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Biomedical subjects

D M de Kretser

Publications and source records attributed to D M de Kretser.

At least 127 records · Page 7Linked to original sources
PubMed1993

Inhibin and relaxin concentrations in early singleton, multiple, and failing pregnancy: relationship to gonadotropin and steroid profiles.

OBJECTIVE: To examine the inter-relationships between inhibin, relaxin, steroid concentrations, estradiol (E2), progesterone (P), and gonadotropins in early pregnancy. DESIGN: Hormone concentrations in plasma were measured during the luteal phase of subjects who became pregnant (n = 58) or failed to become pregnant (n = 47) after ovarian hyperstimulation for in vitro fertilization-gamete intrafallopian transfer (IVF-GIFT) (group 1). A further group of subjects became pregnant (n = 7) or failed to become pregnant (n = 8) during endocrinology tracking of a natural cycle (group 2). Blood was obtained every 3 days in the luteal phase from day 5 in group I (day 0 was oocyte recovery) and from day 0 (first increase in luteinizing hormone [LH]) in group II. RESULTS: Progesterone and E2 were increased over nonpregnant values by day 11 (P) and day 16 (E2) in group I and by day 11 (E2 and P) in group II. Inhibin and relaxin concentrations were significantly increased by day 16 in group I (often by day 11) and by day 14 in group II pregnancy subjects. A direct relationship existed between inhibin, P, relaxin, and human chorionic gonadotropin (hCG). Subjects who had twin pregnancies demonstrated higher concentrations of all hormones and often exhibited increases earlier (by day 11 in group I) than singleton pregnancy subjects. Pregnancies that ended in miscarriages tended to have lower concentrations of P and inhibin. None of the hormones reliably discriminated between the clinical conditions of blighted ovum and of spontaneous abortion, and the predictive value of any hormone measured for miscarriage was not high. CONCLUSIONS: The trend of inhibin and relaxin concentrations closely parallels rises in P during early pregnancy. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are suppressed very early in pregnancy. The suppression of LH and FSH in hyperstimulated cycles is more governed by E2 than inhibin in stimulated cycles. Some subjects destined to miscarry exhibit abnormal endocrine changes very early in the luteal phase.

Abortion, Spontaneous↗
PubMed1993

Serum immunoactive inhibin levels in early pregnancy after in vitro fertilization and embryo transfer.

OBJECTIVE: To determine the maternal serum concentrations of inhibin, E2, P, and hCG in early pregnancies arising from IVF and ET or GIFT and to assess the value of these hormone measurements in determining outcome of pregnancy. DESIGN: Serum immunoactive inhibin, E2, P, and hCG levels were measured in the first trimester of pregnancies after IVF-ET and GIFT procedures. SETTING: In vitro fertilization and ET or GIFT was undertaken at Monash IVF, Melbourne, Victoria, Australia. PATIENTS: At least two blood samples were collected from 117 women between 4 and 11 weeks of gestation. MAIN OUTCOME MEASURES: The hormone concentrations in the IVF-ET and GIFT pregnancies were compared with those in pregnancies and related to outcome of pregnancy. RESULTS: Serum inhibin levels in singleton pregnancies were significantly higher than in comparable normal pregnancies. In contrast to normal conceptions in which inhibin concentrations rose to peak at 11 weeks, the levels found in IVF-ET and GIFT singleton pregnancies were high at 5 weeks' gestation and declined subsequently. In twin pregnancies, the inhibin levels were significantly greater than those in singleton pregnancies. In biochemical pregnancies diagnosed by increasing hCG concentrations in the absence of an embryonic sac, inhibin levels were significantly lower than those found in singleton pregnancy, as were E2, P, and hCG levels. In anembryonic pregnancies, diagnosed by the confirmation of an intrauterine gestation sac with no evidence of a fetal complex, inhibin concentrations were highest at week 4 and declined, being significantly lower at all stages of gestation. In ectopic pregnancy, serum inhibin levels were lower at all stages of gestation, whereas E2 concentrations were not lower until 6 weeks and P levels until week 5. Serum hCG levels were significantly lower at all stages of gestation. In women with spontaneous abortions, inhibin levels were lower than singleton pregnancies at 7 weeks. CONCLUSIONS: Serum inhibin concentrations are elevated in pregnancies arising from ovarian hyperstimulation in the first trimester when compared with those in normal pregnancy, probably as a result of the presence of multiple corpora lutea resulting from ovarian hyperstimulation. Serum inhibin, E2, P, and hCG are useful markers of abnormal pregnancy outcome.

