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The effect of contraceptive steroids on hypothalamic-pituitary function.

A study was performed to obtain additional information about the effects of oral contraceptives on pituitary function. A sequential pituitary stimulation test (SST) was used to study normal control women who then received either a combination pill with 50 mug of ethinyl estradiol or an injectable or oral progestin for three weeks, after which the test was repeated. The same test was also performed on five long-term oral contraceptive users. The SST consists of measurement of growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at frequent intervals after stimulation by hypoglycemia, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. GH and TSH release following stimulation were unaffected by the use of contraceptive steroids, while PRL release was increased by both the combination pill and the progestin alone. LH and FSH release was decreased in the three short-term and most of the long-term users of the combination pills but was not decreased in two of the long-term users as well as in those receiving the progestin alone. These results indicate that the combination oral contraceptives have a direct effect upon the pituitary gland, causing an increase in prolactin release and a decrease in gonadotropin release. This effect varies among individuals receiving the same formulation and may be related to the development of syndrome of postpill amenorrhea-galactorrhea.

Contraceptives, Oral

Plasma thyrotropin-releasing hormone, prolactin, thyrotropin, and thyroxine concentrations following the intravenous or oral administration of thyrotropin-releasing hormone.

In a further evaluation of the use of oral thyrotropin-releasing hormone (TRH) in puerperally lactating women, a radioimmunoassay for its measurement has been developed. Its concentration in plasma as well as that of prolactin (PRL), thyrotropin (TSH) and thyroxine (T4) were measured following either intravenous or oral administration of TRH. Basal concentrations of TRH in 14 normally cycling women ranged from less than 5 to 17 pg/ml. Two luteal phase studies produced peaks in plasma TRH 5 to 10 minutes after 100 micrograms of TRH administered intravenously with a return to basal concentrations within 2 to 3 hours. In 10 normally menstruating women, ingestion of 10 mg of TRH orally resulted in plasma TRH which peaked at 423 +/- 123 pg/ml (standard error of the mean) at 30-minutes. Plasma PRL, TSH, and T4 also increased and remained slightly elevated at 4 hours. These 8-hour studies were performed in a puerperal lactating woman who had ingested 10 mg of TRH orally twice a day for 7 days prior to blood sampling. TRH concentrations declined throughout each day while TSH rose slightly in the first 1 to 2 hours but remained within normal limits. The prolonged administration of 10 mg of TRH orally twice daily to three puerperally lactating women resulted in elevations in plasma TRH 2 to 3 hours following hormone administration, yet no significant increases in plasma TSH were observed. Both endogenous TRH and TSH were measured before and after 22 nursing events in nine puerperally lactating women. There was no change in the concentration of either substance and all values were similar to those obtained in normally menstruating women.

Administration, Oral

Serum prolactin concentrations related to copper or inert intrauterine devices (IUDs) in women.

A report that serum prolactin concentrations were almost doubled by the use of copper IUDs led us to study the effect of both copper and inert IUDs. We studied 105 normal women in whom all other prolactinergic factors had been excluded; 25 of them were using copper IUDs, 25 were using inert IUDs and there were 55 controls. No differences were found in the mean prolactin levels between these groups (4.3, 4.5 and 4.3 microgram/l, respectively). We conclude that copper and inert IUDs do not affect prolactin secretion.

Adult

Pituitary and ovarian function in women receiving hormonal contraception.

A study was performed to further evaluate pituitary-ovarian function in women receiving an oral contraceptive preparation. Basal hormone levels (follicle stimulating hormone, luteinizing hormone, estradiol and prolactin) and gonadotropic response to gonadotropic releasing hormone were studied in 12 healthy, regularly ovulating women in the early follicular and mid-luteal phases of their menstrual cycle (non-treatment control period). These same women were then given NORDETTE (ethinyl estradiol 30 microgram +d-Norgestrel 150 microgram) cyclically for 3 months. In the third month of treatment, the tests were repeated on day 21, i.e. after 21 active pills, and on day 28, i.e. after 21 active and 7 inactive tablets. On active preparation, basal luteinizing hormone, follicle stimulating hormone and estradiol and gonadotropin response to gonadotropin releasing hormone were significantly suppressed. However, by day 28 (after completion of the inactive tablets), basal gonadotropin and estradiol concentrations and the gonadotropic response to gonadotropic releasing hormone were not significantly different to their pretreatment levels. No consistent change in prolactin concentration occurred as a result of oral contraceptive therapy. These results indicate that the 'active' component of even a relatively low-dose pill causes considerable suppression of pituitary-ovarian function but that after 7 days of placebo, pituitary function and basal estradiol secretion have virtually returned to normal.

Adolescent

Clinical response to CB-154 and the pituitary response to thyrotropin-releasing hormone-gonadotropin-releasing hormone in patients with galactorrhea-amenorrhea.

