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The administration of methallibure (2 microg/g BW, daily for 15 days) in Clarias batrachus in prespawning phase (May-June) resulted in decreased weights of seminal vesicle (SV) and testis, and reductions in the concentrations of total proteins, fructose, hexosamines, and sialic acid in SV and testis. The inhibitory changes can be attributed to impairment of steroidogenesis, serum levels of testosterone and estradiol -17beta decreased significantly. Withdrawal of methallibure treatment for 7 and 15 days resulted in gradual recovery and restoration of all the above parameters except the sialic acid levels in the SV and testis, and fructose level in the SV. The methallibure induced regressive changes in the SV and testis were discussed in the light of its GTH inhibiting property.

The objective of this study was to determine whether AIMAX (a dithiocarbamoylhydrazine derivative) is suitable for determining the effects of norepinephrine (NE) depletion on reproduction in domestic animals. Therefore, the effect of AIMAX (n = 6) on concentrations of biogenic amines in the medial basal hypothalamus (MBH) and anterior hypothalamic area (AHA) of ovariectomized (OVX) rats primed with ovarian steroids was compared to that of diethyldithiocarbamate (DDC; n = 5), a potent dopamine-beta-hydroxylase (DBH) inhibitor, which is chemically similar to AIMAX. Rats that received only ovarian steroids and saline injections served as controls (n = 6). Treatment with DDC resulted in sedation and reduced body temperature. In contrast, rats behaved normally after AIMAX treatment. AI-MAX reduced (P < .05) NE but increased (P < .05) dopamine (DA) concentrations in MBH and AHA compared with controls. Similar changes in NE and DA concentrations were observed in DDC-treated rats. However, elevated epinephrine (EPI) levels were measured in MBH and AHA of only DDC-treated rats. Serum LH concentrations were suppressed (P < .005) in both AIMAX- and DDC-treated rats compared with control animals. Because AIMAX, like DDC, suppressed hypothalamic NE content and LH secretion, AIMAX should be useful in studying effects of NE depletion on gonadotropin secretion in domestic animals.

The role of norepinephrine (NE) in the progesterone (P)-dependent endogenous opioid peptide (EOP) suppression of LH and prolactin (PRL) secretion in the pig was studied. Fifteen ovariectomized gilts treated with P (0.85 mg/kg b.w. i.m.) twice daily for 10 days were assigned, 5 gilts each, to the following treatment groups: 1) control, 2) AIMAX (N-methyl-N1[1-methyl-2-propenyl]1,2 hydrazinedicarbothioamide), and 3) anti-GnRH serum. On day 4 of P treatment, AIMAX (125 mg per 1.8 kg feed/day), previously shown to be an NE synthesis inhibitor, was fed daily for 7 days to group 2. On the last day of P treatment, group 3 gilts received an i.v. injection of anti-GnRH serum at 0800 h while Group 1 animals received an i.v. injection of serum collected from hypophysectomized gilts. Jugular blood samples were collected every 15 min for 9 h starting at 1000 h. All gilts received two injections of naloxone (NAL; 1 mg/kg b.w., i.v.) at 1400 h and 1600 h and an injection of a GnRH analogue (D-[Ala6-desGly-NH10]-ethylamide; 5 micrograms/pig, i.v.) at 1800 h. Pretreatment serum LH concentrations were lower (p < 0.05) in AIMAX-treated gilts (0.19 +/- 0.09 ng/ml) than in controls (0.53 +/- 0.09 ng/ml), but were similar to those in GnRH antiserum-treated gilts (0.32 +/- 0.09 ng/ml). NAL increased (p < 0.001) serum LH concentrations in control animals and averaged 1.6 +/- 0.2 ng/ml the first h. AIMAX and anti-GnRH serum blocked the NAL-induced LH secretion. Serum PRL concentrations averaged 6.0 +/- 0.1 ng/ml for all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the present study was to examine the effect of methallibure (MLB), a non-steroid inhibitor of pituitary gonadotrophic activity on serotonin (5-HT) levels in the wall of preovulatory follicles (F1-F4) in the domestic hen. 5-HT was determined spectrofluorometrically. Hens were treated with MLB (10 mg/hen per os) twice a day for 3 successive days. 5-HT was determined in F1-F4 (F1 greater than F2 greater than F3 greater than F4) follicles of the control group, on the next day (MLB-1 group) and 6 days following cessation of MLB administration (MLB-6 group). During MLB treatment egg production was inhibited in all hens. In the MLB-6 group, five hens out of seven took up egg laying on the sixth day after MLB administration. Within each examined group there were no significant differences in 5-HT concentration between F1-F4 follicles. In comparison to the control, MLB caused a significant (P less than 0.01-0.05) increase of 5-HT concentration in F1 (MLB-1 group) and F4 (both MLB-groups). The results obtained indicate that there is a relationship between pituitary activity and 5-HT levels in the preovulatory follicles of the domestic hen.

