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.     

Endocrine studies in postmenopausal women during oral replacement therapy with unconjugated oestrogens

Two groups of postmenopausal women were seen at monthly intervals during a three-month trial of continuous therapy with oral unconjugated oestrogens. Ten women in the first group were administered daily Hormonin No. 1 containing oestriol (E3) 0.135 mg, oestradiol (E2) 0.3 mg and oestrone (E1) 0.7 mg. Eight women in the second group received Hormonin No. 2 containing E3 0.27 mg, E2 0.6 mg and E1 1.4 mg. E1, E2, E3 and dehydroepiandrosterone (DHA) as well as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay. Maturation index of vaginal smears and clinical effects were also evaluated. Oral replacement therapy with these unconjugated oestrogens produced a significant elevation of E1 (p less than 0.05) and E2 (p less than 0.05) to values corresponding well with the premenopausal range measured in our laboratory. Postmenopausal levels of FSH and LH showed only a moderate but significant decrease (p less than 0.05). There was consistent relief of vasomotor symptoms. One case of endometrial focal adenomatous hyperplasia uncovered during the period of treatment was transformed to functional secretory endometrium after an appropriate course with progestogens. Oral administration of unconjugated oestrogens and periodic withdrawal bleeding induced with a progestational agent seems to be an effective method of replacement therapy in postmenopausal women.     

Effect of progesterone, administered via intravaginal rings, on serum concentrations of oestradiol, FSH, LH and prolactin in women

Intravaginal rings containing progesterone were inserted on Day 5 of the cycle to 8 healthy, normally menstruating women. Blood samples were taken during Days 4--22 of the cycle at 2--3-day intervals. The plasma progesterone levels obtained after the insertion were between 7.5 and 21 nmol/l. Four subjects showed no increase in plasma oestradiol concentrations. The subjects showing increased plasma oestradiol levels also showed a positive feedback on LH, resulting in ovulation or an LH peak. The results suggest that progesterone may have a local inhibitory effect on the follicular oestradiol production.     

Studies of the effectiveness of gonadotrophin-releasing hormone, steroids and follicular fluid in modulating ovine gonadotrophin output in vivo and in vitro

Gonadotrophin-releasing hormone (GnRH) readily stimulated LH output by sheep pituitary cells in vitro, and raised plasma LH concentrations in vivo in sheep, in a dose-dependent fashion. However, increases in FSH levels were only marginal by comparison. Dose-dependent decreases in sheep pituitary cell FSH output and in plasma FSH concentrations were caused by sheep follicular fluid and oestradiol-17 beta in vitro, and by bovine follicular fluid and oestradiol benzoate in vivo. In contrast, LH concentrations were only reduced slightly at the higher doses of these reagents. Cumulative suppressive effects of follicular fluid and oestradiol-17 beta (oestradiol benzoate) on FSH levels were observed both in vitro and in vivo. The transient positive feedback effect of oestradiol benzoate on FSH output negated the suppressive effect of bovine follicular fluid on plasma FSH concentrations. Progestagens, androgens and catechol oestrogens also suppressed mean FSH output in vitro, though not as effectively as oestradiol-17 beta. While only 1-5 pg/ml of oestradiol-17 beta was needed to suppress significantly mean FSH output in vitro, greater than 500 pg/ml of the other steroids was required. Seminal plasma inhibin-like peptide failed to suppress mean FSH output by cultured sheep pituitary cells at doses from 1 pg/ml to 500 ng/ml. At higher doses, both FSH and LH output was suppressed and this was accompanied by morphological deterioration of the cells. It is suggested that, to raise plasma FSH concentrations with a view to increasing ovulation rates in sheep, the development of means to reduce the negative feedback effects of steroids, notably oestradiol-17 beta, and inhibin on FSH secretion may be a more appropriate pharmacological strategy than increasing pituitary exposure to GnRH.     

