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Background: Controversial speculation suggestions that dietary intake may affect semen quality and testicular function, however, there are limited comprehensive studies observing dietary patterns., Objective: To study associations between major dietary patterns and markers of testicular function in adulthood., Material and Methods: Observational cross-sectional study of two hundred and ninety men with an average age of 20 years, from the Western Australian Pregnancy Cohort (Raine) Study. Usual dietary intake assessed using a semi-quantitative food frequency questionnaire at 20 years of age. Two dietary patterns previously identified using exploratory factor analysis ("Healthy" or "Western") and participants received z-scores for each dietary pattern. Primary endpoints were testicular volume, total sperm per ejaculate, morning serum testosterone concentration. Secondary endpoints were semen sample parameters, inhibin B and sex steroids (DHT: 3α-diol, 3β-diol; LH; FSH; DHEA; estradiol; estrone)., Result(s): Participants were on average 20.0 ± 0.4 years old, had a median of 2 days sexual abstinence and a body mass index of 24.1 ± 3.9 kg/m 2 , 13% were smokers, 52% were 'moderate' alcohol drinkers, 23% frequently used recreational drugs and 68% reported 'high' physical activity levels. Sperm concentration and DHT 3α-diol were negatively associated with a greater z-score for the "Western" dietary pattern (p = 0.007 and; p = 0.044, respectively), and serum estradiol concentration was positively associated with a "Western" dietary pattern (p = 0.007) after adjustment for BMI, varicocele, cryptorchidism and sexual abstinence., Discussion: Despite associations between greater intake of the "Western" dietary pattern and a decreased male reproductive health markers, our lack of consistent associations of either a "Healthy" or a "Western" dietary pattern, limit clinical or biological significance in isolation., Conclusions: A potential negative association of a "Western" dietary pattern with male reproductive health was detected and should be studied further in population-based studies., (© 2019 American Society of Andrology and European Academy of Andrology.)

Study Question: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood?, Summary Answer: Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder., What Is Known Already: Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function., Study Design, Size, Duration: The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample., Participants/materials, Setting, Methods: Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA >4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk., Main Results and the Role of Chance: Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P < 0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P < 0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR > 4 was associated with a lower serum testosterone (P = <0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015)., Limitations, Reasons for Caution: This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment., Wider Implications of the Findings: Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume., Study Funding/competing Interest(s): This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

As the transient postnatal hormone surge in humans, known as 'minipuberty', occurs simultaneously with key steps in germ-cell development, we investigated whether similar changes occur in the hypothalamic-pituitary-testicular axis of neonatal mice at a time that would coincide with gonocyte transformation into spermatogonial stem cells (SSC). Serum and testes were collected from C57Bl/6 mice at embryonic Day 17 (E17), birth (postnatal Day 0; P0) and daily until P10. Serum FSH and testosterone levels in both serum and testes were analysed and gene expression of FSH receptor (Fshr), luteinising hormone receptor (Lhr), anti-Müllerian hormone (Amh), octamer-binding transcription factor 4 (Oct-4), membrane type 1 metalloprotease (Mt1-mmp), proto-oncogene C-kit and promyelocytic leukaemia zinc finger (Plzf ) was quantified by real-time polymerase chain reaction. We found a transient surge of serum and testicular testosterone levels between P1 and P3 and a gradual increase in FSH from P1 to P10. Testis Lhr expression remained low from P0 until P10 but Fshr expression peaked between P3 and P6 (P<0.01). The same was found for Oct-4 expression (a gonocyte marker), which surged between P3 and P6 (P<0.01). Mt1-mmp expression peaked at P3 (P<0.05). The expression pattern of both C-kit and Plzf (SSC markers) was similar with a steady increase from P1 to P10. These results show a transient activation of the hypothalamic-pituitary-testicular axis postnatally with increases in serum and testicular testosterone at P1-P3 and testicular Fshr (but not Lhr) at P3-P6. These changes coincide with increases in gene expression of Oct4, Mt1-mmp, Plzf and C-kit, reflecting gonocyte activation, migration and transformation into SSC. In conclusion, these findings suggest that 'minipuberty' does occur in mice and that gonocyte transformation may be driven by a transient FSH signalling pathway.