Studies have been made on the effect of LH, FSH, and LH+FSH on the gonadal steroidogenesis in gonadotrophin-deprived common carp. LH alone and in combination with FSH was more effective than FSH in stimulation of steroidogenesis.

Methallibure treatment of mature Cyprinus carpio causes a marked reduction in the steroidogenesis, as indicated by the fall in 3beta-HSD activity in the gonads. Significance of these results is discussed.

The goal of this study was to pharmacologically block central nervous system (CNS) input to gonadotropes in mature ovariectomized gilts to determine the direct actions of estradiol (E2) on pituitary LH release when given at a dose sufficient to elicit a gonadotropin surge. Feeding AIMAX [N-methyl-N'-(1-methyl-2-propenyl)1,2-hydrazinedicarbothioamide; 125 mg/day] for 7 days reduced serum LH concentrations from 1.25 +/- 0.13 (mean +/- SE) to less than 0.18 ng/ml, abolished LH pulses, but did not compromise LH release in response to exogenous GnRH. Serum FSH concentrations were reduced by 27%, whereas serum concentrations of PRL, GH, thyroid hormones and cortisol were not affected after 7 days of AIMAX treatment. Behavior was not altered, aside from a slightly reduced appetite. The LH surge that peaked 48-80 h after injecting E2 benzoate (E2B) into control gilts was blocked in five of eight gilts given AIMAX. Giving GnRH pulses (1 microgram every 45 min) to AIMAX-treated gilts restored mean serum LH concentrations as well as the frequency and amplitude of LH pulses to those of untreated ovariectomized gilts. E2B suppressed the LH response to these GnRH pulses by 88% at 12 h, whereas from 24-96 h after E2B treatment, the LH response to GnRH and mean serum concentrations of LH were again similar to those of controls not given estradiol. These data indicate that induction of the gonadotropin surge by E2 in the gilt requires CNS input. The action of E2 on the pituitary in the presence of unvarying GnRH pulsation may, however, be limited to an early transient inhibition of responsiveness to GnRH, with no subsequent direct stimulation during the period of the surge.

Methallibure treatment is as effective as hypophysectomy in reducing thyroid activity in H. fossilis. Sex steroids (TP and EB) administration restored thyroid activity in methallibure-treated females to normal level, but failed to elicit any response in males. This drug seems to block TSH secretion and thyroid hormone synthesis in H. fossilis.

A study has been made on the effect of methallibure (I.C.I., 33828) on ;the ovary of Carp. C. carpio. Methallibure treatment may exert marked inhibitory influence on vitellogenesis in the fish and cause atresia of vitellogenic follicles, the oogonial proliferation is stepped up. The site and mode of action of methallibure is discussed.

The effects of castration on male spawning behavior, nestbuilding and fertility were measured in a five day spawning trial with an intact female. Spawning and fertility decreased one week following castration while nestbuilding was unaffected. Sham operated males showed normal spawning and fertility. Two weeks postoperatively, fertility and spawning were increased paralleling partial regeneration of the testes. The antigonadotropin methallibure blocked testes regeneration and recovery of spawning in castrated males but it had no effect on reproductive functions of intact males. Spawning did not decrease in one-week castrated males which were administered testosterone enathanate. The results suggest that gonadal androgen facilitates sexual behavior in Macropodus.

The identical response of plasma motilin levels, in duodenal ulcer patients and healthy controls, to a test meal and insulin induced hypoglycaemia, fail to demonstrate any significant abnormalities in motilin release. The close correlation between blood glucose and motilin suggest a possible role of this new hormone in carbohydrate metabolism.

