Influence of synthetic lamprey GnRH-III on gonadotropin release and steroid hormone levels in gilts

Based on the supposition that lamprey GnRH-III (lGnRH-III) elicits FSH releasing activity in swine, synthetic lGnRH-III (peforelin, Maprelin® XP10) was used in puberal estrus synchronized gilts. The secretion of reproductive hormones FSH, LH, estradiol and progesterone was analyzed, and follicle growth and ovulation recorded. Altogether, 24 German Landrace gilts were treated after an 18-day long synchronization of the estrus cycle with Regumate® as follows: 48 h after the last Regumate® feeding they received im either 150 μg Maprelin® XP10 (lGnRH-III, group Maprelin, n = 6), 50 μg Gonavet Veyx® (GnRH-I agonist, group GnRH, n = 6), 850 IE Pregmagon® (eCG, group eCG, n = 6) or saline (group Control, n = 6). Additionally, in eight gilts the concentrations of FSH and LH were analyzed after treatment with 150 μg Maprelin® XP10 (n = 3), 50 μg Gonavet Veyx® (n = 3) or saline (n = 2) at mid-cycle (day 10 of the estrus cycle). Blood samples were collected via implanted jugular vein catheters. Ovarian features were judged endoscopically at the end of the Regumate® feeding and on days 5 and 6 after treatment. Maprelin® XP10 had no effect on FSH release in gilts; neither at the pre-ovulatory period or at mid-cycle. Furthermore, LH levels were unaffected. In contrast, GnRH-I agonist stimulates FSH release, however less compared to LH secretion. LH secretion was induced by GnRH-I both during the follicular phase and at mid-cycle. Equine CG did not stimulate the release of pituitary hormones FSH and LH due to its direct action on the ovary. Increased estradiol concentrations during days 2 to 5 after Regumate® in all treatment groups indicated pre-ovulatory follicle growth in gilts. Equine CG stimulated a higher (P < 0.01) number of ovulatory follicles compared to the other treatment groups. All together, 83 to 100 % of gilts ovulated by day 6 post treatment. In summary, results of our study on reproductive hormone secretion do not provide evidence that synthetic lGnRH-III (Maprelin® XP10) selectively releases FSH in estrus synchronized gilts.     

Restoration of endocrine and ovarian function after stopping GnRH antagonist treatment in goats

We have tested if the high number of unfertilized ova and degenerated embryos found in superovulated goats previously treated with GnRH antagonist can be related to a prolongation of gonadotrophin down-regulation and/or alterations in follicular function during the period of administration of the superovulatory treatment, around 4 days after the end of the antagonist treatment. A total of 15 does were treated with intravaginal progestagen sponges and daily injections of 0.5mg of the GnRH antagonist Antarelix for 6 days, while 5 does acted as controls receiving saline. During the antagonist treatment, the mean plasma LH concentration was lower in treated than control goats (0.5 +/- 0.2 versus 0.7 +/- 0.5 ng/ml, P < 0.0005 ); however, the FSH levels remained unaffected (0.8 +/- 0.4 versus 0.8 +/- 0.5 ng/ml). In this period, treated does also showed an increase in the number of small follicles with 2-3 mm in size ( 10.7 +/- 0.7 versus 8.4 +/- 0.6, P < 0.05), and a decrease in both the number of follicles > or =4 mm in size ( 5.0 +/- 0.3 versus 6.8 +/- 0.5, P < 0.005) and the secretion of inhibin A (120.9 +/- 10.7 versus 151.6 +/- 12.6 pg/ml, P < 0.05). After cessation of the antagonist treatment, there was an increase in LH levels in treated goats from the day after the last Antarelix injection (Day 1), so that LH levels were the same as controls on Day 3 (0.6 +/- 0.1 versus 0.6 +/- 0.2 ng/ml). However, there were even greater numbers of small follicles than during the period of antagonist injections (15.4 +/- 0.6 in treated versus 8.9 +/- 0.7 in control, P < 0.0005 ). Moreover, the number of > or =4 mm follicles and the secretion of inhibin A remained lower in treated goats (3.9 +/- 0.3 follicles and 84.4 +/- 7.0 pg/ml versus 5.4 +/- 0.5 follicles, P < 0.05 and 128.9 +/- 14.2 pg/ml, P < 0.05 ). These results indicate that pituitary secretion of gonadotrophins is restored shortly after the end of antagonist treatment, but activity of ovarian follicles is affected.     

