Testicular sperm retrieval by percutaneous fine needle sperm aspiration compared with testicular sperm extraction by open biopsy in men with non-obstructive azoospermia

The efficiency of testicular sperm retrieval by testicular fine needle aspiration (TEFNA) was compared with open biopsy and testicular sperm extraction (TESE), in 37 rigorously selected patients with non-obstructive azoospermia. All patients underwent TEFNA and TESE consecutively. Thus, each patient served as his own control. The case was regarded as successful if at least one testicular spermatozoon was found allowing intracytoplasmic sperm injection (ICSI) of at least one oocyte. The mean age of the male patients was 32.7 years (range 24-47). Whereas by TEFNA spermatozoa enabling performance of ICSI were found in only four patients out of 37 (11%), open biopsy and TESE yielded spermatozoa in 16 cases (43%). The negative predictive value of high serum follicle stimulating hormone (FSH) concentrations (> or =10 IU/l) (predicting failure to find spermatozoa for ICSI) was low (38.4%). The positive predictive value (predicting the chance to find spermatozoa for ICSI) of normal-sized testicle was not different from that of small-sized (<15 ml) testicle (50%). Complications included one case of testicular bleeding following fine needle aspiration, treated locally, and two cases of extratunical haematomata following TESE requiring no intervention. In patients with non-obstructive azoospermia, TEFNA has a significantly lower yield compared to TESE. Performance of ICSI with testicular sperm in these cases resulted in satisfactory fertilization and high embryo transfer rates. The implantation and pregnancy rates per embryo transfer were 13 and 29% respectively. Neither serum FSH values nor testicular size were predictive of the chances to find spermatozoa for ICSI. Some complications may occur even following TEFNA.     

Initial experience with the MESA and TESE techniques in the treatment of infertile men with azoospermia

The authors evaluate their initial experience and results of the technique of microsurgical aspiration of epididymal sperm (MESA) and extraction of testicular sperm (TESE) combined with intracytoplasmic sperm injection into the oocyte (ICSI) in men with azoospermia. The above methods were used in 16 patients with repeatedly assessed azoospermia. Epididymal sperm was obtained in six instances, testicular sperm in 10 instances. With epididymal sperm after ICSI 50% fertilization was achieved after ICSI, with testicular sperm 51% fertilization of oocytes.     

Neuropilin is a semaphorin III receptor

Testicular biopsy has been widely used for the diagnosis of male infertility. Since the introduction of intracytoplasmic sperm injection (ICSI), sperm recovered from a testicular biopsy specimen can be successfully used for establishing pregnancies. Testicular spermatozoa may be recovered from testicular tissue in patients with excretory azoospermia but also in many patients with secretory azoospermia. In the latter patients spermatozoa may be recovered only after multiple excisional testicular biopsies, irrespective of follicle-stimulating hormone level, testicular size or medical history. Less invasive techniques such as percutaneous fine-needle aspiration have been introduced and may yield comparable success rates in patients with normal testicular function. The use of cryopreserved testicular spermatozoa may become an alternative to repeated surgery for obtaining testicular tissue for subsequent ICSI treatment cycles if larger series confirm the preliminary case reports. The introduction of the use of testicular spermatozoa for ICSI has raised new concerns because potentially genetically immature germ cells are being used from patients who may carry genetic defects causing their infertility problems.     

