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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 1995-2004
Copyright © 2007 by The Endocrine Society

APPROACH TO THE PATIENT

Approach to the Infertile Man

Shalender Bhasin

Boston University School of Medicine, and Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., Professor of Medicine, Boston University School of Medicine, Chief, Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, Massachusetts 02118. E-mail: bhasin{at}bu.edu.


   Abstract
Top
 Abstract
I. The Patient
 II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
 References
 
Introduction: Infertility is one of commonest disorders to afflict young men and women. The evaluation of infertility is initiated typically after 1 yr of failure to conceive.

Diagnostic Evaluation: The couple should be evaluated together to determine whether the problem resides in the male partner, the female partner, or both. The objectives of evaluation are to exclude treatable conditions—gonadotropin deficiency, obstruction, and coital disorders—and identify those who are candidates for assisted reproductive technologies, those who are sterile and should consider adoption or artificial insemination using donor sperm, and those who should undergo genetic screening. All infertile men should undergo several semen analyses according to the World Health Organization manual, as well as measurements of testosterone, LH, and FSH levels. Hormone measurements can help determine whether the patient has gonadotropin deficiency (low testosterone and low or inappropriately normal LH and FSH), primary testicular failure (low testosterone, elevated LH and FSH), spermatogenic failure (normal testosterone and LH, elevated FSH), or androgen resistance (high testosterone, elevated LH). A majority of infertile men have normal testosterone, LH, and FSH levels. Obstruction should be ruled out in azoospermic men with normal testosterone, LH, and FSH levels.

Genetics: Yq microdeletions are the most prevalent cause of spermatogenic failure in men with azoospermia or severe oligozoospermia. Infertile men with azoospermia or severe oligozoospermia should undergo karyotyping and testing for Yq microdeletions. Men with congenital absence of vas should be tested for cystic fibrosis transmembrane conductance regulator mutations.

Therapy: Gonadotropin therapy is highly effective in gonadotropin-deficient men. Intracytoplasmic sperm injection (ICSI) has emerged as the treatment of choice for idiopathic male factor infertility. However, ICSI is expensive and associated with a higher risk of multiple gestation, low birth weight, preterm delivery, perinatal complications, and chromosome aneuploidy than naturally conceived pregnancies. Men considering ICSI should be offered karyotyping, Yq microdeletion testing, and genetic counseling by counselors experienced in reproductive disorders.


   I. The Patient
Top
 Abstract
 I. The Patient
II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
 References
 
A 32-YR-OLD MAN requests evaluation for infertility. He was a full-term healthy baby who underwent normal pubertal development. Married for 3 yr, his 28-yr-old wife has not conceived despite unprotected intercourse. His wife has normal menstrual cycles, and her gynecological evaluation reveals no abnormality. Physical examination reveals a well-developed man with normal facial, chest, and pubic hair. Testicular volume is 18 ml bilaterally. The rest of his examination is normal.

Blood counts and chemistries are normal. Testosterone level is 450 ng/dl, LH is 6 U/liter, and FSH is 12 U/liter. Semen analyses reveal no sperm in two semen samples and sperm density of 1 million/ml in the third sample. Karyotype is 46, XY in all 100 cells.


   II. Case Discussion
Top
 Abstract
 I. The Patient
 II. Case Discussion
III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
 References
 
This patient with azoospermia/severe oligozoospermia, normal testosterone and LH levels, but an elevated FSH level has primary spermatogenic failure. Although in a majority of men with idiopathic oligozoospermia or azoospermia, the cause cannot be identified, microdeletions of the long arm of Y chromosome (Yq) are the most frequent recognizable cause of spermatogenic failure in 46, XY men with nonobstructive azoospermia or severe oligozoospermia. Our patient likely does not have Klinefelter’s syndrome because his testosterone level, testicular volume, and karyotype are normal. Mutations of the androgen receptor (AR) gene may be associated with a variable phenotype that can range from complete feminization to undervirilization and infertility. However, patients with AR mutations typically have high testosterone and elevated LH levels. Obstruction should always be considered in men with azoospermia; however, FSH levels are typically normal in obstructive azoospermia. This patient with severe spermatogenic failure would be an excellent candidate for analysis of Yq microdeletions and consideration of intracytoplasmic sperm injection (ICSI). If some live sperm can be found in the semen, then ICSI can be performed using sperm in the ejaculate. Men in whom no live sperm can be retrieved from the ejaculate may be candidates for ICSI using intratesticular sperm or elongated spermatids obtained from testicular biopsy.


   III. Introduction
Top
 Abstract
 I. The Patient
 II. Case Discussion
 III. Introduction
IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
 References
 
Reproduction and fertility are central to survival of the species; not surprisingly, the biblical and Vedic lore reflects human preoccupation with both conception and infertility. For instance, Sarah, Abraham’s wife, had passed the childbearing age without producing offspring; she encouraged Abraham to take her Egyptian slave girl, Hagar, as a second wife, who bore him Ishmael. Later, Sarah would produce a son of her own, Isaac. In the Hindu Epic Ramayana, King Dashratha, the Father of Lord Rama, married thrice, but he was unable to bear children with any of his queens. King Dashratha’s high priest, Balamiki, held a prayer ceremony, invoked the gods, and offered a concoction to the three queens, following which each of them became pregnant—arguably the first report of successful assisted reproductive technology (ART) treatment.

Infertility continues to be a highly prevalent condition; the proportion of couples seeking medical treatment for infertility is estimated at 4–17% (1, 2). From 3–4% of all couples remain involuntarily childless at the end of their reproductive periods (3). The primary problem resides exclusively in the male partner in 20% of infertile couples; in an additional 26%, problems reside in both the male and the female partner (4).

Given the high prevalence of infertility among men and its impact on an individual’s well-being and health care expenditures, the neglect that this topic has received in endocrine literature is regrettable. The endocrinologists and the professional societies that represent them have abdicated their natural leadership of this field to others, much to the detriment of patients and the field of endocrinology. The reluctance of the endocrinologists stems in part from their unfamiliarity with simple office procedures such as ultrasound and testicular biopsy/aspiration for ICSI and from the suboptimal rendition of this topic in endocrinology curricula.

The endocrinologist should play an important role in coordinating the care of the infertile couple and providing counsel on prognosis and treatment options, including ART programs. The endocrinologist should identify those who have a treatable cause of infertility, such as gonadotropin deficiency or obstruction. The evaluation should determine which couples can benefit from ART and whether the patient has untreatable sterility, in which case the couple should be counseled about adoption or artificial insemination with donor sperm. The endocrinologist should present to the couple a realistic prognosis and the pros and cons of treatment options and should guide the couple away from ineffective interventions.


