Therapeutic significance and the mechanism of action of the LH-RH agonist ICI 118630 in breast and prostate cancer

The influence of the LH-RH agonist ICI 118630 on circulating levels of the pituitary gonadotrophins LH and FSH and the gonadal steroids oestradiol, progesterone, 17-hydroxyprogesterone and testosterone has been studied in phase I clinical trials of the drug in patients with advanced breast or prostate cancer. ICI 118630 initially stimulated plasma levels of LH and FSH. On continued treatment however, the drug reversed this response and produced a rapid decline in plasma testosterone and progesterone in male and female patients respectively. Plasma oestradiol concentrations equivalent to those seen in oophorectomised or postmenopausal women were eventually produced in all 5 female patients treated with ICI 118630. In one patient however persistent follicular activity occurred until her third menstrual cycle. No appreciable side effects of the drug were observed. These data indicate that ICI 118630 initiates a castration-like endocrine response and has potential in the treatment of hormone dependent tumours of the breast and prostate.     

Effects of an organophosphate pesticide, quinalphos, on the hypothalamo-pituitary-gonadal axis in adult male rats

The effects of chronic sub-lethal doses (7-14 mg kg-1 a day for 15 days) of quinalphos were evaluated in adult male rats for changes in testicular morphology, circulatory concentrations of hormones (LH, FSH, prolactin and testosterone), activities of acetylcholinesterase (AChE) and angiotensin converting enzyme (ACE) as well as metabolism of biogenic amines (dopamine, noradrenaline and 5-hydroxytryptamine (5-HT)) in the hypothalamus and pituitary. Hormones were assayed by radioimmunoassay or chemiluminescent immunoassay (testosterone). The enzymes were estimated after spectrophotometry and the biogenic amines by HPLC-electrochemistry. Sub-lethal chronic administration of quinalphos resulted in: decreased testicular mass and AChE activity in central as well as peripheral organs; increased serum LH, FSH, prolactin and testosterone concentrations; decreased pituitary or increased testicular ACE activity; severe disruption of spermatogenesis with increasing doses of pesticide; and no significant effects on dopamine, noradrenaline or 5-HT concentrations in the hypothalamus or pituitary. Administration of oestradiol (50 micrograms per rat a day) during pesticide treatment resulted in: a significant decrease in the mass of the testis and accessory sex organs; decreases in serum LH, FSH, testosterone concentrations; an increase in prolactin concentration; and a decrease in dopamine or an increase in noradrenaline and 5-HT in the hypothalamus or pituitary. Oestradiol had a marked effect: in pesticide-treated animals, the pesticide effects were significantly reversed. This indicates that in pesticide toxicity, the hypothalamo-pituitary-gonadal axis is operational. Since many of the observed pesticide effects could be inhibited by oestradiol, it is suggested that the pesticide acts directly on the gonadotrophins. In conclusion, quinalphos decreases fertility in adult male rats by affecting the pituitary gonadotrophins.     

Role of gonadal negative feedback on the gonadotrophin responses to gonadotrophin-releasing hormone (GnRH) in ram lambs from two lines of sheep selected for their luteinizing hormone response to GnRH.

Divergent selection has resulted in two lines of lambs (high and low) that have a 5-fold difference in their ability to release luteinizing hormone (LH) in response to 5 micrograms of gonadotrophin-releasing hormone (GnRH). Baseline gonadotrophin concentrations, the gonadotrophin responses to a GnRH challenge and the concentrations of testosterone and oestradiol were compared in lambs which were castrated at birth and intact lambs from both selection lines at 2, 6, 10 and 20 weeks of age. The pattern of LH and follicle-stimulating hormone (FSH) secretion was similar in the two lines, but differed between the intact and the castrated lambs. Basal LH and FSH secretion were significantly higher in the castrates than in the intact lambs from both selection lines. The high-line lambs had significantly higher basal FSH concentrations at all ages tested and significantly higher basal LH concentrations during the early postnatal period. The magnitude of the gonadotrophin responses to GnRH differed significantly between the intact and the castrated lambs within each line, the amount of gonadotrophins secreted by the castrated lambs being significantly greater. The removal of gonadal negative feedback by castration did not alter the between-line difference in either LH or the FSH response to the GnRH challenge. Throughout the experimental period, the concentration of testosterone in the intact lambs was significantly greater than in the castrated lambs in both selection lines, but no significant difference was seen in the concentrations of oestradiol. No significant between-line differences were found in the peripheral concentrations of testosterone or oestradiol in the intact lambs from the two selection lines. Therefore, despite similar amounts of gonadal negative feedback in the selection lines, there were significant between-line differences in basal gonadotrophin concentrations, at 2 and 6 weeks of age, and in the LH and FSH responses to an exogenous GnRH challenge, at all ages tested. Removal of gonadal negative feedback did not affect the magnitude of the between-line difference in the response of the lines to GnRH stimulation. The results indicate that the effects of selection on gonadotrophin secretion are primarily at the level of the hypothalamo-pituitary complex.     

