sexually transmitted disease . losin were previously believed to cause retrograde ejac- Some surgical procedures are recognized to cause ulation; however, it has recently been determined thatejaculatory dysfunction, which must be addressed they cause anejaculation via a central mechanism.as part of preoperative informed consent. Any retro- Treatment of psychogenic AE or IE is controversial.peritoneal procedure risks damage to either the sym- The decision may depend on patient preference as wellpathetic nervous system or the hypogastric plexus. as partner age, as a more aggressive approach is war-Retroperitoneal lymph node dissection (RPLND) for ranted in a patient with an older partner. In general,testicular cancer , abdominal aortic aneurysm repair, restoring normal ejaculation to facilitate spontaneousaortic bypass grafting with exogenous materials and pregnancy in patients with anejaculation and inhib-abdominal perineal resection have all been implicated ited ejaculation can be difficult, with high treatmentin postsurgical AE. Since RPLND is often performed failure rates. If the goal is only fertility, a number ofin younger patients who have yet to start families, it options exist. Since many patients with IE continue to 13
Chapter 2: Male causes of infertility have nocturnal emissions , wearing a condom at night the procedure. In addition to collecting the antegrade to collect a specimen for IUI is a simple, non-invasive ejaculate, the bladder is emptied and the fluid proc- method for sperm collection. Some authorities suggest essed to recover any retrograde specimen. If the PVS behavioral therapy to restore spontaneous ejaculation produces a successful antegrade ejaculation without as the first treatment option. In case of failed behav- complication, home intravaginal insemination might ioral therapy, penile vibratory stimulation (PVS) is be offered to couples. Roughly one out of four couples a relatively non-invasive and inexpensive method. will have a pregnancy using home insemination within Electroejaculation (EEJ) and surgical sperm retrieval two years . procedures are reserved as last resorts for obtaining Although the success rate of PVS in psychogenic sperm for later use with IVF-ICSI, because they are inva- AE or IE is unpredictable, semen is retrieved in 55% sive and require anesthesia . It should be empha- of the patients with SCI lesions . The overall suc- sized that semen quality is somewhat diminished when cess rate of PVS does not differ markedly between dif- retrieved with EEJ compared to spontaneous ejacula- ferent types of anejaculation; however, psychogenic tion, although the difference is not statistically signifi- anejaculation patients have higher rates of antegrade cant in neurologically intact men . ejaculation. SCI patients with lesions above T11 have a Medications used to facilitate ejaculation, including significantly higher response to PVS than SCI patients bupropion, buspirone , yohimbine and cyproheptadin e, with lower-level lesions . act through central dopaminergic or antiserotoniner- EEJ also stimulates the nerves for ejaculation. The gic pathways. Unfortunately, most of the literature con- patient is premedicated as for PVS to avoid autonomic sists of small uncontrolled series or case studies, and no dysreflexia and positioned in the right lateral decubitus placebo-controlled studies have been performed from position. The rectal probe is placed against the rectal which to draw satisfactory conclusions . wall at the level of the seminal vesicles and a stimulus In cases where AE or IE is secondary to organic eti- is applied in an increasing pattern until ejaculation ologies, such as in SCI patients, PVS is recommended occurs. Wave voltage ranges from 16 to 22 V at 200– before EEJ with a rectal probe . PVS is successful in 500 mA. Possible complications of EEJ include rectal the majority of cases with lesions above T10 (54%), when injury, autonomic dysreflexia and vomiting. Men with the ejaculatory reflex arc is intact, whereas the success pinprick sensation in the sacral or L4–5 dermatome rate drops significantly with lesions below T10 or with require general anesthesia for EEJ . With SCI lower motor neuron lesions . Pharmacological patients, EEJ recovers semen samples in 95% of PVS interventions have been proposed to enhance the suc- failures. Pregnancy rates of 9% per cycle and 32% per cess rate of PVS, including the use of physostigmine couple have been reported when EEJ is used in com- and midodrine . bination with IUI . However, success is correlated The mechanism of PVS involves initiation of reflex to the total motile sperm count retrieved. The success spinal cord activity and leads to ejaculation. Before the rate per cycle drops to around 1% when the total motile procedure, the bladder is filled with a sperm-friendly sperm number is below 4 × 106, and exceeds 17% when culture media (e.g. Ham’s F-10 [Sigma, St. Louis, MO]). the total motile sperm count is greater than 40 × 106 . The vibrator is applied to the frenular area of the penis, Despite these encouraging outcomes for sperm while the patient is seated or in a supine position. The retrieval with PVS and EEJ, 28% of SCI infertility cent- stimulation has a frequency of 60–120 Hz and the peak- ers lack the equipment or experience with PVS and to-peak amplitude of excursion ranges from 1.5 mm to EEJ, and 34% do not have IUI capabilities. 4.5 mm. A maximum of six stimulation cycles of three minutes, with resting periods of two minutes between, Retrograde ejaculation are applied. In general, the duration of stimulation Retrograde ejaculation (RE) is the misdirected pro- until ejaculation occurs is between 10 seconds and 18 pulsion of semen from the posterior urethra into the minutes. Criteria to discontinue stimulation are blood bladder. RE can either be complete, with a total absence pressure exceeding 200 mmHg systolic or 130 mmHg of ejaculate, or partial, with preservation of a minimal diastolic, severe headaches, or signs of autonomic dys- amount of antegrade ejaculate. In the absence of ante- reflexia. For prevention of autonomic dysreflexia in SCI grade ejaculation, RE is the most common ejaculatory patients (especially in patients with spinal cord lesions dysfunction, accounting for 0.3–2% of cases of male14 at T6 or higher), nifedipine is administered prior to infertility .