Study Question: By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters and influences upon testicular function for a population not selected with regard to fertility?, Summary Answer: While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have no or minimal adverse impact., What Is Known Already: The majority of previous attempts to develop valid reference populations for spermatogenesis have relied on potentially biased sources such as recruits from infertility clinics, self-selected volunteer sperm donors for research or artificial insemination or once-fertile men seeking vasectomy. It is well known that studies requiring semen analysis have low recruitment rates which consequently question their validity. However, there has been some concern that a surprisingly high proportion of young men may have semen variables that do not meet all the WHO reference range criteria for fertile men, with some studies reporting that up to one half of participants have not meet the reference range for fertile men. Reported median sperm concentrations have ranged from 40 to 60 million sperm/ml., Study Design, Size and Duration: The Western Australian Pregnancy Cohort (Raine) was established in 1989. At 20-22 years of age, members of the cohort were contacted to attend for a general follow-up, with 753 participating out of the 913 contactable men. Of these, 423 men (56% of participants in the 20-22 years cohort study, 46% of contactable men) participated in a testicular function study. Of the 423 men, 404 had a testicular ultrasound, 365 provided at least one semen sample, 287 provided a second semen sample and 384 provided a blood sample., Participants/materials, Setting, Methods: Testicular ultrasound examinations were performed at King Edward Memorial Hospital, Subiaco, Perth, for testicular volume and presence of epididymal cysts and varicoceles. Semen samples were provided and analysed by standard semen assessment and a sperm chromatin structural assay (SCSA) at Fertility Specialists of Western Australia, Claremont, Perth. Serum blood samples were provided at the University of Western Australia, Crawley, Perth and were analysed for serum luteinizing hormone (LH), follicular stimulating hormone (FSH), inhibin B, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), estradiol, estrone and the primary metabolites of DHT: 5α-androstane-3α,17β-diol (3α-diol) and 5-α androstane-3-β-17-beta-diol (3β-diol). Serum steroids were measured by liquid chromatography, mass spectrometry and LH, FSH and inhibin B were measured by ELISA assays., Main Results and the Role of Chance: Cryptorchidism was associated with a significant reduction in testicular (P = 0.047) and semen (P = 0.027) volume, sperm concentration (P = 0.007) and sperm output (P = 0.003). Varicocele was associated with smaller testis volume (P < 0.001), lower sperm concentration (P = 0.012) and total sperm output (P = 0.030) and lower serum inhibin B levels (P = 0.046). Smoking, alcohol intake, herniorrhaphy, an epididymal cyst, medication and illicit drugs were not associated with any significant semen variables, testicular volume or circulating reproductive hormones. BMI had a significantly negative correlation with semen volume (r = -0.12, P = 0.048), sperm output (r = -0.13, P = 0.02), serum LH (r = -0.16, P = 0.002), inhibin B (r = -0.16, P < 0.001), testosterone (r = -0.23, P < 0.001) and DHT (r = -0.22, P < 0.001) and a positive correlation with 3αD (r = 0.13, P = 0.041) and DHEA (r = 0.11, P = 0.03). Second semen samples compared with the first semen samples in the 287 participants who provided two samples, with no significant bias by Bland-Altman analysis. Testis volume was significantly correlated positively with sperm concentration (r = 0.25, P < 0.001) and sperm output (r = 0.29, P < 0.001) and inhibin B (r = 0.42, P < 0.001), and negatively correlated with serum LH (r = -0.24, P < 0.001) and FSH (r = -0.32, P < 0.001). SCSA was inversely correlated with sperm motility (r = -0.20, P < 0.001) and morphology (r = -0.16, P = 0.005). WHO semen reference criteria were all met by only 52 men (14.4%). Some criteria were not met at first analysis in 15-20% of men, including semen volume (<1.5 ml, 14.8%), total sperm output (<39 million, 18.9%), sperm concentration (<15 million/ml, 17.5%), progressive motility (<32%, 14.4%) and morphologically normal sperm (<4%, 26.4%), while all five WHO criteria were not met in four participants (1.1%)., Limitations and Reasons for Caution: This was a large cohort study; however, potential for recruitment bias still exists. Men who did not participate in the testicular evaluation study (n = 282) did not differ from those who did (n = 423) with regard to age, weight, BMI, smoking or circulating reproductive hormones (LH, FSH, inhibin B, T, DHT, E2, E1, DHEA, 3α-diol, 3β-diol), but were significantly shorter (178 versus 180 cm, P = 0.008) and had lower alcohol consumption (P = 0.019) than those who did participate., Wider Implications of the Findings: This study demonstrated the feasibility of establishing a birth cohort to provide a relatively unbiased insight into population-representative sperm output and function and of investigating its determinants from common exposures. While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have little adverse impact, and this study suggests that discrepancies from the WHO reference ranges are expected, due to its derivation from non-population-representative fertile populations., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Germinal damage is an almost universal accompaniment of cancer treatment as the result of bystander damage to the testis from cytotoxic drugs and/or irradiation. Cancer treatment for the most common cancers of the reproductive age group in men has improved such that most are now treated with curative intent, and many others are treated with likelihood of prolonged survival, so that the preservation of fertility is an important component of posttreatment quality of life. This has led to the consideration of developing adjuvant treatments that may reduce the gonadal toxicity of cancer therapy. One dominant hypothesis has been based on the supposition that the immature testis was resistant to cytotoxin damage. Hence, if hormonal treatment were able to cause spermatogenic regression to an immature state via an effective withdrawal of gonadotrophin secretion, the testis might be maintained temporarily in a protected state during cytotoxin exposure. However, clinical studies have been disappointing but have also been unable to test the hypothesis definitively thus far, due to the inability to completely suppress gonadotrophin secretion. Similarly, experimental models have also given conflicting results and, at best, a modest cytoprotection. To definitively test this hypothesis experimentally, we used the fact that the functionally hpg mouse has complete gonadotrophin deficiency but can undergo the induction of full spermatogenesis by testosterone. Thus, if complete gonadotrophin deficiency were an advantage during cytotoxin exposure, then the hpg mouse should exhibit some degree of germinal protection against cytotoxin-induced damage. We therefore administered three different cytotoxins (200 mg/kg procarbazine, 9 mg/kg doxorubicin, 8 Gy of X irradiation) to produce a range of severity in testicular damage and mechanism of action to either phenotypically normal or hpg mice. Testis weight and homogenization-resistant spermatid numbers were measured to evaluate the potential protective effects on spermatogenesis. Although the three cytotoxins produced a range of severity of spermatogenic damage, there was no evidence of cytoprotection in the hpg mice that were completely gonadotrophin deficient at the time of treatment. These findings cast doubt on the validity of the hypothesis that spermatogenic regression via gonadotrophin withdrawal can protect the mouse testis against cytotoxin-mediated spermatogenic damage.

