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Biomedical subjects

H M Fraser

Publications and source records attributed to H M Fraser.

At least 91 records · Page 5Linked to original sources
PubMed1991

Control of progesterone and inhibin secretion during the luteal phase in the macaque.

We investigated the temporal relationship between serum concentrations of progesterone and immunoreactive inhibin after treatment with an LHRH antagonist ([N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10++ +] -LHRH), during the mid-luteal phase in the macaque. Further, in an attempt to obtain a model of transitory suppression of luteal function, the effect of treatment with the LHRH antagonist for 1, 2 or 3 days during the mid-luteal phase on serum concentrations of progesterone and immunoreactive inhibin was compared. Differences in the pattern of decline of the two hormones were observed. Progesterone concentrations fell by 6 h after antagonist administration while inhibin was not significantly suppressed until 48 h. Treatment with three injections of LHRH antagonist caused a sustained suppression of luteal function as shown by low serum concentrations of progesterone and inhibin. Recovery of progesterone and inhibin secretion was observed in two out of six macaques treated with two injections of antagonist and in three out of six treated with a single injection. Therefore, with the regimens of LHRH antagonist which we employed this approach was not conducive to obtaining a reliable transitory suppression of luteal function. To elucidate further the gonadotrophin control of inhibin, six macaques were treated with three injections of the LHRH antagonist to induce a permanent suppression of luteal function but received concomitantly either human chorionic gonadotrophin (hCG) or human FSH daily for 5 days (n = 3 per group). FSH failed to prevent the antagonist-induced fall in progesterone and inhibin while hCG treatment completely reversed the inhibitory effects of the LHRH antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Immunocytochemical localization of inhibin alpha-subunit in the human corpus luteum.

The localization of inhibin alpha-subunit within the human corpus luteum was investigated. The antiserum used was raised in sheep against the first 1-23 amino acid sequence of the N-terminus of the human inhibin alpha-subunit. Using the avidin-biotin immunoperoxidase technique, intense immunostaining was localized within the granulosa-lutein cells of the corpus luteum, with absence of staining in the theca-lutein cells and surrounding ovarian tissue. Similar distribution of inhibin alpha-subunit immunostaining was observed in 12 corpora lutea obtained during the early, mid- and late-luteal phases and no changes in intensity were apparent at these different stages. Negative controls were obtained by applying antiserum which had been preabsorbed overnight with excess inhibin peptide in place of primary antiserum and also normal nonimmune sheep serum as a substitute for primary antiserum. These results provide further evidence that the human corpus luteum is a significant source of immunoreactive inhibin during the normal human menstrual cycle. The specific localization within the granulosalutein cells of the corpus luteum suggests that inhibin alpha-subunit production may originate from a discrete cell population within the human corpus luteum.

Corpus Luteum↗
PubMed1990

Inhibitory effects of treatment with an LHRH antagonist on the ovulatory cycle are reduced when administered during the late follicular phase.

To compare the effects of transitory suppression of pituitary gonadotropin secretion by an LHRH antagonist at the mid or late follicular phase of the menstrual cycle, adult macaques with normal menstrual cycles were treated with an LHRH antagonist (N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 ]LHRH (detirelix) administered subcutaneously at a dose of 300 micrograms/kg, daily for 3 days beginning either during the mid or late follicular phase. In all eight animals treated during the mid follicular phase, serum concentrations of LH and FSH declined and remained suppressed for 4 days. This caused a fall in serum concentrations of estradiol and the expected ovulation failed to occur. During the recovery period a marked rise in serum FSH occurred followed by normal follicular development and ovulation 14.8 +/- 0.6 days after the last injection of antagonist. Of the 9 macaques given the same treatment during the late follicular phase, only in two was the expected rise in serum progesterone prevented. In 4 of the animals a transitory suppression in LH and estradiol was observed but this was followed by a recovery and occurrence of an LH surge and rise in serum progesterone indicating ovulation during the course of treatment. In the remaining 3 macaques treatment commenced on the day of the initiation of the LH surge and was associated with a progesterone rise of normal duration but lower than normal magnitude during the early luteal phase. These results show that LHRH antagonist treatment causes rapid inhibition of pituitary-ovarian function when administered up to the mid follicular phase of the cycle and is effective in blocking ovulation. The suppressive effects of the antagonist are reduced when administered during the late follicular phase. This may be due to decreased dependence of the pituitary gonadotrope on LHRH at this time and on decreased dependence of the dominant follicle on the gonadotropins.

