Prolactin secretion in patients with idiopathic diabetes insipidus.

It has been demonstrated that hyperprolactinemia is sometimes present even in patients with idiopathic diabetes insipidus (DI). In this study, we examined the responses of serum prolactin (PRL) to hypertonic saline infusion and TRH injection in 11 patients with idiopathic DI diagnosed by clinical examinations. Serum sodium in these patients (147.5 +/- 3.2 mEq/L) was significantly higher at baseline than in normal subjects (139.7 +/- 2.4 mEq/L). The plasma arginine vasopressin (AVP) level was significantly lower in DI (0.42 +/- 0.24 pg/ml) at baseline than in normal subjects (2.53 +/- 1.03 pg/ml). However, the serum PRL level in both groups did not differ significantly except in one patient with idiopathic DI (35.6 ng/ml). There was no significant correlation between the basal serum sodium and basal serum PRL in either group. After an infusion of hypertonic saline, the serum sodium level gradually increased to 155.6 +/- 3.4 mEq/L in DI and to 146.5 +/- 4.3 mEq/L in the normal subjects. However, this increase did not affect PRL secretion in either group. PRL response to TRH was essentially normal in all patients with idiopathic DI. These results indicate that the secretion of PRL is not generally affected by chronic mild hypernatremic hypovolemia in the patients with idiopathic DI.     

Lactational [correction of Lacational] anovulation in rats and its dependency on progesterone

The relationship between prolactin (PRL) secretion and anovulation in lactating rats was studied. Normal lactating rats and lactating rats treated with antiserum against luteinizing hormone-releasing hormone at the time of postpartal ovulation were used. Normal lactating rats were treated with either a dopamine agonist (CB-154, 150 micrograms/rat) on Day 10 or 13, or pups removal on Day 7 or 10, and thereafter luteolysis and inhibition on PRL secretion were assessed. With the CB-154 treatment, the incidence of luteolysis increased as the lactational period advanced (42% vs 72%), whereas it decreased (73% vs 14%) with the pups removal. Thus, dopamine effectively inhibited PRL secretion during the later lactational stage, but could not do so during the earlier stage when there were mechanisms other than dopamine stimulating PRL secretion. Following luteal regression induced by CB-154, ovulation did not occur if the rats were treated with CB-154 on Day 10, whereas 50% of the rats ovulated within 4 days if treated on Day 13. Furthermore, in the lactating rats treated with anti-luteinizing hormone-releasing hormone serum during late pregnancy, ovulation was not observed until Day 10 of lactation. Since the serum progesterone levels were low in these rats due to the absence of ovulation and lactational corpora lutea, the blockade of ovulation was not due to elevated circulating progesterone during the early lactational period. The mechanism of ovulation blockade during lactation thus seems to shift from being progesterone independent to progesterone dependent at a similar period when the neuroendocrine control of PRL secretion shifts from dopamine independent to dependent.     

Differential involvement of protein kinase C in basal versus acetylcholine-regulated prolactin secretion in rat anterior pituitary cells during aging

Although it is well known that plasma concentration of prolactin (PRL) increases during aging in rats, how the anterior pituitary (AP) aging per se affects PRL secretion remains obscure. The objectives of this study were to determine if changes in the pituitary PRL responsiveness to acetylcholine (ACh; a paracrine factor in the AP), as compared with that to other PRL stimulators or inhibitors, contribute to the known age-related increase in PRL secretion, and if protein kinase C (PKC) is involved. We also determined if replenishment with aging-declined hormones such as estrogen/thyroid hormone influences the aging-caused effects on pituitary PRL responses. AP cells were prepared from old (23-24-month-old) as well as young (2-3-month-old) ovariectomized rats. Cells were pretreated for 5 days with diluent or 17beta-estradiol (E(2); 0.6 nM) in combination with or without triiodothyronine (T(3); 10 nM). Then, cells were incubated for 20 min with thyrotropin-releasing hormone (TRH; 100 nM), angiotensin II (AII; 0.2-20 nM), vasoactive intestinal peptide (VIP; 10(-9)-10(-5) M), dopamine (DA; 10(-9)-10(-5) M), or ACh (10(-7)-10(-3) M). Cells were also challenged with ACh, TRH, or phorbol 12-myristate 13-acetate (PMA; 10(-6) M) following PKC depletion by prolonged PMA (10(-6) M for 24 h) pretreatment. We found that estrogen priming of AP cells could reverse the aging-caused effects on pituitary PRL responses to AII and DA. In hormone-replenished cells aging enhanced the stimulation of PRL secretion by TRH and PMA, but not by AII and VIP. Aging also reduced the responsiveness of cells to ACh and DA in suppressing basal PRL secretion, and attenuated ACh inhibition of TRH-induced PRL secretion. Furthermore, ACh suppressed TRH-induced PRL secretion mainly via the PMA-sensitive PKC in the old AP cells, but via additional mechanisms in young AP cells. On the contrary, basal PRL secretion was PKC (PMA-sensitive)-independent in the old AP cells, but dependent in the young AP cells. Taken together, these results suggest differential roles of PMA-sensitive PKC in regulating basal and ACh-regulated PRL responses in old versus young AP cells. The persistent aging-induced differences in AP cell responsiveness to ACh, DA, TRH, and PMA following hormone (E(2)/T(3)) replenishment suggest an intrinsic pituitary change that may contribute, in part, to the elevated in vivo PRL secretion observed in aged rats.     