The biological basis for the remarkably wide variation in sperm output between and within men remains unclear. Although some contributing factors have been identified, the familial and genetic contributions to variation in human sperm output have been little studied, although such sources of variation are known to be significant in experimental animals. In order to identify such familial and genetic factors in a classical twin study design, we recruited monozygotic and dizygotic twins aiming to study the degree of resemblance between genetically identical and non-identical twins in sperm output, testis size and testicular endocrine function. From an approach to 160 twin pairs on the Australian Twin Register database, eventually 17 pairs of male twins (11 monozygotic and six dizygotic) participated in this study. Sperm concentration and output, right testis size and SHBG all exhibited a strong familial effect but a genetic component could not be confirmed. Total and free testosterone exhibited a genetic component. Although identifying for the first time a clear familial component to normal human spermatogenesis, this study had insufficient power to determine whether there was a genetic component, nor could its design distinguish between genetic or shared (early) environmental determinants for these familial effects. Implications for future twin studies of human testicular function including stronger recruitment strategies, multi-centre studies and surrogate variables for human spermatogenesis are suggested.

Objective: Gonadal dysfunction is common in chronic liver disease, but most of the previous studies have been restricted to men with alcohol-induced liver disease. We have evaluated hypothalamic-pituitary-testicular function in patients with end-stage non-alcoholic liver disease before and at 6 and 12 months after hepatic transplantation., Design: A prospective study of hypothalamic-pituitary-testicular endocrine function before and after cadaveric hepatic transplantation., Patients: Fifty four consecutive patients with end-stage, non-alcoholic liver disease were evaluated before and after liver transplantation., Measurements: Hypothalamic-pituitary-testicular (HPT) axis function was evaluated under basal conditions by single morning measurements of plasma total and free testosterone, sex hormone-binding globulin and by plasma LH and FSH responses to 100 micrograms i.v. GnRH., Results: Men with chronic non-alcoholic liver disease had reduced levels of total and free testosterone and increased levels of SHBG compared with controls with normal liver function. Total and free testosterone were positively correlated with basal and stimulated LH (but not FSH) concentrations. Gonadotrophin responses to GnRH were preserved but delayed compared with healthy controls consistent with a predominantly hypothalamic defect in regulation of pituitary-testicular function. Increasing severity of underlying liver disease was associated with declining total and free testosterone as well as peak GnRH-stimulated LH concentrations. Spironolactone treatment was associated with decreased circulating testosterone levels only in men with liver disease of intermediate severity (Child-Pugh class B). Following hepatic transplantation, total and free testosterone and SHBG concentrations returned progressively towards eugonadal control levels over the first 12 months but total and free testosterone levels remained subnormal., Conclusions: Hypothalamic-pituitary regulation of testicular function is impaired in end-stage non-alcoholic liver disease in proportion to the severity of underlying liver disease. Spironolactone reduces circulating testosterone but only among men with Child-Pugh B liver cirrhosis. Gonadal function improves, but is not normalized, over the first year following successful liver transplantation.

The testis is the most accessible endocrine organ to clinical examination and is highly responsive to environmental factors, including systemic illness. The clinical management of any disorder warrants consideration of the effects of illness and its treatment of male reproductive function. Testicular physiology and clinical evaluation are reviewed, as are the mechanisms of reproductive disruption by systemic disease. Specific diseases and disorders, including renal, liver, respiratory, neurologic, and gastrointestinal diseases, and their effects on the testes are discussed also.

In vitro studies indicate a physiological role for insulin-like growth factor I (IGF-I) in paracrine regulation of testicular function and recent clinical studies suggest a potential role for growth hormone (GH) and/or IGF-I in the treatment of hypogonadotrophic states in males. This study aimed to examine the effects of pretreatment with recombinant human GH (rhGH) or rhIGF-I on the response to gonadotrophins of the non-human primate testis in vivo. Using a balanced Latin square design with repeated measures, six prepubertal male hamadryas baboons (Papio hamadryas hamadryas) were treated in a cross-over sequence for periods of 18 days with daily im injections of rhGH (0.4 IU.kg-1.day-1), rhIGF-I (0.1 mg.kg-1.day-1) or saline with a 2-week washout period between each treatment. A single im injection of hCG (1500 IU) increased serum testosterone (p = 0.0002) but neither rhGH nor rhIGF-I influenced the timing or magnitude of this response (p > 0.5). A single im dose of FSH (75 IU) stimulated immunoreactive inhibin (p = 0.01) but also was unaffected in magnitude or timing by pretreatment with rhGH or rhIGF-I (p > 0.2). Circulating IGF-I levels were increased independently by hCG (p = 0.01) and FSH (p < 0.0001) administration. These findings indicate that neither GH nor IGF-I pre-treatment enhance acute gonadal responses to gonadotrophin stimulation of the prepubertal non-human primate testis in vivo. These findings suggest that GH or IGF-I treatment of hypogonadotrophic men without somatotrophin deficiency is unlikely to be beneficial.