Animals↗
PubMed1990

Long-term suppression of ovarian function by a luteinizing-hormone releasing hormone agonist implant in patients with endometriosis.

Ten endometriosis patients received luteinizing hormone releasing hormone (LH-RH) agonist (buserelin) implant injections (6.6 mg subcutaneously) at days 0, 42, 84 and 126. Serum LH and follicle-stimulating hormone (FSH) were lowered by day 14. Luteinizing hormone remained at basal concentrations while FSH returned to values in the low-normal range of the menstrual cycle by day 35. At the end of the luteal phase during which treatment commenced, estrone and pregnanediol declined and remained at postmenopausal or early follicular phase values until days 305 to 460. Time to first ovulation ranged from 321 to 481 days after starting treatment. After the initial menstruation, only three instances of bleeding occurred during treatment. Pelvic pain was relieved or markedly reduced by day 42 and remained absent throughout the period of ovarian suppression. These results indicate the potential of a long-acting LH-RH agonist implant to form the basis for the treatment of symptomatic endometriosis.

Administration, Intranasal↗
PubMed1990

Inhibin secretion after treatment with an LHRH agonist and subsequent ovarian hyperstimulation induced by FSH in the macaque (Macaca arctoides).

The effect of ovarian hyperstimulation with 'pure' FSH on serum concentrations of immunoreactive inhibin in macaques in which endogenous gonadotrophin secretion and ovarian activity had been suppressed by an LHRH agonist implant was studied. Four stump-tailed macaques were treated with an LHRH agonist implant in the early follicular phase of the cycle. After a transient stimulatory phase oestradiol secretion was markedly suppressed, and the rises in progesterone and inhibin observed after ovulation were absent. At 8 weeks after implant administration, when serum LH was only just detectable, FSH (Metrodin) was administered to the LHRH agonist-treated macaques once daily for 9 days (75 i.u. on Day 0, 35 i.u. Days 1-8). FSH treatment stimulated a marked increase in oestradiol and immunoreactive inhibin secretion in the absence of a rise in serum progesterone concentrations. Comparison of the FSH-induced pattern of inhibin secretion with the profile during the normal menstrual cycle showed that during the normal cycle inhibin is secreted into the peripheral blood almost exclusively during the luteal phase in the macaque, but stimulation of follicular development by exogenous FSH was associated with a rise in inhibin concentrations in the absence of ovulation. These results suggest that this non-physiological rise in inhibin may be one of the factors involved in the changes in endogenous gonadotrophin secretion which can occur during ovarian hyperstimulation.

Animals↗
PubMed1990

Physiological roles of chicken LHRH-I and -II in the control of gonadotrophin release in the domestic chicken.

The physiological roles of chicken LHRH-I and -II (cLHRH-I and -II) in the regulation of gonadotrophin release were investigated in the domestic chicken. Measurements of the neuropeptides, using specific radioimmunoassays, in brain sections cut in three planes or in grossly dissected brain areas, showed that cLHRH-II occurs in low amounts throughout the brain whereas cLHRH-I is most abundant in the diencephalon. Within the diencephalon, the largest amount of cLHRH-I occurred in the median eminence of the hypothalamus. The amount of cLHRH-I in the median eminence was higher (P less than 0.05) in laying than in out-of-lay hens. No cLHRH-II was detected in the median eminence in either reproductive state. The amount of cLHRH-I in the hypothalamus was increased (P less than 0.05) in cockerels at the onset of puberty and in somatically immature birds after castration. There were no correlated changes in the amounts of hypothalamic cLHRH-II measured in the same experimental samples. Active immunization of laying hens against cLHRH-I but not against cLHRH-II resulted in the complete regression of the reproductive system and a depression in the concentration of plasma LH. These observations, taken together, suggest that gonadotrophin secretion in the hen is more likely to be directly regulated by cLHRH-I than by cLHRH-II.