Differential inhibition of human prostaglandin release in vitro by a GnRH antagonist

Previously, we have demonstrated that the production of prostaglandins by human placental tissue varied with gestational age. In addition, we have shown that placental prostaglandin release was affected by GnRH, and that its response was also dependent on the gestational age of the placenta. Thus, we have studied the effect of a GnRH antagonist ([N-Ac-Pro¹, D-p-Cl-Phe², D-Nal (2)^3,6-LHRH, Syntex Research, Palo Alto, CA) on basal prostaglandin release from placentas of 6 to 15 weeks' gestaton and found that this antagonist (1 μg/ml) effects an inhibition of the release of prostaglandin E, prostaglandin F, and 13, 14-dihydro-15-keto-prostaglandin from placentas of 13 and 15 weeks of gestation. This effect was not overridden by GnRH at 10 times the antagonist concentration in the 13-week placental cultures, but was totally reversed by GnRH (10 μg/ml) in the 15-week placental cultures. These data demonstrate that this GnRH antagonist can affect human placental prostaglandin production at 13 to 15 weeks of gestation and indicate that endogenous placental GnRH-like activity may exert a control over placental prostaglandin release at this gestational stage.     

Differential inhibition of human placental prostaglandin release in vitro by a GnRH antagonist

Previously, we have demonstrated that the production of prostaglandins by human placental tissue varied with gestational age. In addition, we have shown that placental prostaglandin release was affected by GnRH, and that its response was also dependent on the gestational age of the placenta. Thus, we have studied the effect of a GnRH antagonist ([N-Ac-Pro1,D-p-Cl-Phe2,D-Nal(2)3,6-LHRH, Syntex Research, Palo Alto, CA) on basal prostaglandin release from placentas of 6 to 15 weeks' gestation and found that this antagonist (1 microgram/ml) effects an inhibition of the release of prostaglandin E, prostaglandin F, and 13,14-dihydro-15-keto-prostaglandin from placentas of 13 and 15 weeks of gestation. This effect was not overridden by GnRH at 10 times the antagonist concentration in the 13-week placental cultures, but was totally reversed by GnRH (10 micrograms/ml) in the 15-week placental cultures. These data demonstrate that this GnRH antagonist can affect human placental prostaglandin production at 13 to 15 weeks of gestation and indicate that endogenous placental GnRH-like activity may exert a control over placental prostaglandin release at this gestational stage.     

Inhibition of pituitary-gonadal function in male rats by a potent GnRH antagonist

The inhibitory effects of the potent GnRH antagonist, [Ac-D-pCl-Phe1,2,D-Trp3,D-Arg6,DAla10]GnRH (GnRHant) upon pituitary-gonadal function were investigated in normal and castrated male rats. The antagonist was given a single subcutaneous (s.c.) injections of 1-500 micrograms to 40-60 day old rats which were killed from 1 to 7 days later for assay of pituitary GnRH receptors, gonadal receptors for LH, FSH, and PRL, and plasma gonadotropins, PRL, and testosterone (T). In intact rats treated with low doses of the antagonist (1, 5 or 10 micrograms), available pituitary GnRH receptors were reduced to 40, 30 and 15% of the control values, respectively, with no change in serum gonadotropin, PRL, and T levels. Higher antagonist doses (50, 100 or 500 micrograms) caused more marked decreases in free GnRH receptors, to 8, 4 and 1% of the control values, which were accompanied by dose-related reductions in serum LH and T concentrations. After the highest dose of GnRHant (500 micrograms), serum LH and T levels were completely suppressed at 24 h, and serum levels of the GnRH antagonist were detectable for up to 3 days by radioimmunoassay. The 500 micrograms dose of GnRHant also reduced testicular LH and PRL receptors by 30 and 50% respectively, at 24 h; by 72 h, PRL receptors and LH receptors were still slightly below control values. In castrate rats, treatment with GnRHant reduced pituitary GnRH receptors by 90% and suppressed serum LH and FSH to hypophysectomized levels. Such responses in castrate animals were observed following injection of relatively low doses of GnRHant (100 micrograms), after which the antagonist was detectable in serum for up to 24 h. These data suggest that extensive or complete occupancy of the pituitary receptor population by a GnRH antagonist is necessary to reduce plasma gonadotropin and testosterone levels in intact rats. In castrate animals, partial occupancy of the available GnRH receptor sites appears to be sufficient to inhibit the elevated rate of gonadotropin secretion.     

