Serum FSH and testicular morphology in male infertility

OBJECTIVE In patients with azoospermia serum FSH helps to differentiate between obstruction or spermatogenetic dysfunction as the possible cause of this condition. The role of FSH in the diagnosis of infertile men with oligoasthenoteratozoospermia is less clearly defined. In order to evaluate the diagnostic significance of serum FSH in the management of male infertility, serum FSH levels were related to testicular morphology from bilateral biopsies of infertile men. DESIGN AND PATIENTS Testicular biopsies were obtained from 213 infertile men and evaluated in semi-thin sections. Biopsies were performed either in order to distinguish between obstructive and non-obstructive azoospermia or because of subnormal semen variables when history, clinical investigation and hormone levels failed to explain infertility. Serum FSH was measured by fluoroimmunoassay. RESULTS Patients were divided into five groups on the basis of morphological criteria. The mean serum FSH value of patients with obstructive azoospermia and normal histology (group 1, n= 14) was normal (3.0 (2.2–4.1) IU/I) (mean (95% confidence limits)). Serum levels of FSH in non-obstructive oligo or azoospermia were as follows: group 2: mixed atrophy of tubular tissue without focal Sertoli cell only syndrome (SCO) (n= 104) (4.5 (4.0–5.1) IU/I), group 3: mixed atrophy with unilateral focal Sertoli cell only (n= 39) (7.4 (6.1–90) IU/I), group 4: mixed atrophy with bilateral focal SCO (n= 36) (107 (8.7–13.0) IU/I). Group 5: bilateral or unilateral total Sertoli cell only (n= 20) (16 0 (12 1–20 9) IU/I). Mean serum FSH levels were significantly different between all groups (P<0.05). CONCLUSIONS Elevation of serum FSH correlates with the appearance of Sertoli cell only tubules. Elevated FSH serum levels make testicular biopsies superfluous for diagnostic purposes, but normal FSH does not exclude severe derangement of spermatogenesis in individual cases.     

Mitochondria-related male infertility

Approximately 15% of human couples are affected by infertility, and about half of these cases of infertility can be attributed to men, through low sperm motility (asthenozoospermia) or/and numbers (oligospermia). Because mitochondrial genome (mtDNA) mutations are identified in patients with fertility problems, there is a possibility that mitochondrial respiration defects contribute to male infertility. To address this possibility, we used a transmitochondrial mouse model (mito-mice) carrying wild-type mtDNA and mutant mtDNA with a pathogenic 4,696-bp deletion (DeltamtDNA). Here we show that mitochondrial respiration defects caused by the accumulation of DeltamtDNA induced oligospermia and asthenozoospermia in the mito-mice. Most sperm from the infertile mito-mice had abnormalities in the middle piece and nucleus. Testes of the infertile mito-mice showed meiotic arrest at the zygotene stage as well as enhanced apoptosis. Thus, our in vivo study using mito-mice directly demonstrates that normal mitochondrial respiration is required for mammalian spermatogenesis, and its defects resulting from accumulated mutant mtDNAs cause male infertility.     

Growth hormone in male infertility

Growth hormone (GH) is expressed in a variety of tissues, including the testes, and has autocrine and paracrine functions as well. This, along with other factors, exerts autocrine and paracrine control over spermatogenesis. GH, used as an adjuvant therapy, induces spermatogenesis in non-responder patients with hypogonadotropic hypogonadism, who are not responding to gonadotropin or pulsatile luteinizing hormone (LH) therapy. GH has an important physiological role to play in spermatogenesis and male fertility.     

Pyospermia and male infertility

Pyospermia is found on the semen analysis of up to 23% of men who are being investigated for infertility. The presence of significant numbers of white blood cells in the semen is correlated with poorer sperm parameters and diminished fertility. It is not known if these changes in sperm function are due to the white blood cells or to an underlying problem that may cause both pyospermia and altered sperm function. It is often assumed that pyospermia is an indication of an underlying genitourinary infection. However, studies have not shown an association between bacteria growing in reproductive tract fluids (semen, urine and expressed prostatic secretions) and pyospermia. Despite this, treating these patients with different antibiotics regimens appears to reduce temporarily the white blood cell count in the semen and improve the fertility rates. Well-controlled studies are needed to determine the role of antibiotics in the treatment of this significant cause of male infertility.     