Hormonal Responses to Synthetic Luteinizing Hormone and Follicle Stimulating Hormone-Releasing Hormone in Man

The effects of the gonadotrophin-releasing hormone, synthetic decapeptide luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH), have been studied in 18 normal men and five women in the follicular phase of their menstrual cycle. Rapid and dose-dependent (25 to 100 μg) increases in serum immunoreactive LH were seen, which reached a peak 20 to 30 minutes after a rapid intravenous injection. Similar but much smaller increases in serum immunoreactive FSH were seen. These conclusions have been validated by using two different immunoassay systems for each hormone. The LH/FSH-RH therefore causes both LH and FSH release in man as in animals but does not affect growth hormone, thyrotrophin, or ACTH. The gonadotrophin responses were the same in the women as in the men but were insufficient in the men to cause statistically significant changes in the serum levels of the gonadal steroid hormones, testosterone or oestradiol, or in their precursors 17 α-hydroxyprogesterone or progesterone. In the women, however, there was a rise in oestradiol after the 100-μg doses. The use of LH/FSH-RH will provide an important test to define the level of the lesion in hypogonadal patients and also should be valuable in the treatment of some types of male and female infertility. A simple and clinically useful LH/FSH-RH test of pituitary function is described (100 μg given intravenously), and the provisional normal responses of LH and FSH at 20 and 60 minutes are given.     

Hormonal profiles after the menopause.

The endocrinological changes of the climacteric have been defined by studying the concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), androstenedione, testosterone, oestrone, and oestradiol in 60 normal postmenopausal women of different menopausal ages. The women were studied in six groups, according to the number of years since their menopause. One year after the menopause androstenedione, oestrone, and oestradiol concentrations were reduced to about 20% of the values recorded during the early proliferative phase of the menstrual cycle. At the same time the mean concentration of FSH had risen by a factor of 13-4 and that of LH by a factor of 3-0. Concentrations of both gonadotrophins reached a peak of 18-4 and 3-4 times the proliferative phase value respectively after two to three years, and then gradually declined in the next three decades to values that were 40-50% of these maximal levels. Testosterone concentrations remained mostly in the normal range for premenopausal women but were depressed to 60% of these levels two to five years after the menopause, and the mean androstenedione levels showed a significant increase in the same group of women. The concentrations of both oestrone and oestradiol remained consistently low for 10 years after the menopause, but oestradiol concentrations inexplicably increased in the last two decades, with levels at the lower end of normal range for reproductive women in six patients.     

Effects of time after ovariectomy, season and oestradiol on luteinizing hormone and follicle-stimulating hormone secretion in ovariectomized ewes.

During the breeding season, five groups of three ewes were implanted at ovariectomy with 0.36, 0.5, 1.0 and 6.0 cm oestradiol implants or implants containing no steroid. Eleven days after receiving implants, blood samples were taken every 10 min for 6 h; implants were then removed. Treatments were repeated three times during each of two consecutive breeding seasons and four times during the intervening anoestrus. In ovariectomized ewes without steroid treatment, luteinizing hormone (LH) pulse frequency increased from early to mid-breeding season, decreased to a minimum at mid-anoestrus and increased to reach a maximum at the mid-point of the second breeding season, subsequently declining. LH pulse amplitude was inversely related to frequency. Basal serum LH concentrations decreased gradually from the first breeding season to reach a minimum at mid-anoestrus and gradually increased to reach a maximum at the end of the second breeding season. Mean serum LH and follicle-stimulating hormone (FSH) concentrations were higher at the end of the second breeding season compared with the beginning of the first breeding season. All parameters of gonadotrophin secretion were decreased much more by oestradiol during the anoestrus than during the breeding season. LH pulse frequency was decreased during anoestrus and at high oestradiol concentrations during the first breeding season. Apart from LH pulse amplitude, the decreases in all parameters of gonadotrophin secretion were less during the second compared with the first breeding season. The minimum effective dose of oestradiol required to decrease mean and basal serum concentrations of LH during anoestrus was lower than in the breeding season. The minimum effective dose of oestradiol required to decrease mean serum concentrations of FSH was lower in the first compared with the second breeding season. Oestradiol depression of LH pulse amplitude and mean serum concentrations of LH and FSH showed a dose dependency during the breeding season. During anoestrus dose dependency was seen for basal concentrations of LH and mean serum concentrations of LH and FSH. We conclude that significant chronic changes in gonadotrophin secretion occur in the ewe with time after ovariectomy. Sensitivity to oestradiol also changes, and the effects of oestradiol are not always dose dependent. We suggest that the circannual pattern of LH pulse frequency and basal LH secretion are directly linked to the circannual cycle of photoperiod.(ABSTRACT TRUNCATED AT 400 WORDS)     