Pulsatile infusion of luteinizing hormone-releasing hormone: Effects on luteinizing hormone secretion and ovarian function in prepuberal gilts

Ten intact and hypophysial stalk-transected (HST), prepuberal Yorkshire gilts, 112–160 days old, were subjected to a pulsatile infusion regimen of luteinizing hormone-releasing hormone (LHRH) to investigate secretion profiles of luteinizing hormone (LH) and ovarian function. A catheter was implanted in a common carotid artery and connected to an infusion pump and recycling timer, whereas an indwelling external jugular catheter allowed collection of sequential blood samples for radioimmunoassay of LH and progesterone. In a dose response study, intracarotid injection of 5 μg LHRH induced peak LH release (5.9 ± 0.65 ng/ml; mean ± SE) within 20 min, which was greater (P < 0.001) than during the preinjection period (0.7 ± 0.65 ng/ml). After HST, 5 μg LHRH elicited LH release in only one of three prepuberal gilts. Four intact animals were infused with 5 μg LHRH (in 0.1% gel phosphate buffer saline, PBS) in 0.5-ml pulses (0.1 ml/min) at 1.5-h intervals continuously during 12 days. Daily blood samples were obtained at 20-min intervals 1 h before and 5, 10, 20, 40, 60 and 80 min after one LHRH infusion. Plasma LH release occurred in response to pulsatile LHRH infusion during the 12-day period; circulating LH during 60 min before onset of LHRH infusion was 0.7 ± 0.16 ng/ml compared with 1.3 ± 0.16 ng/ml during 60 min after onset of infusion (P < 0.001). Only one of four intact gilts ovulated, however, in response to LHRH infusion. This animal was 159 days old, and successive estrous cycles did not recur after LHRH infusion was discontinued. Puberal estrus occurred at 252 ± 7 days in these gilts and was confirmed by plasma progesterone levels. These results indicate that intracarotid infusion of 5 μg LHRH elicits LH release in the intact prepuberal gilt, but this dosage is insufficient to cause a consistent response after HST.     

Physiological role of putative testicular gonadotrophin releasing hormone (GnRH)

Evidence suggests that exogenous GnRH and agonist analogues have short-term stimulatory effects on rat Leydig cell function - when administered intratesticularly. Since rat Leydig cells possess GnRH receptors and their endogenous ligand has not yet been identified the physiological importance of the observations for testis function is unknown. To address this issue we have determined the consequences of blockade of testis GnRH receptors on Leydig cell function under both normogonadotrophic and hypogonadotrophic stimulation of the testis in vivo. A GnRH antagonist (ANT) was used to achieve receptor blockade but during continuous systemic infusion ANT occupied pituitary GnRH receptors and markedly reduced serum LH, FSH, testosterone, and intratesticular testosterone in adult and 30 d old immature male rats. These results were similar to those obtained by administration of a GnRH antiserum which did not bind to testis GnRH receptors. Thus, blockade of testis GnRH receptors during hypogonadotrophism did not produce additional inhibition of steroidogenesis by Leydig cells. However, direct continuous infusion of ANT into one testis produced greater than 90% occupancy of GnRH receptors while reducing GnRH receptors by only 50% in the contralateral testis. Unilateral intratesticular infusion did not reduce serum LH, FSH, Prolactin or testosterone levels despite 75% occupancy of pituitary GnRH receptors. Thus, both ANT infused and saline infused testes were exposed to the same gonadotrophic stimulants but in the former GnRH-R were essentially non-existent. Compared to the control testis, the ANT infused testis showed a 20-30% reduction in LH, FSH, lactogen receptors and 30-40% fall in testosterone content. Identical results were obtained in adult and 30 d-old male rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of hCG, alpha hCG and progesterone release from human placental tissue in vitro by a GnRH antagonist