   IV. Diagnostic Evaluation
Top
 Abstract
 I. The Patient
 II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
 References
 
Duration of failure to conceive before diagnostic work-up is initiated

Determination of when diagnostic evaluation should be initiated is important because a majority of couples failing to conceive for 12 months will conceive spontaneously (5, 6)! The World Health Organization (WHO) defined infertility as the inability of a sexually active couple to achieve pregnancy despite unprotected intercourse for a period of greater than 12 months (7). The WHO definition was based on studies that used time-to-pregnancy estimations and found the probability of conception to be 20% per cycle or approximately 85–90% per year (7, 8, 9, 10). The European Society for Human Reproduction and Embryology (ESHRE) defines infertility as failure of pregnancy to occur within 2 yr of regular coital exposure (11).

These recommendations have important implications. First, the probability of conception in any menstrual cycle is only approximately 30%, even among couples who do not have any medical problem. Second, although some couples who fail to conceive within 12 months will never conceive spontaneously, over 50% will have a live birth within the next 36 months (6). As the duration of nonconception increases, the likelihood of spontaneous conception decreases; among couples reporting infertility for 4 yr, conception rates per month are 1.5% (12, 13). Thus, the pressures to initiate evaluation and treatment should be resisted if the period of nonconception is less than 1 yr. However, in couples with known reproductive disorders, an earlier intervention is justified.

The spontaneous conception rates may be even higher than those estimated previously (14, 15). Among Chinese women 20–34 yr of age (14), monthly fecundity rates were approximately 30–35%; 90% became pregnant in their first six cycles. Among German couples (15), cumulative probabilities of conception were estimated to be 38, 81, and 92% at one, six, and 12 cycles. These data have led to suggestions to reduce the time for initiating evaluation to 6 months. However, reducing the time of unwanted nonconception before initiating evaluation will impact the predictive value of diagnostic tests and cost effectiveness of therapeutic procedures.

Causes and pathophysiology. The frequency of etiological factors varies among different surveys (7, 16, 17). In general, 15–20% of infertile men are azoopsermic (3, 17), and 10% have sperm density below 1 million/ml. A specific cause of infertility is not determinable in 40–60% men (7, 16, 17). Most infertile men have idiopathic oligozoospermia (7, 16, 17).

Correctable or treatable causes of infertility, such as gonadotropin deficiency, obstruction, and coital disorders, are present in only a small fraction, but it is important to recognize them because effective therapies are available (17). Varicoceles are present in 10–30% of infertile men; their role in pathophysiology of infertility remains unclear (18, 19). A number of genetic disorders have been implicated in spermatogenic failure; of these, Klinefelter syndrome and Y chromosome microdeletions are the most prevalent, accounting for 10–20% of patients (17, 20). Although the prevalence of antisperm antibodies in infertile men is higher than in fertile men (21), the mechanisms by which antisperm antibodies cause infertility are unclear.

Diagnostic evaluation of the infertile man. The objectives of evaluation are to exclude treatable conditions—gonadotropin deficiency, obstruction, and coital disorders—and to identify those who are candidates for ART, those who are sterile and should be counseled to consider adoption or artificial insemination using donor sperm, and those who should undergo genetic screening. The key elements of evaluation are the following (Table 1Go and Fig. 1Go):

  1. Evaluate the couple together and determine whether the problem resides in the male partner, the female partner, or both. If the female partner has ovulatory menstrual cycles, tubal patency, and normal FSH, TSH, and prolactin, the problem likely resides in the male partner.
  2. Initiate the work-up by evaluating general health and excluding systemic diseases.
  3. History should focus on duration of infertility, previous fertility in the man or the woman, contraceptive use, sexual function, frequency and timing of intercourse, and sexual practices. Ascertain the timing of pubertal development, shaving frequency, and hair loss. Inquire about scrotal trauma, genitourinary infection, sexually transmitted disease, and scrotal or inguinal surgery including hernioplasty and vasectomy. Ask for history of cancer, especially previous treatment with cancer chemotherapy and radiation to the inguinal or scrotal area. Evaluate hair distribution and escutcheon, body proportions, and voice. Measure testicular volume by Prader orchidometer and palpate epididymis for cysts and vas deferens for total or segmental absence.
  4. Analyze three or more semen samples obtained by masturbation after at least 48-h abstinence; determine sperm density, motility, and morphology, using rigorous quality control in accordance with WHO manual (22, 23).
  5. Measure testosterone, LH, and FSH in early morning to determine whether patient has gonadotropin deficiency (low testosterone and low or inappropriately normal LH and FSH), primary testicular failure (low testosterone, elevated LH and FSH), selective spermatogenic failure (normal testosterone and LH, elevated FSH), or androgen resistance (high testosterone, elevated LH). A majority of infertile men have normal testosterone, LH, and FSH levels (3, 16, 17).
  6. In men with azoospermia and normal testosterone, LH, and FSH levels, exclude obstruction by measuring seminal fructose and obtaining urological evaluation; perform cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis in those with absence of vas.
  7. Check antisperm antibodies in oligozoospermic men with normal hormone levels, history of torsion or testicular injury, or sperm aggregates in semen (21).
  8. Normal testosterone, normal LH, and elevated FSH levels in an azoospermic or severely oligozoospermic man are suggestive of primary spermatogenic failure. These men should undergo measurement of testicular volume, karyotyping. and screening for Yq microdeletions.
  9. Specialized sperm function tests such as the acrosome reaction, zona-free hamster egg penetration test, and human zona binding test, have limited clinical utility; they should be performed only in research studies (22, 23).


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  		TABLE 1. Key considerations in the diagnostic evaluation of an infertile man

 

Figure 1
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  		FIG. 1. An algorithmic approach to the evaluation of an infertile man. 1, Infertile men with nonobstructive azoospermia and severe oligozoospermia with normal or elevated FSH should undergo a karyotype and screening for Yq microdeletions before being referred for ICSI. 2, Men deemed to have hypogonadotropic hypogonadism should be evaluated further by an magnetic resonance imaging scan, prolactin, and measurement of other pituitary hormones to exclude space occupying neoplastic or infiltrative lesions of the hypothalamic pituitary region. T, Testosterone.

 
Genetic causes

Chromosomal disorders. One of 20 infertile men bears a chromosomal abnormality; of these, 80% of cases involve sex chromosomes and 20% involve autosomes (20, 24). The sex chromosomal and autosomal abnormalities occur with 15 and six times greater frequency, respectively, in infertile men than in the general population (20, 24). Klinefelter’s syndrome is the most frequent chromosomal disorder associated with infertility (20, 24).