More rapid restoration of pituitary content of follicle-stimulating hormone than of luteinizing hormone after depletion by oestradiol-17 beta in ewes.

To test the hypothesis that the synthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are differentially regulated after depletion by oestradiol, circulating concentrations of oestradiol were maintained at approximately 30 pg/ml for 16 days in each of 35 ovariectomized ewes. Five other ovariectomized ewes that did not receive oestradiol implants served as controls. After treatment with oestradiol, implants were removed and pituitary glands were collected from each of 5 ewes at 0, 2, 4, 8, 12, 16 and 32 days thereafter and amounts of mRNA for gonadotrophin subunits and contents of LH and FSH were quantified. Before collection of pituitary glands, blood samples were collected at 10-min intervals for 6 h. Treatment with oestradiol reduced (P less than 0.05) steady-state concentrations of LH beta- and FSH beta-subunit mRNAs and pituitary and serum concentrations of these hormones. At the end of treatment the amount of mRNA for FSH beta-subunit was reduced by 52% whereas that for LH beta-subunit was reduced by 93%. Steady-state concentrations of mRNA for FSH beta-subunit returned to control values within 2 days of removal of oestradiol, but 8 days were required for concentrations of FSH in the pituitary and serum to return to control values. Steady-state concentrations of mRNA for LH beta-subunit and mean serum concentrations of LH returned to control values by Day 8, but pituitary content of LH may require as long as 32 days to return to control levels. Therefore, replenishment of FSH beta-subunit mRNA preceded increases in pituitary and serum concentrations of FSH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dexamethasone on plasma concentrations of LH, FSH and testosterone in women with hirsutism.

Thirty sexually mature women with hirsutism were treated with 3 x 1.5 mg dexamethasone per day over a period of three days. Before and after treatment, plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were determined. While an effect of dexamethasone on LH plasma levels could not be established statistically, FSH and testosterone plasma concentrations decreased significantly in comparison to their initial values (p less than 0.01). Special attention is directed to the different effects of dexamethasone on LH and FSH plasma concentrations.     

Modulation of luteinizing hormone and follicle-stimulating hormone in circulation by interactions between endogenous opioids and oestradiol during the peripubertal period of heifers.

The aim of this study was to determine whether the decline in oestradiol inhibition of circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the peripubertal period of heifers is associated with a change in opioid modulation of LH and FSH secretion. Opioid inhibition of LH secretion was determined by response to administration of the opioid antagonist naloxone. Prepubertal heifers (403 days old) were left as intact controls, ovariectomized or ovariectomized and chronically administered oestradiol. Control heifers were used to determine time of puberty. Three weeks after ovariectomy, four doses of naloxone (0.13-0.75 mg kg-1 body weight) or saline were administered to heifers in the treatment groups in a latin square design (one dose per day). Blood samples were collected at intervals of 10 min for 2 h before and 2 h after administration of naloxone. This procedure was repeated four times at intervals of 3 weeks during the time intact control heifers were attaining puberty. All doses of naloxone induced a similar increase in concentration of serum LH within a bleeding period. During the initial bleeding period (before puberty in control heifers), administration of naloxone induced an increase in LH concentration, but the response was greater for heifers in the ovariectomized and oestradiol treated than in the ovariectomized group. At the end of the study when control heifers had attained puberty (high concentrations of progesterone indicated corpus luteum function), only heifers in the ovariectomized and oestradiol treated group responded to naloxone. Opioid inhibition of LH appeared to decline in heifers during the time control heifers were attaining puberty. Heifers in the ovariectomized group responded to naloxone at the time of administration with an increase in FSH, but FSH did not respond to naloxone at any other time. Administration of naloxone did not alter secretion of FSH in ovariectomized heifers. These results suggest that opioid neuropeptides and oestradiol are involved in regulating circulating concentrations of LH and possibly FSH during the peripubertal period. Opioid inhibition of gonadotrophin secretion appeared to decline during the peripubertal period but was still present in ovariectomized heifers treated with oestradiol after the time when age-matched control heifers had attained puberty. We conclude that opioid inhibition is important in regulating LH and FSH in circulation in heifers during the peripubertal period. However, opioids continue to be involved in regulation of circulating concentrations of LH after puberty.     

