Metoclopramide potentiates the hypophyseal reactions to oestradiol

Male rats to which oestradiol benzoate was administered intramuscularly twice a week for three weeks in 1 mg doses as an aqueous microcrystal suspension showed an increase in adenohypophyseal weight, in the number of lactotropic cells in the adenohypophysis (demonstrated by immunohistochemical detection of prolactin) and in polyphenol oxidase (ceruloplasmin) activity in the blood and hypothalamus. The simultaneous administration of metoclopramide (methoxychloroprocainamide) in doses of 10 mg/rat per day in food potentiated the adenohypophyseal reaction to oestradiol (weight and the number of lactotropic cells), but potentiated the polyphenol oxidase reaction only little or not at all. Metoclopramide thus has an anti-dopaminergic effect similar to that of perphenazine and other inhibitors of dopaminergic neurones.     

Antioestrogenic action of the aldosterone antagonist canrenoate K in the rat (adenohypophysis, ceruloplasmin).

In a dose of 7,k mg/rat/day in food, the aldosterone antagonist canrenoate K inhibited the adenohypophyseal reaction (growth, raised thyroxine-binding capacity of the adenohypophyseal proteins in vitro) and the ceruloplasmin reaction (elevation of the serum ceruloplasmin level) to three weeks' intramuscular administration of long-acting oestradiol benzoate in doses of 1 mg twice a week. The effect was similar to that of the antioestrogen clomiphen in a dose of 1.25 mg/rat/day in food. In combined administration of clomiphen and canrenoate K, no summation of their effect was observed. Neither canrenoate nor clomiphen affected the post-oestradiol drop in body weight, but they both potentiated the oestradiol-induced decrease in testicular weight and canrenoate potentiated the effect of oestradiol on uterine weight. It was therefore concluded that the effect of canrenoate is not of a catatoxic nature, i.e. that it is not determined by increased metabolic degradation of oestradiol.     

Interaction of perphenazine and an ergoline derivative on oestrogen-induced adenohypophyseal growth.

Male and female rats were injected twice a week for three weeks with doses of 1 mg oestradiol benzoate (OE), were given perphenazine (P, 2 mg/rat/day) or the ergoline derivative D-6-methyl-8-ergoline-(I)-yl acetic acid amide (Deprenon SPOFA, D, 200 microng/rat/day) in their food or were treated with various combinations of all three factors. OE-induced adenohypophyseal growth was inhibited by D, but the inhibitory effect of D was completely suppressed by P. D also inhibited the OE-induced increase in the thyroxine-binding capacity of the adenohypophyseal proteins, but this inhibition was not suppressed by the simultaneous administration of P. The administration of OE was followed by elevation of the serum ceruloplasmin level, which was not inhibited by P or D, either alone or combined. Ovarian weight rose markedly after D and the increase was inhibited by the simultaneous administration of either OE or P.     

Reactions of hypothalamic ascorbic acid, serum ceruloplasmin and the adenohypophysis to oestradiol: inhibition by L-thyroxine

Four weeks' administration of oestradiol benzoate to male and female rats in doses of 1 mg twice a week leads to adenohypophyseal hyperplasia and to an increase in the thyroxine-binding capacity of the adenohypophyseal proteins in vitro. At the same time, serum polyphenol oxidase (ceruloplasmin) activity rises and the hypothalamic ascorbic acid concentration falls. The simultaneous administration of L-thyroxine (0.1 mg/rat/per day) or dried thyroid (but not D-thyroxine) significantly inhibits these changes (adenohypophysis, ceruloplasmin) or completely suppresses them (hypothalamic ascorbic acid). L-thyroxine evidently blocks the action of oestradiol in the adenohypophysis, the liver and the hypothalamus; the significance of this inhibition is discussed in relation to dopaminergic modulation of the adenohypophyseal reaction to oestradiol.     