A dramatic suppression of hCG, alpha hCG and progesterone release from midgestation, human placentas in vitro was effected when incubated with 1 microgram/ml of an antagonist to GnRH. This inhibition of hormonal release occurred rapidly and was partially restored by the addition of GnRH. Human chorionic somatomammotropin was also suppressed, but only two days following the decline of the other hormones. These data demonstrate that an antagonist to GnRH can rapidly inhibit human placental hormone release.     

Effects of a gonadotrophin-releasing hormone antagonist on gonadotrophin secretion and gonadal development in neonatal pigs

Male (N = 8) and female (N = 8) pigs were assigned to receive saline or a potent GnRH antagonist ([Ac-D2Nal1,D4-Cl-Phe2,D-Trp3,D-Arg6, D-Ala10]- GnRH*HOAc; 1 mg/kg body weight) at 14 days of age. The GnRH antagonist caused LH to decline (P less than 0.01) from 1.7 ng/ml at 0 h to less than 0.5 ng/ml during 4-32 h in males and females. Concentrations of FSH in gilts declined slowly from 75 +/- 8 to 56 +/- 5 ng/ml (P less than 0.05) at 32 h. In males FSH was low (5.7 +/- 0.5 ng/ml) at 0 h and did not change significantly. To observe the effect of long-term treatment with GnRH antagonist, 10 male and 10 female pigs, 3 days of age, were treated with saline or 1 mg GnRH antagonist per kg body weight every 36 h for 21 days. Concentrations of LH were reduced (P less than 0.01) to 0.2-0.4 ng/ml throughout the experimental period in male and female piglets treated with GnRH antagonist. Plasma FSH increased in control females, but remained suppressed (P less than 0.001) in females treated with GnRH antagonist. Treatment with the GnRH antagonist suppressed FSH levels in males on Days 8 and 16 (P less than 0.05), but not on Day 24. Treatment of females with the GnRH antagonist did not influence (P greater than 0.10) oestradiol-17 beta concentrations. Administration of GnRH antagonist to males suppressed testosterone and oestradiol-17 beta values (P less than 0.01) and reduced testicular weight (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effectiveness of an antagonist to gonadotrophin releasing hormone on the FSH and LH response to GnRH in perifused equine pituitary cells,and in seasonally acyclic mares

We wish to use a gonadotrophin-releasing hormone (GnRH) antagonist in the mare as a tool for investigating the control of the oestrous cycle. The aim of this study was to test the effectiveness of the antagonist cetrorelix by testing both in vitro, using perifused equine anterior pituitary cells, and in vivo in seasonally acyclic mares. Pituitary cells were prepared and after 3-4 days incubation, loaded onto columns and given four pulses of GnRH (at 0, 30, 60 and 90 min; dose-response study). After the second GnRH pulse, infusion of cetrorelix began (0, 100, 1000 and 2000 pmol/l) and continued until the end of the experiment. To mimic luteal phase conditions, cells were pre-incubated and perifused with progesterone (25 nmol/l) and GnRH pulses given at 0, 90, 180 and 270 min. Cetrorelix (0 or 1000 pmol/l) began after the second GnRH pulse. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations were measured in 5 min fractions. Both FSH and LH response areas (above baseline) after GnRH were inhibited by 1000 pmol/l cetrorelix (P < 0.01, P < 0.01, respectively) but not by 100 pmol/l cetrorelix. Similarly, in the presence of progesterone, cetrorelix inhibited the FSH (P < 0.001) and LH (P = 0.0002) response area. Seasonally acyclic mares, pre-treated for 3 days with progesterone (150 mg i.m. per day) were given cetrorelix as (i) a loading dose of 1 microg/kg then infusion at 2.2 ng/(kg min) for 90 min, (ii) a s.c. injection at 20 microg/kg, (iii) infusion at 2.2 ng/(kg min) for 48 h, and (iv) no cetrorelix (control mares). At 90 min, 6, 24 and 48 h after cetrorelix was first administered, mares were given a bolus injection of GnRH (22.2 ng/kg i.v.) and the FSH and LH responses measured. All doses of cetrorelix inhibited the FSH response at 90 min. The response was no longer suppressed at 6 h in the 90 min infusion group, showing a rapid recovery from inhibition. At 24 h, the FSH responses in the injected and 48 h infusion group were suppressed. The LH concentrations were low and showed no significant changes. This study has defined the time course and dose of cetrorelix with respect to its effect on FSH in the horse. It is concluded that cetrorelix could be used to elucidate the role of FSH in follicular development in cyclic mares.     