Ten patients with galactorrhea and amenorrhea were treated with 2-bromo-alpha-ergocryptine (CB-154). All patients had normal anteroposterior and lateral x-rays of the sella turcica and normal or low gonadotropin levels. Before treatment, serum prolactin (PRL) levels were between 80 and 1575 ng/ml. Prior to initiating therapy, six patients were further evaluated by the intravenous administration of thyrotropin-releasing of a pituitary etiology in all patients. During treatment, PRL levels were measured at monthly intervals. After 1 month, serum PRL concentrations were reduced between 13% and 99%. In eight subjects there was complete cessation of galactorrhea. During treatment, nine patients resumed ovulatory menstrual cycles and three patients conceived. After discontinuing therapy, five of seven subjects had a recurrence of galactorrhea, amenorrhea, and hyperprolactinemia.

Adult

Factors influencing the dynamics of gonadotropin response following bolus infusion of luteinizing hormone-releasing factor in women with menstrual abnormalities.

Thirty-five women with menstrual abnormalities were given 100 microng of luteinizing hormone-releasing hormone (LHRH) by bolus intravenous injection in an attempt to simplify and quantitate the usefulness of this test in clinical management. Peak and total gonadotropin responses are highly correlated. Peak and total LH are significantly related to basal LH but no similar relationship could be established for follicle-stimulating hormone (FSH). There is no association between gonadotropin response and prolactin levels or body weight. Basal estradiol levels are inversely related to FSH response but not to LH response. It is concluded that the use of an intravenous 100-microng bolus of LHRH is of little use as a clinical test for the gynecologic endocrine patient.

Adolescent

Luteinizing hormone-releasing hormone, ovariectomy, and silastic vaginal rings in the Rhesus monkey.

The interaction of estradiol and luteinizing hormone-releasing hormone (LRH) may be a critical physiologic mechanism regulating the occurrence of ovulation in many species. These studies were conducted to assess (1) the effects of intramuscular injections of LRH in the intact female rhesus monkey and (2) the effects of estradiol in a Silastic delivery system in ovariectomized female rhesus monkeys. No changes in blood levels of luteinizing hormone (LH) were detected in response to 200 micrograms of LRH. Ovulation did not occur 48 hours after treatment. Ovariectomy decreased estradiol, increased LH, and had no effect on prolactin concentrations in sera. Insertion of a vaginal ring containing 10% estradiol increased blood estradiol levels 100-fold. Serum prolactin levels were unaffected; however, LH concentrations were altered in a multiphasic fashion. After the ring had been in place for 15 days, vaginal blood similar to menstrual flow was observed following removal.

Animals

Serum-prolactin in long-lasting lactation amenorrhoea.

Basal serum-prolactin concentrations were high until 15 months post partum in nursing mothers in Central Africa (Lwiro). They were significantly lower in menstruating than in amenorrhoeic nursing mothers. These results support the hypothesis that prolactin is involved in the long-lasting amenorrhoea which occurs in regions where breast-feeding is prolonged for up to 2 years after delivery.

Africa, Central

Bromocriptine for induction of ovulation in normoprolactinaemic post-pill anovulation.

19 women with anovulation after discontinuing oral contraceptive agents and with normal plasma-prolactin concentrations were treated with bromocriptine. Ovulation and menstruation were restored in 9 of the 13 amenorrhoeic and 5 of the 6 oligomenorrhoeic patients. The success-rate (74%) indicates that bromocriptine is an effective treatment for post-pill anovulation in normoprolactinaemic women.

Adolescent

Potent inhibitory effect of a new antiestrogen (RU 16117) on the growth of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.

At the daily dose of 24 mug for a period of 4 weeks, RU 16117 (11alpha-methoxyethinyl estradiol), a new antiestrogen, led to 65% reduction of the number of already established dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats. Not only the tumor number but also the tumor size was reduced by RU 16117 in a manner similar to that seen after ovariectomy. The absence of an inhibitory effect of doses of 0.1 to 12.5 mug 17beta-estradiol (E2) per day, a dose-range which covers the low estrogenic activity of the RU 16117 doses used, suggested that the inhibitory effect of RU 16117 was not due to its estrogenic activity. Decreased levels of receptors for E2, progesterone, and prolactin were found in the tumors remaining after ovariectomy; treatment with the dose of RU 16117 sufficient to inhibit tumor growth (24 mug) had a similar inhibitory effect on the levels of E2 and prolactin receptors. These data suggested that a reduction of hormone receptor levels in the tumor tissue could be a mechanism by which RU 16117 acts as a potent inhibitor of the growth of DMBA-induced mammary carcinoma.

9,10-Dimethyl-1,2-benzanthracene

The relation between plasma oestrogen, progesterone and prolactin concentrations and the efficacy of vaginal prostaglandin E2 gel in initiating labour.