Chronic renal failure causes extensive neuroendocrine disturbance, including marked hypothalamo-pituitary dysfunction which is reversed by renal transplantation but not dialysis. Gonadal dysfunction in uremia is manifest as delayed puberty in adolescents; as testicular atrophy, hypospermatogenesis, infertility, impotence in men; and as anovulation, infertility, and menstrual disturbance in women. Gonadal steroidogenesis and gametogenesis are impaired and gonadotropin levels are increased. In addition to evidence of defects in pituitary and gonadal function, increasing evidence indicates the importance of alterations in hypothalamic regulation of pituitary-gonadal function in the pathogenesis of uremic hypogonadism. Experimental uremia induced by subtotal nephrectomy in mature rats causes gonadal dysfunction, which is principally due to aberrant neuroendocrine regulation of GnRH secretion involving inhibition of GnRH secretion, hypersensitivity to negative testicular feedback, and resistance to naloxone, a triad of features termed ontogenic regression.

To determine the antisteroidogenic effect of ketoconazole (KTZ) in the human testis, we measured the plasma delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, dehydroepiandrosterone (DHEA), progesterone, 17 alpha-hydroxyprogesterone, androstenedione (A), and testosterone (T) concentrations in three men with previously untreated metastatic prostate cancer at various time intervals for 24 h before and 48 h after the administration of 200 mg oral KTZ every 8 h. The adrenal glands of these three patients were suppressed (as measured by the plasma cortisol levels) by the administration of 1.0 mg dexamethasone daily for 7 days before and during the study. After six doses of KTZ, bilateral orchiectomy was performed, and the intratesticular concentration of the aforementioned seven steroids and the intratesticular activities of the 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase enzymes in the delta 4-steroidogenic pathway were determined. These seven intratesticular steroids and three intratesticular enzyme activities were compared to those in five men with previously untreated prostate cancer who underwent orchiectomy as primary treatment for their disease. Plasma A, DHEA, and T all significantly decreased during KTZ therapy. There was no significant change in the other four steroids in the plasma. In the testis, delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, and delta 4-17 alpha-hydroxyprogesterone were all significantly elevated, whereas intratesticular DHEA, A, and T were significantly decreased in the three KTZ-treated patients compared to levels in the five non-KTZ-treated patients. Measurement of the enzyme activities demonstrated a significant reduction in both 17 alpha-hydroxylase and 17,20-desmolase, but no change in 17 beta-hydroxysteroid dehydrogenase, in the KTZ-treated patients compared to the levels in the non-KTZ-treated patients. We conclude that oral KTZ decreases testicular T production by inhibiting the 17,20-desmolase and also the 17 alpha-hydroxylase steps in both the delta 4- and delta 5-T biosynthetic pathways.

The effect of short-term exposure to the insulin-like growth factors (IGF-I and IGF-II) on testosterone production by rat testicular interstitial cells in primary culture has been examined. Both peptides, when present during a 1-h pre-incubation period, increased human chorionic gonadotropin (hCG)-stimulated testosterone release over the following 16-h period. The effect of exposure to IGFs was most marked on maximally hCG-stimulated testosterone release. Maximal stimulation following IGF exposure was 80-85% above that seen without IGFs, and the IGF effect was half-maximal at 1.5-2 micrograms/l of IGF-I or IGF-II. Pre-incubation with IGFs did not alter the concentration of hCG (0.1 microgram/l) at which half-maximal stimulation of testosterone release was seen. Increasing cell density had a marked effect on the testosterone production rate per 10(5) cells, and the stimulatory effect of IGFs was only seen at relatively high cell density (2.8 X 10(5) cells/ml). Varying the period of pre-incubation with IGFs between 0.5 and 16 h, it was found that a 1-h period gave maximal stimulation. We conclude that a short exposure to IGFs is capable of increasing hCG-stimulated steroidogenesis in Leydig cells, and postulate that this effect may be part of an intratesticular paracrine control mechanism.