Y chromosome microdeletion syndrome. The Y chromosome contains an important collection of testis-specific genes necessary for spermatogenesis (25, 26). The human Y chromosome consists of a pseudoautosomal region that recombines with homologous regions of X chromosome; the remaining 95% of Y chromosome that does not recombine with X chromosome is referred to as the male-specific region of Y (MSY) (Fig. 2Go) (25). The MSY contains three classes of sequences: X-transposed, X-degenerate, and ampliconic (25). The ampliconic region contains sequence pairs showing nearly similar nucleotide sequences organized into large palindromes that contain multicopy Y-specific genes that are expressed in the testis (25). Intra-Y gene conversions occur frequently, account for the high degree of sequence similarity between the arms of the palindromes (25, 26), and predispose Y chromosome to high frequency of deletions and rearrangements. The X-transposed sequences have a high degree of homology to X chromosome, whereas X-degenerate sequences represent what is left of ancient autosomes that were transposed to form X and Y chromosomes (25).


Figure 2
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  		FIG. 2. A schematic representation of the human Y chromosome. The pseudoautosomal region refers to that portion of the Y chromosome that recombines with homologous regions of the X chromosome. The remaining 95% of Y chromosome that does not recombine with the X chromosome is referred to as the MSY. Page and colleagues (25 ) discovered that the MSY contains many transcription units that are grouped in three classes: X-transposed, X-degenerate, and ampliconic (35 ). The ampliconic region contains several multicopy Y-specific genes that are expressed in the testis (35 ). The X-transposed sequences have a high degree of homology to X chromosome, whereas X-degenerate sequences represent remnants of ancient autosomal regions that were transposed to form X and Y chromosomes. Yp, Short arm of Y chromosome; Yq, long arm of Y chromosome. [Reproduced with permission from H. Skaletsky et al.: Nature 423:825–837, 2003 (25 ).]

 
Tiepolo and Zuffardi (27) discovered that men with large deletions of Yq were infertile and proposed that loci for "azoospermia factor (AZF)" reside in these Yq regions. Large deletions of Yq that are visible under the light microscope are uncommon in infertile men. However, small deletions of Yq that are not visible under the microscope and are referred to as microdeletions are observed in 10–15% of infertile men with azoospermia or severe oligozoospermia (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). In a survey of 3,073 infertile men, the prevalence of Yq microdeletions was 3.2% in infertile men, 8.3% in men with nonobstructive azoospermia, and 5.5% in men with severe oligozoospermia (Fig. 3Go) (40). Y microdeletions are rare in fertile men and in men with sperm densities greater than 5 million/ml.


Figure 3
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  		FIG. 3. A deletion map of 99 Yq microdeletions, adapted from that published by Ferlin et al. (40 ) and based on an analysis of 3073 consecutive infertile men. The top shows a schematic of the Y chromosome regions: short arm (Yp), long arm (Yq), pseudoautosomal regions 1 (PAR1) and 2 (PAR2). Below this map are depicted the three AZF regions, AZFa, AZFb, AZFc, described by Vogt et al. (34 ). The sequence tagged sites (STSs) that were used to map these deletions are listed. The palindromic structure of AZFbc region with its amplicons arranged in five palindromes are shown with heavy, colored arrows. The location of the five classes of microdeletions in AZFa, AZFb, AZFc, AZFbc, and AZFabc are shown; the numbers in parentheses represent the number of patients with that type of microdeletion. AZFc microdeletions were the most frequent microdeletions accounting for nearly two thirds of all microdeletions. Solid black bars, STSs present; solid gray bars, STSs that normally amplify by PCR, but their presence or absence cannot be determined; white boxes, STSs that normally amplify by PCR but are assumed to be absent in the context of the deletion pattern; dotted lines, STSs absent. A novel Yq microdeletion, gr/gr, characterized by deletion of two of the four DAZ copies and by failure of STS sY1291 to amplify, has recently been described. [Reproduced with permission from A. Ferlin et al.: J Clin Endocrinol Metab 92:762–770, 2007 (40 ).].

 
There is poor correlation between testicular histology and the location and size of the microdeletion. Most infertile men with Y deletions have either azoospermia or severe oligozoospermia (40) (sperm densities < 5 million/ml) and elevated FSH levels (40, 41, 42, 43). Vogt (42) classified Yq microdeletions into three groups depending on the location of microdeletion: AZFa, AZFb, and AZFc. Subsequently, three additional types of microdeletions were recognized: gr/gr deletion, AZFbc, and AZFabc. These six types of microdeletions account for nearly all the Yq microdeletions that have been associated with infertility (Fig. 3Go) (40, 41). AZFc deletions account for two thirds of all Yq deletions (40).

With the recognition that most of the Y microdeletions are caused by intra-Y homologous recombination between repeated sequence blocks that are organized into palindromes, the classification of Yq microdeletions has undergone revision. The new classification is based on the mechanism of deletion: AZFa, P5/proximal-P1, P5/distal-P1, P4/distal P1, and b2/b4-AZFc (40).

Y-specific gene families. Several Y-specific gene families, cloned by deletion mapping of Yq deletions, have been associated with spermatogenesis; the RBM (RNA binding motif containing), the DAZ (deleted in azoospermia), USP9Y, and BPY2 (44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55). DAZ and RBM are multiple-copy gene families that contain RNA binding motifs (45, 46, 47). The precise role of these proteins in germ cell development remains unclear.

Who should be tested for Yq microdeletions? Infertile men with nonobstructive azoospermia or severe oligozoospermia (sperm density < 5 million/ml) in whom the cause of spermatogenic failure is not apparent should be tested for Yq microdeletions.

How is the testing for Yq microdeletions performed? Yq microdeletions are detected by PCR-based mapping of several conserved molecular markers or genes located within and outside the AZF region (43); these tests are available from commercial laboratories. With the availability of precise Y chromosome maps, more specific molecular markers have been developed, and guidelines for standardized testing of Yq microdeletions have been published by the European Molecular Genetics Network (43). High resolution microarrays for chromosome testing are being developed for detection of Y deletions, but are not yet available for clinical use.

Father-to-son transmission of Yq microdeletions. Although most Yq microdeletions occur de novo, transmission of Yq microdeletions from father to son through ICSI has been reported (54, 55). The couples undergoing ICSI should be counseled that their male offspring may be infertile.

