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Biomedical subjects

S F Lunn

Publications and source records attributed to S F Lunn.

At least 37 records · Page 2Linked to original sources
PubMed1994

Blockade of the neonatal rise in testosterone by a gonadotrophin-releasing hormone antagonist: effects on timing of puberty and sexual behaviour in the male marmoset monkey.

In primates, plasma testosterone concentrations are elevated for some 3 months from birth. The function of this rise is uncertain, but studies in rats suggest that its prevention by castration or administration of gonadotrophin hormone-releasing hormone (GnRH) analogues has effects on development and expression of social and sexual behaviours, and adverse long-term effects on fertility. The consequences of suppression of this rise in testosterone by treatment with the GnRH antagonist antide have been investigated in the marmoset monkey. Eight sets of male:male twins were used, one of each set receiving s.c. injections of antide (10 mg/kg), on days 0, 3 and 7, then weekly from birth to 98 days of age, with the twin receiving vehicle only. Plasma samples were taken at weekly intervals for the determination of testosterone concentrations from birth until 2 years of age. Treatment with antide completely abolished the neonatal rise in testosterone seen in control animals. The timing of the onset of the pubertal testosterone rise was not significantly affected by treatment; however, the subsequent pattern of circulating testosterone showed a tendency to decreased plasma concentrations in the neonatally treated group from weeks 25 to 42, relative to controls, and this difference was significant between 43 and 70 weeks. This was associated with a similar depression in bioactive LH concentrations around this time. Thereafter, the testosterone concentrations were similar between treated and control groups. There was no effect of treatment on growth, based on sequential body weight data. At 20 months the animals underwent behaviour tests with ovariectomized females.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Localization of inhibin/activin subunit mRNAs during the luteal phase in the primate ovary.

Localization of inhibin/activin subunit mRNAs within the macaque ovary from the immediate pre-ovulatory period of the menstrual cycle, when serum immunoreactive inhibin begins to rise, to day 9 of the luteal phase, when serum inhibin concentrations are maximal, was investigated using in-situ hybridization. Ovaries were studied on the day of the LH surge (day 0) and on days 2, 5, and 9 of the luteal phase by hybridizing frozen tissue sections with radiolabelled riboprobes specific to the inhibin/activin alpha-, beta A- and beta B-subunits. After autoradiographic exposure for 10 and 21 days, grain concentrations were quantified by image analysis. Moderate expression of alpha-, beta A- and beta B-subunit mRNA was present within the granulosa cells of the pre-ovulatory follicle (day 0). The granulosa-lutein cells of the corpora lutea expressed high levels of alpha-subunit at days 2, 5 and 9. mRNAs for beta A and beta B were detected at low but significant levels in all of the corpora lutea. All healthy antral follicles exhibited a high level of expression of beta B-subunit mRNA in the granulosa cells. On day 2 after ovulation these follicles also expressed high alpha- and moderate beta A-subunit mRNA. On day 9 the beta B-inhibin mRNA in antral follicles was found in association with low expression of the other subunits. Small follicles in ovaries on day 2 expressed moderate alpha- and low levels of beta B-subunit mRNA, while mRNA for beta A was absent. alpha-subunit mRNA expression was present on day 5 while neither beta A- nor beta B-subunit mRNA was detected. On day 9 a proportion of small follicles expressed alpha- and beta A-subunit mRNA. These results demonstrate that marked differences are present in the levels of expression of the three inhibin/activin subunit genes between follicles and the corpus luteum. The predominance of the beta B-subunit mRNA within antral follicles would be consistent with the synthesis of activin. The predominance of the alpha-subunit combined with the low expression of the beta-subunits in the corpus luteum suggests that both biologically active inhibin and free alpha-subunit are produced by the primate corpus luteum.

Activins↗
PubMed1992

Influence of the gonad on the degree of suppression induced by an LHRH agonist implant in the marmoset monkey.