Inhibition by an ergoline derivative (dopaminergic agonist) of oestradiol-induced adenohypophyseal growth and of the decrease in the hypothalamic ascorbic acid (HAA) concentration in rats

The increase in adenohypophyseal weight and the decrease in the ascorbic acid concentration in the hypothalamus of rats injected i.m. twice a week with oestradiol benzoate as an aqueous microcrystal suspension in doses of 2.65 mumol (1 mg) was completely (HAA) or almost completely (adenohypophyseal weight) inhibited by the simultaneous administration of the ergoline derivative D-6-methyl-8-ergoline-(1)-yl acetic acid amide (Deprenon SPOFA) in the diet in daily doses of 0.28 mumol (200 micrograms) per rat. The functional significance of HAA in dopaminergic modulation of oestrogen-induced adenohypophyseal growth is discussed, with special reference to the possible function of HAA as a dopamine-beta-hydroxylase cofactor.     

The effect of hexose monophosphate shunt inhibitors on adenohypophyseal and ceruloplasmin reactions to oestrogen.

Oestradiol benzoate, as an aqueous microcrystal suspension, was administered i.m. to rats in doses of 1 mg twice a week; it induced adenohypophyseal hyperplasia and an increase of the thyroxine-binding capacity of the adenohypophyseal proteins in vitro and raised the blood ceruloplasmin level. The simultaneous administration of a hexose monophosphate shunt inhibitor--6-aminonicotinamide (200 microgram/rat/day in food) or oxythiamine (8 mg/rat/day in food)--did not modify the reaction of the adenohypophysis; the hexose monophosphate shunt thus probably does not play a significant role in the adenohypophyseal reaction to oestrogens. By themselves, both inhibitors raised the blood ceruloplasmin level and their effect summated with that of oestradiol. The mechanism of action of the inhibitors is not known, but a nonspecific stress effect leading to an increase in the ceruloplasmin level as an "acute phase protein" is considered to be the most likely.     

Dopaminergic control of adenohypophyseal growth after oestrogens: negative results with L-DOPA, RO-4-4602, alpha-methyl-DOPA, apomorphine, haloperidol, pyridoxine and cyproheptadine.

Chronic oestrogen treatment augments adenohypophyseal weight and the thyroxine-binding capacity of adenohypophyseal proteins in rats. Since these reactions are both inhibited by ergocornine and ergoline derivatives (as well as by the thyroid hormones, testosterone, anti-oestrogens and antiandrogens), and are potentiation by perphenazine and the dopaminergic neurone blocker Pimozide, the peroral effectiveness of various other substances presumed to act in the region of the dopaminergic or serotoninergic neurones of the hypothalamus was tested. L-DOPA (10 mg/rat/day) did not modify the adenohypophyseal reaction, either alone or combined with the DOPA-decarboxylate inhibitor Ro-4-4602 (1 mg/rat/day). alpha-Methyl-DOPA (10 mg/rat/day), apomorphine (3 mg/rat/day), haloperidol (0.2 mg/rat/day), pyridoxine (20 mg/rat/day) and cyproheptadine (1 mg/rat/day) were likewise ineffective.     

Effect of interaction of oestrogen, testosterone and thyroid hormones on the serum ceruloplasmin level in rats.

Male rats were given oestradiol benzoate (1 mg as an aquaeous microcrystal suspension i.m. twice a week), testosterone isobutyrate (0.5 mg as an aquaeous microcrystal suspension i.m. once a week) and dried thyroid (Thyreoidin SPOFA, 0.2% in food), alone or variously combined. Oestradiol raised adenohypophyseal weight, the binding capacity of the adenohypophyseal proteins for thyroxine and the serum ceruloplasmin level. Testosterone and Thyreoidin inhibited all three of these reactions, but when they were administered together there was no summation of their inhibitory action. The nature of the relationships between the three given proteosynthetic reactions is discussed.     

Modulation of the effect of oestradiol on adenohypophyseal weight: ineffectiveness of nickel chloride, potentiation by cimetidine

Male rats received an i.m. injection of oestradiol benzonate twice a weak, as an aqueous microcrystal suspension in doses of 1 mg, and/or were given, in their food, nickel chloride in daily doses of 10 mg [first experiment] or 20 mg [second experiment] per rat, or cimetidine, an antagonist of H2 receptors, in daily doses of 20 mg [first experiment] or 40 mg [second experiment] per rat. Neither dose of nickel chloride affected the oestrogen-induced growth reaction of the adenohypophysis, the increase in polyphenol oxidase [ceruloplasmin] activity in the blood [the larger dose stimulated it slightly], the increase in hypothalamic polyphenol oxidase activity or the post-oestrogen drop in the hypothalamic ascorbic acid concentration. Both doses of cimetidine potentiated the growth reaction of the adenohypophysis to oestrogens, but did not affect the blood polyphenol oxidase, the hypothalamic polyphenol oxidase or the hypothalamic ascorbic acid reaction. If administered alone, the larger dose of cimetidine mildly reduced serum polyphenol oxidase [ceruloplasmin] activity.     

