Hypothalamic pulse generators.
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Animals↗
Biomedical subjects
H M Fraser
Publications and source records attributed to H M Fraser.
The role of endogenous gonadotropin-releasing hormone in the control of luteinizing hormone and testosterone secretion in the juvenile male monkey, Macaca fascicularis.
To determine what changes occur in the activity of gonadotropin-releasing hormone (GnRH) neurons during pubertal development in primate species we tested the hypotheses that there are morphologic differences between GnRH-containing neurons in juvenile versus adult monkeys, and the low activity of the reproductive axis is governed by hypothalamic GnRH release in monkeys prior to puberty. We removed the brains from 5 juvenile and 5 adult male monkeys (Macaca fascicularis) and blocked, sectioned, and prepared each hypothalamus for light microscopic immunocytochemistry for GnRH-containing cells. The distribution and number of GnRH-containing neurons were similar in adult and juvenile brains; however, GnRH-containing perikarya in adult brains were significantly larger in total cross-sectional area (200 +/- 12 vs. 169 +/- 8 micron 2, P less than 0.05) and in cross-sectional area of the cytoplasm (139 +/- 2 vs. 88 +/- 6 micron 2, P less than 0.05) than in juvenile brains. In another group of 10 juvenile male macaques, we administered an antiserum to GnRH (Fraser #94; 2 ml/kg, i.v.) and monitored the effects on plasma luteinizing hormone (LH) and testosterone concentrations. The percentage of plasma samples with detectable LH levels decreased significantly (from 26.67 +/- 8.3% to 5.3 +/- 3.4%, P less than 0.05) after GnRH antiserum administration; however, plasma testosterone concentrations (0.08 +/- 0.02 ng/ml) remained unchanged. We conclude that during pubertal maturation in primate species there is increased synthesis and release of GnRH from a population of GnRH neurons that are active prior to puberty.
Animals↗
Suppression of follicular maturation by infusion of a luteinizing hormone-releasing hormone agonist starting during the late luteal phase in the stumptailed macaque monkey.
The effect of continuous administration of an LHRH agonist for 14 days on follicular estradiol secretion was studied in adult female stumptailed macaque monkeys. The infusion was started either during the early follicular phase or during the late luteal phase. Both treatments resulted in a rise in serum concentrations of LH and FSH for 2-3 days, after which time values returned to basal levels. Infusion during the early follicular phase induced a rapid rise in serum concentrations of estradiol, which declined after 7-10 days. The normal rise in serum progesterone after midcycle failed to occur, indicating that ovulation had been inhibited. Infusion during the late luteal phase of the cycle prevented the normal rise in serum concentrations of FSH and estradiol at the end of the luteal phase, and there was no indication of follicular estradiol production during the subsequent infusion period. Removal of the minipumps after 14 days was followed promptly by normal cycles, regardless of when the infusion had been started. In a second experiment, infusion of LHRH agonist was started during the luteal phase and extended for 90 days. This resulted in marked and sustained suppression of estradiol secretion and total absence of progesterone rises. These findings show that in the monkey, a rapid and sustained suppression of estradiol production can be obtained if a long term infusion of LHRH agonist is started during the luteal phase of the cycle. Such an approach in women using infusion pumps or sustained delivery preparations may be the most effective way of achieving a medical ovariectomy for the treatment of endometriosis, leiomyomata, and other estrogen-dependent pathological conditions.
Animals↗
Changes in pituitary and ovarian LHRH receptors after active immunization of female rats against LH or LHRH.
The hypothalamic-pituitary-ovarian axis of female rats was disrupted at the site of LHRH stimulation by active immunization against LHRH or at the site of LH action by active immunization against LH. Active immunization against LH was associated with an increase in pituitary LHRH receptors to levels comparable to control values at pro-oestrus whereas immunization against LHRH led to a marked reduction in receptor numbers. Ovarian LHRH receptor concentrations were increased by both treatments. It is concluded, therefore, that (1) LHRH receptors in the pituitary and ovary are not concomitantly controlled, and (2) pituitary receptor numbers are primarily under positive autoregulatory control by LHRH and that ovarian LHRH receptor concentrations may be under long-term influence of LH.
Animals↗
Effects of antiserum to thyrotrophin-releasing hormone on the concentrations of plasma prolactin, thyrotrophin and LH in the pro-oestrous rat.