Chorionic Gonadotropin↗
PubMed1993

Radioimmunoassay of FSH-suppressing protein in the ewe: concentrations during the oestrous cycle and following ovariectomy.

A sensitive and specific heterologous radioimmunoassay for FSH-suppressing protein (FSP or follistatin) was applied to ovine plasma. Following a logit-log dose transformation, parallel dose-response lines were observed between purified bovine 35 kDa FSP used as standard and serial dilutions of ewe plasma. Activin-A, inhibin-A and a range of other proteins showed low (< 0.5%) cross-reactivity in the assay. Daily variations in the peripheral concentrations of FSP were measured across the ovine oestrous cycle. The peripheral concentrations of plasma FSP in adult ewes revealed a significant (P < 0.01) increase (33%) during the luteal phase above follicular phase levels, peaking 10 days after the LH surge. FSP concentrations were determined in arterial and venous plasma from the ovary, head, kidney and liver. A significant (P < 0.05) increase across the ovary was detected with no significant differences across the head, liver and kidney. To investigate the relationship between gonadal FSP and the pituitary, ewes underwent ovariectomy and hypophysectomy. FSP levels rose (100-110%, P < 0.01) during the period of surgery for both bilateral ovariectomy and sham ovariectomy, and then decreased significantly (37-44%) at 4-6 h after surgery. A further rise in plasma FSP (180-200% increase above pretreatment levels, P < 0.001) was observed 10-12 h after ovariectomy and sham ovariectomy. FSP levels then returned to preoperative levels during the following 26 h. Plasma FSP levels in long-term ovariectomized and hypophysectomized ewes were not significantly different from preoperative levels. To determine whether the pattern of plasma FSP seen during the ovariectomy study was due to the effect of the induction of anaesthesia, ewes were treated with sodium thiopentone and halothane or 0.9% (w/v) NaCl by procedures of similar duration to that used during surgery. Both treatments resulted in an elevation of FSP levels (33-62%) over pretreatment values only at the time of induction of anaesthesia. To examine further whether this rise in plasma FSP observed after anaesthesia was due to a stress response and therefore under the control of the pituitary-adrenal axis, ewes were treated with ACTH, dexamethasone or saline only. A further group of sheep were exposed to a barking dog for 10 min. No change in FSP levels compared with pretreatment levels or saline-treated controls were noted following any of these treatments.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Human recombinant inhibin A and testosterone act directly at the pituitary to suppress plasma concentrations of FSH in castrated rams.

The roles of inhibin and testosterone in the negative feedback control of the secretion of FSH were explored in experiments using castrated rams administered human recombinant inhibin A (hr-inhibin) and testosterone propionate (TP). Two experiments were conducted in the non-breeding season. In experiment 1, two groups of long-term castrated rams (wethers) were treated with an i.v. injection of either vehicle or hr-inhibin in two doses (25 and 50 micrograms) given 2 weeks apart. Plasma concentrations of FSH, measured by radioimmunoassay, were suppressed significantly (P < 0.01) and equally by both doses of hr-inhibin with a mean (+/- S.E.M.) maximal suppression of FSH of 19.9 +/- 2.60% occurring 6-10 h after injection. In experiment 2, hypothalamo-pituitary disconnected (HPD) wethers given 125 ng gonadotrophin-releasing hormone (GnRH) every 2 h, were treated with vehicle or 25 or 50 micrograms hr-inhibin before or after treatment (32 mg/day) with TP. A cross-over design was used so that each wether was treated with vehicle and hr-inhibin. Treatment with TP significantly (P < 0.001) suppressed plasma concentrations of FSH by 56%. Both doses of hr-inhibin were similarly effective in significantly (P < 0.05) suppressing plasma concentrations of FSH causing a mean suppression of 31.1 +/- 5.60% 6-10 h after injection. The suppressive effect of hr-inhibin was significantly (P < 0.05) increased when the wethers were treated with TP to a mean suppression of 50.7 +/- 5.6% 6-10 h after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Characterisation of adult Sertoli cell cultures from cryptorchid rats: inhibin secretion in response to follicle-stimulating hormone stimulation.

