High Prolactin Secretion Research Articles

Long-term outcome of multimodal therapy for giant prolactinomas.

Giant prolactinomas are rare tumors characterized by their large size, compressive symptoms, and extremely high prolactin secretion. The aim of this study is to describe our experience with a series of 16 giant prolactinomas cases in terms of clinical presentation, therapeutic decisions, and final outcomes. Retrospective analysis of adult patients diagnosed with giant prolactinomas at the endocrine departments of three university tertiary hospitals. We included 16 patients (43.7 % women); mean age at diagnosis: 42.1 ± 21 years. The most frequent presentation was compressive symptoms. The delay in diagnosis was higher in women (median of 150 months vs. 12 in men; p = 0.09). The mean maximum tumor diameter at diagnosis was 56.9 ± 15.5 mm, and mean prolactin levels were 10,995.9 ± 12,157.8 ng/mL. Dopamine agonists were the first-line treatment in 11 patients (mean maximum dose: 3.9 ± 3.2 mg/week). Surgery was the initial treatment in five patients and the second-line treatment in six. Radiotherapy was used in four cases. All patients but one, are still with dopamine agonists. After a mean follow-up of 9 years, prolactin normalized in 7/16 patients (43.7 %) and 13 patients (81 %) reached prolactin levels lower than twice the upper limit of normal. Mean prolactin level at last visit: 79.5 ± 143 ng/mL. Tumor volume was decreased by 93.8 ± 11.3 %, and final maximum tumor diameter was 18.4 ± 18.8 mm. Three patients are actually tumor free. Giant prolactinomas are characterized by a large tumor volume and extreme prolactin hypersecretion. Multimodal treatment is frequently required to obtain biochemical and tumor control.

Prolactin Regulates Kisspeptin Neurons in the Arcuate Nucleus to Suppress LH Secretion in Female Rats

Prolactin (PRL) is known to suppress LH secretion. Kisspeptin neurons regulate LH secretion and express PRL receptors. We investigated whether PRL acts on kisspeptin neurons to suppress LH secretion in lactating (Lac) and virgin rats. Lac rats displayed high PRL secretion and reduced plasma LH and kisspeptin immunoreactivity in the arcuate nucleus (ARC). Bromocriptine-induced PRL blockade significantly increased ARC kisspeptin and plasma LH levels in Lac rats but did not restore them to the levels of non-Lac rats. Bromocriptine effects were prevented by the coadministration of ovine PRL (oPRL). Virgin ovariectomized (OVX) rats treated with either systemic or intracerebroventricular oPRL displayed reduction of kisspeptin expression in the ARC and plasma LH levels, and these effects were comparable with those of estradiol treatment in OVX rats. Conversely, estradiol-treated OVX rats displayed increased kisspeptin immunoreactivity in the anteroventral periventricular nucleus, whereas oPRL had no effect in this brain area. The expression of phosphorylated signal transducer and activator of transcription 5 was used to determine whether kisspeptin neurons in the ARC were responsive to PRL. Accordingly, intracerebroventricular oPRL induced expression of phosphorylated signal transducer and activator of transcription 5 in the great majority of ARC kisspeptin neurons in virgin and Lac rats. We provide here evidence that PRL acts on ARC neurons to inhibit kisspeptin expression in female rats. During lactation, PRL contributes to the inhibition of ARC kisspeptin. In OVX rats, high PRL levels suppress kisspeptin expression and reduce LH release. These findings suggest a pathway through which hyperprolactinemia may inhibit LH secretion and thereby cause infertility.

Hyperprolactinemia is not associated with hyperestrogenism in noncycling African elephants (Loxodonta africana)