Genetic concerns for the subfertile male in the era of ICSI

The treatment of severe male factor infertility has seen remarkable advances in the last five years with the introduction and widespread use of intracytoplasmic sperm injection (ICSI). Although ICSI represents one of the most important advances in the treatment of the subfertile male, significant concerns exist regarding the potential for transmission of abnormal genes to the offspring because many of the natural barriers to conception have been bypassed. Because these couples were not able to conceive prior to ICSI, the long-term genetic consequences in these offspring are largely undefined at this time. Genetic abnormalities related to male infertility need to be considered in terms of being (1) causative for male infertility and (2) potentially transmissible to the offspring. Reasons for pursuing a genetic evaluation include (1) establishing a diagnosis, (2) establishing a possible genetic origin, (3) clarifying the pattern of inheritance, and (4) providing information on natural history, variation and expression. The three most common known genetic factors related to male infertility are cystic fibrosis gene mutations leading to congenital absence of the vas deferens, Y-chromosome microdeletions leading to spermatogenic impairment, and karyotype abnormalities. When congenital bilateral absence of the vas deferens with azoospermia is encountered, cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are commonly the underlying cause. When testicular failure is manifest by azoospermia or severe oligoszoospermia, Y-chromosome microdeletions may be present in approximately 10-15 per cent of otherwise normal appearing men. Karyotyping can uncover potentially transmissible genetic abnormalities in the infertile male including structural chromosomal disorders such as Klinefelter's (classic 47,XXY), mixed gonadal dysgenesis, chromosomal translocations and XYY syndromes. Finally, potential male infertility genes in animal models are reviewed. Without question, advances in clinical and basic research raise scientific and social issues that must be addressed.     

Testicular needle biopsy, open biopsy, epididymal aspiration and intracytoplasmic sperm injection in obstructive azoospermia

Testicular or epididymal spermatozoa were obtained for in-vitro fertilization and intracytoplasmic sperm injection (ICSI) in 27 cycles out of 33 (in six men the azoospermia proved to have testicular causes). Testicular needle biopsy carried out in addition to surgical open biopsy proved to be an effective method to obtain spermatozoa for ICSI from patients with obstructive azoospermia. Thus it might be possible to replace scrotal operations by simple needle biopsies. Embryos resulting from ICSI with testicular spermatozoa were used in 19 transfers that resulted in six pregnancies. One pregnancy resulted from six embryo transfers from ICSI after microsurgical-epididymal sperm aspiration (MESA). The normal fertilization rates with testicular (37.3%) and MESA spermatozoa (53.7%) did not differ significantly from each other, but with testicular spermatozoa the rate was significantly lower than that obtained with ejaculated spermatozoa and ICSI (59.7%) in the matched couples. The abnormal fertilization of oocytes with one pronucleus was significantly higher with testicular spermatozoa than with ejaculated spermatozoa in the control couples.     

Inhibin B in men with normal and disturbed spermatogenesis

Inhibin, a dimeric gonadal glycoprotein, inhibits the production and/or secretion of follicle stimulating hormone (FSH). The major species currently recognized are inhibin A (alphabeta A subunit) and inhibin B (alphabeta B subunit). In men, inhibin B seems to be the physiologically important form of inhibin. Therefore we measured serum inhibin B using a new two-site immunoenzymatic assay in 14 men (mean +/- SEM age, 34.5 +/- 0.7 years) with sperm counts >20 x 10(6)/ ml, in 35 men (mean +/- SEM age, 36.4 +/- 1.3 years) with oligozoospermia (sperm count <20 x 10(6)/ml) and in men with azoospermia (three orchidectomized men, three men with Klinefelter's syndrome, 10 men with Kallmann's syndrome). We compared inhibin B concentrations with serum FSH and sperm concentrations. In men with normal sperm concentrations (44.7 +/- 6.4 x 10(6)/ml), the concentration of inhibin was 223 +/- 18 pg/ml and of FSH 5.0 +/- 0.7 IU/l; in patients with low sperm concentrations (3.7 +/- 0.8 x 10(6)/ml), the concentration of inhibin B was 107 +/- 12 pg/ml and of FSH 12.2 +/- 1.5 IU/l. In all patients, except those with hypogonadotrophic hypogonadism, the relationship between inhibin B and FSH concentrations was inverse (r = -0.69, P < 0.0001). In all patients the sperm concentration was positively correlated with inhibin B concentrations (r = 0.70, P < 0.0001) and negatively correlated with FSH concentrations (r = -0.37, P < 0.01). We conclude that inhibin B may be a marker of exocrine testicular function and could offer improved diagnosis and treatment modalities for male infertility.     