Testes from adult (90-120-day-old) rats, which had been made cryptorchid 28 days previously, were dispersed by successive treatment with trypsin, collagenase and hyaluronidase. The resulting crude cell suspension was fractionated on discontinuous Percoll density gradients to yield five distinct cell bands (1-5), at the interface between successive layers of Percoll. Crude cells and purified fractions were cultured for up to 7 days, and inhibin was subsequently measured in the media by radioimmunoassay and in vitro bioassay. Sertoli cells from density gradient bands 2 (1.03-1.04 g/ml) and 3 (1.04-1.05 g/ml) showed minimal germ cell or peritubular cell contamination, as determined by morphological and histochemical techniques. Cells from these bands secreted significantly higher levels of immunoactive inhibin/microgram DNA/48 h under both basal and either follicle-stimulating hormone (FSH)- (100 ng/ml) or dibutyryl cAMP-stimulated (100 micrograms/ml) conditions than did cells from the other bands. While there was a decline in basal secretion of inhibin with increasing duration of culture, the capacity of the purified Sertoli cells (bands 2 and 3) to respond to both FSH and dibutyryl cAMP increased over the culture period. The addition of dibutyryl cAMP (31.25-500 micrograms/ml) to the purified Sertoli cells also caused a stimulation of bioactive inhibin. Immunoactive inhibin production by purified Sertoli cells was unaffected by the addition of either rat LH (8 ng/ml) or testosterone (10(-6) M). The data describe a method for the isolation of adult Sertoli cells from cryptorchid testes, and demonstrate their responsiveness to both FSH and dibutyryl cAMP in vitro using the measurement of immunoactive inhibin as a marker of Sertoli cell function.

Animals↗
PubMed1992

The physiology of testicular inhibin and related proteins.

The roles of inhibin and related proteins in the male remain unclear, although it is becoming increasingly evident that they play a part in FSH regulation and testicular function, including spermatogenesis. The difficulties associated with these questions have been the limited availability of inhibin and related proteins for in vivo studies, the absence of specific assay methods, and the unclear relationship of inhibin and testosterone in the regulation of FSH secretion. With the availability of human recombinant preparations and the current development of new assays, it is anticipated that many of these questions will be resolved.

Animals↗
PubMed1992

Quantitative ultrastructural analysis of sperm tails reveals flagellar defects associated with persistent asthenozoospermia.

Sperm tail morphology was examined in 10 infertile asthenozoospermic men to determine whether poor sperm motility was caused by ultrastructural defects of the flagellum. In this quantitative analysis, the numbers of outer doublet and central pair microtubules, outer and inner dynein arms and radial spokes were counted in transverse sections of 75 axonemes from each patient and compared with similar data previously collected from 10 men with normal semen characteristics. Four patients had axonemal defects: two had severe microtubule abnormalities and two had more subtle but statistically significant deficiencies of dynein arms. These abnormalities would not have been detected by more commonly used qualitative examination. Three patients had no detectable ultrastructural abnormalities of the sperm tail, possibly indicating a metabolic deficiency. A further three patients had mid-piece abnormalities. Two had few, if any, flagellar mitochondria and the third patient had irregular and disorganized mitochondria. Quantitative ultrastructural analysis has revealed axonemal abnormalities in seven of 10 patients with previously unexplained asthenozoospermia.

Humans↗
PubMed1992

Inhibin and inhibin alpha-chain precursors are produced by immature rat Sertoli cells in culture.