Sexual and aggessive behaviour of castrated male sheep after injection of gonadal steroids and implantation of androgens in the hypothalamus: A preliminary study

The combined effects of hypothalamic steroid implants and subcutaneous hormone injections on the courtship, copulatory and aggressive behaviour of five castrated male sheep (wethers) were assessed in thrice weekly tests with sexually receptive ewes. The animals were prepared with bilateral guide tubes for the insertion of removable hormone-containing cannulae aimed at the preoptic/anterior hypothalamic region of the brain. The sheep were treated as follows: weeks 1-4, cholesterol implants + oestradiol dipropionate injections; weeks 5-7, dihydrotestosterone propionate implants + oestradiol dipropionate injections; weeks 10-12, testosterone terone propionate implants + oil injections; weeks 13-15, testosterone propionate implants + dihydrotestosterone propionate injections. During peripheral treatment with oestradiol dipropionate (weeks 1-4), two of five sheep displayed ejaculatory reflexes in the absence of erection and intromission. Moreover, no obvious behavioural effects could be attributed to the additional presence of central dihydrotestosterone propionate implants (weeks 5-7). By contrast, testosterone propionate implants at the same central sites (weeks 10-12) maintained sexual behaviour in four of five sheep, induced mounting in the remaining animal and stimulated aggressive behaviour in all five sheep. Subsequently, additional peripheral treatment with dihydrotestosterone propionate (weeks 13-15) also stimulated three of the animals to exhibit penile erections.     

Seasonally and experimentally induced changes in testicular function of the Australian bush rat (Rattus fuscipes)

Serum concentrations of LH, FSH and testosterone were measured monthly throughout the year in male bush rats. Testicular size and ultrastructure, LH/hCG, FSH and oestradiol receptors and the response of the pituitary to LHRH were also recorded. LH and FSH rose in parallel with an increase in testicular size after the winter solstice with peak gonadotrophin levels in the spring (September). The subsequent fall in LH and FSH levels was associated with a rise in serum testosterone which reached peak levels during summer (December and January). In February serum testosterone levels and testicular size declined in parallel, while the pituitary response to an LHRH injection was maximal during late summer. The number of LH/hCG, FSH and oestradiol receptors per testis were all greatly reduced in the regressed testes when compared to active testes. In a controlled environment of decreased lighting (shortened photoperiod), temperature and food quality, the testes of sexually active adult males regressed at any time of the year, the resultant testicular morphology and endocrine status being identical to that of wild rats in the non-breeding season. Full testicular regression was achieved only when the photoperiod, temperature and food quality were changed: experiments in which only one or two of these factors were altered failed to produce complete sexual regression.     

Roles of the dominant follicle and the pattern of oestradiol in induction of preovulatory surges of LH and FSH in prepubertal heifers by pulsatile low doses of LH

Prepubertal crossbred beef heifers were injected (i.v.) with 50 micrograms bovine LH every 2 h for 48 h (first injection at 0 h). At 28 h, number and diameter of ovarian follicles were determined by ultrasonic scanning, and unilateral removal of either the ovary bearing the largest follicle (Group UL, N = 5) or the opposite ovary (Group UO, N = 4) was performed; control animals remained intact (Group I, N = 5). Blood samples were taken every 2 h (starting at 0 h) for a 60-h period to assess concentrations of gonadotrophins and oestradiol. Preovulatory-like surges of LH occurred in 0/5, 4/4 and 5/5 heifers for Groups UL, UO and I respectively; the time of the LH surge did not differ between animals in Groups I and UO (mean = 40 h). FSH in Group UL heifers rose to a plateau immediately after unilateral ovariectomy; this pattern was not observed in the other two groups (P less than 0.01). The area under the curve for FSH was significantly different (P less than 0.05) among groups after 28 h. Preovulatory-like surges of FSH occurred coincidently with those of LH, except for one Group I heifer. An increase in the concentrations of oestradiol between 0 and 28 h was detected in all animals. Profiles of oestradiol during this period did not differ between heifers that had an LH surge (Group UO and I) and those that did not (Group UL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that oestrogen exerts an equivalent negative feedback action on LH secretion in male and female ferrets