Effects of Ovariectomy and Prolactin on Mammary Gland Expressions of Transforming Growth Factor alpha and Epidermal Growth Factor Receptor mRNAs in Mice

Beginning 15 days after ovariectomy (OVX), a high mammary tumor strain of SHN virgin mice at 3 months of age received subcutaneous injections of danazol (0.5 mug / 0.1 ml olive oil, once a day), perphenazine (0.05 mg / 0.1 ml saline, twice a day) or ovine prolactin (oPRL: 0.25 mg / 0.05 ml buffer, twice a day) for 3 days to modulate their circulating PRL levels. The serum PRL level was significantly decreased by danazol and increased by perphenazine compared to the intact and OVX-control groups. The expression of both transforming growth factor alpha (TGFalpha) mRNA and epidermal growth factor receptor (EGFR) mRNA in the mammary gland was increased by danazol. However, TGFalpha mRNA expression was decreased by perphenazine. Meanwhile, mammary end-bud formation was inhibited in danazol-treated group. All findings suggest that the manifestation of the effect of TGFalpha on mammary gland is rather suppressed by PRL, while mammary gland growth needs the participation of PRL; in other words, PRL is dominant to TGFalpha on the mammary gland growth. OVX resulted in a significant decrease of TGFalpha mRNA expression in the mammary gland despite of little alteration in serum PRL, confirming the previous observations. The similar trend was observed in ICR mice; however, the response to hormonal modulation is generally less susceptible than SHN mice.     

Gastrointestinal Disturbances Associated with Withdrawal of Ataractic Drugs

The psychological effects of abrupt withdrawal of ataractic drugs have been studied by others. Physical symptoms also occur under such circumstances and include abdominal pain, nausea and vomiting. Forty patients were divided into four groups of 10, each group receiving one of the following drugs: chlorpromazine, thioridazine, perphenazine or chlorprothixene. This medication was then suddenly withdrawn. In each of the chlorpromazine and thioridazine groups, three patients had gastrointestinal symptoms within 48 hours, lasting one to eight days. One patient on chlorprothixene, 450 mg. daily, experienced symptoms for six days. Perphenazine withdrawal produced no such symptoms. Thioridazine has little antiemetic action but perphenazine is prescribed for vomiting; hence it seems unlikely that the reported symptoms are due to a rebound action on the vomiting centre.These findings are relevant to the situation of withdrawal of ataractics prior to administration of anesthetics and to drug studies involving cross-over from an active compound to a placebo. The increasing use of ataractics suggests that this additional diagnostic possibility should be considered in the presence of obscure gastrointestinal symptoms.     

Increased number of beta-adrenergic receptors on cells of the rat adenohypophysis after thyroid hormone administration

The authors studied the effect of administration of thyroid hormones on the beta-adrenergic receptors of rat adenohypophyseal cells. The administration of triiodothyronine and thyroxine was followed by an increase in specific binding for 3H-dihydroalprenolol. No significant differences were found in cyclic adenosine monophosphate levels before and after isoprenaline stimulation. The significance of changes in these receptors for the hyperplastic reaction after oestrogens is discussed with reference to the inhibitory effect of the thyroid hormones on hyperplasia of the adenohypophyseal cells after the administration of oestradiol.     