Galactorrhea in subclinical hypothyroidism

Galactorrhea was found in 5 patients with subclinical hypothyroidism. The galactorrhea consisted of the discharge of a few drops of milk only under pressure. Serum T4 was in the lower level of the normal range, but serum T3 was normal (T4: 6.3 +/- 1.2 micrograms/dl, T3: 113 +/- 7 ng/dl). Basal serum TSH and PRL were slightly increased only in 2 and 1 cases, respectively. The PRL responses to TRH stimulation were exaggerated in all cases, although the basal levels were normal. An enlarged pituitary gland was observed in 1 patient by means of CT scanning. All patients were treated by T4 replacement. In serial TRH tests during the T4 replacement therapy, the PRL response was still increased even when the TSH response was normalized. Galactorrhea disappeared when the patients were treated with an increased dose of T4 (150-200 micrograms/day). Recurrence of galactorrhea was not observed even though replacement dose of T4 was later decreased to 100 micrograms/day in 4 cases. In patients with galactorrhea of unknown origin, subclinical hypothyroidism should not be ruled out even when their serum T4, T3, TSH and PRL are in the normal range. The TRH stimulation test is necessary to detect an exaggerated PRL response, as the cause of the galactorrhea. To differentiate this from pituitary microadenoma, observation of the effects of T4 replacement therapy on galactorrhea is essential.     

Inversely related evolution of growth hormone and prolactin secretions in long-term tissue cultures of human pituitary adenomas from acromegalic patients

Summary Pituitary tumoral tissue from 20 acromegalic patients was cultured for up to 120 d in a medium containing 5 nM cortisol. In all cultures, growth hormone (GH) release decreased. At the beginning of the culture, prolactin (PRL) was detected in 18 adenomas, varying from 0.5 to 1000 ng per flask per day. Thereafter, in 10 cases PRL secretion increased from 3 to 50 times the basal level, most frequently after a lapse of 9 to 30 d. PRL secretion remained low in three cases, undetectable in one case only. When added at 350 nM, cortisol increased GH secretion up to 20-fold and simultaneously decreased PRL secretion by as much as 10% of the basal level. Withdrawing cortisol reversed the situation. Immunocytochemical studies of the tumor at surgery showed, besides GH immunoreactive (IR) cells, PRL-IR cells (from rare cells to 10% of total cells) in 15 adenomas, correlating with the first days of culture PRL levels. In cultured explants, mitoses were never found. In 5 nM cortisol medium, the number of GH-IR cells decreased and PRL-IR cells increased or appeared. With 350 nM cortisol, the number of GH-IR cells increased, and PRL-IR cells were scarce or absent. Immunoreactivities for GH and PRL were found in different cells. Care was taken to exclude cultures containing normal pituitary tissue, and because no mitoses were found, these results suggest that most somatotropic adenomas can reversibly shift their secretion from GH to PRL in culture. This capacity to secrete PRL, hidden or low in vivo, is revealed by the favorable low cortisol conditions present in vitro.     

I. The 24-hour profile of prolactin in depression

The 24-hour profile of plasma PRL was studied in 10 patients with unipolar depression and 8 patients with bipolar depression and compared to 18 control profiles obtained in healthy subjects. Alterations in the basal PRL secretion as well as the characteristics of the 24-hour rhythm were found in all patients but differed strikingly according to the type of depressive illness. The basal PRL level was elevated in unipolars, mainly as a result of increased secretion during wakefulness, and lowered in bipolars because of a lack or reduction of sleep-associated elevation. The nocturnal rise of PRL was maintained in unipolars but absent in 75% of the bipolar subjects. The variability of PRL levels around the 24-hour mean appeared to be reduced in both types of affective illness. These abnormalities in the 24-hour profile of PRL could serve as a biological marker of sub-types of depression.     

