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Biomedical subjects

H M Fraser

Publications and source records attributed to H M Fraser.

At least 109 records · Page 6Linked to original sources
PubMed1987

Clinical applications of LHRH analogues.

What is the current state of clinical application of inhibition of gonadal activity with LHRH agonists or antagonists? It seems unlikely in the short term that antagonists will be widely applied due to the short-acting nature of the present compounds and their troublesome side-effects. In contrast clinical studies with a number of agonists have demonstrated their efficacy in producing a hypogonadal state safely with rapid recovery following cessation of therapy. Although nasal administration may be suitable for short-term suppression (up to 28 days) it seems likely that long-acting depot preparations will be useful for more prolonged suppression. Perhaps the easiest application to determine will be the profound suppression required to produce medical castration in hormone-dependent tumours. The combination of agonist and receptor blocker is attractive particularly when the receptor blocker like cyproterone acetate also suppresses the release of LH, FSH and adrenocorticotrophic hormone. In cancer of the prostate and breast the side-effects due to inhibition of secretion of testosterone and oestradiol are tolerable although the only benefit over castration is the avoidance of minor surgery. The agonists should improve significantly the existing treatment for precocious puberty, endometriosis, uterine fibroids, polycystic ovary syndrome (PCO) and induction of ovulation although large scale trials comparing different therapies and doses are required. Finally, the concept of combination therapies to block further the influence of steroid hormones suggests challenging possibilities for even more effective therapy.

Administration, Intranasal↗
PubMed1987

The use of an LHRH agonist, buserelin, in the long-term management of premenstrual syndromes.

Buserelin, an LHRH agonist, was given by nasal spray to 20 women with premenstrual syndrome. In 10 women benefits were such that they continued treatment for periods varying from 5 to 15 months. There were significant improvements in mood and physical symptoms, and side-effects such as hot flushes were mild. The remaining 10 women were all made worse by the spray and stopped it within 2 months. Ovulation was blocked in all women though six showed evidence of ovulation during the first treatment month, and two women later in treatment. Of the long-term group, six eventually became amenorrhoeic, and four continued to menstruate. There was a significant improvement in symptoms during treatment in the long-term group. Physical symptoms continued to be worse before any menstrual bleeding. Mood change lost its relationship to menstruation. The adverse effects in the short-term group were sometimes severe and it is necessary to identify the characteristics of the woman who are likely to show such reactions before recommending this treatment for more general use.

Adult↗
PubMed1987

Compensatory response of the luteinizing-hormone (LH)-releasing hormone (LHRH)/LH pulse generator after administration of a potent LHRH antagonist in the ram.

It is established that the blockade of the pituitary LHRH receptor by an LHRH antagonist will suppress pituitary LH secretion and reduce serum concentrations of gonadal steroids. Little is known, however, about the activity of the LHRH/LH pulse generator during this inhibitory period or during the recovery phase. To investigate this, a potent LHRH antagonist [N-Ac-D-pCl-Phe1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6, D-Ala10 LHRH was injected iv into sexually active rams and the changes in the blood plasma concentrations of LH, FSH, testosterone, and PRL were measured in samples collected every 15 min for 24-48 h. The treatment induced an immediate blockade of pulsatile LH secretion and a parallel decline in blood levels of testosterone. Plasma levels of FSH were not suppressed by treatment with the LHRH antagonist and there was no consistent effect on plasma levels of PRL. The duration of the inhibition of LH was dose dependent lasting 4.3 +/- 0.4 h, 18.0 +/- 1.0 h, and 31.8 +/- 1.3 h for the low (6 micrograms/kg), medium (36 micrograms/kg), and high (365 micrograms/kg) doses of LHRH antagonist, respectively. During the recovery period there was an approximate 2-fold increase in the frequency of LH pulses. These results suggest a compensatory response to the decline in the negative feedback effect of testosterone secretion. Even the lowest dose of antagonist elicited a decrease in the level of testosterone and an increase in LH pulse frequency. At this dose, the decline in testosterone was very transitory indicating an acute sensitivity of the hypothalamus to changes in the negative feedback signal. These results suggest that the suppression of LH and testosterone secretion in the ram by LHRH antagonist is associated with a compensatory increase in the activity of the LHRH pulse generator.

Animals↗
PubMed1987

Suppression of luteal function by a luteinizing hormone-releasing hormone antagonist during the early luteal phase in the stumptailed macaque monkey and the effects of subsequent administration of human chorionic gonadotropin.