Gonadally intact male ferrets in breeding condition, which received an aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD) s.c. in Silastic capsules, had significantly more LH pulses and higher mean LH concentrations in plasma than did control males implanted with empty capsules. Aromatase activity in the hypothalamus + preoptic area and temporal lobe was strongly suppressed by ATD treatment whereas circulating concentrations of testosterone and oestradiol were not affected. These results suggest that oestradiol, formed via neural aromatization of circulating testosterone, contributes to the feedback regulation of LH secretion in breeding male ferrets just as oestradiol of ovarian origin controls LH secretion in females. No sex difference was observed in the rate at which mean plasma LH concentrations rose after the removal from gonadectomized ferrets of s.c. Silastic capsules containing oestradiol. Daily s.c. injections of oestradiol in oil caused an equivalent, dose-dependent inhibition of LH pulse frequency and mean LH concentrations in plasma of male and female ferrets. These findings suggest that the negative feedback control of pulsatile LH secretion by oestrogen is not sexually differentiated in this reflexly ovulating species. The ferret appears to differ from spontaneously ovulating mammalian species in which the female is generally more sensitive than the male to the inhibitory feedback action of oestradiol on LH secretion.     

Effects of androgen administration on sexual invitations by female rhesus monkeys (Macaca mulatta).

Pairs of adult rhesus monkeys of opposite sexes (12 pairs) were studied during 1-h mating tests (986 tests). Ovariectomized females received 5 microgram oestradiol intravaginally throughout to keep them attractive to males and maintain a relatively constant level of male sexual activity. Females were given subcutaneous silastic implants of testosterone to change their sexual receptivity. A threefold change in sexual invitations resulted from the implantation and removal of testosterone in the absence of any major changes in the behaviour of their male partners. These changes in invitational behaviour therefore reflected an action of the hormone upon an internal mechanism within the female subserving sexual motivation which was independent of changes in the behaviour of the male. Radioimmunoassay of plasma testosterone (109 samples) and plasma oestradiol (86 samples), and gas-liquid chromatography of vaginal secretions (306 samples), facilitated the monitoring of variables needed to interpret the results.     

Female effect in sheep. I. The effects of sexual receptivity of females and the sexual experience of rams

When in contact with receptive or non-receptive ewes, the presence of females increased LH peak frequency both in experienced and inexperienced rams (P less than 0.05). The highest response was found in experienced rams stimulated by sexually receptive ewes. In this group only, the mean testosterone levels increased during stimulation (P less than 0.05). Sexual behavior did not differ between experienced and inexperienced males. The sexual receptivity of the females and the sexual experience of rams appear to interact and thus facilitate the rams' LH and testosterone responses to the presence of ewes.     

Seasonal variation in the feedback of sex steroid hormones on serum LH concentrations in the male horse

The possibility of seasonal variation in the feedback effect of testosterone or oestradiol was investigated by giving replacement treatment to geldings for 2-3 weeks during breeding and non-breeding seasons. In the non-breeding season, testosterone suppressed LH values (mean +/- s.e.m., ng/ml) in all geldings (before treatment, 7.5 +/- 2.3; final treatment week, 1.8 +/- 0.2; P less than 0.05), whereas early in the breeding season, testosterone caused a prolonged rise in LH (before, 6.8 +/- 2.3; final week, 18.9 +/- 6.4; P less than 0.05). In all testosterone experiments, LH returned to pretreatment levels within 2 weeks after treatment. Oestradiol treatment caused a prolonged increase (P less than 0.05) in LH concentrations (mean +/- s.e.m., ng/ml) in both seasons (breeding: before 5.2 +/- 1.1; final week, 16.2 +/- 4.8; non-breeding before, 10.9, 20.1 +/- 5.2). We conclude that in geldings the feedback effect of testosterone varies with season and, further, that testosterone replacement may be able to restore to geldings the stallion's seasonal pattern of LH secretion. The results suggest that, in male horses, testosterone and possibly oestradiol, are important components in the neuroendocrine pathway controlling seasonal breeding and, moreover, are essential for the generation of a positive signal for LH secretion in the breeding season.     