African elephants in US zoos are not reproducing at replacement levels. This is in part due to physiological problems, one of which is abnormal ovarian cyclicity that has been linked to increased prolactin secretion (hyperprolactinemia). A relationship between increased estrogen production (hyperestrogenism) and hyperprolactinemia has been found in other species. Therefore, the objective of this study was to determine if elevated prolactin was associated with increased estrogen concentrations in non-cycling African elephants. In cycling elephants (n=12), prolactin secretion followed a normal cyclic pattern, with higher concentrations observed during the follicular phase; overall mean concentration was ∼18ng/ml and baseline prolactin was ∼6ng/ml. Non-cycling females (n=18) were categorized into three groups: (1) low prolactin (<15ng/ml; n=3); (2) moderate hyperprolactinemia (16–30ng/ml; n=7); and marked hyperprolactinemia (>31ng/ml; n=8). Mean urinary estrogen conjugate concentrations ranged from 5.4 to 41.4ng/mg Crt, and were similar between normal cycling (15.4±1.5ng/mg Crt) and non-cycling, low prolactin elephants (18.4±7.3ng/mg Crt), but were lower in moderate (9.4±1.3ng/mg Crt) and marked hyperprolactinemic (9.8±1.1ng/mg Crt) groups (P<0.05). In conclusion, African elephants appear to be sensitive to alterations in prolactin production, with both low (e.g., a non-cycling pattern) and high prolactin secretion being associated with abnormal ovarian activity. However, hyperestrogenism was not related to hyperprolactinemia in the non-cycling females.

Changes in endocrine profiles during ovsynch and ovsynch plus norprolac treatment in Murrah buffalo heifers at hot summer season

The aim of this study was to compare the changes in hormonal profiles during ovsynch and ovsynch plus norprolac treatment in Murrah buffalo heifers following timed artificial insemination (TAI) at stressful summer months, through intensive endocrine analysis. The norprolac (an anti-prolactin drug) at the dose rate of 10.0 mg/animal /day effectively suppressed the level of prolactin upto 30 hours. The hormones quantified in blood plasma samples collected before, during and after ovsynch and ovsynch plus norprolac treatment were LH, prolactin, progesterone, estradiol-17beta and total estrogens. The plasma prolactin and progesterone concentrations were negatively correlated (r = - 0.24) during summer estrous cycle, which indicated prolactin-induced suppression of progesterone secretion through poor luteal development. The ovsynch treatment reduced the incidence of anestrous from 45% before treatment to only 18% after treatment. The norprolac induced prolactin suppression improved the efficiency of ovsynch treatment upto 100% cyclicity after treatment in comparison to 36% acyclicity before treatment. In both the treatments 45% and 55% of animal became pregnant after TAI, respectively. The high prolactin secretion contributed to poor fertility by lowering gonadal hormones (estradiol-17beta, total estrogens and progesterone) production in summer months. This finding of endocrine changes suggests that ovsynch protocol for estrus synchronization has potential application for improvement of fertility in repeat breeding buffaloes even during extreme summer months through suppression of prolactin secretion.

Seasonal variation and circadian rhythmicity of the prolactin profile during the summer months in repeat-breeding Murrah buffalo heifers

The present study was undertaken to determine a detailed endocrine profile for prolactin and progesterone during the oestrous cycle in repeat-breeding Murrah buffalo heifers during summer and winter. Hormone concentrations were quantified in blood plasma samples collected over the oestrous cycle in both winter and summer, as well as in samples collected during the summer months to observe circadian rhythmicity. The mean plasma prolactin concentration during the winter months ranged from 3.10 +/- 0.48 to 9.17 +/- 1.39 ng mL(-1); during the summer months, plasma prolactin concentrations ranged from 248.50 +/- 16.03 to 369.63 +/- 25.13 ng mL(-1). During the winter months, the mean plasma progesterone concentration ranged from 0.20 +/- 0.00 to 3.04 +/- 0.34 ng mL(-1), which was significantly higher (P < 0.01) than the prolactin concentrations recorded in the summer months (range 0.20 +/- 0.00 to 1.48 +/- 0.13 ng mL(-1)). Plasma prolactin and progesterone concentrations were negatively correlated (r = -0.24) during the summer oestrous cycle, which indicates prolactin-induced suppression of progesterone secretion through poor luteal development. During the summer, a circadian rhythmicity was observed in buffaloes and the results indicate that high prolactin secretion contributes to poor fertility by lowering gonadal hormone (progesterone) secretion. It was concluded from the present study that prolactin and progesterone profiles during the summer and winter months are directly correlated with the reproductive performance of buffaloes. The finding also validates the hypothesis that hyperprolactinaemia may cause acyclicity/infertility in buffaloes during the summer months due to severe heat stress.