Animals↗
PubMed1990

Pituitary-testicular function is suppressed by an LHRH antagonist but not by an LHRH agonist in the marmoset monkey.

The use of pituitary desensitization by an LHRH agonist (buserelin) to examine pituitary-testicular function was investigated in a New World primate. Six adult male marmoset monkeys were injected s.c. with an LHRH agonist implant (1.5 mg in a rod 0.5 cm long). Pharmacokinetics, determined by radioimmunoassay of urinary buserelin, revealed a rapid initial release of the agonist followed by a steady decline during a 200-day period. The LHRH agonist treatment resulted in a rapid initial rise in plasma LH followed by a return to mean values similar to those seen in the control samples by 7 days after implantation. Using the present protocol, no evidence of subsequent pituitary desensitization or suppression of testicular function was observed, plasma concentrations of LH and testosterone remaining within the normal range during the 200-day study period. In contrast, pituitary-testicular function was suppressed in the male marmoset after blockade of pituitary LHRH receptors by an LHRH antagonist. Five adults were treated with a single s.c. injection of the antagonist [Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-Ser(Rha)6,AzGlyNH2(10)]-LHRH at a dose of 300 micrograms/kg. The LHRH antagonist induced a marked suppression of plasma LH and testosterone by 6-8 h, the low levels being maintained for 24-48 h. These results show that, whereas treatment with an LHRH antagonist can inhibit pituitary-testicular function in the male marmoset, it may be that desensitization cannot be induced by the LHRH agonist used.

Animals↗
PubMed1990

Inhibin secretion during the ovulatory cycle and pregnancy in the common marmoset monkey.

Changes in plasma concentrations of immunoreactive inhibin in the reproductively cyclic, pregnant and ovariectomized female marmoset monkey (Callithrix jacchus) were measured with a heterologous radioimmunoassay. The pattern of inhibin secretion in five marmosets studied individually during four consecutive cycles was shown to resemble that of progesterone. In these animals, data were pooled according to stage of cycle on the basis of plasma progesterone concentrations. Mean values for inhibin were 5465 and 4972 U/l during the early and late follicular phase. Concentrations rose during the luteal phase to 8431, 12,246 and 12,557 U/l for the early, mid- and late luteal phase respectively. The hormonal profile of inhibin during the normal cycle is similar in both marmoset and stumptailed macaque; however, the marmoset has a 28-fold greater level of inhibin during the luteal phase. In six marmosets in which pregnancy occurred, inhibin concentrations showed no decline at the end of the conceptual cycle and remained increased with respect to the follicular phase throughout the subsequent gestation. Inhibin levels were non-detectable (less than 1000 U/l) in ovariectomized and acyclic marmosets. These results suggest that the corpus luteum is the major source of inhibin in this New World monkey, in common with man and the Old World primates.

Animals↗
PubMed1989

Rapid inhibitory effects of an LHRH agonist implant on the oestrogen-induced LH surge and the induction of a defective luteal phase after an agonist-induced ovulation in the macaque.

Three experiments were performed to evaluate in detail pituitary--ovarian function during the first 21 days after treatment with a luteinizing hormone releasing hormone (LHRH) agonist implant. First, six adult macaques with normal menstrual cycles received an LHRH agonist implant during the late luteal or early follicular phase. To investigate the rapidly of effects on pituitary responsiveness the macaques were treated with 50 micrograms LHRH at the time of implant (day 0) and at days 4, 10 and 21. Effects on serum LH and FSH were determined on basal samples and at 30 and 60 min. At 4 days, LH and FSH were elevated as a result of the implant and no further response to LHRH challenge was observed. By 10 days, LH had returned to the pretreatment range but was unresponsive to the LHRH challenge; by 21 days, LH was lower than the pretreatment range and again LHRH failed to induce a significant response. Serum FSH concentrations also declined during treatment, but in contrast to LH, a significant response to LHRH was observed on day 10. Secondly, the ability to respond to an oestrogen provocation test was examined in six macaques with normal menstrual cycles treated with the LHRH agonist implant during the late luteal or early follicular phase and 7 days later with 50 micrograms/kg oestradiol benzoate in oil s.c. to induce an LH/FSH surge. In control animals, oestrogen treatment resulted in a positive feedback surge, reaching a maximum at 48 h post-injection. In contrast, agonist-treated animals showed complete abolition of the expected increase in LH and FSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Testosterone regulation of proopiomelanocortin messenger ribonucleic acid in the arcuate nucleus of the male rat.