The possible role of thyrotrophin-releasing hormone (TRH) in causing the pro-oestrous surge of prolactin was investigated in conscious female rats by passive immunization with a specific anti-TRH serum raised in sheep. Blood samples were withdrawn through a previously implanted intra-atrial cannula. The i.p. injection of 1 ml anti-TRH serum, but not non-immune sheep serum, at 13.00 h of pro-oestrus delayed by about 1 h the onset of the prolactin surge, but the peak of the surge was similar to that in animals injected with the non-immune serum. The plasma concentrations of TSH were significantly reduced by the anti-TRH serum, but plasma concentrations of LH were not significantly affected. These results show that TRH may play an important role in the timing and initiation, but not the maintenance of the prolactin surge in the pro-oestrous rat.
Animals↗
Suppression of luteal progesterone secretion in the stumptailed macaque by an antagonist analogue of luteinizing hormone releasing hormone.
The dependence of progesterone secretion from the corpus luteum on pituitary gonadotrophin was examined in the cyclic stumptaile macaque by studying the effects of a single s.c. injection of a potent LH releasing hormone (LHRH) antagonist, [N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10] LHRH. A dose of 100 micrograms antagonist/kg administered on days 9/10 of the luteal phase in three monkeys caused a marked temporary suppression of serum concentrations of LH and progesterone during the following 32h but levels still remained detectable and after 2 days serum hormone concentrations returned to the normal luteal-phase range. When the same animals were treated with 300 micrograms antagonist/kg at the same period during a subsequent cycle, serum LH levels were close to or at the limits of detection of the bioassay for the next 48h and progesterone concentrations declined steadily, reaching non-detectable values by 48h. In two monkeys the progesterone levels remained suppressed and they menstruated prematurely; in the third monkey the progesterone concentration rose to just above baseline and menstruation occurred at the expected time. Administration of 300 micrograms antagonist/kg on days 6/7 of the luteal phase in a further three monkeys also suppressed progesterone concentrations but not to baseline values, and after 2 days a normal progesterone profile was regained. These results suggest that the corpus luteum of the stumptailed macaque is largely dependent on pituitary gonadotrophin support during the mid to late luteal phase.
Animals↗
Physiological control of growth hormone secretion by thyrotrophin-releasing hormone in the domestic fowl.
Immature cockerels (4- to 5-weeks old) were passively immunized, with antiserum raised in sheep, against thyrotrophin-releasing hormone (TRH). The administration of TRH antiserum (anti-TRH) at doses of 0.5, 1.0 or 2.0 ml/kg lowered, within 1 h, the basal concentration of plasma GH for at least 24 h. The administration of normal sheep serum had no significant effect on the GH concentration in control birds. Although the GH response to TRH (1.0 or 10.0 micrograms/kg) was not impaired in birds treated 1 h previously with anti-TRH, prior incubation (at 39 degrees C for 1 h) of TRH (20 micrograms/ml) with an equal volume of anti-TRH completely suppressed the stimulatory effect of TRH (10 micrograms/kg) on GH secretion in vivo. These results suggest that TRH is physiologically involved in the hypothalamic control of GH secretion in the domestic fowl.
Animals↗
Effect of immunoneutralization of thyrotrophin-releasing hormone on the release of thyrotrophin and prolactin during suckling or in response to electrical stimulation of the hypothalamus in the anaesthetized rat.
The aim of the present study was to use the technique of immunoneutralization with anti-thyrotrophin-releasing hormone (anti-TRH) serum to investigate the role of TRH in mediating the TSH and prolactin responses to electrical stimulation of the hypothalamus and the prolactin response to suckling in lactating rats. Electrical stimulation of either the median eminence or paraventricular nuclei of male or female rats anaesthetized with urethane resulted in significant increases in the plasma concentrations of both TSH and prolactin. Injection of sheep anti-TRH serum blocked the rise in plasma TSH concentration in response to stimulation of either brain area, but did not block the increase in plasma prolactin concentration. In anaesthetized, lactating female rats, the suckling stimulus produced a significant increase in the plasma prolactin concentration, but did not alter the plasma TSH concentration. Injection of anti-TRH serum, but not control non-immune or anti-bovine serum albumin, significantly decreased the basal release of TSH but did not abolish the prolactin response to suckling. These results show that TRH is the principal mediator of the neural control of TSH release in the rat, but is not crucial for the release of prolactin in response to either hypothalamic stimulation or suckling.
Animal Population Groups↗
Shrinkage of a uterine fibroid after subcutaneous infusion of a LHRH agonist.