Hyperprolactinémie et fonction sexuelle chez l’homme

Erectile dysfunction (ED), generally associated with reduced sexual desire and sometimes with orgasmic or ejaculatory dysfunction, is the major presenting symptom of hyperprolactinemia (HPRL) in men, a condition which should not be missed since many cases are due to pituitary tumors, likely to result in serious complications. It is generally believed that the mechanism of prolactin (PRL)-induced sexual dysfunction is a decrease in testosterone secretion. In fact, serum testosterone is normal in many hyperprolactinemic males and testosterone-independent mechanisms are also involved, probably mainly involving cerebral neurotransmitter systems. Systematic determinations of serum PRL have found very low prevalences of marked HPRL (>35 ng/ml) in ED patients (0.76% in a compilation of more than 3,200 patients) and pituitary adenoma (0.4%). In addition, the association of HPRL with ED may have been coincidental in some of these cases, since 10% of HPRLs diagnosed by the usual immunological assays are due to macroprolactins, which are biologically inactive or minimally active variants of PRL. Specific identification of PRL requires PRL chromatography which is only available in some specialized laboratories. No consensus has yet been reached concerning screening for HPRL in ED. Systematic determination of serum PRL may be justified, as HPRL is a serious but reversible disease, while there is presently no reliable clinical, psychometric or hormonal criteria (including serum testosterone level) allowing to restrict its determination to certain categories of ED patients without a risk of missing certain cases of HPRL. In the case of consistent HPRL, looking for hypothalamic or pituitary tumor is mandatory. Dopamine-agonist therapy is the first-line treatment for PRL-induced sexual dysfunction. Sexual counselling may be necessary for some patients.     

Measurement of peptide secretion and gene expression in the same cell

A combined reverse hemolytic plaque-in situ hybridization assay was developed to allow analysis of the relationship between peptide secretion and gene expression within individual cells. We used the pituitary lactotroph as a model system, but this strategy should be widely applicable. It can be used to test hypotheses regarding if and when peptide secretion and gene expression are coupled in any system in which antibodies to the secreted peptide and probes complementary to the mRNA are available. Using the mRNA hybridization signal to identify certain cell types, this method may also be useful in further studies on the biochemical mechanism of peptide secretion. In addition, questions regarding whether a cell known to secrete a given peptide contains other specific mRNAs and the relationship between these mRNAs and the secretion of the peptide can be studied using this strategy. We found striking heterogeneity among lactotrophs in both gene expression and PRL secretion and a lack of correlation of these parameters within individual lactotrophs under every treatment examined. We also present the first direct visualization and quantitation of the percentage of nonsecreting PRL mRNA-containing cells after estradiol treatment and in the presence or absence of the PRL secretagogue, TRH. Finally, we found that in ovariectomized rats, nonsecreting lactotrophs exhibited significantly higher levels of PRL mRNA than lactotrophs that were actively secreting PRL during the assay.     

Endogenous expression of Neuregulin-1 (Nrg1) as a potential modulator of prolactin (PRL) secretion in GH3 cells

The binding of Neuregulin-1 (Nrg1) to the epidermal growth factor family of receptor tyrosine kinases (ErbB) mediates intercellular and intracellular communication and regulates a broad spectrum of biological processes, such as tumorigenesis and myelination. Recombinant Nrg1 has been shown to control prolactin (PRL) secretion from rat prolactinoma GH3 cells. However, the endogenous expression of Nrg1 and its role in PRL secretion in GH3 cells are not known. In this study, we demonstrate that type III Nrg1 isoforms are endogenously expressed in GH3 cells. An in vitro functional analysis by using short interfering RNA against Nrg1 has revealed that endogenous Nrg1 regulates PRL secretion from GH3 cells in part in an ErbB-3-receptor-dependent manner, with no significant effects on growth hormone secretion. Therefore, Nrg1 is a specific modulator of PRL secretion in GH3 cells. Additionally, the co-localization of Nrg1 and ErbB-2 receptor, which is shared by both ErbB-3 and ErbB-4 receptors in the formation of heterodimers, has been detected in one out of five human prolactinoma tissues. Our findings suggest that GH3 cells intrinsically express a group of type III Nrg1 isoforms that regulate PRL secretion through an autocrine/paracrine mechanism. Further investigation into the role of Nrg1 on PRL secretion should provide clues to advance the clinical management of prolactinoma.     