Stimulation of Sertoli cells from immature rats with dibutyryl cyclic (dbc) AMP resulted in a decrease in the ratio of inhibin biological (B):immunological (I) activities in vitro. To establish the basis for this decrease, culture medium from Sertoli cells stimulated with dbcAMP was fractionated by dye-affinity chromatography, reverse-phase HPLC, and preparative PAGE. Two peaks of inhibin activity were identified: a predominantly bioactive 29-kDa peak I material (B:I ratio = 5.0) and a bio-inactive, immunoactive 27-kDa peak II material (B:I ratio = 0.1). Evidence of a subunit structure was established by iodination and immunopurification using an inhibin alpha-subunit antiserum. On reduction, peak I (29-kDa) material showed bands of 19 kDa and 14 kDa, whereas peak II (27-kDa) material showed a single 20-kDa band. On the basis of HPLC retention position, molecular mass, evidence of subunit structures and their molecular masses, and inhibin in vitro bio- and immunoactivities, peak I and II materials were most likely inhibin and the alpha-subunit precursor protein pro-alpha C. Western blotting of Sertoli cell culture medium using antiserum directed against the NH2 terminal region (alpha N) of the alpha-subunit precursor also indicated the presence of 24-kDa alpha N. It is concluded that after dbcAMP stimulation, Sertoli cells produce 29-kDa inhibin and the alpha-subunit precursor proteins pro-alpha C and alpha N. The production of the alpha-subunit precursor in addition to inhibin provides an explanation for the decrease in the inhibin B:I ratio following dbcAMP stimulation of Sertoli cells in culture.

Animals↗
PubMed1992

Circulating maternal immunoreactive inhibin levels during pregnancy in the rat: effects of oophorectomy, hypophysectomy, hemihysterectomy, delayed implantation and pseudopregnancy.

This study examines the source of inhibin in the maternal circulation of pregnant rats by measuring serum immunoactive inhibin levels following a range of experimental procedures. Ovariectomy at days 7, 13 or 19 of gestation, with maintenance of pregnancy by supplementation with progesterone and oestradiol dipropionate, led to a profound fall of serum inhibin levels in comparison with controls, demonstrating that the ovary is a major source of circulating inhibin. This conclusion was supported by the inhibition of the late rise (days 16-22) in serum inhibin in pregnant rats which were hypophysectomized on day 15 and maintained with oestrogen and progesterone supplementation. These data support the view that the rise in serum inhibin from days 16 to 22 is due to re-activation of follicular development in preparation for the post-partum oestrus. Reduction of fetal numbers by hemihysterectomy on days 7, 13 or 19 did not alter serum inhibin levels. Induction of delayed implantation by ovariectomy on day 3 and progesterone supplementation together with initiation of reimplantation by the addition of oestradiol dipropionate on day 7 or 11 did not significantly alter inhibin levels. The induction of pseudopregnancy by mating to vasectomized rats did not result in the maintenance of stable serum inhibin levels until oestrous cycles recommenced. Taken together, the studies have identified the ovary as the predominant source of circulating maternal inhibin levels throughout pregnancy in the rat.

Animals↗
PubMed1992

Characterization of inhibin and related proteins in bovine fetal testicular and ovarian extracts: evidence for the presence of inhibin subunit products and FSH-suppressing protein.

Bovine fetal gonads have been shown previously to contain inhibin bio- and immunoactivity although the ratio of these activities was markedly lower in testicular compared with ovarian extracts throughout gestation. The basis for this difference is examined in this study. Fetal testicular and ovarian high-speed supernatant preparations from bovine fetuses aged 180 to 270 days of gestation were sequentially fractionated by dye affinity chromatography, gel permeation chromatography, reversed phase high-performance liquid chromatography and preparative polyacrylamide gel electrophoresis and monitored by inhibin radioimmunoassay and in-vitro bioassay. Three immunoactive fractions were identified in testicular extracts with molecular masses of 30 kDa (Peak I), 43 kDa (Peak IIa) and 29 kDa (Peak IIb). Peak I material only was bioactive. On the basis of these characteristics, Peak I is probably 31 kDa inhibin as previously described, and Peaks IIa and IIb are probably different inhibin alpha subunit precursor fragments. In ovarian extracts, two bio- and immunoactive fractions were identified with molecular masses of 30 kDa (Peak I) and 29 kDa (Peak II). On the basis of size, and biological and immunological activities, the ovarian extract Peak I material is probably bovine 31 kDa inhibin, while the Peak II material is probably a novel inhibin-like protein. FSH-suppressing protein (or follistatin) bio- and immunoactivities were also identified in both testicular and ovarian extracts. It is concluded that the low ratio of inhibin biological/immunological activity in testicular extracts is attributed to the presence of high concentrations of immunoactive alpha subunit precursor fragments which are low to non-detectable in ovarian extracts. These results support our previous hypothesis that, in contrast to the ovary, the inhibin alpha subunit is produced in excess in the fetal testis.