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Adult↗
Effect of treatment with GnRH antagonist, GnRH antiserum and bromocriptine on pituitary-testicular function of adult rats.
Gonadotropin secretion of adult male rats was inhibited by one-week treatment with a GnRH antagonist analogue (N-acetyl-Ala1,D-p-Cl-Phe2,D-Trp3,6-GnRH, Ant.) or a GnRH antiserum (A/S). Since Ant. but not A/S binds to GnRH receptors (R), it was expected that comparison of the two treatment regimes would elucidate a physiological role for testicular GnRH-R. Furthermore, the effect of combined gonadotropin and prolactin deficiency was studied in rats treated with Ant. and bromocriptine (BR). Available pituitary GnRH-R were decreased by both Ant. and A/S (P less than 0.01), but not by BR. Testicular content of free GnRH-R was decreased by Ant. by 70-80% (P less than 0.01), probably owing to occupancy, but A/S and BR had no effect on these binding sites. Serum LH and FSH fell by about 75% with Ant. and A/S treatments (P less than 0.01), and Prl by 90% with BR (P less than 0.01). Intratesticular testosterone (T) decreased significantly with Ant. and A/S treatment (P less than 0.01-0.05), but was unaffected by BR. Only Ant. and BR treatments together, but neither alone, were able to suppress Leydig cell capacity to produce T in vitro. Relative blockade of C21 steroid side-chain cleavage by Ant. and A/S was suggested by elevated progesterone (P) and/or P/T ratios in the serum and testis tissues. Ant. and A/S had no effect on testicular LH and FSH-R, but both decreased testicular Prl-R by about 50% (P less than 0.01-0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pituitary-testicular function in immature rats after treatment with GnRH antagonist, GnRH antiserum and bromocriptine.
The effects of a GnRH antagonist analogue (N-acetyl-Ala1,D-p-Cl-Phe2,D-Trp3,6-GnRH, Ant.) and a GnRH antiserum (A/S) on the development of pituitary-testicular function were studied in immature (23/24-31/32-day-old) rats. In another experiment the Ant. treatment was combined with bromocriptine (BR)-induced hypoprolactinaemia. Ant. and A/S decreased serum and pituitary levels of LH and FSH, and BR those of Prl (P less than 0.01-0.05). Testicular testosterone (T) and progesterone (P) contents were significantly decreased only by Ant. (P less than 0.01). Ant. decreased the weights of the testes, ventral prostates and seminal vesicles, as well as testicular LH, FSH and Prl receptors (R) (P less than 0.01-0.05). BR decreased LH-R but had no effect on Prl-R. Both Ant. and A/S decreased available pituitary GnRH-R (P less than 0.01), but free testicular GnRH-R were reduced only by Ant. BR increased GnRH receptors in the pituitaries. It is concluded that Ant.-induced low gonadotropin levels in immature animals inhibit the developmental increase of testicular weight, gonadotropin and Prl-R, steroidogenesis and androgen action on accessory sex glands. Hypoprolactinaemia had an additive inhibitory effect to the antigonadal effects of Ant. The testis tissue of immature (23/24-day-old) animals already contains GnRH-R. In general, developing animals are clearly very sensitive to the antigonadal actions of Ant. and BR, whereas the effect of GnRH-A/S is less pronounced than in adults.
Animals↗
Use of a superactive luteinizing hormone releasing hormone (LHRH) agonist in the treatment of menorrhagia.
A luteinizing hormone releasing hormone agonist, D-Ser(But)6des Gly10-LHRH ethylamide, was administered intranasally to four women with unexplained ovulatory menorrhagia. Dramatic reductions in excessive menstrual blood losses were induced without significant side-effects, although the pattern of loss returned to pretreatment levels within 2 months of ceasing therapy.
Adult↗
Effects of chronic luteinizing hormone-releasing hormone agonist treatment on dysfunctional uterine bleeding in the stumptailed macaque.
Dysfunctional uterine bleeding is a disorder which presents problems for effective treatment and management. We have utilized the ability of chronic LRH agonist treatment to suppress ovarian steroid production to examine its effects on stumptailed macaques with a detailed history of excessive days of menstrual bleeding. Five monkeys were treated for 6 months with daily injections of D-Ser[But]6 LRH (1-9) nonapeptide-ethylamide. This was successful in suppressing ovarian steroid production in all monkeys as indicated by the maintenance of serum concentrations of oestradiol at less than 100 pg/ml and progesterone at less than 1 ng/ml. All monkeys menstruated for their typical time period during the first treatment cycle, but thereafter bleeding stopped in 2 monkeys and was considerably reduced in a further 2. In the remaining monkey, no significant improvement occurred. The results indicate that suppression of ovarian function in this way may have a significant role to play in the treatment of dysfunctional uterine bleeding.