In a previous study pituitary-testicular function was shown to be maintained in a New World primate after the administration of an LHRH agonist implant. In the present study the mechanism of action of the same LHRH agonist (buserelin) on pituitary-gonadal function in the marmoset was investigated and a comparison made between the effects of treatment in three intact males, six adult cyclic females with regular ovulatory cycles, and six long-term ovariectomized animals. These were injected s.c. with an LHRH agonist implant (1.5 mg buserelin in a rod 0.5 cm long). In both the males and intact females, basal plasma LH concentrations were maintained within the normal range throughout the expected duration of agonist action (at least 3 months). Despite this, an absence of response to an LHRH challenge indicated that pituitary desensitization had occurred. In the intact females, ovulation was inhibited in five of six animals, plasma progesterone concentrations initially being maintained but subsequently remaining suppressed until 136 +/- 18 (S.E.M.) days after treatment. Responsiveness to administered LHRH returned prior to onset of return to ovarian cycles. In contrast, in ovariectomized marmosets, plasma LH was markedly suppressed to concentrations which were at or below the limit of detection of the assay and were therefore less than those observed in the buserelin-implanted intact animals. These results show that apparently normal pituitary-gonadal function in this species disguises an underlying pituitary desensitization to LHRH. This allows continuation of testosterone secretion in the male, but in the female ovulation is prevented, presumably as a result of failure of the desensitized pituitary to produce an LH surge.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Immunoneutralization and immunocytochemical localization of inhibin alpha subunit during the mid-luteal phase in the stump-tailed macaque.

The putative endocrine role of inhibin in the control of FSH secretion during the luteal phase in the primate was investigated by immunoneutralization. Antisera against the 1-23 amino acid sequence of the N-terminus of the human inhibin alpha subunit were raised in a ewe and three macaques. Antisera (10-20 ml) were administered to macaques on day 8/9 of the luteal phase and serum samples collected during the treatment cycle and post-treatment cycle for determination of FSH, oestradiol and progesterone. In addition, localization of inhibin within the macaque ovary at this stage of the luteal phase was investigated using the ovine antiserum. Intense immunostaining was localized within the granulosa-lutein cells of the corpus luteum with absence of staining in the theca-lutein cells or other ovarian compartments. Administration of antisera was without significant effect on serum concentrations of FSH when compared with control animals, either during the first 24 h of detailed observation or for the following 10-day period of the late luteal phase and subsequent early follicular phase. These results provide further evidence that the corpus luteum is the major source of inhibin immunoreactivity during the primate menstrual cycle, but fail to support an endocrine role for inhibin in the suppression of FSH secretion.

Animals↗
PubMed1991

Effect of late follicular phase administration of antide on ovulation and inhibin secretion in macaques.

In previous studies, the LHRH antagonist detirelix, administered to stumptailed macaques during the menstrual cycle, was only partially effective in blocking pituitary-ovarian function when given during the late follicular phase. Since the antagonist was suppressive when administered during the early luteal phase, we investigated the ability of antide, a putative long-acting LHRH antagonist, to cause inhibition of the LH surge or luteal function when administered during the late follicular phase. Six animals with regular ovulatory cycles were treated on day 10 of the follicular phase with 1mg/kg antide s.c. All animals demonstrated a continued rise in serum concentrations of estradiol which were followed by an LH surge beginning 2-5 days after antide injection and serum progesterone and inhibin secretion which indicated normal luteal function. In a second experiment, six animals were treated on day 10 of the follicular phase with 3mg/kg antide s.c. In three animals, this caused a fall in serum concentrations of estradiol and the expected LH surge and rises in progesterone and inhibin secretion indicating ovulation failed to occur. In 2 animals, the LH surge was not prevented but the consequential rise in progesterone and inhibin was attenuated. In the remaining animal the cycle appeared unaffected. Pharmacokinetics of antide revealed an initial high release rate during the first 4 days (1mg/kg) or 6 days (3mg/kg) followed by a period of sustained release at a relatively low level. These results show that antide is partially effective in blocking ovulation at a high dose in the macaque and may result in an inadequate luteal phase, presumably as a result of its extended action.

Animals↗
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

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

Naloxone reversal of stress-induced suppression of LH release in the common marmoset.

There is considerable evidence suggesting that endogenous opioid peptides (EOP) might play a role in the defensive response to stressful stimuli. The stress associated with receipt of aggression from a female conspecific and physical restraint for collection of serial blood samples (at 10-min intervals) resulted in a significant (p less than 0.05) suppression of LH secretion in the oestradiol primed ovariectomized marmoset. Administration of the opioid receptor antagonist, Naloxone (1 mg/kg) immediately before and after receipt of aggression completely prevented the stress-induced decrease in LH release. This suggests that EOP may mediate, at least in part, this stress induced decline in LH release in the marmoset.

Aggression↗
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

Systems for collection of urine in the captive common marmoset, Callithrix jacchus.

Two systems are described for the collection of 24 h urine samples from the common marmoset (Callithrix jacchus). Using 84 adult animals, 1210 24-h samples were collected. Mean urinary excretion was 14.4 +/- 7.5 ml/24 h (n = 1210, mean +/- SD). No differences were observed between sexes (for 52 females, 24 h volume = 15.1 +/- 8.0 ml; for 32 males, 24 h volume = 12.5 +/- 6.0 ml). No significant differences were observed between pregnant and non-pregnant females with respect to 24 h urine volume, and bilateral gonadectomy did not influence subsequent urinary excretion in either sex. For 161 pairs of observations, the intake of drinking water (11.7 +/- 10.2 ml/24 h) and the volume of urine excreted (12.6 +/- 7.1 ml/24 h) showed a positive correlation (r = 0.406 d.f. 159, P less than 0.001: y = 0.558x + 4.247).