The relationship between sexual and aggressive behaviour, and pituitary and testicular activity during the seasonal sexual cycle of rams, and the influence of photoperiod

Six adult Soay rams were housed under artificial lighting conditions with alternating 16-week periods of long (16 h light: 8 h darkness) and short days (8L:16D) During long days the rams were reproductively quiescent: the abrupt change from long to short days induced a specific succession of responses in the reproductive system. Plasma LH and FSH levels began to increase after 2-4 weeks, followed almost immediately by a rise in plasma testosterone levels accompanied by growth of the testes. Testicular activity continued to increase during short days and the greatly elevated androgen levels apparent after 5-10 weeks caused changes in the peripheral target organs, including growth of the epididymides, development of the sexual flush on the exposed ventral skin and heightened genital sensitivity. High testosterone levels were also associated with an increase in aggressive (scored by a mechanical device) and sexual (incidence of Flehmen) behavior which was at peak about 1 month after the start of the peak androgen levels. The change to long days was associated with a decrease in plasma gonadotrophin levels within 2 weeks followed by a progressive decline in all reproductive parameters measured. Implantation of a low dose of testosterone (200 mg) during the period of reproductive quiescence induced the development of the sexual flush and an increase in genital tactile sensitivity, although behaviour was not significantly affected. The annual changes in reproductive physiology and behaviour of 12 Soay rams living under natural lighting conditions were recorded for comparison with the experimental situation. The nadir of the sexual cycle was in the spring and early summer, and the sequence of events culminating in the mating season in the autumn was similar to that induced experimentally.     

Hormonal requirements for the growth and differentiation of hamster preantral follicles in long-term culture

Preantral follicles from pro-oestrous and oestrous hamsters were isolated enzymically (Stages 1-5) and by microdissection (Stage 6) and cultured for up to 168 h in the absence or presence of 100 ng ovine FSH or LH separately or combined or 1 or 10 micrograms progesterone or estradiol-17 beta in serum-free defined medium and exposed to 1 muCi [3H]thymidine for 24 h before termination. In the presence of insulin and hydrocortisone but not gonadotrophins, the morphology of follicles from pro-oestrous animals at Stages 1-4 (1-4 layers granulosa cells; no theca) were unaffected for up to 48 h whereas for Stages 5 (5-6 layers granulosa cells and developing theca) and 6 (7-8 layers granulosa cells and theca), atresia was prominent by 24 h. FSH significantly reduced the percentage of atretic follicles in Stages 1-5 throughout the culture period; but was effective only up to 96 h for Stage-6 follicles. LH was also effective, albeit to a lesser extent. FSH increased follicular labelling indexes during every 24-h labelling period and, during a pulse-chase period, follicular DNA content and granulosa cell numbers. FSH, but not LH, induced differentiation by 96 h of preantral follicles at Stage 6 into small antral stages (Stages 7-8). FSH and LH together induced almost the same effect as FSH alone. However, neither progesterone nor oestradiol had any significant long-term effects on DNA synthesis and oestradiol induced atresia beyond 24 h. Both FSH and LH induced follicular maturation in vitro as evident from increases in progesterone, androstenedione and oestradiol production. Follicles (Stages 1-4) collected from oestrous hamsters responded to FSH to a lesser extent than did those from pro-oestrous animals, possibly because of in-vivo exposure to periovulatory changes in gonadotrophins; however, an antrum formed in Stage-6 follicles by 72 h.     

Reproductive and endocrine function in rams exposed to the organochlorine pesticides lindane and pentachlorophenol from conception.