Fertility and testicular function were studied in eight men with severe homozygous (Pi ZZ variant genotype) alpha-1 antitrypsin (AAT) deficiency. Age- and marital duration standardized fertility, clinical androgenic features, mean testicular volume, plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and semen analysis were all normal apart from a reduction in semen volume. Mean plasma total and free testosterone were elevated and the percentage free testosterone reduced compared with age-matched, healthy fertile controls indicative of increased sex-hormone binding globulin (SHBG) levels representing an early marker for subclinical hepatic dysfunction associated with AAT-deficiency. In view of the preservation of normal fertility and testicular function despite chronic respiratory disease and premature death with deleterious AAT gene variants, it is proposed that the high prevalence of genetic polymorphism in the AAT protein may be maintained by the chronological asynchrony of the periods of maximal male reproductive activity (40 years) and the late onset (greater than 40 years) of symptoms in severe AAT deficiency rather than by any balance between reduced reproductive fitness of homozygotes and heterozygote advantage.

We have investigated testicular function in 28 insulin-dependent diabetic men under the age of 50 years and 119 age-matched controls. Diabetics had reduced testicular volume, semen volume, total and total motile sperm output while plasma LH and FSH levels were elevated. Reduction in semen volume and impotence were more common in long-standing complicated diabetes. Glycosylated hemoglobin (GHb) levels were positively correlated with plasma LH levels (r = 0.46, p less than 0.02) but there was no direct correlation of glycemic control and spermatogenesis. The differences in testicular function were due to decreased spermatogenesis and could not be explained by other forms of testicular pathology or the presence of diabetic neurovascular complications. We conclude that the function of the hypothalamic pituitary testicular axis is impaired in diabetic men, that this impairment is at least partly related to the degree of preceding glycemic control and that multiple levels of the axis may be dysfunctional.

A prospective survey of 289 unselected men, attending a male infertility clinic (200 subjects) or as donors presenting for an artificial insemination programme (89 subjects) was performed. High titres of sperm agglutinating antibodies (greater than 1/32) were present only in a group of (6.5%) of infertile men but not in volunteer donors. Low titres occurred with similar frequencies (12%) in both groups. The sperm immobilizing antibody test was less sensitive and more specific but of no additional diagnostic benefit. Patients with high titres of sperm antibodies had evidence of testicular damage with decreased testicular volumes, elevated serum FSH and LH levels and reduced sperm density and motility whereas low titres were not associated with any testicular or seminal pathology. These data suggest a sub-group of infertile men have evidence of spermatogenic damage and impaired sperm function associated with high titres of sperm antibodies. Immunologic infertility in these men may reflect either an underlying autoimmune orchitis or a secondary immune reaction following testicular damage of various causes.

Gonadal function was assessed in seventeen adult male renal transplant recipients, with well established good homograft function, for a mean of 4.9 years. Patients were assessed clinically and by measurement of basal concentrations of FSH, LH, prolactin, testosterone and oestradiol, FSH and LH responses to bolus injections of LHRH and semen analysis. Retrospectively all had symptoms consistent with marked hypogonadism prior to transplantation but in nine out of sixteen this was reversed with transplantation. Residual hypogonadism was evident in seven of sixteen patients and correlated with duration of haemodialysis longer than 1 year (P less than 0.01). Even among patients with clinically normal gonadal function, defects in the hypothalamic--pituitary--testicular axis remained. Elevated basal serum FSH, excessive FSH responses to LHRH and lowered basal serum testosterone were found. In the group with residual hypogonadism more marked changes, including elevated basal LH and excessive LH responses to LHRH, were also found. Fertility was recorded in two men on three occasions since transplantation. Sperm counts were normal in five and abnormal in four patients. Testicular volume and sperm density were inversely correlated with basal and stimulated FSH and LH levels.