Influence of body weight on gonadotrophins and steroid hormone levels in menstruating women

In order to study the effect of obesity or underweight on gonadotropins and steroid hormone levels, serum concentrations of FSH, LH. Testosterone, Estradiol, Estrone, 17-OH-Progesterone and SHBG were measured by RIA in obese, underweight and control women, all menstruating in the follicular phase. Serum concentrations of all parameters measured did not differ significantly in the underweight and control groups. All obese women had higher levels of estrone than the control group, and only obese patients with a body mass index above 39 showed a lower SHBG level than that of the control group. The data suggest that the increased levels of estrone could play a role in the amenorrhea of obese women.     

Effect of beta-adrenergic drugs on LH, FSH, and growth hormone (GH) secretion in conscious, ovariectomized rats

The effects of third ventricular (3V) injection of the beta-adrenergic antagonist, propranolol (PROPR), a selective beta 1-antagonist, metoprolol (MET), a selective beta 2-antagonist, IPS 339, and a beta-adrenergic agonist (-) isoproterenol (ISOPR), on plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and growth hormone (GH) were studied in conscious, ovariectomized (OVX) rats. Samples were removed from unrestrained rats which had been previously implanted with atrial and 3V cannulae, and plasma hormone levels were determined by radioimmunoassay (RIA). Intraventricular injection of PROPR (30 micrograms), MET (40 micrograms), or IPS 339 (20 micrograms) induced a gradual elevation in plasma GH concentrations, whereas ISOPR (30 micrograms) reduced plasma GH. ISOPR (30 micrograms) brought about a decrease in plasma LH concentrations, but PROPR, MET and IPS 339 had no effect on LH levels. PROPR (30 micrograms) increased plasma FSH concentrations, but there was no significant effect of MET, IPS 339 or ISOPR on FSH secretion. The results indicate that the beta-adrenergic system can inhibit the release of GH, LH, and FSH. This system appears to have a tonic inhibitory effect on GH and FSH but not LH release in the OVX rat.     

Direct effect of prolactin, induced by TRH injection, on ovarian oestradiol secretion in the ewe

The effect of sustained high plasma levels of prolactin, induced by repeated 2-h i.v. injections of thyrotrophin-releasing hormone (TRH; 20 micrograms), on ovarian oestradiol secretion and plasma levels of LH and FSH was investigated during the preovulatory period in the ewe. Plasma levels of progesterone declined at the same rate after prostaglandin-induced luteal regression in control and TRH-treated ewes. However, TRH treatment resulted in a significant increase in plasma levels of LH and FSH compared to controls from 12 h after luteal regression until 5 to 6 h before the start of the preovulatory surge of LH. In spite of this, and a similar increase in pulse frequency of LH in control and TRH-treated ewes, ovarian oestradiol secretion was significantly suppressed in TRH-treated ewes compared to that in control ewes. The preovulatory surge of LH and FSH, the second FSH peak and subsequent luteal function in terms of plasma levels of progesterone were not significantly different between control and TRH-treated ewes. These results show that TRH treatment, presumably by maintaining elevated plasma levels of prolactin, results in suppression of oestradiol secretion by a direct effect on the ovary in the ewe.     