Animals↗
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↗
PubMed1988

Effects of acute stress on the patterns of LH secretion in the common marmoset (Callithrix jacchus).

Stressful stimuli associated with aggressive encounters and low social rank may affect female fertility in a variety of mammalian species. In these experiments we examined the effects of aggressive encounters and physical restraint in a primate chair on the patterns of LH secretion in ovariectomized, oestrogen-primed female marmosets. Receipt of aggression from a female conspecific, followed by physical restraint for collection of blood samples (at 10-min intervals for 4 h), resulted in marked declines in LH concentrations during oestradiol-induced LH surges in five animals (from 112 +/- 24 micrograms/l to 45 +/- 12 micrograms/l; group means +/- S.E.M.; P less than 0.05). This was due to reductions in LH pulse amplitude rather than to changes in pulse frequency. Decreases in plasma concentrations of LH were reversed by treating females with exogenous LH-releasing hormone (LHRH). Cortisol treatment had no effect on LH levels during oestrogen-induced LH surges. Effects of aggressive encounters and physical restraint on plasma LH were not therefore due to reduced pituitary responsiveness to LHRH or to increased plasma concentrations of cortisol. In separate experiments it was found that physical restraint alone had no effect on plasma LH in habituated subjects, and that decreases in plasma LH after receipt of aggression only occurred if animals were subsequently placed in the restraint chair. A summation of stressful effects is therefore required to produce the fall in circulating LH. A summation of social and other environmental stressors may also underlie the reduced fertility seen in free-living animals.

Acute Disease↗
PubMed1987

Post-partum changes in hormones and sexual behaviour in captive groups of marmosets (Callithrix jacchus).

Video-tape recordings were made of behavioural interactions in eight family groups of marmosets for 24-30 days after parturition. Blood samples were collected from females for measurement of plasma luteinizing hormone (LH) and progesterone. A pre-ovulatory LH surge occurred in six females between days 10-18 (mean +/- sem, 13.8 +/- 1.3 days). In these groups, sexual interactions increased in frequency during the post-partum period and males began to initiate mounts on days 1, 2, 2, 6, 8 and 10 respectively. Mount and ejaculation frequencies increased significantly during the peri-ovulatory phase as compared to the pre-ovulatory phase and females were more proceptive and receptive than in the early post-partum period. Peri-ovulatory increases in sexual activity were more pronounced in 3 groups in which females had failed to conceive. In the remaining 3 groups, sexual interactions tended to continue at higher levels into the post-ovulatory phase when the females were pregnant. In captive marmoset groups, copulatory behaviour during the post-partum period is stimulated by changes in non-behavioural cues from the female (increased sexual attractiveness to the male) as well as by changes in her behaviour (proceptivity, receptivity) which vary in importance between individuals.

Aggression↗
PubMed1983

Body weight changes throughout pregnancy in the common marmoset Callithrix jacchus.

Adult female common marmosets were weighed weekly for periods of 6-30 months. Of 27 animals, 25 were pregnant at some stage of the investigation. Patterns of body weight change throughout singleton, twin and triplet pregnancies were obtained and compared. Maternal weight increase was dependent on the number of young in utero; however, little or no change in weight was observed during the first 13 weeks of gestation, irrespective of the number of offspring delivered subsequently. The overall maternal:fetal body weight ratio was 1.00:0.21, ranging from 1.00:0.11 for singleton to 1.00:0.26 for triplet pregnancies. Lactation had little or no effect on maternal body weight during the first 4 weeks postpartum.

Animals↗
PubMed1983

Plasma testosterone response to hCG stimulation in the male marmoset monkey (Callithrix jacchus jacchus).

In adult animals the intramuscular injection of hCG was followed by a rapid rise in plasma testosterone levels within 2-3 h and at doses of 40 and 80 i.u. hCG this primary response was followed by a second peak of testosterone at 48 h. Prepubertal marmosets also responded to hCG stimulation with a rapid increase in plasma testosterone levels within 3 h, but the magnitude of this peak was lower than that observed in adult animals and no biphasic pattern was observed. In adult and prepubertal animals a second dose of hCG (40 i.u.) administered 24 h after the initial injection failed to produce a further rapid increment in plasma testosterone levels.

Aging↗