CUSHING'S SYNDROME

Sixteen cases of verified Cushing''s syndrome, and twelve cases of probable Cushing''s syndrome were reviewed and data on them were compared with various reports on Cushing''s syndrome in the literature.The diagnosis hinges upon a high index of suspicion, and one or several of the major criteria may be lacking.Ultimate establishment of correct diagnosis should be based largely on the clinical features, although stimulation and suppression tests may help to confirm a clinical diagnosis.In well-established clinical cases, with borderline laboratory confirmation, exploration may be justified, especially if tests fail to identify a specific cause.In cases of adrenal cortical tumor, all pathological tissue should be removed if possible, with great care to support and stimulate the remaining atrophic adrenal gland during and following operation.In cases of bilateral adrenal cortical hyperplasia, the problem is one of how much to remove. At present most investigators advocate radical subtotal resection, leaving less than 10 per cent of one side.     

Low serum levels of FSH, LH and prolactin in luteal phase inadequacy

In order to elucidate the relationship between prolactin (PRL) levels and corpus luteum function in humans, assessment of temporal relationship between levels of PRL, LH, FSH, estradiol and progesterone was made in eleven normal cycling women and six short luteal women. All hormones were determined by specific radioimmunoassay. The mean PRL level in the luteal phase was higher than that in the follicular phase in normal women. On the other hand, no difference mean was seen between the PRL levels of follicular and luteal phases in short luteal women. In addition, follicular and luteal phase secretion of PRL in the short luteal phase (SLP) was lower than that in the normal control. LH and FSH in the follicular and luteal phases, estradiol secretion in the late follicular and early to mid-luteal phases in SLP were also lower than those in the control. These observations were consistent with the hypothesis that SLP is a sequel to aberrant folliculogenesis. In addition, it is inferred that low PRL levels in the SLP might be due to inadequate augmentation by estrogen, rather than giving PRL any positive controlling role in the maintenance of corpus luteum function.     

The physiology and mechanisms of the stress-induced changes in prolactin secretion in the rat

It is well known that stress in a number of forms induces the secretion of prolactin (PRL) in a number of species. What is not well known is that under certain conditions stress will also induce a decrease in PRL secretion. The conditions whereby stress decreases PRL are those where PRL secretion is elevated such as during the proestrous afternoon surge and during the nocturnal surge of pseudopregnancy. The physiologic significance of the stress-induced increase of PRL is suggested to be important in maintaining the competence of the immune system. The significance of the stress-induced decrease of PRL does not appear to have a major consequence on the physiology of reproduction in the rat and it is suggested that future studies be directed towards its significance in the immune system. The literature is reviewed dealing with the regulation of PRL secretion with emphasis on the factors that generate PRL surges in the rat. In addition the mechanism(s) of the stress-induced increase and decrease is (are) also examined. A hypothesis is presented suggesting an interaction between tuberoinfundibular dopamine secretion and a hypothalamic prolactin releasing factor in the generation of PRL surges and the differential effects of stress on PRL secretion.     

Prolactin secretion and its response to stress during the estrous cycle of the rats

Serum and pituitary prolactin (PRL) concentrations were measured during the estrous cycle of the rat with particular attention to the afternoons of the days of proestrus and estrus. Homogenizing machines, a Polytron and Sonifier, were used to extract PRL from the pituitary gland. The effects of ether anesthesia and restraint were also examined on the afternoons of both proestrus and estrus. The occurrence of a surge in PRL secretion during proestrus was confirmed with a peak at 1500 h, and this was accompanied by a decline in pituitary PRL content. A relatively high level of serum PRL was observed in the afternoon of estrus, during which time pituitary PRL content increased progressively. Ether anesthesia had no effect on the proestrus PRL surge, while restraint enhanced it. On the afternoon of estrus, restraint completely suppressed the rise in serum PRL, but ether anesthesia failed to suppress it completely. From these results, the following conclusions were drawn: 1) the PRL surge on the afternoon of proestrus occurs without synthesis of the hormone in the pituitary; 2) PRL secretion on the afternoon of estrus is accompanied by its synthesis in the gland; 3) the PRL response is distinct for each type of stress applied; and 4) PRL secretion is thus regulated by different mechanisms in proestrus and estrus.     