Oestradiol and the preovulatory surges of luteinising hormone and follicle stimulating hormone in ewes during the breeding season and transition into anoestrus

This study was designed to see if giving exogenous oestradiol, during the follicular phase of the oestrous cycle of intact ewes, during the breeding season or transition into anoestrus, would alter the occurrence, timing or magnitude of the preovulatory surge of secretion of luteinising hormone (LH) or follicle stimulating hormone (FSH). During the breeding season and the time of transition, separate groups of ewes were infused (intravenously) with either saline (30 ml h⁻¹; n = 6) or oestradiol in saline (n = 6) for 30 h. Infusion started 12 h after removal of progestin-containing intravaginal sponges that had been in place for 12 days. The initial dose of oestradiol was 0.02 μg h⁻¹; this was doubled every 4 h for 20 h, followed by every 5 h up to 30 h, to reach a maximum of 1.5 μg h⁻¹. Following progestin removal during the breeding season, peak serum concentrations of oestradiol in control ewes were 10.31 ± 1.04 pg ml⁻¹, at 49.60 ± 3.40 h after progestin removal. There was no obvious peak during transition, but at a time after progestin removal equivalent to the time of the oestradiol peak in ewes at mid breeding season, oestradiol concentrations were 6.70 ± 1.14 pg ml⁻¹ in ewes in transition (P < 0.05). In oestradiol treated ewes, peak serum oestradiol concentrations (24.8 ± 2.1 pg ml⁻¹) and time to peak (41.00 ± 0.05 h) did not differ between seasons (P > 0.05). During the breeding season, all six control ewes and four of six ewes given oestradiol showed oestrus with LH and FSH surges. The two ewes not showing oestrus did not respond to oestrus synchronisation and had persistently high serum concentrations of progesterone. During transition, three of six control ewes showed oestrus but only two had LH and FSH surges; all oestradiol treated ewes showed oestrus and gonadotrophin surges (P < 0.05). The timing and magnitude of LH and FSH surges did not vary with treatment or season. In blood samples collected every 12 min for 6 h, from 12 h after the start of oestradiol infusion, mean serum concentrations of LH and LH pulse frequency were lower in control ewes during transition than during mid breeding season (P < 0.05). Oestradiol treatment resulted in lower mean serum concentrations of LH in season and lower LH pulse frequency in transition (P < 0.05). We concluded that enhancing the height of the preovulatory peak in serum concentrations of oestradiol during the breeding season did not alter the timing or the magnitude of the preovulatory surge of LH and FSH secretion and that at transition into anoestrus, oestradiol can induce oestrus and the surge release of LH and FSH as effectively as during the breeding season.     

Effect of Synthetic Luteinizing Hormone Releasing Hormone (LH FSH-RH) in Women with Menstrual Disorders

Synthetic luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH) (50 μg) was given intravenously to six women with oligomenorrhoea and to four women with secondary amenorrhoea. Peripheral venous blood was withdrawn at regular intervals over a 24-hour period. The concentrations of LH, FSH, and oestradiol-17β were determined by radioimmunoassay. In all subjects there was a variable rise in LH (3-16 times the mean basal level): in six a small rise in FSH (two to three times the mean basal level) and in seven a twofold to threefold rise in oestradiol three to eight hours after the rise in gonadotrophins.     

Placebo-controlled study of effects of epimestrol on the pituitary-testicular axis in normal men

Twenty healthy male volunteers were randomly allocated to the treatment with either 15 mg/day of epimestrol or placebo for 10 days. The plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), oestradiol (E2) and prolactin (PRL) were measured before, during and 4 days after the medication by radioimmunoassays. Data were statistically evaluated by means of an analysis of covariance. Circulating LH and FSH, and also T and E2 significantly increased in the epimestrol treated subjects. In the placebo treated subjects no significant changes in the plasma hormone levels were observed. There were no significant changes in the plasma levels of PRL in either group.     

The significance of FSH elevation in young women with disorders of ovulation.