Receptivity of female rats

Receptivity of female rats has been investigated under chronic experimental conditions. A receptivity index has been worked out for quantitative evaluation. It proved suitable for disclosing stimulatory (2.5 mg noretynodrel, oestradiol propionate) as well as inhibitory (etynodiol diacetate) effects. 2.5 mg noretynodrel has a biphasic effect; causing an inhibition and later an increase in receptivity. Receptivity of untreated female rats is low and can be increased by various steroids; the best treatment was 50 micrograms oestradiol monopropionate administered twice weekly, but this resulted in an inverse mating reaction, with frequent copulations in every phase of the cycle. In untreated females the number of copulations varied widely. Previous deliveries did not influence receptivity and frigidity was also observed.     

The effects of perphenazine and bromocriptine on follicular dynamics and endocrine profiles in anestrous pony mares

Nineteen anestrous pony mares were used in a project designed to determine the effects of altered prolactin concentrations on follicular dynamics and endocrine profiles during spring transition. The dopamine antagonist, perphenazine, was administered daily to mares (0.375 mg/kg body weight) in Group A (n = 6), while Group B mares (n = 7) received 0.08 mg/kg metabolic weight (kg75) dopamine agonist, 2-bromo-ergocriptine, intramuscularly twice daily. Mares in Group C (n = 6) received 0.08 mg/kg75, i.m., saline twice daily. Treatment began January 20, 1994, and continued until ovulation occurred. Mares were teased 3 times weakly with an intact stallion. The ovaries of the ponies were palpated and imaged weekly using an ultrasonic B-mode unit with a 5 Mhz intrarectal transducer until they either exhibited estrual behavior and had at least a 20-mm follicle, or had at least a 25-mm follicle with no signs of estrus. At this time, ovaries were palpated and imaged 4 times weekly. Blood samples were obtained immediately prior to ultrasonic imaging for measurement of prolactin, FSH and estradiol-17 beta. Perphenazine treatment advanced the spring transitional period and subsequent ovulation by approximately 30 d. Group A exhibited the onset of estrual behavior earlier (P < 0.01) than control mares. In addition, Group A mares developed large follicles (> 30 mm) earlier (P < 0.01) than Group B mares, with least square means for Groups A and B of 47.0 +/- 8.8 vs 88.1 +/- 8.2 d, respectively. Control mares developed 30-mm follicles intermediate to Groups A and B at 67.3 +/- 8.8 d. Bromocriptine decreased (P < 0.05) plasma prolactin levels throughout the study, while perphenazine had no significant overall effect. However, perphenazine treatment did increase (P < 0.05) mean plasma prolactin concentrations from Day 31 to 60 of treatment. There were no differences in mean plasma FSH or estradiol-17 beta between treatment groups. We concluded that daily perphenazine treatment hastened the growth of follicles and subsequent ovulation while bromocriptine treatment appeared to delay the growth of preovulatory size follicles without affecting the time of ovulation.     

Estradiol-induced adenohypophyseal growth reaction and beta-adrenergic receptors.

The effect of administration of estradiol benzoate on beta-adrenergic receptors of rat adenohypophyseal cells was studied. Twenty days' administration of estradiol benzoate was followed by an increase of adenohypophyseal weight and a decrease in specific binding of 3H-dihydroalprenolol (3H-DHA). In contrast to thyroid hormone treatment which induced an increase in 3H-DHA binding, thyroid hormone treatment decreased both the growth reaction and the reaction of beta-adrenergic receptors after estradiol. Although the relationship between the adenohypophyseal receptors and the growth reaction is unclear, changes in beta-adrenergic receptors after hormonal therapy can be one of pathophysiological conditions that may influence this reaction.     

The effect of thioridazine on haloperidol induced behavioral hypersensitivity

Behavioral Hypersensitivity (BH) to dopamine agonists occurs following chronic treatment with most neuroleptics including haloperidol. In the present study we observed that the concurrent administration of thioridazine and haloperidol prevented the development of BH. In contrast, another neuroleptic, fluphenazine, coadministered with haloperidol, potentiated the degree of BH relative to animals treated with haloperidol only. In rats already made hypersensitive by chronic treatment with haloperidol, a 4 week subsequent treatment with normal saline, thioridazine alone of thioridazine in combination with haloperidol, produced normal behavioral responsiveness. These results suggest that thioridazine prevents the development of BH and can reverse the expression of haloperidol-induced BH.     

Repurposing of antipsychotics perphenazine for the treatment of endometrial cancer

Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.     

