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Nine adult female stumptailed monkeys (Macaca arctoides) treated chronically with daily s.c. injections of d-Ser(But)6 des-Gly10,Proethylamide9, luteinizing hormone releasing hormone (LH-RH agonist) to inhibit ovulation, were tested for their ability to respond to an oestrogen provocation test (positive feedback). On two occasions during treatment with the LH-RH agonist (first test between 10 and 35 weeks after treatment had started; second test between 30 and 60 weeks after) the animals were given an i.m. injection of 50 μg oestradiol benzoate/kg in arachis oil. Controls were tested between days 1 and 5 of the normal cycle. In the control monkeys oestrogen induced a clear rise in LH and FSH concentrations in the blood, with highest values between 48 and 60 h after treatment. In marked contrast, none of the animals treated with LH-RH agonist showed this pattern of response. In the first test, five of the nine monkeys showed no rise in LH while in the remaining animals the response was diminished or delayed, and in the second test all nine failed to show a significant rise in LH. In all agonist-treated monkeys oestrogen failed to cause an FSH rise in either test.
Thus, chronic treatment with LH-RH agonist in the monkey either abolishes, diminishes or delays the oestrogen-induced LH surge. Since, in the primate, oestrogen appears to release LH by acting directly on the pituitary gland exposed to pulses of LH-RH from the hypothalamus it appears that the LH surge is inhibited primarily because the pituitary gland has been exposed to prolonged stimulation by the agonist.
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Department of Surgery, Ninewells Hospital, Dundee, Angus
(Received 9 November 1976)
The use of antibodies to luteinizing hormone releasing hormone (LH-RH) to study the physiological role of LH-RH would be increased if the antibody could be neutralized at a selected time without otherwise interfering with the hypothalamo-pituitary system. A possible method is to saturate passively transferred antibody in the blood with a fragment of LH-RH which cross-reacts immunologically with the antibody but does not have LH-RH activity.
This study was designed to investigate whether the inhibition of ovulation produced by an antiserum to LH-RH injected into rats at 12.00 h on the day of pro-oestrus could be prevented by subsequent injection of the 3-10 octapeptide fragment of LH-RH on the same day. This fragment is biologically inactive (Rivier, Amoss, Rivier & Vale, 1974). The antiserum was raised in a rabbit to LH-RH (Hoechst) conjugated to bovine serum albumin by carbodiimide
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ABSTRACT
We investigated the temporal relationship between serum concentrations of progesterone and immuno-reactive 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. These results give further support to the concept that the secretion of inhibin, like progesterone, is integrated with the LH control of the corpus luteum. The slower decline in inhibin after LHRH antagonist suggests that the gonadotrophic stimulus to the corpus luteum results in a more prolonged stimulus for inhibin than for progesterone secretion, or that inhibin has a longer metabolic clearance rate.
Journal of Endocrinology (1991) 128, 107–113
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Pituitary testicular function in the neonate
The early postnatal period of male primates (including humans) is associated with activation of the hypothalamicpituitary-testicular axis. Circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) begin to rise in male infants during the second week of postnatal life, reach a peak between 2 and 4 months, and decline thereafter, reaching juvenile levels by 1 year of age (Forest 1990) (Fig. 1). Total testosterone levels rise commensurate with the increase in neonatal LH, reaching peak values that approach the low normal adult male range between 1 and 3 months of age, and then fall in concert with declining LH values to juvenile levels by 6 to 8 months of age (Forest 1990). Comparable patterns of neonatal endocrine changes have been reported in the chimpanzee, rhesus monkey, cynomolgus monkey, mangabey and marmoset (Steiner & Bremner 1981, Fuller et al. 1982, Mann et al. 1983,
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ABSTRACT
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 > 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 (> 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.
J. Endocr. (1987) 115, 273–282
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Cancers of the breast, endometrium and ovary can display endocrine sensitivity—and a proportion of such tumours regress when deprived of hormones (Hawkins & Miller, 1988). As a consequence, endocrine deprivation therapy is a major treatment modality, particularly in patients with breast cancer (Miller, 1990).