In previous studies a single sc injection of the LHRH antagonist [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 ]LHRH during the luteal phase of the stumptailed macaque menstrual cycle caused a transient suppression of serum LH and progesterone concentrations. To investigate whether a more prolonged suppression of LH release during the early luteal phase could result in a sustained suppression of progesterone, 10 monkeys were treated with 3 consecutive daily injections of 300 micrograms LHRH antagonist/kg beginning on days 0 (n = 2), 1 (n = 1), 2 (n = 1), 3 (n = 2), 4 (n = 2), and 5 (n = 2) after the LH surge. When the antagonist was administered on the day of the LH surge, serum concentrations of bioactive LH were still elevated on the following day, but then fell to low levels. Serum progesterone concentrations were subnormal in these monkeys for the next 10 days, but recovered toward the late luteal phase. In the 8 monkeys receiving antagonist starting between days 1-5 after the LH surge, serum concentrations of bioactive LH were suppressed to near the detection limit of the assay for 4 days after the first injection. Seven of the 8 monkeys demonstrated a progressive decline in serum progesterone concentrations to undetectable values which remained for the duration of the luteal phase. In the remaining monkey the decline in progesterone was less marked; this animal presented a normal progesterone profile 3 days after the last antagonist injection. Premature menses occurred in all 8 monkeys; the next ovulation occurred 18.9 +/- 0.3 days after the last antagonist injection. To test luteal function after antagonist treatment during the early luteal phase and to mimic the rescue of the corpus luteum during a fertile cycle and assess the contraceptive effects of antagonist, hCG in daily doses of 30, 60, 90, 180, and 360 IU was administered starting on day 7 of the luteal phase to monkeys previously treated with three daily injections of 300 micrograms antagonist/kg during the early luteal phase. Control monkeys received hCG injections alone. In the controls, hCG administration elevated serum progesterone concentrations to 15-20 ng/ml. In three monkeys in which antagonist administration did not commence until day 5 or 6, hCG overcame the suppressive effect of the antagonist. However, in seven monkeys in which antagonist administration began on days 1-4, hCG caused only a small progesterone rise (maximal range, 1.8-4.9 ng/ml), about 20% of that observed in control monkeys receiving hCG.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

LRH agonist buserelin as a post-partum contraceptive: lack of biological activity of buserelin in breast milk.

To evaluate the possibility of using the LRH agonist buserelin as a contraceptive for lactating women we have investigated the passage of buserelin into breast milk and explored possible biological activity in the infant. Eleven mothers received 600 micrograms buserelin by nasal spray. Buserelin was measured by radioimmunoassay in the breast milk of these mothers, and values ranged from undetectable levels (less than 15 pg/ml) to 8800 pg/ml. The maximum amount of buserelin that an infant could ingest during an average feed would be 1-2 micrograms. In adult men ingestion of 600 micrograms buserelin dissolved in cows milk was without biological effect upon both serum and urinary levels of luteinizing hormone. There was no change in the levels of LH found in the urine of infants fed by women who had received 600 micrograms buserelin by nasal spray. We conclude that the small amount of buserelin passing into the breast milk of these volunteers was without biological activity when ingested by the infant.

Administration, Intranasal↗
PubMed1987

An implant of a gonadotropin releasing hormone agonist (buserelin) which suppresses ovarian function in the macaque for 3-5 months.

Four adult female stumptailed macaque monkeys with regular menstrual cycles and one with irregular cycles and dysfunctional uterine bleeding were treated with a single implant containing 2.6 mg of the GnRH agonist buserelin in a matrix of polylactide/glycolide copolymer (75:25). The implant was used as a cylindrical rod of 0.8 X 0.12 cm and implanted sc in the abdominal wall. The insertion of the implant was followed by a modest rise in serum concentrations of LH and FSH lasting 3-4 days before falling to basal values. The release profile of buserelin from the implant was measured in urine by a radioimmunoassay detecting the intact molecule and its major metabolites. Immunoreactive buserelin in urine was high between days 1-3 after implant after which there was a rapid decline to form a plateau between days 15-70 followed by a further gradual decline. This prolonged release of buserelin suppressed ovulation for a mean of 148 days (range 105-182 days) as indicated by absence of serum progesterone rises. Serum FSH concentrations were low for at least 75 days and during this time serum oestradiol concentrations were uniformly suppressed in all monkeys. Once the buserelin release from the implant declined serum FSH concentrations began to rise. There was a variable delay of 7-60 days before this rise in FSH was associated with stimulation of ovarian oestradiol secretion followed by rises in serum progesterone concentrations indicative of ovulation. Apart from the first menses after insertion of implant, 4 of the monkeys became amenorrhoeic for the period of anovulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of gonadotrophin-releasing hormone agonist-induced suppression of LH and FSH on follicle growth and corpus luteum function in the ewe.