Water and sodium transport: effects of calcium channel blocker and calmodulin antagonists on the apical and basolateral membranes of amphibian epithelia

Ca2+ channel blocker (sensit) and calmodulin antagonists (thioridazine, perphenazine, oxyprothepine) applied to the mucosal side of frog urinary bladder, weakened the response of epithelial cells to vasopressin. Thioridazine (2.7 X 10(-5) mol X l-1) and sensit (1.7 X 10(-4) mol X l-1) applied to the serosal side rapidly increased the permeability of the epithelia for sodium and potassium ions along the concentration gradient (from serosa to mucosa). The same concentrations of these blockers when applied to the mucosal side of frog urinary bladder selectively decreased vasopressin stimulated water permeability and did not influence ionic permeability. Both thioridazine and sensit decreased the short-circuit current across frog skin. The results show that the Ca2+ channel blocker and the calmodulin antagonists tested influenced water and ionic transport across the epithelial cell membranes, and had different effects upon the apical and the basolateral cell membranes.     

Inhibition of thyroxine binding to adenohypophysial proteins in vitro by 2,4-dinitrophenol administered in vivo.

Male and female rats were given oestradiol benzoate (1 mg as a microcrystal aqueous suspension i.m. twice a week), 0.0033% 2.4-dinitrophenol (DNP) in their food (about 1 mg/rat/day), or 0.1% DNP in their food (about 30 mg/rat/day), or both oestradiol and DNP. The smaller DNP dose mildly stimulated food consumption and did not affect body weight. The larger dose strongly inhibited food consumption in the first two weeks of the experiment; consumption then returned to the control level, but body weight fell markedly at the same time. After 3 weeks' administration of both the small and the large dose of DNP, adrenal weight in the males was raised and the weight of the gonads was unchanged. The large DNP dose severely reduced the weight of the seminal vesicles and the uteri. It also inhibited the accumulation of radioiodine in the thyroid of both males and females. Isolated administration of the oestrogen raised adrenal weight in the males and ovarian and uterine weight in the females; it reduced the weight of the testes and seminal vesicles. These reactions were not affected by DNP. A pronounced oestradiol-induced increase in the weight of the adenohypophyses was accompanied by raised thyroxine binding to the adenohypophysial proteins in vitro. DNP inhibited the growth reaction of the adenohypophysis to the oestrogen only slightly and non-significantly, but significantly inhibited the thyroxine binding reaction to the adenohypophysial proteins in vitro. By itself, DNP had no effect on adenohypophysial weight, but reduced thyroxine binding to the adenohypophysial proteins in vitro, especially in males. The effect of DNP was similar to that of thyroxine observed in earlier experiments; nothing is known of its mechanism.     

Delayed effects on plasma concentration of testosterone and testicular morphology by intramuscular low-dose di(2-ethylhexyl)phthalate or oestradiol benzoate in the prepubertal boar

The immediate and delayed effects of prepubertal exposure to di(2-ethylhexyl)phthalate (DEHP) or oestradiol benzoate on the plasma concentrations of testosterone, oestradiol and LH, as well as testicular morphology were examined in prepubertal boars. In a split litter design experiment, prepubertal boars were intramuscularly exposed to DEHP, oestradiol or vehicle during five weeks, starting at six weeks of age. The dose of DEHP was 50mg/kg of bodyweight twice weekly, which is in the same range as recently used oral doses in rodents. Oestradiol-benzoate was administered at 0.25mg/kg of bodyweight twice weekly. One set of animals was examined immediately after the exposure, and the other set was examined at an age of 7.5 months. During the exposure period concentrations of LH in plasma were lower (p=0.02) in the oestradiol-treated animals than in the control group. In the group exposed to oestradiol, the relative to the body weight of the testicles tended to be lower (p=0.07) than control immediately after five weeks of exposure, and the relative to the body weight of the seminal vesicles tended to be lower (p=0.05) than control at 7.5 months of age. In the DEHP-exposed group an elevated (p=0.005) concentration of testosterone and increased (p=0.04) area of the Leydig cells in the testicles compared to the control group were seen at 7.5 months of age. These data suggest that DEHP early in life causes delayed effects on the reproductive system in the adult.