Cardiorespiratory and thermoregulatory effects of endophyte-infected fescue in exercising horses

Prolactin is a hormone with diverse biological effects in various species. The secretion of prolactin in horses is affected by season, thyrotropin-releasing hormone, dopaminergic and antidopaminergic agents, exercise and stressful stimuli, meal feeding, estrogen treatment, and antiopioidergic agents. The need of prolactin for mammary growth and lactation in mares has been elucidated from research on endophyte-infected fescue grazing and its associated problems in late gestation. This has led to the development of treatments for fescue toxicity and protocols for inducing lactation in nonpregnant mares. Treatment with prolactin has demonstrated that it is involved with the shedding of the winter coat in spring (increasing concentrations) and likely with the growth of the winter coat in the fall (decreasing concentrations). Prolactin secretion is highly correlated with the photoperiod and is low in winter and high in summer. The coincidence of rising prolactin concentrations in blood with the onset of ovarian activity during the spring transition period in mares led to research showing that prolactin treatment, or inducement of high prolactin secretion by means of antidopaminergic agents, in winter can induce ovarian activity and ovulation in seasonally anovulatory mares. The combination of a small amount of estrogen in addition to an antidopaminergic agent has been shown to produce a synergy resulting in very high prolactin concentrations in blood. The results of 39 years of research on equine prolactin illustrate nicely how the gradual accumulation of knowledge derived from basic research questions can generate applied solutions to real-world problems.

Effect of Seasonal Changes in Daylength on Human Neuroendocrine Function

The circadian pacemaker imposes stereotypic patterns of daily variation on the activity of human neuroendocrine systems. In a number of cases, these patterns exhibit waveforms that are characterized by distinct diurnal and nocturnal periods with relatively discrete transitions between them (corresponding to a biological day, a biological dusk, a biological night, and a biological dawn). In humans, for example, diurnal periods of absence of melatonin secretion, low prolactin secretion, and falling levels of cortisol alternate with nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol. In response to light, the circadian pacemaker synchronizes the timing of the biological day and night so that their timing and duration are appropriately matched with the timing and duration of the solar day and night. As the pacemaker carries out this function, it is able to adjust the duration of the biological day and night to match seasonal variation in the duration of the solar day and night. Thus, after humans have been chronically exposed to long nights (scotoperiods), the duration of nocturnal periods of active melatonin secretion, high prolactin secretion and rising levels of cortisol is longer than it is after they have been chronically exposed to short nights. Furthermore, the sleep-related peak of growth hormone secretion is half as high after exposure to long nights as it is after exposure to short nights. These responses to seasonal changes in duration of the natural scotoperiod are suppressed in most individuals – especially men – who live in modern urban environments in which they are exposed to artificial light after dark and artificial darkness during the daytime.

Role of high prolactin secretion in development of postmenopausal osteoporosis verified with dexa

Role of high prolactin secretion in development of postmenopausal osteoporosis verified with dexa

Conservation of photoperiod-responsive mechanisms in humans.

In animals, circadian pacemakers respond to seasonal changes in day length by making corresponding adjustments in the durations of diurnal and nocturnal periods of circadian rhythms; these adjustments mediate effects of photoperiod on breeding and other seasonally recurring phenomena. Little is known about photoperiod responses of human circadian pacemakers. To investigate this question, we recorded and compared circadian rhythm profiles of 15 individuals after chronic exposures to short (8 h) and long (14 h) nights. As occurs in animals, durations of nocturnal periods of active melatonin secretion (11.9 +/- 1.6 vs. 10.3 +/- 1.3 h, df = 14, t = 4.583, P < 0.0005, paired t test), high prolactin secretion (12.9 +/- 2.1 vs. 9.9 +/- 2.2 h, df = 11, t = 2.917, P < 0.01), and sleep (10.6 +/- 0.8 vs. 7.6 +/- 0.4 h, df = 14, t = 17.122, P < 0.0005) were longer after exposure to long nights than after short ones. Durations of nocturnal periods of low rectal temperature (11.6 +/- 2.3 vs. 9.5 +/- 1.6 h, df = 12, t = 3.912, P < 0.001) and rising cortisol secretion (10.8 +/- 1.6 vs. 9.3 +/- 1.9 h, df = 14, t = 3.130, P < 0.005) were also longer. Some of these differences persisted during 24-h periods of enforced wakefulness in constant dim light, indicating that prior exposure to the two regimes induced abiding changes in the timing of internal processes, such as circadian pacemaker oscillations, that control the durations of nocturnal and diurnal periods of the rhythms.