Other genetic syndromes associated with infertility in men (Table 2Go). Approximately three fourths of men with congenital absence of the vas deferens harbor mutations of the CFTR gene (56); many do not have the pulmonary manifestations of cystic fibrosis. Mutations of the cAMP response element modulator (CREM) have been associated with infertility and postmeiotic maturation arrest (57, 58, 59). Testicular dysfunction and infertility may be manifestations of other genetic disorders, such as hemochromatosis, sickle cell disease, thalassemia major, and myotonic dystrophy (60, 61, 62, 63). Mutations in AR gene have been associated with infertility and undervirilization in phenotypic males, but the overall prevalence of AR mutations among infertile men is low (64, 65). The length of the CAG trinucleotide repeat in exon 1 of AR gene that encodes for the polyglutamine tract is inversely related to its transactivational activity (66, 67, 68); however, data on the association of polyglutamine length with infertility among men are conflicting (66, 67, 68). Mutations of anosmin, GnRH receptor, GPR54, DAX-1, SF-1, NELF, and FGFR1 genes have been associated with idiopathic hypogonadotropic hypogonadism (IHH) (69, 70). Hemochromatosis is associated with treatable hypogonadotropic hypogonadism; some men with hemochromatosis might also have primary testicular failure (17).


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  		TABLE 2. Genetic testing in infertile men

 

   V. Treatment of Infertile Men
Top
 Abstract
 I. The Patient
 II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
VI. Genetic Testing and...
 VII. Guidelines
 References
 
  1. Testosterone, human chorionic gonadotropin (hCG), clomiphene citrate and other aromatase inhibitors, and bromocriptine have not been shown to be effective in men with idiopathic oligo/azoospermia; direct the couple away from such unproven therapies (17). Testosterone therapy can further suppress spermatogenesis (17).
  2. Men with hypogonadotropic hypogonadism in whom pituitary neoplastic lesions and hyperprolactinemia have been excluded are candidates for gonadotropin or pulsatile GnRH therapy.
  3. Men with obstructive azoospermia should be referred to a urologist for surgical correction. With microsurgical techniques, restoration of patency can be achieved in 70–90% of patients, although restoration of fertility is achieved only in 50%. In men with failed vasectomy reversal, verification of patency restoration and surgical revision, if indicated, or ICSI using epididymal sperm are reasonable options.
  4. Men with idiopathic oligozoospermia should undergo genetic testing and be referred to a specialized fertility center for consideration of ART treatment, which may include in vitro fertilization (IVF) or ICSI. IVF should be attempted if there are more than 2 million motile sperm. If there are less than 2 million sperm in the ejaculate, less than 5% sperm with normal morphology, or less than 5% sperm with progressive motility, ICSI should be offered.
  5. Men with nonobstructive azoospermia should be offered karyotype and screening for Yq microdeletions. Although ICSI using intratesticular sperm has been successful (71, 72, 73, 74), the success rates of ICSI for azoospermic men using intratesticular or epididymal sperm are lower than that for ejaculated sperm (71, 72, 73, 74). In some men with nonobstructive azoospermia, no sperm or spermatids may be retrievable from testicular biopsy, whereas for some couples the expense of ICSI may be prohibitive; for these couples, artificial insemination by donor sperm and adoption are realistic options.

Other health considerations in treating infertile men

Some causes of infertility (Klinefelter’s syndrome, IHH) in men also are associated with androgen deficiency. Also, spermatogenic failure may be associated with impaired Leydig cell function (75). In men with gonadotropin deficiency, hCG and pulsatile GnRH therapy may restore both spermatogenesis and testosterone concentrations. However, exogenous testosterone administration suppresses spermatogenesis; infertility is a common complication of androgen abuse by body builders. Infertile men with cryptorchidism are at increased risk for testicular cancer (76); it is unclear whether infertility, in the absence of cryptorchidism, increases the risk of testicular cancer, as some reports have suggested (77).

Hormonal treatment of men with hypogonadotropic hypogonadism. Gonadotropin therapy and pulsatile GnRH are highly effective in inducing spermatogenesis in men with IHH (78, 79, 80, 81, 82, 83, 84). The two therapies do not differ in the time to first appearance of sperm, sperm densities, or pregnancy rates (78, 80, 81); however, because of its cumbersome nature, few centers use pulsatile GnRH therapy. Also, pulsatile GnRH therapy is not an option for patients with panhypopituitarism.

The therapy of IHH is started with hCG 1000 U three times weekly; the dose is adjusted to achieve nadir testosterone level measured 48 h after hCG injection in the mid-normal range. Recombinant human LH also has become available for clinical use. If after 6–9 months of hCG or recombinant human LH therapy no sperm is detected in the semen, recombinant or highly purified human FSH is added at a dose of 75 U three times weekly. The dose may be increased by 75 U three times weekly every 3 months depending upon the clinical response. Men with postpubertal onset of hypogonadotropic hypogonadism are more likely to respond to hCG alone with reinitiation of spermatogenesis than those with prepubertal onset who are likely to require addition of FSH.

Pulsatile GnRH administration is initiated at an initial dose of 25 ng/kg per pulse administered sc every 2 h by a portable infusion pump (79). Adjust the dose of GnRH until serum testosterone level is in the midnormal range. Doses ranging from 25 to 200 ng/kg may be required to induce virilization (79). After successful induction of secondary sex characteristics, GnRH dose can be reduced. The gonadal function can be maintained in a majority of IHH men by pulsatile GnRH therapy (79).

The best predictors of response to gonadotropin therapy are testicular volume and time of onset of gonadotropin deficiency (pre- or postpubertal) (78, 82, 84). Those with testicular volumes greater than 8 ml reflecting less severe gonadotropin deficiency and postpubertal onset of gonadotropin deficiency are more likely to respond than those with testicular volumes less than 4 ml and prepubertal onset (78, 84). Cryptorchidism is a negative prognostic factor for fertility induction. Prior androgen therapy does not affect outcome.

ICSI for male factor infertility. ICSI has emerged as the treatment of choice for idiopathic male factor infertility (85, 86, 87, 88, 89, 90, 91, 92). In a 2002 ESHRE survey, the clinical pregnancy rates for each aspiration and transfer for ICSI were 27 and 29%, respectively (91); these success rates have been steady for several years (85, 86, 87, 88, 89, 90, 91, 92). The pregnancy rates per transfer are higher if fresh sperm is used instead of cryopreserved sperm, and higher if fresh embryos are used instead of frozen-thawed embryos (85, 86, 87, 88, 89, 90, 91, 92). The fertilization rates are better for ejaculated sperm than for epididymal and testicular spermatozoa (89). The pregnancy rates are similar for obstructive and nonobstructive azoospermia (71, 72, 73, 74). The results of ICSI are affected by the age of the female partner and the quality of the oocyte. The success rates of ICSI are lower in men in whom sperm has been retrieved from the testis by biopsy and in men with necro- or globozoospermia. In men with obstructive azoospermia (86, 87, 88, 89, 90, 91, 92), there is insufficient evidence to recommend any specific sperm retrieval procedure before ICSI (74).