Given that endocrine factors also play a critical role in the aetiology of certain tumours (Preston-Martin, Pike, Ross et al. 1990), hormone manipulation might also prevent cancer. Initiatives attempting hormone-prevention of cancer have been given impetus by the availability of relatively non-toxic drugs such as luteinizing hormone-releasing hormone (LHRH) agonists and antioestrogens which block hormone action without the morbidity and irreversibility of surgical and radiological procedures. In this commentary we evaluate current thinking behind the use of hormone suppressant drugs as a method of prevention of cancer and conclude that such an approach is feasible but, in parallel with steroid contraception, there are important long-term consequences
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Rats were immunized against luteinizing hormone releasing hormone (LH-RH) and ovulation and follicular development were studied 12, 24 and 48 weeks later. The abolition of regular cyclic patterns of vaginal smears and the absence of luteal tissue in all but one of 32 rats showed that the immunization was effective in blocking ovulation. Follicular growth varied between rats and appeared to be dependent on whether the inhibition of LH-RH had been sufficient to affect the secretion of basal levels of gonadotrophins. Low levels of gonadotrophins were associated with poor follicular development, uterine atrophy and leucocytic vaginal smears, whereas levels of gonadotrophins similar to those in the dioestrous controls led to adequate follicular growth in the absence of ovulation, the production of cystic follicles, uterine stimulation and persistent vaginal oestrus. A group of rats was ovariectomized 12 weeks after immunization against LH-RH; animals with low antibody titres and large follicles responded with increases in the levels of LH and FSH in the blood, whereas in those with high antibody titres and little follicular development the concentrations of gonadotrophins remained low. The reproductive capacity of rats immunized against LH-RH was tested by caging them with normal male rats from 3 weeks after immunization. Although mating occurred in three rats during the first month, no offspring were produced. No matings occurred in the remaining 41 weeks.
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MRC Unit of Reproductive Biology, 2 Forrest Road, Edinburgh, EH3 9ER and * Agricultural Research Council's Poultry Research Centre, King's Buildings, West Mains Road, Edinburgh, EH9 3JS
(Received 22 August 1977)
The decapeptide luteinizing hormone releasing hormone (LH-RH) stimulates the release of luteinizing hormone (LH) in birds as well as in mammals (Van Tienhoven & Schally, 1972) and a substance immunochemically similar to LH-RH is present in the chicken hypothalamus (Jeffcoate, Sharp, Fraser, Holland & Gunn, 1974). Avian LH-RH has still to be isolated and sequenced, however, and there is some doubt about whether the decapeptide is the naturally occurring LH-RH in the bird (Jackson, 1971).
In the hen, release of LH is induced by the positive feedback action of progesterone (Wilson & Sharp, 1975) which is presumably associated with the release of chicken LH-RH. To gain further information about the identity of chicken LH-RH and to investigate the site
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Abstract
The pattern of inhibin concentrations in blood during the menstrual cycle in primates has suggested an endocrine role of inhibin in the negative feedback control of FSH secretion during the luteal phase. Conversely, the fall in inhibin during the late luteal phase may play a role in the rise in serum FSH during the luteal-follicular phase transition. This hypothesis was examined by determining the effects of manipulation of inhibin on FSH secretion in stumptailed macaques. During the mid-luteal phase the putative inhibin feedback was inhibited by i.v. administration of 20 ml of ovine antiserum to human recombinant inhibin in 4 macaques. FSH secretion was unaffected during the initial 24 h period post-treatment and the timing of the rise in FSH which occurred during the subsequent luteal-follicular phase transition was normal. To determine whether the elevated serum concentrations of FSH observed during the early follicular phase could be reduced by administration of inhibin, 5 cyclic macaques were treated with 200 μg of recombinant human inhibin i.v. Serum FSH concentrations were unaltered. These results suggest that inhibin does not play a major role in modulating FSH secretion during the luteal-follicular phase transition.
Journal of Endocrinology (1994) 142, 181–186
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Immunization against luteinizing hormone releasing hormone (LH-RH) in adult male rats produced a progressive decline in LH and FSH in the circulation to low or non-detectable levels. d-Serine-tertiary-butyl6,des-glycine-NH2 10 LH-RH ethylamide is an analogue of LH-RH having highly active LH-RH properties in the normal rat. Because it is also immunologically different from LH-RH it can stimulate gonadotrophin release from the anterior pituitary gland of rats immunized against LH-RH without interference from the antibody. The analogue stimulated LH and FSH release in rats 15 weeks after immunization against LH-RH when antibody titre was highest, and after long-term (35 weeks) immunization against LH-RH. d-Serine-tertiary-butyl6,des-glycine-NH2 10 LH-RH ethylamide and related analogues are therefore potentially useful for reversing the effects of immunization against LH-RH.