Effect of follicular fluid treatment on follicle-stimulating hormone, luteinizing hormone and compensatory ovarian hypertrophy in prepuberal gilts

Prepuberal 130-day-old gilts were treated with 10 ml of charcoal-stripped porcine serum (PS), whole porcine follicular fluid (WpFF) or charcoal-stripped pFF (CpFF) twice daily beginning the day before and continuing 8 days after unilateral ovariectomy (ULO). Follicle-stimulating hormone (FSH) declined for the first 14 h after ULO in WpFF and CpFF gilts and then by 24 h returned to values observed at or before ULO, whereas FSH was increased nearly twofold at 14 h in PS gilts. At 8 days after ULO the remaining ovaries from PS-treated gilts were heavier than ovaries from follicular fluid-treated gilts. In a second experiment, ovariectomized 130-day-old gilts were assigned to either a group infused with PS, a group infused with 5 ml CpFF, or a group infused with 10 ml Cpff at 18 and 2 h before a gonadotropin-releasing hormone (GnRH) challenge. Porcine follicular fluid had no effect on luteinizing hormone (LH) response to GnRH, depressed the FSH response to a 10-micrograms challenge of GnRH, but had no effect on FSH response to a 50-micrograms challenge of GnRH. In a third study, gilts were subjected to sham ovariectomy (Sham) or ULO at 130 days of age. GnRH (10 micrograms) was given on Days 1, 2 or 8 after surgery. The response to GnRH in ULO versus Sham gilts did not differ for FSH or LH on any day.(ABSTRACT TRUNCATED AT 250 WORDS)     

The importance of thyroid hormone in experimental ovarian cyst formation in gilts

The role of the thyroid gland in ovarian cyst formation in farm animals and in women has rarely been considered. Experimental data on the induction of polycystic ovarian disease (PCOS) in rats indicates the importance of thyroid function to the mechanism of this disorder. The objective of this work was to prove the role of thyroid hormones in gonadotropin-induced cystic ovarian disease (COD) in gilts.In hypothyroid gilts (oral administration of 1 g of methylthioracyl (MTU) daily for 24 days), ovarian cysts were induced by injections of pregnant mares' serum gonadotropin (PMSG) (equine chorionic gonadotropin (eCG)) and human chorionic gonadotropin (hCG) (400 IU and 200 IU daily for 10 days, respectively). Gonadotropins were also injected into hyperthyroid gilts (400 μg of L-thyroxine daily for 24 days). Suitable control groups (no treatment, injected with gonadotropins, hypothyroid by application of MTU and hyperthyroid by administration of L-thyroxine) were set up. Thyroid function was monitored by estimating the total thyroxine in blood plasma using the radio-immunoassay (RIA) method. After treatment, all animals were laparatomized on Days 5–6 of the cycle and the blood samples from peripheral and utero-ovarian veins were collected by cannulation for 2–3 days following surgery. All gilts were then slaughtered and ovaries and other hormonal glands were excised, inspected and preserved for further analysis.The experimental results showed that thyroid hormones in gilts demonstrate an antagonistic influence on the cyst-formative action of gonadotropins. Hypothyroid status increased ovarian sensitivity to gonadotropin action. This was visualised by marked hypertrophy of the ovaries and multiple follicular cysts were also found in both ovaries. In contrast, the hyperthyroid animals showed a reduced sensitivity to the cyst-formative action of gonadotropins (decrease of ovarian dimensions, small numbers of cysts). The mechanism of antagonistic thyroid-gonadotropin relations may be based on negative interactions between thyroid hormones and gonadotropin receptors in the ovaries, and/or on central or peripheral interrelations between thyroid hormones and oestrogens.     