Complications of ICSI. Multiple gestation, with its associated risks of low birth weight and preterm delivery, is the most frequent complication of ICSI (85, 88, 93, 94); the incidence of multiple gestation is 25–35% (86, 88, 95, 96, 97, 98, 99). The risk of obstetric and perinatal complications is higher for pregnancies resulting from ICSI than for naturally conceived pregnancies (85). Chromosomal abnormalities have been reported with higher frequency in offspring of ICSI than controls; there is also a small but significant increase in the frequency of chromosome aneuploidy, especially sex chromosome aneuploidy, among offspring of ICSI (97, 98, 99). The frequency of major congenital malformations is not significantly different between ICSI and IVF (98). When multiplicity is taken into account, the incidence of major or minor malformations is not increased. Even among singleton births resulting from ARTs, the risk of low birth weight, preterm delivery, and adverse perinatal outcomes is increased (85, 95, 97). The developmental outcome of children born after ICSI at 2 and 5 yr is not significantly different from those born after IVF (93, 94, 100). Some reports have suggested increased risk of imprinting disorders, hypospadias, and some types of childhood cancers (101, 102); this issue needs further investigation. Long-term data on the mental and physical well-being of children born through ICSI are not available. Spontaneous pregnancies in infertile women are associated with higher risk for obstetrical complications and perinatal mortality than spontaneous pregnancies in fertile women (85). It is not apparent whether the complications observed in ICSI pregnancies and births are the consequence of the procedure or of parental infertility. Also, pregnancy complications, perinatal outcomes, and congenital malformation rates are not significantly different for IVF and ICSI (17, 86, 103).

Although ICSI is an effective therapy for many couples with male factor infertility, it is expensive and its long-term safety is unclear. ESHRE has established an ICSI Task Force to collect the outcomes data, including the follow-up of children after ICSI.

Treatment options for patients with azoospermia. The prognosis for men with nonobstructive azoospermia and total teratozoospermia has improved with the advent of ICSI (71, 72, 73, 74). There are several reports of successful pregnancies in partners of men with Klinefelter syndrome by ICSI using sperm retrieved from testicular biopsy (104, 105). Success rates for ICSI in azoospermic men using testicular sperm are lower than those in oligozoospermic men using ejaculated sperm (71, 72, 73, 74, 86). Couples undergoing ICSI using testicular sperm should be counseled about the risk of sex chromosome aneuploidy and other genetic disorders in the offspring (41, 54, 55, 106). Also, adoption, artificial insemination using donor sperm, and acceptance of childlessness are realistic options.


   VI. Genetic Testing and Counseling
Top
 Abstract
 I. The Patient
 II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
VII. Guidelines
 References
 
Genetic testing of infertile couples and the offspring is important, especially in couples who are being considered for ICSI.

  1. All infertile men with nonobstructive azoospermia, severe oligozoospermia, or very small testes should be offered a karyotype (Table 2Go) (85, 106).
  2. Screen infertile men with azoospermia or severe oligozoospermia for Yq microdeletions (40, 41).
  3. Azoospermic men with at least one absent vas deferens or with evidence of normal spermatogenesis should be tested for CFTR mutations (Table 2Go) (56).
  4. Consider CREM mutations in men with postmeiotic maturation arrest (57, 58, 59).
  5. Genetic testing is indicated in men in whom personal or family history suggests disorders that have a genetic basis such as hemoglobinopathies and myotonic dystrophy (61, 62, 63); these patients also need genetic counseling.
  6. Prenatal testing, including chorionic villous sampling, may be appropriate in some couples undergoing ICSI and should be offered on an individualized basis.

Infertile couples considering ART should receive genetic counseling from a counselor who has expertise in reproductive disorders. Infertile couples should understand that:

  1. The genetic defects responsible for infertility in the parent may be transmitted to the offspring through ICSI. Y deletions will be transmitted to male offspring (54, 55, 106).
  2. Children born through ICSI have increased risk of sex chromosome aneuploidy (86).
  3. Children born through ICSI to infertile couples may have a higher risk of being infertile or subfertile (41). These children, upon reaching adulthood, may need counseling and surveillance of their reproductive function.


   VII. Guidelines
Top
 Abstract
 I. The Patient
 II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
References
 
Several societies, including the American Urological Association, American Society for Reproductive Medicine, ESHRE, and European Association of Urologists, have published guidelines for the management of infertile men (13, 94, 107, 108, 109, 110). Guidelines for standardized testing for Yq microdeletions, semen analyses, genetic counseling, and prenatal diagnosis have also been published (43, 94). This review has incorporated most of these recommendations.


   Footnotes
 
Abbreviations: AR, Androgen receptor; ART, assisted reproductive technology; AZF, azoospermia factor; CFTR, cystic fibrosis transmembrane conductance regulator; CREM, cAMP response element modulator; hCG, human chorionic gonadotropin; ICSI, intracytoplasmic sperm injection; IHH, idiopathic hypogonadotropic hypogonadism; IVF, in vitro fertilization; MSY, male-specific region of Y chromosome; Yq, long arm of Y chromosome.

Received March 20, 2007.

Accepted April 4, 2007.


   References
Top
 Abstract
 I. The Patient
 II. Case Discussion
 III. Introduction
 IV. Diagnostic Evaluation
 V. Treatment of Infertile...
 VI. Genetic Testing and...
 VII. Guidelines
 References
 