Continuous infusion of a gonadotrophin-releasing hormone (GnRH) agonist (buserelin) by osmotic minipump from day 1 of the luteal phase in five Welsh ewes resulted in a sustained suppression of plasma concentrations of FSH which increased three- to eightfold within 2 days after the end of infusion 29 days later. Plasma concentrations of LH increased three- to eightfold over the first 5 days of infusion and then became basal and non-pulsatile until 1 day after the end of infusion. Duration of the luteal phase and plasma concentrations of progesterone were not significantly different in control and treated ewes. Pulses of LH in control ewes were followed by increases in concentrations of progesterone in samples collected at 10-min intervals for 7 h on days 10 and 14 of the luteal phase. However, progesterone was also released in a pulsatile manner in the absence of LH pulses in both control and GnRH agonist-treated ewes. After natural luteolysis, no ovulation or corpus luteum function occurred in treated ewes up to 15 days after the end of treatment on day 29, even though oestrus, indicating follicular development and oestrogen secretion, had occurred 8-11 days after treatment ended. After 30 days of infusion the ovaries of GnRH agonist-treated ewes contained no follicles greater than 2.5 mm in diameter. In follicles of 1-2 mm in diameter the basal and LH-stimulated production of oestradiol and testosterone in vitro were similar in both control and GnRH agonist-treated ewes, and a similar proportion of these follicles was oestrogenic (greater than 370 mol oestradiol per follicle) in GnRH agonist-treated and control ewes. These results show (1) that progesterone secretion by the corpus luteum of the ewe can be sustained in the presence of basal concentrations but absence of pulsatile secretion of LH, and progesterone is released in a pulsatile manner whether or not LH pulses are present, (2) that follicular development beyond 2.5 mm in diameter in the ewe is dependent upon adequate stimulation by both LH and FSH and (3) that the continuous infusion of GnRH agonist is a simple method for providing reproducible suppression of LH and FSH and follicular development in the ewe to allow the study of gonadotrophin action on the ovary in vivo.

Animals↗
PubMed1986

Toward removing uterine fibroids without surgery: subcutaneous infusion of a luteinizing hormone-releasing hormone agonist commencing in the luteal phase.

Intermittent sc injection of a LHRH agonist reduced uterine fibroid size in 5 women. Commencement of the LHRH agonist buserelin on day 21 of the menstrual cycle induced a marked increase in plasma LH and FSH concentrations, followed by rises in estradiol (E2) and progesterone. LH and FSH levels fell to within the normal range by 120 h after beginning buserelin, despite continuing administration of the agonist. After menstruation, marked sustained suppression of cyclical gonadotropin and steroid concentrations occurred: mean values of FSH, LH, and E2 were 4.9 +/- 0.5 (+/- SE) mIU/ml, 5.9 +/- 0.6 mIU/ml, and 47.9 +/- 10.8 pg/ml, respectively, during the 20 weeks of buserelin treatment. During treatment, E2 concentrations remained below 50 pg/ml in 98 of 116 weekly observations. Uterine fibroids shrank after 8 or 10 weeks of buserelin administration, as assessed by ultrasound or gynecological examination. Compared to their initial volume, mean uterine fibroid volume after 20 weeks of buserelin infusion decreased from 220 +/- 51 to 98 +/- 26 cm3, which was 39.4 +/- 6.9% of the pretreatment volume. We conclude that sc administration of a LHRH agonist beginning in the luteal phase markedly reduced the size of uterine leiomyomata, suppressed, but did not abolish, pituitary and ovarian function, and warrants further evaluation as an option or adjunctive therapy to uterine myomectomy or hysterectomy.

Adult↗
PubMed1986

Effect of LHRH immunoneutralization on follicular development, the LH surge and luteal function in the stumptailed macaque monkey (Macaca arctoides).