High serum follicle stimulating hormone (FSH) values are consistent with ovarian failure. We studied the progress of 67 women aged under 35 years with oligomenorrhoea or secondary amenorrhoea in whom the serum FSH value was greater than 20 U/1. Twenty-four patients remained amenorrhoeic, but 17 ovulated and six conceived, two on two occasions. Coincident mean serum luteinising hormone (LH) concentrations were significantly lower and mean total urinary oestrogen concentrations were significantly higher in patients who subsequently ovulated, but the degree of increase in FSH did not correlate well with later ovarian function. Treatment with oestrogens, clomiphene citrate, human pituitary gonadotrophin, and bromocriptine was of no benefit in inducing an ovarian response while FSH concentrations remained raised. Our results suggest that a considerable proportion of younger women with ovulatory disorders associated with FSH values in the menopausal range will spontaneously resume ovulation and some will conceive.     

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.     

Interactions between inhibin, oestradiol and progesterone in the control of gonadotrophin secretion in the ewe

Experiments were carried out to test the hypothesis that inhibin and oestradiol act synergistically to inhibit the secretion of FSH, to test for effects of progesterone, and to compare the FSH and LH responses to ovarian feedback. In Exp. 1, with 11 ovariectomized and 12 intact Romanov ewes during the anoestrous season, doses of oestradiol (administered by means of subcutaneous implants) that restored normal LH pulse frequencies were insufficient to restore normal concentrations of FSH. In Exp. 2, with 48 ovariectomized Welsh Mountain ewes during the breeding season, a factorial design with 4 ewes per cell was used to assess the responses in LH and FSH to 3 doses of oestradiol (s.c. implants) and 4 doses of bovine follicular fluid ('inhibin', 0.2-1.6 ml s.c. every 8 h). This was done initially in the absence of progesterone and then after 7 days of treatment with progesterone (s.c. implants). Analysis of variance revealed a significant synergistic interaction between oestradiol and inhibin on the plasma concentrations of FSH. Progesterone had little effect. In contrast, there was a significant synergistic interaction between oestradiol and progesterone on the concentrations of LH. 'Inhibin' also inhibited LH secretion but this effect was independent of the two steroids. We conclude that there are basic differences in the way that ovarian feedback acts to control the secretion of LH and FSH in the ewe. FSH secretion appears to be primarily controlled by the synergistic action of oestradiol and inhibin on the anterior pituitary gland, while the secretion of LH is inhibited during the follicular phase by an effect of oestrogen at pituitary level and during the luteal phase by the synergistic action of oestradiol and progesterone at the hypothalamic level. Inhibin, or another non-steroidal factor in follicular fluid, may also play a minor role in the control of LH secretion.     

Effects of oestradiol on LH, FSH and prolactin in ovariectomized ewes

This study was conducted to test the hypothesis that the rate (dose/time) at which oestradiol-17 beta (oestradiol) is presented to the hypothalamo-pituitary axis influences secretion of LH, FSH and prolactin. A computer-controlled infusion system was used to produce linearly increasing serum concentrations of oestradiol in ovariectomized ewes over a period of 60 h. Serum samples were collected from ewes every 2 h from 8 h before to 92 h after start of infusion, and assayed for oestradiol, LH, FSH and prolactin. Rates of oestradiol increase were categorized into high (0.61-1.78 pg/h), medium (0.13-0.60 pg/h) and low (0.01-0.12 pg/h). Ewes receiving high rates of oestradiol (N = 11) responded with a surge of LH 12.7 +/- 2.0 h after oestradiol began to increase, whereas ewes receiving medium (N = 15) and low (N = 11) rates of oestradiol responded with a surge of LH at 19.4 +/- 1.7 and 30.9 +/- 2.0 h, respectively. None of the surges of LH was accompanied by a surge of FSH. Serum concentrations of FSH decreased and prolactin increased in ewes receiving high and medium rates of oestradiol, when compared to saline-infused ewes (N = 8; P less than 0.05). We conclude that rate of increase in serum concentrations of oestradiol controls the time of the surge of LH and secretion of prolactin and FSH in ovariectomized ewes. We also suggest that the mechanism by which oestradiol induces a surge of LH may be different from the mechanism by which oestradiol induces a surge of FSH.