  1. Templeton A 2000 Infertility and the establishment of pregnancy–overview. Br Med Bull 56:577–587[Free Full Text]
  2. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G 2005 Definition and prevalence of subfertility and infertility. Hum Reprod 20:1144–1147[Abstract/Free Full Text]
  3. Bhasin S, de Kretser DM, Baker HW 1994 Clinical review 64: pathophysiology and natural history of male infertility. J Clin Endocrinol Metab 79:1525–1529[CrossRef][Medline]
  4. Templeton AA 1992 The epidemiology of infertility. In: Templeton AA, Drife JO, eds. Infertility. London: Springer-Verlag Telos; 23–32
  5. van der Steeg JW, Steures P, Hompes PG, Eijkemans MJ, van der Veen F, Mol BW 2005 Investigation of the infertile couple: a basic fertility work-up performed within 12 months of trying to conceive generates costs and complications for no particular benefit. Hum Reprod 20:2672–2674[Abstract/Free Full Text]
  6. Snick HK, Snick TS, Evers JL, Collins JA 1997 The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Hum Reprod 12:1582–1588[Abstract/Free Full Text]
  7. World Health Organization 2000 WHO manual for the standardised investigation and diagnosis of infertile couple. Cambridge, UK: Cambridge University Press
  8. Juul S, Karmaus W, Olsen J 1999 Regional differences in waiting time to pregnancy: pregnancy-based surveys from Denmark, France, Germany, Italy and Sweden. The European Infertility and Subfecundity Study Group. Hum Reprod 14:1250–1254[Abstract/Free Full Text]
  9. Jensen TK, Slama R, Ducot B, Suominen J, Cawood EH, Andersen AG, Eustache F, Irvine S, Auger S, Jouannet P, Vierula M, Jorgensen N, Toppari J, Skakkebaek NE, Keiding N, Spira A 2001 Regional differences in waiting time to pregnancy among fertile couples from four European cities. Hum Reprod 16:2697–2704[Abstract/Free Full Text]
  10. Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton RA, Coulson C, Lambert PA, Watt EM, Desai KM 1985 Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 291:1693–1697[Medline]
  11. Crosignani PG, Rubin B 1996 The ESHRE Capri Workshop. Guidelines to the prevalence, diagnosis, treatment, and management of infertility. Hum Reprod 11:1775–1807[Free Full Text]
  12. Habbema JD, Collins J, Leridon H, Evers JL, Lunenfeld B, te Velde ER 2004 Towards less confusing terminology in reproductive medicine: a proposal. Fertil Steril 82:36–40[CrossRef][Medline]
  13. Dohle GR, Colpi GM, Hargreave TB, Papp GK, Jungwirth A, Weidner W 2005 EAU guidelines on male infertility. Eur Urol 48:703–711[CrossRef][Medline]
  14. Wang X, Chen C, Wang L, Chen D, Guang W, French J 2003 Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 79:577–584[CrossRef][Medline]
  15. Gnoth C, Godehardt D, Godehardt E, Frank-Herrmann P, Freundl G 2003 Time to pregnancy: results of the German prospective study and impact on the management of infertility. Hum Reprod 18:1959–1966[Abstract/Free Full Text]
  16. Forti G, Krausz C 1998 Clinical review 100: evaluation and treatment of the infertile couple. J Clin Endocrinol Metab 83:4177–4188[Free Full Text]
  17. Baker HWG 2001 Male infertility. In: DeGroot LG, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: Saunders Company; 3199–3228
  18. Evers JL, Collins JA 2004 Surgery or embolization for varicocele in subfertile men. Cochrane Database Syst Rev CD000479
  19. Ficarra V, Cerruto MA, Liguori G, Mazzoni G, Minucci S, Tracia A, Gentile V 2006 Treatment of varicocele in subfertile men. The Cochrane Review—a contrary opinion. Eur Urol 49:258–263[CrossRef][Medline]
  20. Chandley AC 1979 The chromosomal basis of human infertility. Br Med Bull 35:181–186[Free Full Text]
  21. Mazumdar S, Levine AS 1998 Antisperm antibodies: etiology, pathogenesis, diagnosis, and treatment. Fertil Steril 70:799–810[CrossRef][Medline]
  22. Wang C, Chan SY, Ng M, So WW, Tsoi WL, Lo T, Leung A 1988 Diagnostic value of sperm function tests and routine semen analyses in fertile and infertile men. J Androl 9:384–389[Abstract/Free Full Text]
  23. World Health Organization 1987 Laboratory manual for the examination of human semen and semen-cervical mucus interaction. Cambridge, UK: Cambridge University Press
  24. Bojesen A, Juul S, Gravholt CH 2003 Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 88:622–626[Abstract/Free Full Text]
  25. Skaletsky H, Kuroda-Kawaguchi T, Minx P, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G, Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S, Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen C, Ozersky P, Pepin K, Rock S, Rohlfing T, Scott K, Schultz B, Strong C, Tin-Wollam A, Yang SP, Waterston RH, Wilson RK, Rozen S, Page DC 2003 The male-specific region of the Y chromosome is a mosaic of discrete sequence classes. Nature 423:825–837[CrossRef][Medline]
  26. Hawley RS 2003 The human Y chromosome; the rumors of its death have been greatly exaggerated. Cell 113:825–828[CrossRef][Medline]
  27. Tiepolo L, Zuffardi O 1976 Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet 34:119–124[CrossRef][Medline]
  28. Najmabadi H, Huang V, Yen P, Subbarao MN, Bhasin D, Banaag L, Naseeruddin S, de Kretser DM, Baker HW, McLachlan RI 1996 Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J Clin Endocrinol Metab 81:1347–1352[Abstract]
  29. Reijo R, Alagappan RK, Patrizio P, Page DC 1996 Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet 347:1290–1293[CrossRef][Medline]
  30. Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D, Hovatta O, de la Chapelle A, Silber S, Page DC 1995 Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 10:383–393[CrossRef][Medline]
  31. Kent-First M, Muallem A, Shultz J, Pryor J, Roberts K, Nolten W, Meisner L, Chandley A, Gouchy G, Jorgensen L, Havighurst T, Grosch J 1999 Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection. Mol Reprod Dev 53:27–41[Medline]
  32. Pryor JL, Kent-First M, Muallem A, Van Bergen AH, Nolten WE, Meisner L, Roberts KP 1997 Microdeletions in the Y chromosome of infertile men. N Engl J Med 336:534–539[Abstract/Free Full Text]
  33. Ma K, Sharkey A, Kirsch S, Vogt P, Keil R, Hargreave TB, McBeath S, Chandley AC 1992 Towards the molecular localisation of the AZF locus: mapping of microdeletions in azoospermic men within 14 subintervals of interval 6 of the human Y chromosome. Hum Mol Genet 1:29–33[Abstract/Free Full Text]