An interview with Sue Hall Esleck. Interview by Connie R. Curran

The present report covers the results of a 38-month period in which 2853 consecutive intracytoplasmic sperm injection (ICSI) cycles were performed in 1953 couples. These couples were afflicted with male factor infertility and had at least one previous failed conventional in vitro fertilization (IVF) treatment cycle. In other couples, the husband had semen parameters incompatible with conventional IVF or suffered from excretory or secretory azoospermia where it was possible to recover spermatozoa by microsurgical epididymal sperm aspiration (mesa) or by testicular sperm extraction (tese) procedure. Overall, the 2-PN fertilization rate was 62% per retrieved metaphase II oocyte and 70% per successfully injected metaphase II oocyte. Embryo transfer was performed in 91% of started cycles. The cumulative pregnancy rate (positive HCG) was 34% per started ICSI treatment and 37% per embryo transfer.     

Multiple testicular sampling in non-obstructive azoospermia--is it necessary?

Spermatogenesis may be focal in non-obstructive azoospermia. The present study was conducted to determine whether the performance of multiple, rather than a single testicular sample contributes to obtaining spermatozoa in amounts sufficient for fertilization and cryopreservation in non-obstructive, azoospermic patients. Furthermore, the aim was to clarify the significance of location for retrieval from the testis in such cases. Three biopsies were taken from identical locations in 55 testes of 29 men with non-obstructive azoospermia: (i) the rete testis region, ii) the midline, and (iii) the proximal region of the testis. When sperm cells were detected, they were used for intracytoplasmic sperm injection (ICSI), and the remainder were then cryopreserved in as many aliquots as possible (adjusted for ICSI procedure). Spermatozoa were found in 28 testes (50.9%) of 18 men (62.1%). In the testes from which spermatozoa were obtained, they were present in three, two or one locations in 15 (53.6%), five (17.9%) and eight (28.6%) cases respectively. The possibility of finding spermatozoa was not influenced by the location in the testis. Multiple testicular sperm extraction is recommended in cases of non-obstructive azoospermia, since it may enhance diagnostic accuracy of absolute testicular failure and increase the number of sperm cells retrieved.     

Indications and results of the cryopreservation of testicular sperm. The CECOS experience. CECOS French Federation

A survey of indications and results of cryopreserved testicular spermatozoa has been performed by French Federation of CECOS from 1 January 96 to 31 December 97. 340 sperm cryopreservations (264 with testicular sperm) has been performed: 252 in excretory azoospermia, 88 in non obstructive azoospermia. 30 cycles of ICSI was performed with frozen-thawed spermatozoa with 6 clinical pregnancies (20%).     

Management of testicular biopsies in secretory azoospermias

Management of testicular biopsies in non-obstructive azoospermia is unclear: there is non-factors that are predictive of eventual sperm presence or absence and there is no consensus neither for open testicular biopsy versus percutaneous testis biopsy nor for fresh testicular sperm extract ion and synchronous ICSI versus frozen samples for a later sample.     

The effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection

Factors other than spermatozoa could be the major determinant of the success of assisted reproduction treatment in cases of male infertility. Our aim was to evaluate the effect of the wife's age and ovarian reserve on assisted reproduction success rates in the most severe type of male infertility, i.e. azoospermia. A total of 249 consecutive couples suffering from male infertility caused by azoospermia underwent microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI). Of these men, 186 had irreparable obstructive azoospermia, and 63 had non-obstructive azoospermia due to testicular failure. Neither the pathology, the source, the quantity, nor the quality of spermatozoa had any effect on fertilization or pregnancy rates. Maternal age and ovarian reserve (number of eggs) had no effect on fertilization or embryo cleavage, but did dramatically affect the embryo implantation, pregnancy and delivery rates. Wives of azoospermic men who were in their 20s had a 46% live delivery rate per cycle, wives aged 30-36 years had a 34% live delivery rate per cycle, wives aged 37-39 years had a 13% live delivery rate per cycle, and wives > or = 40 years had only a 4% live delivery rate per cycle. The number of eggs retrieved also affected pregnancy and delivery rate, but to a lesser extent than age. In virtually all cases of obstructive azoospermia, and in 62% of cases with non-obstructive azoospermia caused by germinal failure, sufficient spermatozoa could be retrieved to perform ICSI, with normal fertilization and embryo cleavage. However, the pregnancy rate and the live delivery rate were dependent strictly on the age of the wife, and on her ovarian reserve. Unfortunately, exaggerated claims of high pregnancy rates can thus easily be made by manipulating, in a very simple way, selection for female factors.     

Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection

Some men with non-obstructive azoospermia harbour fully formed spermatozoa within their testicular tissue that can be used to achieve pregnancy via intracytoplasmic sperm injection (ICSI). Recently, Reijo et al. (1995) provided compelling evidence that the DAZ gene cluster is a strong candidate for one of the elusive azoospermia factors (AZF) located on the long arm of the Y chromosome. The DAZ gene cluster is deleted in 13% of azoospermic men and a small percentage of severely oligozoospermic men. Vertical transmission from father to son of AZF region deletions has also been described. Presumably these fathers were oligozoospermic. This led us to ask whether the azoospermic male with deletions of the AZF/DAZ region can also complete minimal spermatogenesis and whether any spermatozoa found could participate in fertilization, embryo development and pregnancy. Three out of six (50%) of the azoospermic men with AZF/DAZ deletions had spermatozoa identified within their harvested testicular tissue. When these spermatozoa were used for ICSI, fertilization occurred in 36% of injected oocytes. This compared favourably with testicular spermatozoa retrieved from non-obstructive azoospermic men without AZF/DAZ gene deletions. In one case, a twin conception resulted, which represents the first term pregnancy reported using spermatozoa from an AZF/DAZ deleted azoospermic male. Therefore it is necessary to take the possibility of transmission of infertility or sterility to our patients' offspring seriously when utilizing today's reproductive technologies, as spermatogenesis in men with AZF/DAZ deletions is by no means an exceptional occurrence.     

Do men undergoing sterilizing cancer treatments have a fertile future?

This study was designed to assess the effect of cancer treatments on the natural and assisted reproductive potential of men. A cohort of men with cancer, in whom radiotherapy and/or chemotherapy was planned, were invited to participate. Twenty-two pre- and post-treatment semen samples were analysed. The reproductive potential of participants was assessed with respect to the current range of fertility treatment options available. Abnormal sperm concentrations were found in 27% of patients pre-treatment compared to 68% post-treatment following a mean latency of 20 months from treatment. Fifty-nine percent of patients experienced a clinically significant decrease in sperm, concentration following radiotherapy and/or chemotherapy; 23% developed azoospermia following treatment. Eighty-two percent of patients with testicular malignancy had oligo- or azoospermia post-treatment. Only one patient had a clinically significant reduction in the percentage of motile spermatozoa post-treatment. Cryopreservation of semen prior to treatment improved the fertility prospects of 55% of patients. Intracytoplasmic sperm injection (ICSI) enhanced the fertility prospects of a further 14%. In the absence of, or after depletion of, cryopreserved semen, ICSI could enhance the fertility prospects of 45% of patients. Fertilization has been achieved by ICSI using spermatozoa retrieved by testicular biopsy from an azoospermic testicular cancer survivor 8 years after chemotherapy. It was concluded that chemotherapy and/or radiotherapy may depress semen concentration to the extent of rendering a man infertile. The severity of the reduction in sperm concentration following treatment is unpredictable but likely to be most severe in those with testicular malignancy and those treated with radiotherapy or alkylating chemotherapy agents. Not all men are keen to undergo an appraisal of their post-treatment fertility potential, for reasons which are unclear. Improving awareness and education of patients concerning the effects of both cancer and cancer treatments on reproductive potential is essential. With the advent of ICSI, it is possible to offer a very reasonable chance of conception in all men with cancer who present for cryopreservation of semen prior to treatment in whom spermatozoa (even in very low concentrations) are present in the ejaculate.     