Animals↗
PubMed1992

The axonemal ultrastructure of spermatozoa from men with asthenospermia.

OBJECTIVE: To determine with the use of transmission electron microscopy (TEM) the proportion of patients with the semen pattern of severe asthenospermia (less than 20% motility) that have an abnormality of sperm axonemal structure as the basis for this disorder. DESIGN: Transverse sections of sperm tail axonemes were quantitatively analyzed, and the mean frequency per axoneme of the doublet microtubules, central pair, outer dynein arms, inner dynein arms, and radial spokes were determined. SETTING: Patients were being investigated for male infertility at the Reproductive Medicine Clinic at Monash Medical Centre (Melbourne). Semen samples were processed for and analyzed by TEM in the university laboratory. PATIENTS: Ten asthenospermic patients in whom repeated semen analysis demonstrated a percentage of sperm motility less than 20% were selected. MAIN OUTCOME MEASURE(S): The main measure was the quantitative analysis of sperm axonemes. The hypothesis that a reduction of axonemal components causes lowered motility derived from the results. RESULTS: Individual asthenospermic patients demonstrated significant reductions in at least three axonemal structures when compared with the normal mean. Statistical analysis of the grouped data showed that all axonemal components were significantly lower than the normal mean. CONCLUSIONS: The consistent reduction of axonemal components strongly suggests that axonemal deficiencies are the cause of lowered motility in asthenospermic patients.

Adult↗
PubMed1991

The role of calcium in luteinizing hormone/human chorionic gonadotrophin stimulation of Leydig cell immunoactive inhibin secretion in vitro.

The mechanism by which luteinizing hormone (LH) stimulates Leydig cell immunoactive inhibin (I-inhibin) secretion was investigated using Percoll-purified adult rat Leydig cells. Using a maximally stimulating dose of LH (16 ng/ml). Leydig cell I-inhibin secretion was non-detectable at 1-2 h of incubation, but subsequently increased at all time points during a 25 h incubation period. LH stimulated both Leydig cell content and release of I-inhibin. Increasing concentrations of LH stimulated both inhibin and testosterone immunoactivity in the incubation media over a similar dose-response range, with a 2- to 4-fold rise in I-inhibin secretion at maximal doses of LH. Dibutyryl cAMP stimulated testosterone secretion in a manner similar to that of LH, but I-inhibin secretion was less sensitive than testosterone and a significant stimulation was observed only at the highest doses (200-1000 micrograms/ml). LH-stimulated I-inhibin secretion was significantly decreased when Leydig cells were incubated in calcium-depleted (0.15 mM Ca2+ + 1 mM EGTA) or low [Ca2+] media (0.15 mM) as compared to normal (1.15 mM) or high [Ca2+] (2-5 mM) media. In contrast, LH-stimulated testosterone secretion remained unchanged by altering extracellular [Ca2+], and although decreased in the presence of EGTA, testosterone secretion remained significantly greater than basal levels. Furthermore both diltiazem and verapamil completely blocked the LH and dibutyryl cAMP-stimulated increase in Leydig cell I-inhibin, but did not reduce either LH or dibutyryl cAMP-stimulated testosterone production to basal levels. We conclude that LH stimulates both I-inhibin synthesis and release by adult rat Leydig cells in culture, by mechanisms involving calcium.

Animals↗
PubMed1991

Young's syndrome (obstructive azoospermia and chronic sinobronchial infection): a quantitative study of axonemal ultrastructure and function.