GnRH regulates the secretion of LH and FSH, which stimulate the secretion of testicular hormones. Acting in a reciprocal fashion, these hormones, including testosterone and inhibin, exert a negative feedback effect on GnRH and gonadotropin secretion. Endogenous opioid peptides (EOPs) have been implicated to play a role in steroid-mediated regulation of gonadotropin secretion. In this context, certain steroid hormones (e.g. testosterone) increase EOP activity and ultimately inhibit GnRH secretion; however, the cellular mechanism by which this occurs is unknown. beta-Endorphin is one of these EOPs, and it is derived from a larger precursor molecule, POMC. We tested the hypothesis that testicular hormones and testosterone, in particular, stimulate POMC gene expression in the arcuate nucleus of the male rat brain. First, we compared POMC mRNA levels between intact and castrated male rats. Adult male rats were killed 4 days (n = 4) and 21 days (n = 5) after castration. Intact animals (sham-operated; n = 6) were used as controls. Using in situ hybridization and a computerized image analysis system, we measured the POMC mRNA content in individual cells of the arcuate nucleus. POMC mRNA signal was significantly lower (P less than 0.0003) in both 4-day (126 +/- 2 grains/cell) and 21-day (117 +/- 5 grains/cell) castrates than in controls (142 +/- 2 grains/cell). In a second experiment we tested whether testosterone would reverse the castration-induced loss of POMC message. Again, we castrated animals and immediately implanted them with either empty (sham; n = 6) or testosterone-containing Silastic implants (n = 5) of a size that would deliver physiological levels of testosterone (3.6 +/- 1.5 ng/ml). We observed that testosterone-treated animals had significantly higher levels of POMC mRNA signal (121.8 +/- 3.8 grains/cell) than sham-treated castrates (111.4 +/- 3.6 grains/cell; P less than 0.03) and that the testosterone-treated castrates had POMC mRNA signal levels indistinguishable from those of intact controls (122.0 +/- 1.1 grains/cell). These observations lend credence to the theory that one mechanism by which testosterone may regulate GnRH secretion is by increasing the synthesis of POMC in the arcuate nucleus.

Animals↗
PubMed1989

Luteinizing hormone releasing hormone agonist for contraception in breast feeding women.

During the period of lactation there is a need for a reliable method of contraception since the suppressive effects of lactation on ovulation decline as the duration of breastfeeding is decreased. The aim of this study was to establish that chronic treatment with a LHRH agonist would prevent ovulation throughout the period of lactation and to evaluate the effects of the treatment on estrogen production, bleeding patterns, and nursing practice. Starting 6 weeks postpartum, nine mothers took 300 micrograms LHRH agonist (buserelin), intranasally once daily for the remainder of the duration of breastfeeding [216 +/- 18 days (mean +/- SEM)]. Urinary excretion of LH, estrone, and pregnanediol was compared to that of nine control breastfeeding mothers. In the control subjects follicular development, as assessed by rises in estrone, was minimal during the first 90 days of the study. Thereafter, phases of estrogen secretion were observed. Ovulation occurred in seven of the nine mothers on one to six occasions; time to first ovulation varied from 90-296 days. In the women taking buserelin, LH and estrone were initially stimulated for 1 and 2 weeks, respectively, then declined to basal levels. No ovulations occurred in the treated group. In six treated mothers only minor fluctuations in estrone were observed during the remainder of agonist treatment. In three subjects more frequent and sustained episodes of estrogen secretion were observed, but in contrast to the controls the rises in estrone were not followed by a typical LH surge or a rise in pregnanediol. Bleeding occurred in eight of the nine of the control mothers on one to seven occasions during the study period. The first bleed in five of the mothers was anovular, while other menstrual bleeds occurred in response to falling levels of pregnanediol. Of the mothers taking buserelin, one was amenorrhoeic, and five had only one light bleeding associated with the initial stimulation of estrone. Of the three women with continued fluctuations of estrone, one had three light bleeds, one experienced frequent spotting, while one had regular bleeding. No other side-effects, such as hot flashes or changes in nursing practices, were reported. Our results indicate that LHRH agonist treatment has the potential to be developed as an acceptable method of contraception during the postpartum period. The duration of treatment may be long enough to have a significant effect on maternal-infant well-being without encountering significant problems associated with low estrogen output.