催乳素对培养的绵羊睾丸间质细胞睾酮分泌的影响

在绵羊睾丸间质细胞体外无血清长期培养的条件下,研究了催乳素对睾丸间质细胞睾酮分泌的调节作用。实验结果表明,催乳素可增强细胞对人绒毛膜促性腺激素(hCG)刺激的反应。催乳素的这种作用呈双相调节。睾酮分泌量显著高于hCG和催乳素单独作用时的总和。在hCG存在下,不同的底物转化为睾酮的量不同。其中雄烯二酮和孕酮转化为睾酮的方式存在着双相性。脱氢表雄酮转为睾酮的量少,不存在双相性,而与其剂量成正比。催乳素在hCG存在下可调节底物转化为睾酮。低剂量的催乳素(1ng/ml)可使一定剂量的孕酮(10～30ng/ml)转化为睾酮的量明显增加,而高剂量的催乳素(>10ng/ml)却明显地抑制孕酮转化为睾酮。催乳素可明显地抑制雄烯二酮转化为睾酮,与剂量无关。可见催乳素对于孕酮和雄烯二酮这两个关键底物转化为睾酮的调节是不同的。催乳素增强hCG刺激睾酮分泌的作用可能部分是通过其促进孕酮转化为睾酮来实现的。     

Effect of prolactin on ovarian steroidogenesis

This review summarizes evidence that prolactin (PRL) is involved directly in the regulation of ovarian steroidogenesis. The scope of this paper will be limited to two areas. The first area involves the regulation of the corpus luteum function and the second the effect of PRL on steroidogenesis during the follicular phase of the oestrous cycle. Cyclic changes of plasma PRL levels and the ovarian receptors which bind PRL have been observed during the oestrous cycle of domestic animals. The luteotropic effect of PRL and its failure is also presented. PRL may exert a physiological effect on follicle steroidogenesis but its effect depends on the level of follicle maturation. The effect of PRL treatment on estrogen production by follicular cells in vivo and in vitro was studied. The results of many papers indicate suppression of estrogen secretion by the direct action of PRL at the ovarian level. However, there is abundant evidence, that PRL is involved directly in regulation of ovarian steroidogenesis, the precise mechanism remains to be discovered.     

Clinical analysis of 100 medicolegal cases.

OBJECTIVE--To find the reasons for legal claims against hospital doctors. DESIGN--Prospective analysis of requests for medical opinion submitted by solicitors during 1984-93 on legal claims against hospital doctors. SUBJECTS--100 successive cases: 98 from the United Kingdom and two from the Republic of Ireland. MAIN OUTCOME MEASURES--Principal underlying causes of claims. RESULTS--In 44 cases there was no serious clinical error. Of the 56 cases of clinical fault, seven were a failure of communication by doctors, 15 were an isolated error in otherwise good clinical management, 21 were errors that might not have occurred with better control of clinical practice (doctors exceeding their competence, poor clinical judgment, and poor teamwork), and 13 were major errors due to carelessness or incompetence. In 34 cases there was evidence of clinical fault that might escape clinical audit and medicolegal processes. Most of these legal claims have been or are likely to be withdrawn: only five plaintiffs have settled out of court, and 11 are pursuing their actions. CONCLUSIONS--To reduce the incidence of errors, hospital doctors should consult colleagues about difficult cases and specialists should maintain a broad interest in disease. The NHS clinical complaints procedure should be extended to cover potential claims, and serious cases should be subject to independent external assessment by experienced consultants.     

Prolactin reference range and pulsatility in male dogs

Little is known about serum prolactin (PRL) concentrations and secretion patterns in male dogs. Blood samples (n = 65) were collected from crossbred dogs and from Beagles and German Shepherd dogs to describe the PRL reference range, and from five male Beagles at 15-min intervals for 6 h (n = 24 samples/dog) to describe the ultradian rhythm of this hormone. Serum PRL was measured by a homologous endpoint enzyme immunometric assay. The reference range was established from nondetectable to 6.0 ng/mL. There was an effect of breed; serum PRL concentrations in Beagles were higher (P < 0.05) than in crossbreeds and German Shepherds. However, there was no significant correlation between PRL concentration and age of the dog. During the ultradian study, PRL was characterized by a fluctuating baseline with occasional distinct elevations, indicating a pulsatile secretion. The mean basal PRL concentration was 1.4 +/- 0.6 ng/mL and the mean AUC was 9.9 +/- 2.7 ng/mL/6h. Prolactin pulse frequency ranged from one to two peaks/6h, pulse duration between 15 and 75 min, and amplitude from 1.7 to 2.4 ng/mL. In conclusion, this reference range, pulsatility and breed differences should be taken into account when interpreting serum PRL concentrations, for clinical or research purposes.     