There is controversy over the potential endocrine modulating influence of pesticides, particularly during sensitive phases of development. In this study, ram lambs were exposed to lindane and pentachlorophenol from conception to necropsy at 28 weeks of age. The rams (and their mothers) were given untreated feed (n = 7) or feed treated with 1 mg kg-1 body weight per day of lindane (n = 12) or pentachlorophenol (n = 5). Semen was collected from 19 weeks onwards and reproductive behaviour was tested at 26 weeks. Serum was collected every 2 weeks and at 27 weeks every 15 min for 6 h during both day and night, and for 1 h before and 5 h after stimulation with GnRH, adrenocorticotrophic hormone and thyroid-stimulating hormone. The pesticides did not affect body weight and ejaculate characteristics, or cause overt toxicity. In pentachlorophenol-treated rams, scrotal circumference was increased. However, seminiferous tubule atrophy was more severe and epididymal sperm density was reduced in comparison with untreated rams at necropsy (P < 0.05). Thyroxine concentrations were lower in pentachlorophenol-treated rams than in untreated rams (P < 0.05). However, after thyroid-stimulating hormone treatment, the thyroxine response was unaltered. Reproductive behaviour was reduced in lindane-treated rams compared with control rams (P < 0.05). Serum LH and oestradiol concentrations during reproductive development, LH pulse frequency at 27 weeks and testosterone secretion after GnRH treatment were lower in lindane-treated rams than in untreated rams (P < 0.05). In summary, the effects of pentachlorophenol on the testis may be linked to a decrease in thyroxine concentrations, and reduced reproductive behaviour in lindane-treated rams may be related to decreased LH, oestradiol and testosterone concentrations.     

Effect of LH on progesterone and oestradiol production in vivo and in vitro by preovulatory rat follicles

Temporal changes in follicular oestradiol production induced in vitro and in vivo by LH were studied. In-vitro changes were measured by incubating preovulatory rat follicles for 12 h, changing the medium every 2 h. Follicles isolated at various intervals after an injection of 10 i.u. hCG were incubated for 2 h to measure changes in oestradiol production in vivo. In both studies there was an increase in oestradiol production lasting 4 h followed by a sharp decline. Progesterone production was also increased by LH in vitro or hCG in vivo, but remained high. A second exposure to LH did not raise oestradiol synthesis, but increased progesterone synthesis in vitro only. The decline in oestradiol production is most probably due to a decrease in C17-20 lyase activity, because addition of testosterone, but not of 17 alpha-hydroxyprogesterone, increased oestradiol production. Incubation of preovulatory follicles in the absence of LH or incubation of follicles derived from animals in which the spontaneous LH surge was blocked by an injection of pentobarbitone sodium also resulted in a decrease of oestradiol and an increase in progesterone production. This oestrogen-progesterone shift was also caused by a decrease in C17-20 lyase activity. The results demonstrate that the changes in steroid production in vivo and in vitro are similar and occur in the presence and absence of LH. It is concluded that the decrease in oestradiol production is dependent on the decrease in the activity of enzymes converting progesterone to aromatizable androgens.     

Effects of sexual stimulation on plasma levels of LH and testosterone in rams from high- and low-fertility flocks

Plasma LH and testosterone levels did not differ significantly between high and low fertility rams before or after sexual stimulation (ejaculation or teasing). Repeated stimulation caused significant elevation of mean plasma LH and an almost significant rise in testosterone concentration. Plasma testosterone peaks followed those of LH after 30-60 min. A single sexual stimulation did not always cause an LH peak or increase the mean LH level.     

Temporal variation in LH and testosterone responses of rams after the introduction of oestrous females during the breeding season

The response of sexually experienced Ile-de-France rams to the presentation of oestrous females in October at sunrise (Subgroup S) or at 11:00 h (Subgroup N) was studied and compared with unstimulated controls (Subgroup C). Animals (12 per group) were bled for 7 h at 20-min intervals, starting 3 h before stimulation by oestrous females (3 per group). Eight rams from Subgroup S showed an increase of LH pulse frequency and only 3 in Subgroup N (P less than 0.03). In Subgroup S the introduction of females led to 2- and 3-fold increases in LH pulse frequency during the stimulation period compared with values in Subgroup C or before the stimulation period (3, 1.6 and 1 peaks/rams/6 h respectively; P less than 0.05). The presence of females also led to an increase in mean testosterone concentrations, and small increases in basal and mean LH values. No differences were found in LH peak amplitudes. In Subgroup N only inconsistent evidence of increases in mean LH and testosterone values was found. No differences between Subgroups S and N in behavioural patterns during stimulation were detected. We conclude that the presence of females affects LH pulse frequency at sunrise but not at noon during the breeding season and this effect is at least partly independent of sexual behaviour. These results suggest a possible circadian variation in CNS sensitivity involving the hypothalamic regulation of LH secretion in response to the presence of oestrous females.     