Chapter 2: Male causes of infertility Presentation of RE is similar to AE: orgasm without sodium bicarbonate solutions until the urine has a phejaculation. A postorgasmic urine analysis that reveals of 7.6–8.1 and an osmolarity of 300–500 mOsm/L. Thea significant number of sperm after centrifugation is patient then masturbates and urine is collected fordiagnostic of retrograde ejaculation . sperm harvesting. Alternatively, the bladder can be For antegrade ejaculation to occur, the prostate, drained and filled with a sperm-friendly culture mediabladder neck, external sphincter, seminal vesicles, vas (e.g. Ham’s F-10 [Sigma, St. Louis, MO]) via a small-deferens and perineal musculature must all be ana- diameter catheter prior to ejaculation. The patient thentomically and functionally intact and follow a coordi- masturbates and sperm is obtained through voiding ornated series of events to propel semen in an antegrade catheterization after ejaculation.direction through the urethral meatus. Medications,neurological conditions (e.g. diabetic autonomic neu- Failure to deposit ejaculate in theropathy, SCI) and surgical procedures (e.g. transure-thral resection or incision of the prostate, pelvic or posterior fornixanterior spinal surgery) that interfere with this mecha- Erectile dysfunctionnism result in retrograde ejaculation. In a significant Erectile dysfunction (ED), defined as the inability toportion of RE patients, no causative factor can be achieve or maintain penile rigidity sufficient for inter-determined. Fortunately, idiopathic cases respond well course, is more prevalent among infertile men thanto therapy . their fertile counterparts (28% vs. 11%). Psychological Treatment of RE aims either to restore antegrade stress , one of the risk factors of ED, is especially rec-ejaculation or to retrieve sperm for IUI or IVF-ICSI. ognized as a cause of ED in cultures that put greatRestoring antegrade ejaculation focuses on increasing emphasis on fertility. Also, the long period of diagnos-the sympathetic tone of the bladder neck or decreas- tic studies and treatment regimens may have a negativeing parasympathetic activity. If successful, the return impact on sexuality .of antegrade ejaculation may be sufficient to allow for First-line therapy for erectile dysfunction consistsnatural conception, or may provide enough quality of oral pharmacotherapy and vacuum erection devices.sperm to use with IUI. Second-line therapy options include intracavernosal Imipramine , given as a daily dose of 25–50 mg injection of vasoactive agents and intraurethral appli-for seven days prior to planned intercourse, has been cation of alprostadil. Surgical implantation of penilesuccessfully used to treat RE, with the return of ante- prosthesis is considered a third-line therapy in patientsgrade ejaculation in 65–100% of patients and a rate of who are unresponsive to medical treatment.spontaneous pregnancy of 40% . Anticholinergics, In the USA, oral pharmacotherapy approved for theα-adrenergic agonists or combinations may also be treatment of erectile dysfunction consists of sildenafil,used to modulate bladder neck activity, but they are not vardenafil and tadalafil, all of which are phosphodieste-as effective as imipramine, which should be considered rase type 5 (PDE5) inhibitors. PDE5 is an enzyme thatthe first-line therapeutic agent for RE. hydrolyzes cyclic guanosine monophosphate (cGMP) Surgical interventions to restore bladder neck in the cavernosal tissue of the penis. Increased levels ofintegrity, including endoscopic injections of bulk- cGMP lead to smooth muscle relaxation and ultimatelying agents at the bladder neck to promote closure to penile erection.or open surgical restoration (Abrahams procedure), Sildenafil was the first approved PDE5 inhibitorhave been demonstrated to have limited success and in this class. It is administered in 25, 50 and 100 mgare not recommended by most authorities in the era doses and is effective 30–60 minutes after administra-of IVF-ICSI. tion. Efficacy may be maintained up to 12 hours and Attempts can be made to harvest sperm from urine adverse effects are mild in nature, including headachefor later use with IUI if medical management fails to and flushing.return antegrade ejaculation. Since the acidity and Vardenafil , administered in 5, 10 and 20 mg doses,high osmolarity of urine is detrimental to the motil- is effective 30 minutes after administration. In vitro itity and viability of spermatozoa, two different tech- is 10-fold more potent than sildenafil, although thisniques are commonly employed to adjust the urine pH does not necessarily apply to clinical efficacy. Adverseand osmolarity within the bladder. The less invasive effects observed include headache, flushing and nasalmethod involves alkalinization of the urine by drinking congestion. 15