Alterations in gonadotropin secretion and ovarian function in prepubertal gilts by elevated environmental temperature

The effect of chronic exposure to elevated environmental temperature on gonadotropin secretion and ovarian function was studied in prepubertal gilts. Gilts were maintained under control (15.6 degrees C) or elevated temperature (33.3 degrees C) conditions from 150 to 180 days of age. Endocrine and ovarian responses to bilateral (BLO), unilateral (ULO), and sham ovariectomy were evaluated between 175 and 180 days of age. During the 96-h sampling period after BLO, plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were suppressed in heat-stressed females. Similarly, elevated temperatures abolished the transient rise in FSH and subsequent follicular growth normally associated with ULO. In contrast, environmental treatment had no effect on the secretion of FSH and LH after sham ovariectomy, yet the number of small follicles was lower in gilts exposed to elevated temperatures than in females maintained under control conditions. These results indicate that a chronic exposure to elevated environmental temperature during pubertal development diminished the ability of the hypothalamo-hypophyseal axis to secrete FSH and LH, which had physiological consequences on follicular growth. When provided an appropriate stimulus (ULO), an acute period of FSH secretion and subsequent development of follicles failed to occur in females exposed to elevated temperatures. Consequently, we propose that delayed puberty in gilts during periods of elevated environmental temperatures is due, in part, to a diminished capacity for gonadotropin secretion.     

Control of ovulation with a GnRH analog in gilts and sows

Methods for the control of ovulation with GnRH or the GnRH analog D-Phe6 -LHRH (GnRH-A), were evaluated in gilts and sows as the last step in development of a fixed-time Al protocol. This involved 3 field trials using 2,744 gilts (10 units) and 71,628 sows (33 units). In Trial 1, the GnRH-A (75 microg) was given subsequent to treatment with altrenogest for cycle control or eCG for the stimulation of uniform follicle development in gilts. The release of LH was followed by ovulations which commenced within 36.4 +/- 3.3 hr and were terminated at 39.0 +/- 2.8 hr after administration of GnRH-A. This degree of synchronization of ovulations enabled the use of fixed-time AI. Consequently, subsequent to pretreatment with altrenogest and eCG, in 10 production units 1,285 gilts received 50 microg GnRH-A and 1,459 gilts 500 IU hCG serving as positive controls (Trial 2); all the gilts were inseminated 24 and 42 hr after treatment. Pregnancy rate and piglet index (n of piglets per 100 first inseminations) following GnRH-A vs hCG were 78.8% and 779 vs 74.4% and 728, respectively (P < 0.05). In field trials with first litter gilts and multiparous sows (33 units holding from 250 to 6,000 sows), 1,000 IU eCG was used for estrus control after weaning and 25 microg or 50 microg GnRH-A were given 55 to 58 hours after eCG (n = 19,954 and 20,701) (Trial 3). Sows treated during the same time period with 300 microg GnRH plus 300 IU. hCG (n = 30,973) served as positive controls; all sows were inseminated 24 and 42 hours after treatment. Pregnancy rates for 50 microg GnRH-A, 25 microg GnRH-A and 300 microg GnRH plus 300 IU hCG were 83.0%, 81.7% and 80.7%, and the piglet indices 913, 899 and 880, respectively (P < 0.05). Unit size and parity had significant effects on fertility and productivity. In all studies, results with 50 microg GnRH-A were superior. In year-long studies, highest levels of fertility in response to these treatments were seen from December to May.     

Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer

The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor κB (NFκB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK).     