Distribution of spermatogenesis in the testicles of azoospermic men: the presence or absence of spermatids in the testes of men with germinal failure

The aim of the study was to determine whether a prior diagnostic testicle biopsy can predict success or failure of testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI) in patients with non-obstructive azoospermia caused by testicular failure, and what is the minimum threshold of sperm production in the testis which must be surpassed for spermatozoa to reach the ejaculate. Forty-five patients with non-obstructive azoospermia caused by testicular failure underwent diagnostic testicle biopsy prior to a planned future TESE-ICSI procedure. The diagnostic testicle biopsy was analysed quantitatively, and correlated with the quantitative findings of spermatogenesis in patients with normal spermatogenesis, as well as with the results of subsequent attempts at TESE-ICSI. Men with non-obstructive azoospermia caused by germinal failure had a mean of 0-6 mature spermatids/seminiferous tubule seen on a diagnostic testicle biopsy, compared to 17-35 mature spermatids/tubule in men with normal spermatogenesis and obstructive azoospermia. These findings were the same for all types of testicular failure whether Sertoli cell only, maturation arrest, cryptorchidism, or post-chemotherapy azoospermia. Twenty-two of 26 men with mature spermatids found in the prior testis biopsy had successful retrieval of spermatozoa for ICSI, 12 of their partners became pregnant, and are either ongoing or delivered. The study suggests that 4-6 mature spermatids/tubule must be present in the testis biopsy for any spermatozoa to reach the ejaculate. More than half of azoospermic patients with germinal failure have minute foci of spermatogenesis which are insufficient to produce spermatozoa in the ejaculate. Prior diagnostic testicle biopsy analysed quantitatively (for the presence of mature spermatids) can predict subsequent success or failure with TESE-ICSI. Incomplete testicular failure may involve a sparse multi-focal distribution of spermatogenesis throughout the entire testicle, rather than a regional distribution. Therefore, it is possible that massive testicular sampling from many different regions of the testes may not be necessary for successful TESE-ICSI.     

Approaches for obtaining sperm in patients with male factor infertility

OBJECTIVE: To describe methods of sperm retrieval for intracytoplasmic sperm injection (ICSI) in patients with male factor infertility and to review the clinical results using sperm from the different sources. DESIGN: The literature on sperm-obtaining methods and ICSI was reviewed. Studies related to this topic were identified through MEDLINE. RESULTS(S): This review describes the evolution of sperm retrieval methods. Sperm can be obtained by microepididymal sperm aspiration (MESA), percutaneous sperm aspiration (PESA), and testicular sperm extraction (TESE), from patients with congenital absence of the vas deferens or acquired vas obstruction. When ICSI is performed with ejaculated, epididymal, or testicular sperm, good fertilization and pregnancy rates are achieved without significant differences among the various sperm sources. The original percutaneous sperm aspiration method has been modified slightly and yields successful results. CONCLUSION(S): Viable pregnancies can be achieved with ICSI by using not only ejaculated sperm, but also epididymal and testicular sperm. Microepididymal sperm aspiration, percutaneous sperm aspiration, modified percutaneous sperm aspiration, and testicular sperm extraction can be considered standard procedures to treat male factor infertility.     

Surgical sperm retrieval and intracytoplasmic sperm injection as treatment of obstructive azoospermia

Male genital tract obstructions may result from infections, previous inguinal and scrotal surgery (vasectomy) and congenital bilateral absence of the vas deferens (CBAVD). Microsurgery can sometimes be successful in treating the obstruction. In other cases and in cases of failed surgical intervention, the patient can be treated by microsurgical or percutaneous epididymal sperm aspiration (MESA, PESA) or testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). We present the results of 39 ICSI procedures for obstructive azoospermia in 24 couples. The aetiology of the obstruction was failed microsurgery in 11 patients, CBAVD in nine and genital infections in four. Sperm retrieval was accomplished via MESA in four cases, PESA in 18 cases and via TESE in 11 cases. TESE was only applied when PESA failed to produce enough spermatozoa for simultaneous ICSI. In six patients, the ICSI procedure was performed with cryopreserved spermatozoa after an initial PESA procedure. Fertilization occurred in 47% of the metaphase II oocytes; embryo transfer was performed in 92% of procedures and resulted in a clinical pregnancy in 13/39 procedures. Ongoing pregnancy was achieved in 10/39 procedures. One pregnancy was terminated early after prenatal investigation showed a cytogenetic abnormality (47,XX+18, Edwards syndrome). The other nine pregnancies resulted in the live birth of 10 children, without any congenital abnormalities. Epididymal and testicular retrieved spermatozoa were successfully used for ICSI to treat obstructive azoospermia, and resulted in an ongoing pregnancy in 10 of 24 couples (41.6%) after 39 ICSI procedures, a success rate of 25.6% per treatment cycle and of 27.7% per embryo transfer.     

Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone

GnRH antagonists plus testosterone (T) suppress LH and FSH levels and inhibit spermatogenesis to azoospermia or severe oligozoospermia. High-dose T treatment alone has been shown to be an effective male contraceptive (contraceptive efficacy rate of 1.4 per 100 person yr). Combined GnRH antagonist and T induces azoospermia more rapidly and at a higher incidence than T alone; this combination has therefore been proposed as a prototype male contraceptive. However, because GnRH antagonists are expensive to synthesize and difficult to deliver, it would be desirable to rapidly suppress sperm counts to low levels with GnRH antagonist plus T and maintain azoospermia or severe oligozoospermia with T alone. In this study, 15 healthy men (age 21-41 yr) with normal semen analyses were treated with T enanthate (TE) 100 mg im/week plus 10 mg Nal-Glu GnRH antagonist sc daily for 12 weeks to induce azoospermia or severe oligozoospermia. At 12-16 weeks, 10 of 15 subjects had zero sperm counts, and 14 of 15 had sperm counts less than 3 x 10(6)/mL. The 14 who were suppressed on combined treatment were maintained on TE alone (100 mg/week im) for an additional 20 weeks. Thirteen of 14 subjects in the TE alone phase had sperm counts maintained at less than 3 x 10(6)/mL for 20 weeks. Ten remained persistently azoospermic or had sperm concentration of 0.1 x 10(6)/mL once during maintenance. Mean LH and FSH levels in the subjects were suppressed to 0.4+/-0.2 IU/L and 0.5+/-0.2 IU/L in the induction phase, which was maintained in the maintenance phase. The 1 subject who failed to suppress sperm counts during induction had serum LH and FSH reduced to 0.3 and 0.5 IU/L, respectively. The subject who failed to maintenance had LH and FSH suppressed to 1.0 and 0.2 IU/L, respectively, during the induction phase but these rose to 1.6 and 2.1 IU/L, respectively, during maintenance. Failure to suppress or maintain low sperm counts may be related to incomplete suppression of serum LH and FSH levels. We conclude that sperm counts suppressed with GnRH antagonist plus T can be maintained with relatively low dose TE treatment alone. This concept should be explored further in the development of effective, safe, and affordable hormonal male contraceptives.     

Correlation of testicular pathology and sperm extraction in azoospermic men with ejaculated spermatids detected by immunofluorescent localization

Limiting testicular biopsy for intracytoplasmic sperm injection (ICSI) to those with a high chance of having testicular spermatozoa has not been possible because of the poor predictive value of current clinical and laboratory methods. In order to predict testicular pathology and sperm extraction, we characterised the semen of 28 men with azoospermia due to gonadal failure in terms of the presence of spermatids using an immunological method. The results were compared with the assessment of testicular biopsies by histology and the extraction of spermatozoa into culture medium. Washed cellular elements in the ejaculate were smeared on microscope slides and fixed in 100% methanol, before incubation with acrosome-specific monoclonal antibody (18.6), fluorescein isothiocyanate-labelled anti-mouse goat IgG, and examination by epifluorescent microscopy. Semen from men with oligozoospermia and obstructive azoospermia served as positive and negative controls, respectively. Twelve patients who had positive immunofluorescence (one or more spermatids present) had spermatozoa retrieved from their testes (five hypospermatogenesis, seven focal spermatogenesis), and 16 patients with negative immunofluorescence (spermatids absent) had apparent Sertoli cell-only syndrome (12) or maturation arrest histological pattern (four). However, four patients with apparent Sertoli cell-only syndrome had testicular spermatozoa present after extraction from the biopsy. Plasma follicle stimulating hormone concentration and testicular volume did not predict retrieval of seminal spermatids or testicular spermatozoa. We conclude that the immunofluorescent localization of one or more spermatids in the ejaculate can be used to predict the likelihood of obtaining testicular spermatozoa for ICSI. However, in some patients with Sertoli cell-only syndrome, spermatozoa could still be recovered in the absence of apparent seminal spermatids.     