A dose of 100 microliter of a potent ovine LHRH gamma globulin inhibited ovulation in the cyclic rat when administered at 12:00 h on the day of pro-oestrus. A dose of 10 ml of the preparation was administered i.v. to female stumptailed macaques to achieve circulating antibody titres 3-4-fold higher than in the rat. In an ovariectomized macaque, this caused a marked fall in serum concentrations of LH to less than 10% of pretreatment values and also a significant, though less pronounced, fall in FSH. Six monkeys were treated with the LHRH gamma globulin during the mid-late follicular phase of the cycle. In 2 monkeys in which serum oestradiol concentrations were less than 100 pg/ml at the time of antibody administration, the rising oestradiol levels were abruptly suppressed and the normal mid-cycle LH surge failed to occur. Serum concentrations of LH and FSH declined to low levels for 8-10 days after which time normal follicular development occurred. In the remaining 4 monkeys in which follicular development was more advanced as indicated by serum oestradiol concentrations of greater than 100 pg/ml, the antibodies induced either a transient decline or had no effect on the rising serum concentration of oestradiol. An LH/FSH surge followed by a rise in serum progesterone occurred in these macaques. When the antibodies were administered to a further 6 macaques, which had also been treated with oestradiol benzoate during the early follicular phase to induce an LH surge, the neutralization of LHRH again failed to block the surge even when the dose of antibody was increased to 20 ml. The results show that LHRH antibodies were unable to block the LH surge in the macaque. They contrast with results obtained with LHRH immunoneutralization in the sheep, rat, hamster, mouse and bird and suggest that the ability of oestrogen to induce an LH surge by acting directly on the LHRH-primed anterior pituitary gland is more dominant in the primate.

Animals↗
PubMed1986

Suppression of follicular development after chronic LHRH immunoneutralization in the ewe.

Active immunization of 6 Damline ewes against LHRH during seasonal anoestrus resulted in an inhibition of ovarian cyclicity throughout 2 subsequent breeding seasons. This was associated with a significant suppression of plasma LH and FSH concentrations but no significant effect on prolactin. The ovaries of LHRH-immunized ewes 30 months after primary immunization contained no follicles greater than 2.5 mm in diameter and a greater proportion of follicles between 1 and 2 mm were atretic than in control ewes (N = 8). In-vitro production of testosterone and androstenedione were similar in follicles 1-2 mm in both control and LHRH-immunized ewes (N = 6) and all had little or no ability to secrete oestradiol. However, basal and hCG-stimulated progesterone secretion was suppressed in the follicles from LHRH-immunized ewes. These results show that follicular development beyond 2.5 mm in the ewe is dependent on adequate stimulation by both LH and FSH.

Anestrus↗
PubMed1986

Blockade of pulsatile LH, FSH and testosterone secretion in rams by constant infusion of an LHRH agonist.

Adult Soay rams were infused for 21 days with 50 micrograms buserelin/day, using s.c. implanted osmotic mini-pumps. The continuous treatment with this LHRH agonist induced a supraphysiological increase in the blood concentrations of LH (15-fold) and testosterone (5-fold) followed by a decrease below pre-treatment values after 10 days. The blood concentrations of FSH showed only a minimal initial increase but the subsequent decrease was dramatic, occurring within 1 day. By Day 10 of treatment, the blood concentrations of all 3 hormones were low or declining, LH pulses were absent in the serial profiles based on 20-min blood samples and the administration of LHRH antiserum failed to affect the secretion of LH or testosterone. By Day 21, the secretion of FSH, LH and testosterone was maximally suppressed. The i.v. injection of 400 ng LHRH was totally ineffective at stimulating an increase in the blood concentrations of LH while the i.v. injection of 50 micrograms ovine LH induced a normal increase in the concentrations of testosterone; this confirmed that the chronic treatment with the LHRH agonist had desensitized the pituitary gonadotrophs without markedly affecting the responsiveness of the testicular Leydig cells. The ratio of bioactive: radioimmunoactive LH did not change during the treatment. The long-term effect of the infusion was fully reversible as shown by the increase in the blood concentrations of FSH, LH and testosterone and the return of normal pulsatile fluctuations in LH and testosterone within 7 days of the end of treatment.

Animals↗
PubMed1986

Effects of an LH-releasing hormone antagonist on the secretion of LH, FSH, prolactin and ovarian steroids at different stages of the luteal phase in the stumptailed macaque (Macaca arctoides).