The ultrastructure and function of nasal cilia and sperm tails were examined in 23 men with Young's syndrome and compared with data previously collected from 10 normal subjects. Quantitative electron microscopic assessment showed that sperm tails from patients with Young's syndrome contained significantly fewer central pair microtubules, radial spokes, and inner dynein arms, and their cilia contained less inner dynein arms than normal subjects. The Young's syndrome patients had normal in vitro ciliary beat frequency (11.4 +/- 0.9 Hz), and 12 of the 23 had normal nasal mucociliary clearance (15.0 +/- 5.0 minutes). However, the remaining 11 had markedly abnormal nasal mucociliary clearance in vivo. In these patients, the deficiency of ciliary inner dynein arms did not appear to affect ciliary function in vitro but may under mucus loading lead to abnormal in vivo ciliary function. The consistent abnormalities shown in cilia and sperm tails, though apparently minor, constitute a common factor in both the reproductive and respiratory tracts which may, in combination with abnormalities in the in vivo environment, lead to the features of Young's syndrome.

Adult↗
PubMed1991

Elevation of follicular phase inhibin and luteinizing hormone levels in mothers of dizygotic twins suggests nonovarian control of human multiple ovulation.

OBJECTIVE: To determine whether multiple ovulation in mothers of spontaneous dizygotic (DZ) twins is because of higher hypothalamic stimulation or is in response to lower serum levels of ovarian inhibin. DESIGN: Serum hormone levels were measured at five times throughout the cycle in a sample of eight mothers of DZ twins and paired controls. On day 12, ovarian ultrasonography was performed. SETTING: Blood samples were collected in participants' homes except on day 12 when they were collected at the ultrasonography clinic. PATIENTS, PARTICIPANTS: Human volunteers who had at least one set of spontaneous DZ twins were paired with controls matched for age and parity. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Serum inhibin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels on approximate cycle days 1,2,8,12, and 21. RESULTS: Serum inhibin levels were elevated throughout the cycle (significantly on day 1) in mothers of DZ twins. Also elevated were early follicular FSH levels, LH levels throughout the follicular phase (significantly on days 1,2, and 8), and early to midfollicular E2 (significantly on day 8) in DZ mothers, indicative overall of greater follicular activity. CONCLUSION: It is concluded (1) that the primary cause of multiple ovulation in humans is not a decrease in inhibin secretion from the ovary; (2) the increased secretion of FSH and LH may be caused by elevated secretion of, or sensitivity to gonadotropin-releasing hormone; and (3) the elevated inhibin and E2 levels are a response to increased gonadotropin release.

Female↗
PubMed1991

Concentrations of immunoactive inhibin in serum during human pregnancy: evidence for an ovarian contribution.

Immunoactive inhibin (ir-inhibin) concentrations in maternal serum during normal human pregnancy have been established in two separate studies employing cross-sectional and longitudinal sampling regimes. Ir-inhibin concentrations rose from the mid-luteal phase (geometric mean + 95% confidence intervals 1.490 (1.086-2.028) U mL-1) to peak at week 11 of gestation (3.77 (3.26-4.35) U mL-1), declined to a plateau from 14 to 25 weeks with means ranging from 1.8 to 2.3 U mL-1, and subsequently rose slowly to a peak of 6.53 U mL-1 at 41 weeks. In the longitudinal study, similar results were obtained and no differences were found in maternal inhibin levels in women carrying male or female fetuses. Paired cord blood and maternal samples showed no significant difference in ir-inhibin concentrations irrespective of the sex of the fetus. However, in all such pregnancies amniotic fluid ir-inhibin levels were 2-3 fold greater than maternal or fetal levels raising the possibility that the amnion may secrete inhibin. In 12 women without functional ovaries in whom a singleton pregnancy was achieved by donation of oocytes and in vitro fertilization, the ir-inhibin levels showed a similar pattern in the first trimester of pregnancy but the concentrations achieved were markedly lower (peak 1.1 U mL-1 at 9 weeks). In five women from the group in whom samples were available late in gestation, three showed greater than normal levels and two had subnormal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Amniotic Fluid↗