Molecular pathophysiology and clinical manifestations of gonadotropin receptor defects

The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) bind specific receptors, members of the G protein-coupled receptor superfamily. Mutations of gonadotropin receptors are classified into activating (constitutively active or gain-of-function mutations) and inactivating (loss-of-function mutations). Activating mutations of the LH receptor have been described in familial and sporadic forms of male-limited pseudoprecocious puberty, whereas they do not appear to have any particular phenotype in females. The only activating mutation of the FSH receptor described to date was found in a hypophysectomized man who was fertile despite undetectable serum gonadotropin levels; the effects of constitutive FSH receptor activity in the context of normal pituitary function are not known. Homozygous inactivating mutations of the LH and FSH receptor invariably lead to amenorrhea in genotypical female subjects. In males, inactivation of the LH receptor in its more severe form results in a clinical picture similar to the syndrome of complete androgen resistance, but milder forms of hypoandrogenization have been described as well. In males, homozygous inactivation of the FSH receptor can also be associated with infertility. Finally, polymorphic variants of the FSH receptor are present in the normal population.     

Regulation of biologically active dimeric inhibin A and B from infancy to adulthood in the male

Inhibins are glycoprotein members of the transforming growth factor-beta family that have been implicated in the control of spermatogenesis by exerting a negative feedback on FSH secretion. In addition, locally produced inhibins may play a role in paracrine regulation of testicular function. Immunoassays were used to measure the two biologically active dimeric forms of inhibin (inhibin A and B) in serum, seminal plasma, and urine. To better define their actions, inhibins were measured in the male during infancy, sexual maturation, and senescence. Inhibin B but not A was measurable in the serum of male newborns, infants, children, and adults. In adult males, measurable levels of inhibin B were detected in the seminal plasma but not the urine. The circulating levels of inhibin B increased shortly after birth and peaked at 4-12 months of age (210 +/- 31 pg/mL). The concentration measured in the serum then decreased to a low of 81 +/- 12 pg/mL of inhibin B from 3-9 yr of age followed by a gradual increase beginning with the onset of puberty and reaching another peak of 167 +/- 20 pg/mL in males who were 20-30 yr of age. Inhibin B levels then gradually declined with increasing age up through 90 yr of age. Serum levels of gonadotropins and total testosterone production were also measured in these same males. There was a brief increase in the gonadotropins (FSH and LH) during the few months of postnatal development, followed by a decrease to basal levels until the onset of puberty at 10-14 yr of age. Testosterone was also increased in the serum of infants from day 1 through 12 months of age, which decreased in young children but increased again following the elevation of gonadotropins during puberty. In adults aged 20-90 yr, serum levels of inhibin B were inversely proportional to levels of FSH but not LH or testosterone. In males in which a semen analysis was performed, those males with normal semen analysis had a significantly higher inhibin B levels, sperm production, and lower FSH levels than males with either oligospermia or nonobstructive azoospermia. The levels of Inhibin B found in circulation were a good marker for testicular function and could be useful in the diagnosis of patients with semen abnormalities or a complete absence of spermatogenesis. Because this glycoprotein is secreted in high amounts in the prepubertal testis up to 3 yr of age, inhibin B could potentially be used as a marker in the diagnosis of cryptorchidism and precocious puberty.