  34. Vogt P, Chandley AC, Hargreave TB, Keil R, Ma K, Sharkey A 1992 Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene. Hum Genet 89:491–496[Medline]
  35. Ferlin A, Moro E, Garolla A, Foresta C 1999 Human male infertility and Y chromosome deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum Reprod 14:1710–1716[Abstract/Free Full Text]
  36. Foresta C, Moro E, Ferlin A 2001 Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 22:226–239[Abstract/Free Full Text]
  37. Maurer B, Gromoll J, Simoni M, Nieschlag E 2001 Prevalence of Y chromosome microdeletions in infertile men who consulted a tertiary care medical centre: the Munster experience. Andrologia 33:27–33[CrossRef][Medline]
  38. Simoni M, Gromoll J, Dworniczak B, Rolf C, Abshagen K, Kamischke A, Carani C, Meschede D, Behre HM, Horst J, Nieschlag E 1997 Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil Steril 67:542–547[CrossRef][Medline]
  39. Simoni M, Kamischke A, Nieschlag E 1998 Current status of the molecular diagnosis of Y-chromosomal microdeletions in the work-up of male infertility. Initiative for international quality control. Hum Reprod 13:1764–1768[Free Full Text]
  40. Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, Lenzi A, Foresta C 2007 Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-yr experience in Italy. J Clin Endocrinol Metab 92:762–770[Abstract/Free Full Text]
  41. Cram DS, Osborne E, McLachlan RI 2006 Y chromosome microdeletions: implications for assisted conception. Med J Australia 185:433–434[Medline]
  42. Vogt PH 1998 Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. Mol Hum Reprod 4:739–744[Abstract/Free Full Text]
  43. Simoni M, Bakker E, Krausz C 2004 EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions. State of the art 2004. Int J Androl 27:240–249[CrossRef][Medline]
  44. Ma K, Inglis JD, Sharkey A, Bickmore WA, Hill RE, Prosser EJ, Speed RM, Thomson EJ, Jobling M, Taylor K, Wolfe J, Cooke HJ, Hargreave TB, Chandley AC 1993 A Y chromosome gene family with RNA-binding protein homology: candidates for the azoospermia factor AZF controlling human spermatogenesis. Cell 75:1287–1295[CrossRef][Medline]
  45. Najmabadi H, Chai N, Kapali A, Subbarao MN, Bhasin D, Woodhouse E, Yen P, Bhasin S 1996 Genomic structure of a Y-specific ribonucleic acid binding motif-containing gene: a putative candidate for a subset of male infertility. J Clin Endocrinol Metab 81:2159–2164[Abstract]
  46. Saxena R, Brown LG, Hawkins T, Alagappan RK, Skaletsky H, Reeve MP, Reijo R, Rozen S, Dinulos MB, Disteche CM, Page DC 1996 The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned. Nat Genet 14:292–299[CrossRef][Medline]
  47. Eberhart MC, Maines JZ, Wasserman SA 1996 Meiotic cell cycle requirement for a fly homologue of human DAZ. Nature 381:783–785[CrossRef][Medline]
  48. Cooke H, Lee M, Kerr S, Ruggiu M 1996 A murine homologue of the human DAZ gene is autosomal and expressed in male and female gonads. Hum Mol Genet 5:513–516[Abstract/Free Full Text]
  49. Ruggiu M, Speed R, Taggart M, McKay SJ, Kilanowski F, Saunders P, Dorin J, Cooke HJ 1997 The mouse Dazla gene encodes a cytoplasmic protein essential for gametogenesis. Nature 389:73–77[CrossRef][Medline]
  50. Tsui S, Dai T, Roettger S, Schempp W, Salido EC, Yen PH 2000 Identification of two novel proteins that interact with germ-cell-specific RNA-binding proteins DAZ and DAZL1. Genomics 65:266–273[CrossRef][Medline]
  51. Sargent CA, Boucher CA, Kirsch S, Brown G, Weiss B, Trundley A, Burgoyne P, Saut N, Durand C, Levy N, Terriou P, Hargreave T, Cooke H, Mitchell M, Rappold GA, Affara NA 1999 The critical region of overlap defining the AZFa male infertility interval of proximal Yq contains three transcribed sequences. J Med Genet 36:670–677[Abstract/Free Full Text]
  52. Foresta C, Ferlin A, Moro E 2000 Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum Mol Genet 9:1161–1169[Abstract/Free Full Text]
  53. Yen PH, Chai NN, Salido EC 1996 The human autosomal gene DAZLA: testis specificity and a candidate for male infertility. Hum Mol Genet 5:2013–2017[Abstract/Free Full Text]
  54. Cram DS, Ma K, Bhasin S, Arias J, Pandjaitan M, Chu B, Audrins MS, Saunders D, Quinn F, de Kretser D, McLachlan R 2000 Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions. Fertil Steril 74:909–915[CrossRef][Medline]
  55. Page DC, Silber S, Brown LG 1999 Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 14:1722–1726[Abstract/Free Full Text]
  56. Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher TA, White MB, Milunsky A 1992 Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA 267:1794–1797[Abstract]
  57. Weinbauer GF, Behr R, Bergmann M, Nieschlag E 1998 Testicular cAMP responsive element modulator (CREM) protein is expressed in round spermatids but is absent or reduced in men with round spermatid maturation arrest. Mol Hum Reprod 4:9–15[Abstract/Free Full Text]
  58. Peri A, Krausz C, Cioppi F, Granchi S, Forti G, Francavilla S, Serio M 1998 Cyclic adenosine 3',5'-monophosphate-responsive element modulator gene expression in germ cells of normo- and oligoazoospermic men. J Clin Endocrinol Metab 83:3722–3726[Abstract/Free Full Text]
  59. Blendy JA, Kaestner KH, Weinbauer GF, Nieschlag E, Schutz G 1996 Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature 380:162–165[CrossRef][Medline]
  60. Abbasi AA, Prasad AS, Ortega J, Congco E, Oberleas D 1976 Gonadal function abnormalities in sickle cell anemia. Studies in adult male patients. Ann Intern Med 85:601–605[Medline]
  61. Kletzky OA, Costin G, Marrs RP, Bernstein G, March CM, Mishell Jr DR 1979 Gonadotropin insufficiency in patients with thalassemia major. J Clin Endocrinol Metab 48:901–905[Abstract]
  62. Marchini C, Lonigro R, Verriello L, Pellizzari L, Bergonzi P, Damante G 2000 Correlations between individual clinical manifestations and CTG repeat amplification in myotonic dystrophy. Clin Genet 57:74–82[CrossRef][Medline]
  63. Takeda R, Ueda M 1977 Pituitary-gonadal function in male patients with myotonic dystrophy-serum luteinizing hormone, follicle stimulating hormone and testosterone levels and histological damage of the testis. Acta Endocrinol (Copenh) 84:382–389[Medline]
  64. Hiort O, Holterhus PM, Horter T, Schulze W, Kremke B, Bals-Pratsch M, Sinnecker GH, Kruse K 2000 Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab 85:2810–2815[Abstract/Free Full Text]