Daily administration of 10 mg of Methallibure (ICI 33,828) for 6 days to male castrate rats resulted in significant depression of serum radioimmunoassayable luteinizing hormone (LH). Subsequent challenge with 100 ng of synthetic luteinizing hormone-releasing hormone (LHRH) showed these rats to release sufficient pituitary LH to achieve plasma levels equal to those of LHRH treated castrate controls. Although an effect at the level of the pituitary remains to be conclusively ruled out, these results suggest that the predominant in vivo effect of Methallibure in the castrate male rat is to suppress pituitary LH release due to diminished secretion of LHRH by the hypothalamus.

Injection of prostaglandin (PG) F-2 alpha or its analogues has provided a technique to induce parturition after Day 110 of gestation in the sow. The mean interval from PG injection to parturition ranges from 24 to 28 h, but only 50-60% of the sows farrow during an 8-10 h working day, and as many as 20% of sows may begin parturition before the injection of PG or less than 22 h after the injection. The duration of parturition is positively associated with the incidence of stillbirths and perinatal death so that techniques to reduce the duration of parturition may save piglets. Early parturition has been prevented by feeding sows progestagens, PG synthesis inhibitors and hypothalamic function inhibitors. These compounds were detrimental to piglet survival if they delayed parturition too long after the expected time of parturition. Parturition was delayed in sows up to 1.5 days by altrenogest, 1.6 days by meclofenamic acid, 2.7 days by indomethacin, and 3 days by methallibure without increased incidence of stillborn piglets compared with control sows. Injection of PG after administration of altrenogest or meclofenamic acid was successful in experiments with sows; parturition could be confined to a 5-day working week with no increase in stillborn piglets compared with control sows. Relaxin injected at 48 and 24 h before or only 24 h before injection of PG increased the proportion of sows farrowing 22-32 h after PG to 86.2% compared with sows injected only with PG (53.3%, P less than 0.01). Oxytocin injected 20 h after injection of PG increased the proportion of sows farrowing 20-28 h after PG to 90.4% compared with sows injected only with PG (49.2%, P less than 0.005). Injection of 25-60 i.u. ACTH on Day 110 of gestation did not shorten the length of gestation, but did decrease the incidence of still born piglets by 0.2 piglets/litter (P less than 0.05). An injection of the beta-adrenergic antagonist, carazolol, during labour before the birth of the first piglet decreased the duration of parturition and the incidence of stillborn piglets particularly in primiparous sows (P less than 0.05). Carazolol injected with oxytocin 20 h after injection of PG decreased the interval from PG to parturition by 2 h compared with sows injected with only PG and oxytocin.(ABSTRACT TRUNCATED AT 400 WORDS)

The subcellular distribution of free and esterified cholesterol in mouse testis and the changes occurring in cholesterol content of whole testes and cell fractions after inhibition of gonadotropins with methallibure (ICI 33, 828) and restimulation with human chorionic gonadotropin (HCG) are reported in the present paper. In subcellular fractions, the bulk of free cholesterol is associated with organelles sedimented in the microsomal fraction while esterified cholesterol is mainly stored in isolated lipid droplets. The latter compartment increases in methallibure-treated mice 2.3 fold and is remarkably depleted after administration of HCG. There is a close parallelism between the changes in esterified cholesterol content and the variation in the numbers of lipid droplets found in electron micrographs of interstitial cells of mice receiving similar treatments. By contrast no significant changes were noticed in either free cholesterol concentrations of the microsomal fractions or in the fine structure of organelles associated with this fraction. The dynamic nature of steroidogenesis in the microsomal fraction requires the existence of a free cholesterol pool with a high turnover rate for use as an intermediate in androgen synthesis. On the other hand, the large content of free cholesterol in microsomes and its stability under different conditions suggest the presence of a cholesterol compartment with a slow turnover, as a constituent of the membranes.

This study describes a morphological change in the germinal vesicle (GV) of the sow oocyte during the follicular phase preceding the ovulatory LH surge. Estrus synchronization obtained with methallibure treatment provided a reference point for dating the onset of the follicular phase of each sow in the experiment. The oocyte GV's of preovulatory follicles having a diameter of less than 2 mm (during the first 2 to 3 days of the follicular phase) showed uniformly dispersed chromatin with no condensation, while the GV's of oocytes from preovulatory follicles of more than 2 mm diameter (from days 2 and 3 of the follicular phase to day 5) presented condensed chromatin in the shape of a crown or horseshoe surrounding the nucleolus, and irregular chromatin clusters in the nucleoplasm; these clusters were usually found lying against the nuclear membrane.