Plasma gonadotrophin and ovarian steroid concentrations in women with menstrual cycles with a short luteal phase

Daily plasma concentrations of FSH, LH, oestradiol-17 beta and progesterone were compared for 12 cycles with a short luteal phase and 19 cycles with a luteal phase of normal length (i.e. cycles in which the luteal phase lasted 12 or more days). FSH and LH concentrations were suppressed in short luteal-phase cycles in the early follicular phase and the length of the follicular phase was prolonged (median duration, 14.5 days, range 13-21 days: compared with 12 days, range 9-17, in control cycles; P less than 0.025). Preovulatory oestradiol-17 beta values and the mid-cycle concentrations of FSH and LH were similar in both groups. Plasma progesterone values in the luteal phase were similar in both groups over the 2nd to 5th days inclusive after the midcycle LH peak but declined in the short luteal phases thereafter. In short luteal-phase cycles, menstruation occurred in the presence of higher levels of oestradiol-17 beta and progesterone than in cycles of normal length and the rise of gonadotrophin in the late luteal phase of the cycle was delayed. These findings suggest that in cycles with a short luteal phase there is a lack of synchrony between the ovarian and menstrual events.     

Pulsatile infusion of gonadotrophin releasing hormone (GnRH): investigative and therapeutic applications

Normal gonadotrophin secretion, and therefore normal ovarian function, depend on delivery to the pituitary of the hypothalamic neuropeptide gonadotrophin releasing hormone (GnRH) in a pulsatile pattern. In the mid-follicular phase of the menstrual cycle, for example, discrete pulses of luteinizing hormone (LH) can be observed at approximately 90 min intervals. Many disorders of ovulation are caused by abnormalities of this natural pulsed signal. We have developed and used a small portable infusion pump to deliver GnRH to women with hypothalamic amenorrhoea; our studies, and those of other groups, have shown that successful ovulation and pregnancy result from such treatment. The results of treatment at St Mary's Hospital show that 16 women with hypogonadotrophic amenorrhoea received a total of 31 cycles of treatment with pulsatile GnRH; 25 (81%) of these cycles were ovulatory and 11 of the 14 women who were trying to conceive became pregnant. There was only one multiple pregnancy (twins).     

Homologous desensitization of gonadotropin-releasing hormone (GnRH) receptors in the goldfish pituitary: effects of native GnRH peptides and a synthetic GnRH antagonist.

Gonadotropin-releasing hormone (GnRH) stimulates release of gonadotropin hormone (GTH) through interaction with high affinity receptors in the goldfish pituitary. In the present study, we investigated desensitization of two native GnRH peptides, [Trp7, Leu8]-GnRH (sGnRH) and [His5, Trp7, Tyr8]-GnRH (cGnRH-II), using superfused fragments of goldfish pituitary in vitro. Pulsatile treatment with either sGnRH or cGnRH-II (2-min pulses given every 60 min) resulted in dose-dependent secretion of GTH from the goldfish pituitary; cGnRH-II had a greater GTH release potency and displayed a greater receptor binding affinity than sGnRH. Both sGnRH and cGnRH-II-induced GTH release were partially inhibited by concomitant treatment with either [D-Phe2, Pro3, D-Phe6]-GnRH or [D-pGlu1, D-Phe2, D-Trp3.6]-GnRH. These antagonists had greater receptor binding affinities than the native peptides, with no stimulatory action on GTH release in the absence of the GnRH agonists. Continuous treatment with either sGnRH or cGnRH-II (10(-7) M), rapidly desensitized pituitary GTH release in a biphasic fashion; initially there was a rapid increase in GTH release of approximately 10-20-fold (phase 1), followed by a sharp decline in GTH release, reaching a stable concentration 2-3-fold above the basal level (phase 2). Further stimulation of the pituitaries with sGnRH or cGnRH-II (10(-7) M) (second treatment) after 60 min recovery resulted in a significantly lower sGnRH or cGnRH-II-induced GTH release compared to that observed during the initial treatment period.(ABSTRACT TRUNCATED AT 250 WORDS)