We report a case of infertility with bilateral testicular enlargement and hypogonadism due to amyloidosis. Testicular biopsy revealed complete replacement with amyloid and subsequent investigation demonstrated primary hypogonadism with marked elevation of gonadotropins, azoospermia, mild renal failure and lack of progression of generalized amyloidosis during 2 years.

Testicular exocrine (semen analysis) and endocrine (plasma LH, FSH, prolactin and testosterone) function was assessed in 119 consecutive healthy men presenting for screening as potential sperm donors. Since these volunteers were unbiased with respect to their fertility status, this sample of the general male population was suitable to determine normal ranges and the influence of a variety of physical (height, weight, standardized body weight, varicocele) and demographic (age, marital and fertility status, tobacco and alcohol consumption) factors on normal human testicular endocrine and exocrine function, without the confounding effects of bias in selection of subjects. The statistical distribution of all seminal parameters was non-gaussian, but cube-root transformation of the data normalized the distribution, allowing for parametric statistical analysis. The median (and 95% confidence limits) for the various semen parameters was 73.0 (10.6-235.3) million sperm per ml; 189.0 (12.6-868) million sperm per ejaculate; 50.4 (5.9-181.9) million motile sperm per ml; 133.0 (6.9-661.7) million motile sperm per ejaculate; 54.0 (7.0-172.9) million morphologically normal sperm per ml and 138.5 (7.5-672) million morphologically normal sperm per ejaculate. Testicular volume was correlated positively with measures of physique such as standardized body weight (r = 0.25, P less than 0.01) and body surface area (r = 0.30, P less than 0.002), and negatively with plasma levels of FSH (r = -0.31), P less than 0.002) but not LH. Sperm output was positively correlated with testicular volume (r = 0.28, P less than 0.005) and negatively correlated with plasma FSH (r = -0.31, P less than 0.002) and plasma LH (r = -0.31, P less than 0.002). Smoking was associated with a highly significant reduction in sperm output and motility. Men with varicocele (25%) were significantly taller, had slightly lower haemoglobin levels and moderate left (but not right) testicular atrophy, but neither seminal nor hormonal parameters were different from men without varicocele. There was no difference in any markers of human testicular function between men according to marital or fertility status, grades of moderate alcohol consumption or the presence of low titres of sperm antibodies.

Testicular damage was evaluated in twelve men by determination of sperm counts, serum FSH, LH, and testosterone up to 3 1/2 years after treatment with radioactive iodine (131I) therapy for thyroid cancer. Dose-dependent spermatogenic damage with elevation of serum FSH was evident. Full recovery in one and partial recovery in another patient was documented during 2 1/2 years of follow-up. Serial study in two patients documented a small but significant effect of 50 mCi 131I on serum FSH levels and clinically important effects appear to be restricted to men having multiple doses totalling over 100 mCi.

Paired testicular volumes and weights, as well as age, height, and weight, were recorded from a series of 1056 consecutive necropsies on adult males ranging in age from 18 to 96 years. These data were analyzed to examine the effects of age, nutritional state (standardized body weight), and illness on testicular size. Testicular volume and weight were related by a constant density of 1.038 g/ml, regardless of testicular size, age or illness. Mean testicular volume was correlated with height (r = 0.470), weight (r = 0.504), body surface area (r = 0.549) and standardized body weight (r = 0.152). Advancing age, malnutrition, alcoholism, malignancy, and a chronic, terminal illness were each individual risk factors for reduced testicular size, whereas diabetes, narcotic or other drug usage, and pelvic injury were not associated with reduced testicular volume. Since advancing age, reduced standardized body weight, and some disease states were all associated with diminution of testicular size, the interaction of age, malnutrition, and illness on testicular size were examined by statistical modeling, using multivariate logistic regression and covariance analysis. The associations of alcoholism, malignancy, and chronic, terminal illness with decreased testicular volume were independent of aging or nutritional state. The effects of chronic, terminal illness were mostly explained by the concurrent effects of reductions in standardized body weight (malnutrition). After exclusion of men with diseases shown to be associated with decreased testicular size, he specific effects of age alone demonstrated a reduction in testicular volume only in the 8th decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)