Methallibure administration caused reduction of gonadal weights in female rats and mice indicative of suppression of pituitary gonadotrophins. In the ovaries of the methallibure treated females, there was a great atresia of the follicles and of the corpora lutea. Methalbure caused atrophic changes in the endometrial lining of the vagina. Uterine horns became thin after methallibure treatment. A significant decrease in protein, RNA and sialic acid concentration in uterus and vagina was observed following methallibure treatment. Uterus of treated animals showed decreased glycogen contents. Histological and biochemical changes in the female genital tract of rats and mice suggested that the drug caused antifertility effect due to its possible antiestrogenic action.

The following results were obtained from experimental studies into selection of laboratory rats for fertility and random mating with oestrus being synchronised by means of Suisynchron-Prämix, through eight generations: --Success of selection without synchronised oestrus was higher than that with synchronised oestrus by selection according to the basic index and with one and the same selection intensity. --Litter size and weight were higher in the selected variants, as a result of increased potential fertility (rate of ovulation). --In the population with selection and synchronised oestrus a negative relationship was found to exist between the directly correlated selection results regarding fertility parameters, on the one hand, and the effect of synchronisation, on the other. --Both the rates of ovulation and litter parameters were lower in the population with selection and synchronised oestrus, as a result of synchronisation. --The effect of synchronised oestrus on the population with selection and synchronised oestrus was partially eliminated owing to selection for fertility.

Suisynchron was applied to 2,258 gilts, including 850 from breeding farms. Forty-four pigs were checked to elucidate the influence of sexual maturity on the success of oestrus synchronisation. Suisynchron-Prämix was fed to the animals over 20 days, the daily dose for each pig having been 5 g. Twenty-four hours were allowed to elapse from the last administration before 1,500 I.U. PMSG were injected. Synchronised oestrus occurred in 81.2 per cent of all pigs between four and six days from serum injection. Fertilisation in response to first insemination was recorded from 72.9 percent of the pigs, their fertility rate being 9.7 piglets from each farrowing sow. The results of oestrus synchronisation obtained from fattening pigs were somewhat inferior to those recorded from pigs of breeding units. Suisynchron and serum of pregnant mares can synchronise oestrus in 91 per cent of all mateable sows with no previous cycle. The fertility rates recorded from such pigs did not exceed 59 per cent or were between 28.9 and 31.9 per cent lower than those recordable from pigs with a cycle history prior to the use of Suisynchron.

Effects of methallibure (I.C.I. 33828) have been studied on the reproductive organs of female gerbils, Meriones hurrianae. Methallibure administration caused reduction of gonadal weight indicating suppression of pituitary gonadotrophins. In the ovaries of the treated females extensive atresia of follicles and of corpora lutea was observed. In addition methallibure interrupted the sex cycle, and a dioestrous vaginal pattern was retained throughout medication. A significant decrease in the level of RNA, protein and sialic acid in the uterus and vagina and of glycogen in the uterus was found. Histological and biochemical changes in the ovaries and uteri suggest a possible direct antioestrogenic action of the compound.

1. Synergistic action of alpha-chlorohydrin with methallibure (ICI, 33828) on the testicular function of Presbytis entellus entellus Dufresne has been studied. 2. Chronic administration of alpha-chlorohydrin alone (140 mg/day for 40 days) caused testicular lesion resulting in a massive atrophy of the spermatogenic elements. Epididymal epithelium was regressed and the lumen was devoid of spermatozoa. 3. alpha-Chlorohydrin inhibited the synthesis of RNA and sialic acid in the testes and epididymides. Total cholesterol per gram of testis and alkaline phosphatase activity were increased after alpha-chlorohydrin administration. 4. These effects could be achieved with a lower dose of alpha-chlorohydrin (1/4) when administered in combination with a gonadotrophin inhibitor, i. e. ICI, 33828 (Methallibure). Methallibure alone (200 mg/kg: total dose) has no damaging effects on the testes and epididymides. But it altered testicular cholesterol and enzyme activity. 5. In conclusion, an effective inhibition of spermatogenesis could be achieved by synergistic action of the two different drugs i. e. alpha-chlorohydrin and ICI, 33828 (Methallibure).