  65. Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, Foresta C 2006 Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf) 65:606–610[CrossRef][Medline]
  66. Lim HN, Chen H, McBride S, Dunning AM, Nixon RM, Hughes IA, Hawkins JR 2000 Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet 9:829–834[Abstract/Free Full Text]
  67. Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL 1997 Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab 82:3777–3782[Abstract/Free Full Text]
  68. Dadze S, Wieland C, Jakubiczka S, Funke K, Schroder E, Royer-Pokora B, Willers R, Wieacker PF 2000 The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin. Mol Hum Reprod 6:207–214[Abstract/Free Full Text]
  69. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno Jr JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley Jr WF, Aparicio SA, Colledge WH 2003 The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1627[Abstract/Free Full Text]
  70. Karges B, de Roux N 2005 Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocr Dev 8:67–80[Medline]
  71. Friedl S, Raziel A, Strassburger D, Schaster M, Soffer Y, Ron-El R 2002 Factors influencing the outcome of ICSI in patients with obstructive and nonobstructive azoospermia: a comparative study. Hum Reprod 17:3114–3121[Abstract/Free Full Text]
  72. Vernaeve V, Tournaye H, Osmanagaoglu K, Verheyen G, Van Steirteghem A, Deveroey P 2003 Intracytoplasmic sperm injection with testicular spermatozoa is less successful in men with nonobstructive azoospermia than in men with obstructive azoospermia. Fertil Steril 79:529–533[CrossRef][Medline]
  73. Monzo A, Kondylis F, Lynch D, Mayer J, Jones E, Nehchiri F, Morshedi M, Schuffner A, Muasher S, Gibbons W, Oehninger S 2001 Outcome of intracytoplasmic sperm injection in azoospermic patients: stressing the liaison between the urologist and reproductive medicine specialist. Urology 58:69–75[CrossRef][Medline]
  74. Van Peperstraten A, Proctor ML, Johnson NP, Philipson G 2006 Techniques for surgical retrieval of sperm prior to ICSI for azoospermia. Cochrane Database Syst Rev 3:CD002807
  75. Andersson AM, Jorgensen N, Frydelund-Larsen L, Rajpert-De Meyts E, Skakkebaek NE 2004 Impaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls. J Clin Endocrinol Metab 89:3158–3160[Free Full Text]
  76. Raman JD, Nobert CF, Goldstein M 2005 Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol 174:1819–1822[CrossRef][Medline]
  77. Kaleva M, Toppari J 2005 Cryptorchidism: an indicator of testicular dysgenesis? Cell Tissue Res 322:167–172[CrossRef][Medline]
  78. Liu L, Banks SM, Barnes KM, Sherins RJ 1988 Two-yr comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 67:1140–1145[Abstract]
  79. Spratt DI, Finkelstein JS, O’Dea LS, Badger TM, Rao PN, Campbell JD, Crowley Jr WF 1986 Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of the hormone’s physiologic effects. Ann Intern Med 105:848–855[Medline]
  80. Buchter D, Behre HM, Kliesch S, Nieschlag E 1998 Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol 139:298–303[Abstract]
  81. Kliesch S, Behre HM, Nieschlag E 1994 High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol 131:347–354[Abstract]
  82. Finkel DM, Phillips JL, Snyder PJ 1985 Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 313:651–655[Abstract]
  83. Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E 2002 Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone. Eur J Endocrinol 147:617–624[Abstract]
  84. Liu PY, Gebski VJ, Turner L, Conway AJ, Wishart SM, Handelsman DJ 2002 Predicting pregnancy and spermatogenesis by survival analysis during gonadotropin treatment of gonadotrophin-deficient infertile men. Hum Reprod 17:625–633[Abstract/Free Full Text]
  85. Allen VM, Wilson RD, Cheung A 2006 Pregnancy outcomes after assisted reproductive technology. J Obstet Gynecol Can 28:220–250
  86. Palermo GD, Schlegel PN, Hariprashad JJ, Ergun B, Mielnik A, Zaninovic N, Veeck LL, Rosenwaks Z 1999 Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Hum Reprod 14:741–748[Abstract/Free Full Text]
  87. Bonduelle M, Camus M, De Vos A, Staessen C, Tournaye H, Van Assche E, Verheyen G, Devroey P, Liebaers I, Van Steirteghem A 1999 Seven yrs of intracytoplasmic sperm injection and follow-up of 1987 subsequent children. Hum Reprod 14(Suppl 1):243–264
  88. Wright VC, Schieve LA, Reynolds MA, Jeng G, Kissin D 2004 Assisted reproductive technology surveillance–United States, 2001. MMWR Surveill Summ 53:1–20[Medline]
  89. Tarlatzis BC, Bili H 2000 Intracytoplasmic sperm injection. Survey of world results. Ann NY Acad Sci 900:336–344[Abstract/Free Full Text]
  90. Nyboe Andersen A, Erb K 2006 Register data on Assisted Reproductive Technology (ART) in Europe including a detailed description of ART in Denmark. Int J Androl 29:12–16[CrossRef][Medline]
  91. Andersen AN, Gianaroli L, Felberbaum R, de Mouzon J, Nygren KG 2006 Assisted reproductive technology in Europe, 2002. Results generated from European registers by ESHRE. Hum Reprod 21:1680–1697[Abstract/Free Full Text]
  92. Nygren KG, Andersen AN 2002 Assisted reproductive technology in Europe, 1999. Results generated from European registers by ESHRE. Hum Reprod 17:3260–3274[Abstract/Free Full Text]
  93. Ponjaert-Kristoffersen I, Bonduelle M, Barnes J, Nekkebroeck J, Loft A, Wennerholm UB, Tarlatzis BC, Peters C, Hagberg BS, Berner A, Sutcliffe AG 2005 International collaborative study of intracytoplasmic sperm injection-conceived, in vitro fertilization-conceived, and naturally conceived 5-yr-old child outcomes: cognitive and motor assessments. Pediatrics 115:e283–e289
  94. Boivin J, Appleton TC, Baetens P, Baron J, Bitzer J, Corrigan E, Daniels KR, Darwish J, Guerra-Diaz D, Hammar M, McWhinnie A, Strauss B, Thorn P, Wischmann T, Kentenich H 2001 European Society of Human Reproduction and Embryology. Guidelines for counselling in infertility: outline version. Hum Reprod 16:1301–1304[Abstract/Free Full Text]
  95. Schieve LA, Ferre C, Peterson HB, Macaluso M, Reynolds MA, Wright VC 2004 Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States. Obstet Gynecol 103:1144–1153[Abstract/Free Full Text]
  96. Van Steirteghem A, Bonduelle M, Devroey P, Liebaers I 2002 Follow-up of children born after ICSI. Hum Reprod Update 8:111–116[Abstract/Free Full Text]