Administration, Intranasal↗
PubMed1989

Controlled release of a GnRH agonist from a polyhydroxybutyric acid implant: reversible suppression of the menstrual cycle in the macaque.

The use of polyhydroxybutyric acid as a matrix for delivery of the GnRH agonist buserelin was studied in adult stumptailed macaques with regular menstrual cycles. This material contained 5.0 mg buserelin in a disk of 0.6 cm diameter and 0.15 cm thickness. The effects on pituitary-ovarian function were examined and buserelin release profiles from 30,000 and 150,000 molecular weight polyhydroxybutyric acid matrices were compared. In an attempt to reduce the high initial release rate of buserelin from these disks, and to prolong the effective period of release, implants of 30,000 molecular weight were coated with cyanoacrylate. The implants were removed after 28, 35 or 42 days for the 30,000, the 150,000 and the coated implants, respectively. The urinary excretion profile for the agonist revealed a high initial release of buserelin from these implants followed by a rapid decline. The coated disks released significantly less (p less than 0.05) buserelin over the first 3 days than did either of the uncoated implants, but maintained release of the agonist over a longer period. Inhibition of ovulation and suppression of estradiol secretion lasted for the duration of treatment in 3 of 5 macaques receiving the 30,000 implant, and in 5 of 5 receiving the 150,000 or the coated implant. In 3 macaques in whom the coated implant was left in situ, ovulation was suppressed for 104 +/- 3.7 days. These results demonstrate that a polyhydroxybutyric acid matrix can be used as a depot formulation for a GnRH agonist and that improved control of release of the agonist can be achieved by coating such implants with cyanoacrylate. This approach may be useful in experimental and clinical situations and may be applicable for delivery of other peptide hormones.

Animals↗
PubMed1989

Blockade of the oestrogen-induced LH surge in the ovariectomized common marmoset (Callithrix jacchus) by an LHRH antagonist.

Six long-term ovariectomized adult marmoset monkeys were treated at 0 h with 35 micrograms oestradiol benzoate s.c. to induce an LH surge. They were also treated with detirelix (an LHRH antagonist) at 0 h, 12 h and 24 h (Exp. 1), or at 0 h and 24 h (Exp. 2) at a dose of 300 micrograms/kg s.c., or received the detirelix vehicle alone at 0 h, 12 h and 24 h (Exp. 3). All animals received the three treatments, with at least 4 weeks between experiments. Blood samples were collected at 0 h and at 6-12 h intervals for 72 h after oestradiol for the determination of plasma LH by bioassay. In control animals, oestrogen treatment resulted in a decline in plasma LH from 30.0 +/- 5.8 at 0 h to 12.8 +/- 2.6 ng/ml at 6 h (negative feedback), followed by a positive feedback surge, reaching a maximum of 148.0 +/- 34.6 ng/ml at 24 h. Values then declined to pretreatment levels by 56 h. In contrast, antagonist-treated animals showed complete abolition of the expected increase at 24 h, the low levels of the negative feedback phase being maintained for 36-72 h. These results show that hypothalamic LHRH release is essential during the oestrogen-induced LH surge, and that a direct oestrogen-induced component at the pituitary level is not expressed in the absence of LHRH in the marmoset.