Gonadotrophin content in the pituitary gland and blood serum as well as ovarian 32P uptake were studied in response to methallibure treatment in H. fossilis. There was a marked reduction in the gonadotrophic activity of the pituitary gland and blood serum within 3 weeks of methallibure treatment (100 microng/g). A simultaneous significant reduction was also recorded in the ovarian activity of these fish. The fall in ovarian activity caused by methallibure could not be prevented by the administration of LH, FSH or LH+FSH. After cessation of methallibure treatment, LH+FSH (50 microng each) administration restored ovarian activity. It is evident from these results that methallibure alters the secretion of gonadotrophin, and also prevents its action on the ovary.

The effect of pituitary gonadotropic inhibitor--methallibure on the weight and blood flow through reproductive tract was studied in immature hens. It was found that methallibure lowers the weight of the reproductive tract and simultaneously inhibits (about 2--3 times) the blood flow through the ovary and oviductal segments. However, the action of methallibure is of short duration and it is limited to the time of its administration only.

The effect of methallibure on ovary of H. fossilis was studied. Intraperitoneal administration of methalibure (100 microgram/g body weight) once a week for 4 weeks was very effective in suppressing the gametogenic and endocrine activities of ovary. The regressed condition of ovary was also apparent in GSI (2.84 to 1.09) readings. This decreased state of activity was further confirmed by reduced ovarian 32P uptake (28.00 to 18.10). The results obtained after the administration of the above compound on ovary were similar to those of surgical hypophysectomy.

Gonadotrophins influence in ovarian portal graft growth is studied. Grafts are made or in immature female rats and let to growth for one month, either in adult female rats and let to growth for six months. FSH and LH production is stopped with methallibure. In the two cases the graft, tumourous or not, is under the gonadotrophins dependancy, but others, gonadal or hypophysal, factors have a part in its growth.

Methallibure treatment (1 mg fed on alternate days to a female and a male kept in 1 liter of 25% seawater) started from 1 or 7 days postpartum (early gestation) inhibited gestation in the wild guppy, Poecilia reticulata. A few of the fish treated from 7 days postpartum (2/9) did give birth, but the young either were dead at birth or did not survive long after birth. When treatment was started 2 weeks postpartum (midgestation), gestation was not inhibited, but 25% of the young were born dead while the rest showed retardation of postnatal growth. Several possible interpretations of the results are discussed.

Variations in the prolactin content of the pituitary gland in response to different treatments were studied in a freshwater catfish, H. fossilis. One week of saline (1% NaCl medium) treatment reduced the pituitary prolactin content but enhanced the serum prolactin level showing release of prolactin from the pituitary gland. Two weeks of saline treatment reduced pituitary as well as serum prolactin content presumably a result of reduced prolactin synthesis in the pituitary gland. This reduction of synthetic activity in this species is probably due to a drop in prolactin requirement. All the antithyroid durgs tested as well as L-thyroxine decreased the pituitary prolactin content. Methallibure administration induced the release of prolactin from the pituitary as evidenced by the lowered prolactin level in this gland and a simultaneous increase in the prolactin content of the serum.

Thyrotrophin was injected i/p at 2 I.U. daily simultaneously with oral administration of Turisynchron at 100 mg/kg or Suisynchron at 125 mg/kg daily for five days to Wistar rats. The uptake of radio-iodine by the thyroid was reduced, and there were slight changes in thyroid structure. Suisynchron produced a milder inhibition of thyroid regulatory mechanisms than Turisynchron.

The following results were obtained from experimental studies into effects of selection for fertility and into synchronised oestrus though eight generations of laboratory rats: -- The result of selection recordable from the population with selection only was better than that recorded from the population with selection and synchronised oestrus. This has been attributed to higher correlation between phenotype and genotype in the selection variant. -- Direct negative impact of synchronised oestrus on selection index was recorded from a population with random mating. -- The effects of synchronised oestrus regarding selection success were offset but not entirely ruled out by selection. -- Through the generations of both populations with synchronised oestrus the effects of synchronisation were lowered due to both physiological adaptation to Suisynchron application and contraselection with regard to suitability for synchronisation.