In an attempt to relate the efficacy of treatment to endogenous hormone levels, plasma oestrogen, progesterone and prolactin levels were analysed in women at term following the vaginal administration of prostaglandin E2 gel to induce labour. Patients who went into labour after treatment had significantly higher oestradiol-17 beta levels before treatment compared with those requiring formal surgical induction the following day. No difference could be demonstrated in levels of progesterone or prolactin in the two groups of patients. The significance of these results is discussed.

Estradiol

Hormonal profiles in lactating and non-lactating women immediately after delivery and their relationship to breast engorgement.

Prolactin, human placental lactogen (HPL), oestrone, oestradiol and progesterone levels in plasma were measured before and during the first seven days after delivery in women who did not breast feed. The results confirmed the rapid clearance of placental steroids from the circulation after delivery. Plasma prolactin levels remained elevated during the early puerperium and the range of values were the same in non breast-feeding women and a group of breast feeding women. Of the 25 women studied, six developed breast engorgement. No difference in hormonal profiles were found leading to the conclusion that there is no endocrine basis for breast engorgement in non-breast feeding women.

Adult

Prolactin secretion during prolonged lactational amenorrhoea.

Basal serum prolactin levels were elevated up to 66 weeks postpartum in lactating amenorrhoeic women. The serum prolactin level in fully breast-feeding women was significantly higher than in women who were partially breast-feeding. The mean basal serum prolactin level in menstruating, lactating women was significantly higher than the mean level in women who had weaned and had normal menstrual cycles. The rise in prolactin due to suckling was seen up to 66 weeks postpartum. The marked variability and lack of reproducibility of individual suckling responses may obscure the importance of prolactin secretion in the postpartum period. Nevertheless, this study confirms that prolactin secretion is increased in women with prolonged lactational amenorrhoea.

Amenorrhea

Hormone serum levels and hormone receptor contents of endometria in women with normal menstrual cycles and patients bearing endometrial carcinoma.

Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (HPRL), 17 beta-estradiol (E2) and progesterone (P) were estimated in 46 subjects with normal menstrual cycles in whom hysterectomies were performed. Estrogen (ER) and progesterone receptor (PgR) levels in endometrial samples of these patients were estimated, and histological dating of the cycle day was carried out. Similarly, hormone serum levels and ER as well as PgR were estimated in 17 patients with endometrial carcinoma. No correlation between LH, FSH, HPRL and ER as well as PgR was noted in the normal subjects. Correlation between P and ER was observed in this group. Parallel variations between E2 and PgR were recorded in the normal females. In the carcinoma group no correlations between hormone serum levels and receptor contents were found, but ER and PgR correlated with each other. Receptor levels was highest in the well-differentiated group of endometrial carcinoma. The present experiments provide a rationale for progestagen therapy of carcinoma of the endometrium.

Endometrium

Acute and chronic estrogen effects upon serum somatomedin activity, growth hormone, and prolactin in man.

Estrogen (E) reduces bioassayable GH-dependent serum somatomedin (SM) activity in acromegalics without affecting plasma growth hormone (GH) levels and inhibits the rise of SM activity normally produced by GH administration in GH-deficient subjects. We have now investigated the effect of E administration on serum SM activity and on plasma GH and prolactin (PRL) in 6 adult male subjects without pituitary pathology. Chronic E administration (ethinyl estradiol 0.5 mg/day for 7 to 70 days) reduced serum SM activity by 40 to 62% in each of 4 subjects (P less than 0.02 to less than 0.001). In 3 of the subjects, basal GH levels increased by 75 to 300% (P less than 0.05 to less than 0.001) and basal PRL levels increased by 90 to 200% (P less than 0.01 to less than 0.001). While iv administration of normal saline did not significantly affect either SM or GH, iv administration of E (bolus injection of 25 mg conjugated estrogens, USP) to 5 subjects resulted in: a) a 46 to 80% decrease in serum SM activity in all subjects, proceeding with an apparent half-life of 2 hours, becoming significant (P less than 0.05) at 2 hours (1 subject) to 3 hours (4 subjects), maximal at 6 hours, and persisting for 12 to 24 hours; b) GH elevation to 3 to 16 times baseline level (P less than 0.01) at 2 to 3 hours in 4 subjects; and c) no significant change of PRL levels in any subject. The mean GH response to iv E was maximal at a time (2 hours) when the mean SM activity had decreased only 20% and subsided well before the nadir of SM activity. The one patient without GH response to chronic or acute E administration may have been affected by absorption of triamcinolone being applied topically during the study. These results demonstrate that in males with normal pituitary function, E reduces serum SM activity, enhances basal GH and PRL secretion, and, upon iv injection, stimulates acute GH release. Although opposite chronic E effects upon GH and SM activity support a putative negative SM-GH feed-back mechanism, iv E administration apparently provokes acute GH release by a different mechanism. The half-life of serum SM activity in the human is probably much shorter than previously estimated.

Adult