A model for the study of testicular function in experimental uremia induced by subtotal nephrectomy in mature male rats is described. Glomerular filtration rate was reduced by 87%, resulting in stable uremia for up to 13 weeks with characteristic biochemical changes and reduction in weight of testes, prostate, seminal vesicles, and epididymis but not of heart, liver, spleen, or epididymal fat-pads in comparison with pair-fed and sham-operated, ad libitum-fed littermate controls. Basal serum LH, FSH, and testosterone were reduced and PRL levels increased in chronic uremic rats compared with pair-fed and sham-operated controls. Intratesticular and peripheral venous testosterone levels were reduced by 73-85%, whereas spermatic vein testosterone levels were reduced by 47% suggesting a reduction in blood flow to the uremic rat testis. Sensitivity of uremic Leydig cells to human CG stimulation was normal to increased both in vivo and in vitro without changes in LH receptor affinity or numbers. Fertility was markedly impaired in uremic rats but was restored to normal by either human CG or testosterone treatment. Spermatogenesis was minimally depressed after up to 3 months of uremia. These studies suggest that this experimental paradigm is a suitable model for studying the pathogenesis of early changes in uremic hypogonadism. The predominant early changes of uremic hypogonadism are due to central defects in regulation of pituitary LH secretion with consequent testicular and peripheral hypoandrogenism but initial preservation of spermatogenesis.

As part of a study of the testicular production and action of insulin-like growth factor-I (IGF-I), adult rat testes were extracted with acidified methanol, yielding an immunoreactive IGF-I fraction corresponding in size to human IGF-I. The mean IGF-I content (+/- SEM) of testes weighing approximately 1.1 g was 51.5 +/- 5.6 ng/testis, and was not due to serum contamination. After a 3-day fast testicular IGF-I decreased by 80%, whereas serum IGF-I levels declined by 90%. Testicular homogenates and isolated Leydig cells were shown to contain specific IGF-I receptors, Ka = 2 X 10(9) M-1, with 10% IGF-II cross-reactivity. The concentration of these receptors was 2 pmol binding sites per testis, or 3.3 fmol per 10(6) Leydig cells. However IGF-I at 250 ng/ml had no effect on basal or hCG-stimulated testosterone production by isolated Leydig cells, measured over 3 h. Although an effect of IGF-I over longer incubation periods cannot be excluded, it is also possible that testicular IGF-I has a mitogenic role, rather than acting on differentiated testicular functions.

Testicular function was assessed in 24 men after renal transplantation who were on either Cyclosporin A (CSA) (8 men) or a combination of azathioprine and prednisone (AZP) (16 men) as immunosuppressive therapy. The different regimes were not associated with any differences in clinical or hormonal (LH, FSH, prolactin, testosterone, estradiol) indices of testicular function although adrenal androgen (dehydroepiandrosterone sulphate) was suppressed in prednisone-treated men. Overall, however, poor graft function was associated with abnormal testicular function. Renal allograft function rather than immunosuppressive regime was the major determinant of gonadal function.

BACKGROUND: Androgens and the androgen receptor (AR) have well known roles in male reproduction, and recent genetic mouse models inactivating the Ar gene have conclusively defined a role for androgens in female reproduction. In males, AR gene inactivation severely disrupts spermatogenesis by interrupting completion of meiosis, thereby eliminating production of mature sperm leading to male sterility. These effects have overshadowed the study of additional post-meiotic androgen effects required for the production of fully functional spermatozoa, as well as the production of females with complete androgen insensitivity which cannot be produced by natural breeding. However, these limitations have been overcome by the creation of global and cell-specific AR knockout (ARKO) mouse models using Cre–LoxP genetic engineering. [ABSTRACT FROM PUBLISHER]