The role of the pituitary gonadotrophins in controlling luteal function in the stumptailed macaque has been investigated by examining profiles of serum concentrations of LH, FSH, progesterone and oestradiol in daily blood samples from 13 monkeys during the menstrual cycle, and in blood samples taken at hourly intervals between 09.00 and 21.00 h on different days of the luteal phase in 13 cycles. The effects of acute withdrawal of gonadotrophins was investigated by administering a single injection of 300 micrograms LHRH antagonist/kg body weight at different stages of the luteal phase during 28 cycles. Although there were high basal values and marked fluctuations of bioactive LH during the first 4 days after the LH peak, progesterone profiles showed no corresponding short-term changes, there being a slow and steady rise in progesterone concentrations during the sampling periods. After day 5, basal LH secretion decreased, but high amplitude LH pulses were identified which were associated with episodes of progesterone secretion. Administration of the LHRH antagonist caused a suppression of bioactive LH and progesterone concentrations at all stages of the luteal phase, although some basal secretion of progesterone was maintained through the 24-h period of effective antagonist gonadotroph blockade. Luteal function recovered apparently normally in all monkeys treated in the early-mid-luteal phase. Serum concentrations of FSH and oestradiol fluctuated comparatively less during the 12-h sampling periods, and the antagonist had less suppressive effects on the concentrations of these hormones. The LHRH antagonist had no apparent effect on prolactin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The roles of inhibin and gonadotrophin-releasing hormone in the control of gonadotrophin secretion in the ewe.

The respective roles and relative importance of ovarian inhibition and hypothalamic stimulation in the differential control of the secretion of FSH and LH were studied in the ewe. In the first experiment two groups of ten intact ewes were injected i.v. twice daily with 9 ml charcoal-extracted bovine follicular fluid (bFF), a preparation rich in inhibin (3.65 ku./ml), throughout the luteal phase of the oestrous cycle. Compared with the control ewes, this treatment significantly reduced pituitary and plasma FSH concentrations and increased the frequency and amplitude of the LH pulses, but did not affect pituitary LH concentrations. In a second experiment, five control and five bFF-treated ewes from experiment 1 were ovariectomized and the injection regime was altered to 2.5 ml s.c. every 8 h. This treatment was maintained for 21 days. In control ewes, plasma FSH concentrations rose significantly within 12 h and continued to rise for 3-4 days. Treatment with bFF abolished this increase and maintained plasma FSH concentrations below those observed in intact ewes. The rise in mean plasma LH concentrations evoked by ovariectomy was also partially inhibited in the bFF-treated ewes. The response to the gonadotrophin-releasing hormone (GnRH) agonist buserelin (5 micrograms i.v.) was measured 6, 12 and 18 days after ovariectomy. In control ewes the agonist consistently evoked large surges of both hormones but in bFF-treated ewes the FSH response was completely blocked and the initial phase of the LH response (the first 'pool') was greatly reduced. In experiment 3, six ewes were ovariectomized and passively immunized against GnRH 3 days after oestrus. The increase in plasma LH which normally follows ovariectomy was completely abolished and mean concentrations remained very low and did not change over the following 14 days. In contrast, mean FSH concentrations rose significantly within 12 h of ovariectomy and continued to rise until the third day, after which they fell gradually. Treating three of the ewes with bFF (2.5 ml s.c. every 8 h) 8 days after ovariectomy and immunization further reduced the FSH concentrations. When the ewes were injected repeatedly (200 ng i.v., hourly for 5 h) with [D-penicillamine-(But)6]-GnRH(1-9)nonapeptide-ethylamide, a synthetic GnRH analogue which does not bind to the antiserum, there was a rapid rise in the secretion of LH in both control and bFF-treated animals but, as with the responses to buserelin, the initial response was significantly lower in bFF-treated than in control ewes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Effect of an intranasal LHRH agonist on gonadotrophins and hot flushes in post-menopausal women.

Alterations in circulating gonadotrophins have been reported at the time of onset of menopausal flushes. In order to study this association D-SER(TBU)6-EA10-LHRH, a luteinizing hormone releasing hormone (LHRH) agonist was given intranasally at a dose of 200 micrograms twice daily to 12 post-menopausal women to study its effect on gonadotrophin secretion and hot flushes. Following an initial period of 3-5 days of increased gonadotrophin secretion, pituitary desensitization occurred, with a significant suppression of circulating LH and follicle-stimulating hormone (FSH) levels (P less than 0.001) and a reduction in gonadotrophin pulse amplitude (P less than 0.05). This was accompanied by a significant diminution of the pituitary's response to exogenous LHRH (P less than 0.05). However, no significant alteration in the incidence of hot flushes was observed on such therapy.

Administration, Intranasal↗