Stimulus requirements for prolactin and LH secretion in incubating ring doves

To study the regulation of prolactin secretion and incubation behavior during breeding, stimuli available during the prehatching period were manipulated, and plasma prolactin and LH and pituitary prolactin concentrations were assayed. Four groups were compared: (a) nest and eggs removed (b) eggs replaced with infertile eggs, (c) eggs replaced with infertile eggs and partners separated, and (d) unmanipulated controls. The increase in prolactin secretion that normally occurs at the end of incubation was reversed when the nest and eggs were removed but was unaffected by the absence of the mate. Prolactin secretion was not maintained in males sitting beyond the normal incubation period (on infertile eggs), while it was maintained in females but only in the presence of the mate. In the control birds, the increase in plasma prolactin was accompanied by an increase in pituitary content; while in the manipulated groups, an inhibition of prolactin secretion was associated with a transient increase in pituitary content. Plasma LH levels were low in control birds during the time of high prolactin secretion, and in all groups where the disruption of normal breeding stimuli caused an early fall in prolactin, there was a concomitant increase in LH secretion. In animals which had been separated from their mates and provided with a nest bowl and eggs, continuous observations of incubation behavior were made and plasma was sampled every third day. Parallel changes in prolactin and sitting behavior occurred in some of the animals, while others continued to incubate after prolactin had declined. In no instance did an animal which maintained high prolactin show a decline in incubation. This suggests that prolactin can serve to maintain incubation, while incubation does not necessarily stimulate prolactin secretion at this phase of the breeding cycle.

Gynaecological importance of unusual pituitary tumours.

Sixty-eight women with pituitary tumours exhibiting gynaecological symptoms have been reviewed. Fifty-two tumours were prolactinomas while 6 were growth hormone secreting, 6 ACTH secreting, 1 was a large 'inert' adenoma and 3 were late-presenting craniopharyngiomas. Several of the prolactinomas exhibited unusual features including excessively high prolactin secretion, a wide spectrum of sensitivity to bromocriptine, rapid expansion in pregnancy, association with the empty sella syndrome and even a secondary malignancy. The behaviour of tumours secreting other hormones but presenting with gynaecological symptoms is described.

The effects of modifying incubation on prolactin secretion in free-living pied flycatchers

Plasma prolactin concentrations in female pied flycatchers are high during incubation, but fall from 156 ± 27 to 67 ± 6 ng/ml ( P < 0.01) between 2 and 4 days after the young hatch. The timing of the fall in prolactin could be determined by factors associated with the hatching of the eggs and growth of the offspring; alternatively, prolactin may remain high for a fixed period (16 days) after the onset of incubation. To distinguish between these possibilities, eggs were exchanged between nest boxes to ensure incubation periods of either 10, 14, or 19 days by different females. The results showed that the period of high prolactin secretion was shortened by 2–4 days where the eggs hatched early, but, conversely, was not lengthened in those females with extended incubation periods, the levels actually falling in these birds before the eggs hatched. There was, however, a secondary rise in prolactin 3 days after hatching, when the level of 114 ± 11 ng/ml 22 days after the onset of incubation was much higher than that (30 ± 4 ng/ml) at a comparable stage in the control females. Thus, high prolactin secretion cannot be maintained for longer than 16–17 days in incubating birds, but newly hatched, naked young can stimulate prolactin release in female flycatchers over a flexible period.