Animals↗
Cytogenetic analysis of mouse oocytes after experimental induction of follicular overripening.
Graafian follicle overripening was induced in (1) adult mice by inhibiting the ovulatory discharge of gonadotrophins with antibodies to LH-RH and (2) immature mice by injection of PMSG to promote follicular maturation before the neuroendocrine system was competent to produce an ovulatory stimulus. The numbers of follicles capable of meiotic maturation after exogenous LH were sharply reduced during the period of overripening and there was a corresponding increase in the proportion of cystically enlarged follicles, many of which were undergoing atresia. Freshly ovulated ova were collected after delaying ovulation for 2 days and prepared for cytogenetic study of metaphase chromosomes. The incidence of non-disjunction and other errors was indistinguishable from that of ova collected after spontaneous ovulation during 4- or 5-day cycles.
Animals↗
Induction of early rutting in male red deer (Cervus elaphus) by melatonin and its dependence on LHRH.
Eight red deer stags, 2 control, 3 control-immunized (i.e. a low titre of LHRH antibodies after active immunization 2 years earlier) and 3 superior cervical ganglionectomized, were given a s.c. implant of melatonin in May at the nadir of the sexual cycle; 5 other stags remained untreated. All the melatonin-treated animals shed the velvet-like skin from the antlers in June or July at least 1 month before the untreated controls, and had an early increase in blood plasma testosterone concentrations. The treated stags were also precocious in the development of rutting behaviour, although this inductive effect was blocked dramatically in the control-immunized stags after a booster immunization against LHRH; these animals failed to show any further reproductive development and cast their antlers. It is concluded that continuous exposure to melatonin in early summer will induce premature seasonal testicular development, an effect dependent on the secretion of LHRH, and similar to that produced by exposure to short daylengths.
Animals↗
Effect of immunoneutralization of LH releasing hormone on LH, FSH and ovarian steroid secretion in the preovulatory phase of the oestrous cycle in the ewe.
Immunoneutralization of LH releasing hormone (LHRH) by the i.v. administration of LHRH antiserum in the preovulatory period in the ewe resulted in a prompt abolition of the pulsatile secretion of LH without alteration of basal plasma levels of LH. This resulted in an immediate cessation of the pulsatile secretion of ovarian oestradiol, with no change in the secretion rate of androstenedione or plasma levels of FSH. The ovarian secretion rate of testosterone increased significantly. Twenty to 22h after the injection of LHRH antiserum, pulsatile secretion of LH and ovarian oestradiol and androgen secretion remained suppressed while plasma levels of FSH had increased significantly. The bolus injection of ovine LH (10 micrograms, i.v.) at this time caused a significant increase in oestradiol, androstenedione and testosterone, these responses being inversely related to the titre of LHRH antiserum in the plasma at this time. These results show that (1) the secretion of oestradiol from the preovulatory sheep follicle is entirely dependent on the pulsatile secretion of LH and (2) since the secretion of ovarian androgens was not inhibited, LH may exert a short-term control over the aromatase enzyme system controlling the conversion of androgen to oestrogen in the granulosa cell of the preovulatory sheep follicle.
Androstenedione↗
GnRH and its analogues. Current therapeutic applications and new prospects.
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Contraceptives, Oral, Hormonal↗
Intranasal treatment with luteinising hormone releasing hormone agonist in women with endometriosis.
An agonist analogue of luteinising hormone releasing hormone (buserelin) was successfully used to treat women with endometriosis. A dose of 200 micrograms administered intranasally thrice daily was found to be effective in five patients, in whom the endometriotic lesions resolved after six months' treatment. Failure occurred in a sixth patient, who received only 400 micrograms once daily. Anovulation was induced in all subjects together with suppression of menstruation after the first month of treatment. Symptoms of abdominal pain, dysmenorrhoea, and dyspareunia were relieved during treatment, and one previously infertile patient conceived within two months of stopping treatment. No side effects were reported with this dosage, and the results suggest a new form of treatment for patients with endometriosis.
Adult↗