Acute changes in plasma testosterone levels and their relation to measures of sexual behaviour in the male house mouse (Mus musculus)

There is an increasing amount of evidence, from several mammalian species, that plasma testosterone levels increase acutely when the male is exposed to sexual stimuli. Work reported here investigates whether such responses occur in male mice, and whether their incidence is related to measures of sexual behaviour. Close proximity of oestrous female mice was found to result in increased plasma testosterone levels in some strains within 15 min. Immediately after a sexual behaviour test, plasma testosterone levels were higher in males showing sexual responses. There were correlations between testosterone levels and mount latency, but none with ejaculation latency. Testosterone levels were greatest at the initiation of mounting responses, and declined during copulation, although not significantly.     

Studies on factors affecting release of gonadotrophins during the superfusion of isolated rat pituitaries.

Isolated pituitary glands from adult male rats were maintained in a continuous flow system. Gn-RH (1000 pmol/ml) caused a characteristic release of cyclic AMP, LH, and FSH. Cyclic AMP (1000 nmol/ml) liberated a similar amount of both gonadotrophins. Theophylline (1 mmol/ml) enhanced the effect of cyclic AMP by 21% for LH and 41% for FSH. The infusion of oestradiol (184 pmol/ml) alone or before Gn-RH infusion did not produce a significant effect on the secretion of either gonadotrophin or cyclic AMP. In contrast, there was a significant reduction in the amount of LH (P less than 0-025) and FSH (P less than 0-05) released by pituitaries infused with oestradiol and cyclic AMP.     

Influence of season and low-level oestradiol immunoneutralization on episodic LH and testosterone secretion and testicular steroidogenic enzymes and steroidogenic acute regulatory protein in the adult ram

The regulation of LH-dependent and -independent increases in testosterone secretion by key proteins in the testes of adult rams was investigated. Serial blood samples were collected from groups of four control and passively immunized (oestradiol antiserum for 3 weeks) rams and the animals were gonadectomized in either the non-breeding season (April) or the breeding season (September). LH pulse frequency and basal (interpulse) concentrations were several times greater (P < 0.01) in the breeding season than in the non-breeding season. Neither of these parameters nor LH pulse amplitude were affected by oestradiol immunization. Parameters of testosterone episodic secretion and response to an injection (i.v.) of 15 micrograms NIH-LH-S25 were also greater (P < 0.05) in the breeding season and, with the exception of pulse frequency, in immunized rams versus controls. Substrate utilization established that testosterone biosynthesis was predominantly via the 5-ene pathway. Increases in blood testosterone concentration in the breeding season were associated with a fivefold higher (P < 0.01) activity of cytochrome P450 17alpha-hydroxylase/C-17,20 lyase (P450(17alpha)) and a 65% higher (P < 0.05) relative amount of mRNA for cytochrome P450 cholesterol side-chain cleavage enzyme complex (P450scc) in the testis. Of the steroidogenic enzyme activities examined, only that for 17beta-hydroxysteroid dehydrogenase (17beta-HSD) tended to be increased by oestradiol immunization. Blood concentrations of cholesterol lipoproteins and expression of the testicular low density lipoprotein receptor were not affected by season or immunization. The amount of steroidogenic acute regulatory protein (StAR) mRNA was 65% higher (P < 0.01) in the breeding season and 20% higher (P < 0.01) in immunized rams versus controls. These results indicate that greater LH stimulation may increase testosterone biosynthesis in the breeding season by increasing StAR mRNA (and presumably delivery of cholesterol to P450scc) and the activity of P450(17alpha), and possibly that of P450scc (activity not measured). More moderate increases in StAR mRNA and 17beta-HSD activity may explain, in part, the increases in testosterone secretion with oestradiol immunization.     

Production of oestradiol, camp and 125I-hcg binding by rat ovaries during the reproductive cycle.

Plasma concentration of oestradiol in female rats is dynamically altered in the reproductive cycle, depending on the biosynthesis and secretion of oestradiol secretion by the ovaries. The present study has followed oestradiol and cAMP concentration in the plasma and ovaries, and 125I-HCG binding during the pro-oestrus, oestrus and di-oestrus. Oestradiol concentration in plasma and its production by the ovaries were found to be highest in the pro-oestrus and lowest in the oestrus. These changes depend on the production and secretion of gonadotrophins. The mediator of gonadotropin action is cAMP whose ovarian concentration is lowest in the oestrus. LH stimulates the cAMP synthesis in the ovaries during the cyclic stages, without any significant difference being apparent between the various stages. 125I-HCG binding is highest in the di-oestrus stage, when concentration of endogenous gonadotrophins is low.