Genetic causes of male infertility

Male infertility, affecting around half of the couples with a problem to get pregnant, is a very heterogeneous condition. Part of patients are having a defect in spermatogenesis of which the underlying causes (including genetic ones) remain largely unknown. The only genetic tests routinely used in the diagnosis of male infertility are the analyses for the presence of Yq microdeletions and/or chromosomal abnormalities. Various other single gene or polygenic defects have been proposed to be involved in male fertility. Yet, their causative effect often remains to be proven. The recent evolution in the development of whole genome-based techniques may help in clarifying the role of genes and other genetic factors involved in spermatogenesis and spermatogenesis defects.     

Management of male infertility.

The causes of infertility are known in a small proportion of patients, and only a few are treatable: gonadotrophin deficiency, genital tract obstruction, sperm autoimmunity, coital dysfunction and reversible effects of toxins, drugs or intercurrent illnesses. Other patients have reduced sperm quality or function that may be associated with previous testicular damage, varicocele or non-specific genital tract inflammation. No treatments have been proved to increase semen quality and fertility in this group; intracytoplasmic sperm injection is the most appropriate management if a natural pregnancy is unlikely to occur. Apart from the transmission of genetic and chromosomal disorders and a small increase in the number of sex chromosomal aneuploidies associated with severe spermatogenic defects, the risk of serious adverse effects in intracytoplasmic sperm injection offspring is low. The pathogenetic mechanisms of the most common forms of defective sperm production are unknown, which prevents the logical development of effective treatment.     

Chromosomal alterations and male infertility

Reduced male fertility can be caused by genetic factors affecting gamete formation or function; in particular, chromosome abnormalities are a possible cause of male subfertility as shown by their higher frequency in infertile men than in the general male population. Meiotic studies in a number of these males have shown spermatogenesis breakdown, often related to alterations in the process of chromosome synapsis. Indeed, any condition that can interfere with X-Y bivalent formation and X-chromosome inactivation is critical to the meiotic process; furthermore, asynapsed regions may themselves represent a signal for the meiotic checkpoint that eliminates spermatocytes with synaptic errors. We performed cytogenetic, hormonal and seminal studies in 333 infertile patients selected because azoospermic, severely oligozoospermic or normozoospermic with failure to fertilize the partner's oocytes in an in vitro fertilization (IVF) program. Our findings: 1) confirm the high incidence of chromosomal anomalies among infertile males; 2) highlight the relevance in male infertility of quantitative/positional modifications of the constitutive heterochromatin; and 3) underline the relevance of cooperation between andrologists and cytogenetists prior to every kind of assisted reproduction, above all prior to intracytoplasmic sperm injection, in which selective hurdles eliminating abnormal germ cells are bypassed.     

Cancer and male infertility.

An increasing proportion of boys and young men with cancer will survive their disease and desire fertility. Unfortunately, the cancer treatment, and in some cases the malignant disease itself, may have a negative and permanent impact on the individual's fertility potential. This effect is highly dependent on the type and dose of therapy as well as the age at which it has been given. Basic knowledge in this field is necessary to enable oncologists and fertility specialists to counsel these patients about their fertility prospects and, if appropriate, advise them to take precautions (e.g. the cryopreservation of semen) to safeguard their fertility. Another aspect of the relationship between cancer and infertility is the possibility that men with testicular dysfunction may have an increased risk of testicular cancer. Screening for early testicular malignancy may therefore be advisable in some groups of men with poor semen quality.     

Incidence of sulphasalazine-induced male infertility.

Sperm analysis of 21 patients taking sulphasalazine for inflammatory bowel disease revealed that 86% had abnormal semen analysis and 72% had oligospermia.     