Animals↗
PubMed1989

Immunoreactive inhibin concentrations in serum throughout the menstrual cycle of the macaque: suppression of inhibin during the luteal phase after treatment with an LHRH antagonist.

Concentrations of immunoreactive inhibin in serum samples collected daily from six adult stumptailed female macaques during normal menstrual cycles were measured with a heterologous radioimmunoassay. Serum inhibin concentrations were low during the follicular phase of the cycle. After ovulation they began to rise, reaching a plateau between 8 and 11 days, before falling in parallel with the decline in luteal progesterone secretion. The dependence of the inhibin secretion by the corpus lutem on pituitary gonadotrophins was investigated by the administration of an LHRH antagonist [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 ]LHRH once daily for 3 days beginning on day 8 of the luteal phase in six macaques. LHRH antagonist treatment markedly suppressed serum levels of inhibin and progesterone and these remained at the level found in the follicular phase for the remainder of the luteal phase. These results show that inhibin in the macaque is secreted into the peripheral blood almost exclusively during the luteal phase, being highest when FSH is at its nadir. Suppression of serum inhibin concentrations during the luteal phase by LHRH antagonist suggests that its secretion is integrated with the LH control of the corpus luteum.

Animals↗
PubMed1988

LHRH analogues: their clinical physiology and delivery systems.

LHRH, produced in the hypothalamus from a precursor molecule, forms an essential link between the central nervous system and the anterior pituitary gland and the control of reproduction. It is secreted in a pulsatile manner and in patients who lack the hormone it is necessary to replace LHRH in a near-physiological mode. Chronic exposure of the pituitary gonadotrophes to LHRH by infusion and to LHRH agonists leads to suppression of pituitary-gonadal function by mechanisms which involve: 1. The over-riding of pulsatile gonadotrophin release; 2. Desensitization of the gonadotrophe, particularly at the post-receptor level; 3. Inducing production of altered forms of gonadotrophin with reduced biological activity. An effective and reversible suppression of pituitary-ovarian function can be readily obtained by administering LHRH agonists by nasal spray or by slow-release depot formulations lasting 1-3 months. LHRH agonist therapy is without serious side-effects but more work is required to evaluate the role of oestrogen in maintaining bone density. Suppression of the gonadotrophe can also be obtained by the more conventional approach of receptor blockade by LHRH antagonists. These have the advantage of causing immediate pituitary suppression but higher doses are required than for agonists. LHRH antagonists suitable for clinical evaluation have only recently become available.

Female↗
PubMed1988

Assessment of the role of Leydig cell products other than testosterone in spermatogenesis and fertility in adult rats.

Adult male rats were treated with ethane dimethanesulphonate (EDS) to destroy the Leydig cells and were then supplemented for 3-10 weeks with testosterone esters (TE) by injection every 3 days. The latter treatment prevented Leydig cell regeneration but maintained quantitatively the androgen-dependent aspects of spermatogenesis, as judged by germ cell counts at stage VII of the spermatogenic cycle. Other than the absence of Leydig cells, the testes of EDS-treated, TE-supplemented rats showed only two morphological changes, (1) the appearance of mast cells throughout the interstitium, and (2) a 3- to 4-fold increase in the number of degenerating germ cells (secondary spermatocytes) at stages XIV-I; this was reflected in a significant decrease in the ratio of spermatids to pachytene spermatocytes at stage VII. These changes were not observed in either oil-treated or TE-treated control rats although similar, but less marked, changes in cell degeneration at stages XIV-I were observed in rats actively immunized against oxytocin. Epididymal sperm number was reduced marginally (approximately 15%) in EDS-treated, TE-supplemented rats while sperm motility was affected even less. In a serial mating trial, some of these treated rats showed evidence of subfertility/infertility, but this was mostly transient and may have been the result of epididymal effects of EDS. These results suggest that Leydig cell products other than testosterone are not essential for maintenance of spermatogenesis and fertility in rats, although because of increased germ cell degeneration during the final stages of meiosis (perhaps as the result of oxytocin withdrawal), a small reduction in sperm count may occur.

Animals↗