Dopaminergic neuronal function, anterior pituitary dopamine content, and serum concentrations of prolactin, luteinizing hormone and progesterone in the aged female rat

The serum concentrations of prolactin (PRL), progesterone and luteinizing hormone (LH), and the content and rate of synthesis of dopamine (DA) in selected brain regions were determined in young (3–6 months), intermediate (13–15 months) and aged (24–25 months) female Long-Evans rats. Young rats were examined on the days of diestrus 2 and estrus. Intermediate rats were divided into 2 groups, a group which was cycling regularly (examined on the day of estrus) and a group which exhibited constant estrus. Aged rats were divided into 3 groups one which cycled regularly (examined on day of estrus), one which exhibited constant estrus, and one which exhibited repetitive pseudopregnancies. Serum PRL was increased in all intermediate and aged rats when compared to values in young animals. Serum LH was increased and progesterone decreased in those intermediate and aged rats which exhibited constant estrous reproductive patterns. The DA content was generally decreased in the median eminence, posterior pituitary, striatum, nucleus accumbens and olfactory tubercle of all aged rats, while the rate of DA synthesis was decreased only in the median eminence of aged, non-cycling rats. This suggests that all DA neuronal systems except those in the tuberoinfundibular system are able to compensate for the age-related loss. Despite the apparent reduction of tuberinfundibular DA neuronal function the concentration of DA in the anterior pituitary, which is believed to represent amine released from the neurons, is dramatically increased in intermediate age rats in constant estrus, and in all groups of aged rats. The maintenance of high PRL secretion despite the elevated content of DA in the anterior pituitary suggests in age-related defect in the dynamics of DA in this gland; this defect may contribute to the loss of reproductive function in the aging rat.

Effect of ambient osmolarity and calcium on prolactin cell activity and osmotic water permeability of the gills in the teleost Sarotherodon mossambicus

In the presence of low ambient calcium levels, prolactin cell activity is directly related to the height of the osmotic gradient between blood plasma and external medium, and not to ambient osmolarity. Prolactin cell activity is minimal in fish adapted to iso-osmotic saline. The osmotic water permeability of the gills is inversely related to the height of the osmotic gradient and to prolactin cell activity. In gills of fish from iso-osmotic saline the osmotic water permeability is maximal. This high permeability is reduced after injection of ovine prolactin. It is concluded that the rate of prolactin secretion is related directly to the rate of the osmotic water fluxes—and, possibly, passive ion fluxes—the fish are facing, irrespective of the direction of these fluxes. In the presence of high calcium levels, however, prolactin cell activity as well as osmotic water permeability of the gills were low and independent of ambient osmolarity. Prolactin injections did not influence the osmotic water permeability of gills from high-calcium-adapted fish. High prolactin secretion in freshwater-adapted fish is likely due to the presence of low environmental calcium levels and a high osmotic gradient between blood and environment. Low prolactin secretion in seawater fish—fish that are facing an even higher osmotic gradient—is probably caused by the high ambient calcium and magnesium levels, which may make prolactin superfluous for the control of the osmotic water permeability.

Effects of prolactin and ergot alkaloids on the tubero-infundibular dopamine (DA) neurons.

Using the Falck-Hillarp fluorescence technique, the effect of various hypophyseal hormones on the rate of depletion of catecholamines (CA) from certain central neuron systems was investigated in the rat, after inhibition of CA synthesis. Prolactin, but not LH, FSH, ACTH, or vasopressin, caused a dose-dependent increase in the turnover of dopamine (DA) in nerve terminals of the external layer of the median eminence. The effects were marked in hypophysectomized males and females, with or without castration, and less marked in castrated males and females and in normal males. In normally cycling females, prolactin caused a blockade of the cyclic changes in activity in the tubero-infundibular DA neurons, resulting in constant high turnover as is found in diestrus. Prolactin had no effects on the ascending noradrenaline (NA) neurons terminating in the hypothalamus or on the nigro-neostriatal DA neurons. During lactation, an endocrinological state with high prolactin secretion, the DA turnover in the external layer of the median eminence is very high. Both this increase in DA turnover and the increase found during pregnancy were reduced by hypophysectomy or by administration of ergocornine methanesulfonate (ECO-580) and 2-Br-α-ergokryptine methanesulfonate (CB-154), two drugs that probably decrease prolactin secretion from the anterior pituitary. The present results suggest that the tubero-infundibular DA neurons are part of a feedback system involved in the regulation of prolactin secretion from the anterior pituitary. The hypothesis is forwarded that one of the functions of the tubero-infundibular DA neurons is to stimulate the secretion of PIF at the level of the median eminence, and thus to exert an inhibitory effect on prolactin release. Previous studies have indicated a role of the tubero-infundibular DA neurons in the regulation of FSHRF-LHRF release. This complex role of the DA neurons is discussed.