Hormonal regulation of pituitary FSH sialylation in male rats

Sialic acid content in FSH is modulated by GnRH and sexual steroids. Galβ1,3GlcNAcα2,3-sialyltransferase (ST3Gal III) and Galβ1,4GlcNAcα2,6-sialyltransferase (ST6Gal I) incorporate sialic acid residues into FSH oligosaccharides. The aim of the present study was to assess pituitary FSH molecular microheterogeneity and ST3Gal III/ST6Gal I expression during sexual development and after castration in male rats. Preparative isoelectric focusing and lectin chromatography were used to isolate FSH glycosylation variants according to charge and complexity of their oligosaccharides; RT-PCR and immunohistochemistry were employed to analyse sialyltransferase expression. Sexual development was associated with a progressive shift towards more acidic/sialylated FSH glycoforms concomitantly with an increment in ST6Gal I gene and protein expression. After castration, a transient decrease followed by a marked increase in ST6Gal I expression were observed. Less acidic/sialylated FSH glycoforms bearing incomplete oligosaccharides increased after castration, despite high ST6Gal I expression. ST3Gal III expression remained unchanged in all the experimental conditions examined. These results show that the synthesis of FSH isoforms possessing α2,6-linked sialic acid is hormonally regulated in male rats.     

Mesalazine-induced reversible infertility in a young male

Mesalazine is a well-established treatment for ulcerative colitis. A young man treated with mesalazine for proctitis was found to have pathological semen with a count of only 3 x 10(6) sperm cells/ml. He failed to achieve conception with his wife. When mesalazine treatment was stopped, semen analysis returned to near normal and pregnancy ensued. Due to recurrent disease activity, mesalazine treatment was reinstituted. This was followed by deterioration of the patient's semen.     

Questionnaire survey of male infertility in cystic fibrosis

Most male cystic fibrosis (CF) patients are infertile due to obstructive azospermia but little is known about the best time to counsel patients on infertility. All male patients attending the Adult Nottingham CF unit were invited to complete an anonymous questionnaire on infertility. The response rate was 60%. The median age that the patients first became aware of male infertility was 17 years (range 13-24) but the preferred age of receiving this information was 14 years (range 8-16). Patients first learnt about male infertility from the CF team (six patients), parents (five), from written information (two) or unexpectedly (five). Five out of 18 patients had undergone seminal analysis at a median age of 26 years but 17/18 patients felt that this should be offered routinely. Our survey has shown that patients would like infertility discussions at a younger age and routine seminal analysis.     

FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility

OBJECTIVE: To evaluate the ability of a prediction model to identify the individual starting dose of FSH for ovulation induction using a step-down regimen. DESIGN: Retrospective analysis of clinical data in an academic fertility unit. Fifty-six normogonadotropic anovulatory infertile patients who failed to ovulate or conceive with clomiphene citrate were included. They were treated with exogenous gonadotropins with a flexible starting dose for ovulation induction using a step-down regimen. The clinically applied starting dose of exogenous gonadotropins was compared with the calculated response-dose using a previously published prediction model. RESULTS: Patients were arbitrarily divided into three groups according to the day of the first decrease in gonadotropin dose: (a) early step-down (day 3 or earlier); (b) standard step-down (day 4 or later); (c) no step-down. These groups had average starting doses of 28.5 IU (group a) and 13 IU (group b) above the calculated response-dose, and 43 IU (group c) under the calculated response-dose. A significant correlation between day of first step-down and the difference between clinically applied and calculated response-dose was observed (P<0.0001, F-test for ANOVA). CONCLUSIONS: The patient group with the best step-down profile for ovulation induction exhibited the closest match between the clinically applied and calculated starting dose of gonadotropins. Therefore, this study provides support for the concept that the individual effective FSH starting dose for gonadotropin induction of ovulation in anovulatory infertile patients can be predicted on the basis of initial screening characteristics, such as body mass index, clomiphene resistance or failure, free IGF-I and FSH. This may result in more effective patient treatment protocols, reduced complication rates and health-economic benefits.