The effects of intracerebroventricular infusion of prolactin in luteinizing hormone, testosterone and growth hormone secretion in male sheep

This study tested a hypothesis that the enhancement of the prolactin (PRL) concentration within the central nervous system (CNS) disturbs pulsatile luteinizing hormone (LH) and growth hormone (GH) secretion in rams that are in the natural breeding season. A 3h long intracerebroventricular (icv.) infusion of ovine PRL (50 microg/100 microl/h) was made in six rams during the daily period characterized by low PRL secretion in this species (from 12:00 to 15:00 h); the other six animals received control infusions during the same time. Blood samples were collected from 9:00 to 18:00 h at 10 min intervals. A clear daily pattern of LH secretion was shown in control animals, with the lowest concentration at noon and an increasing basal level around the time of sunset (P < 0.001). No significant changes in LH concentration occurred in PRL-infused animals and the concentration noted after infusion of PRL was significantly (P < 0.05) lower than after the control infusion. The frequency of LH pulses tended to decrease in rams after PRL treatment. The changes in LH secretion clearly carried over to the secretion of testosterone in the rams of both groups. The GH concentrations changed throughout the experiment in both groups of rams, being higher after the infusions (P < 0.001). However, the mean GH concentration and GH pulse amplitude noted after PRL infusion were significantly lower (P < 0.001 and P < 0.05, respectively) from those recorded in the control. The continued fall in PRL secretion observed in rams following PRL infusion (P < 0.05 to P < 0.001) indicates a high degree of effectiveness of exogenous PRL at the level of the CNS. In conclusion, maintenance of an elevated PRL concentration within the CNS leads to disturbances in the neuroendocrine mechanisms responsible for pulsatile LH and GH secretion in sexually active rams.     

In vivo and in vitro effect of naloxone on prolactin response to TRH in rat

In adult male Wistar rats submitted to a standardized noise stress, intravenous TRH induced a prolactin (PRL) secretory response. Prior IV naloxone administration not only lowered plasma PRL levels in those stressed rats but abolished also the stimulatory action of TRH. This effect was further studied by superfusion experiments on enriched PRL cell suspensions (70% lactotrophs) from female adult Wistar rats. Naloxone kept unaffected the basal PRL secretion but lowered significantly that induced by TRH. These experiments suggest a dual effect of naloxone on rat PRL secretion, one exerted on central opioid receptors lowering stress-related increased basal PRL levels, the other inhibiting the TRH-dependent PRL secretion exerted at the lactotroph level itself.     

Significant qualitative differences exist between thyrotropin and prolactin secretory dynamics induced by pituitary cell swelling

Cell swelling produced by a variety of techniques is a potent stimulus intensity-related inducer of an immediate secretory burst of thyroid-stimulating hormone (TSH) and prolaction (PRL) secretion from anterior pituitary cells. A 2-min "square wave" exposure to either hyposmolarity or isotonic urea induced stimulus intensity-correlated TSH and PRL secretory bursts peaking within 3 min, but the PRL zenith occurred 1 min later than that of TSH. With continuous exposure to these stimuli, TSH secretion rapidly decreased and remained only slightly above the unstimulated rate after 5 min. PRL secretion fell to and remained below the unstimulated level after 10 min. After stopping the stimulus, another secretory burst ("off" response) occurred with PRL, but not with TSH. A progressive "ramp" increase in stimulus intensity over 18 min induced a corresponding gradual increase in TSH secretion; there was a progressive depression, rather than increase, in PRL secretion during the stimulus ramp, with an off response secretory burst when the stimulus was discontinued. Removal of extracellular Ca2+ or addition of verapamil to the medium did not alter the dynamics of hyposmolarity-induced TSH secretion, but markedly altered those of PRL secretion; there was no off response PRL secretion and a hyposmolar ramp induced a corresponding gradual increase in PRL secretion, with a return to baseline after removing the stimulus. The dramatic qualitative differences in the response of the thyrotroph and lactotroph may reflect differences between the cell types in the size of secretory vesicles, membrane potential, the mechanism of exocytosis, and/or the role of Ca2+ influx across the plasmalemma.