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A 54-year-old woman with hyperprolactinemia and amenorrhea that occurred with phenothiazine and tricyclic antidepressant use developed a stage IBG2 endometrial adenocarcinoma. This is believed to be the first case reported of endometrial carcinoma associated with drug-induced hyperprolactinemia.
I have reported the case of a woman with Sheehan's syndrome who had hyperprolactinemia rather than prolactin deficiency. The patient showed no increase in serum thyrotropin in response to TRH challenge and failed to show a normal increase in serum GH and cortisol after insulin-induced hypoglycemia. A blunted FSH response to LH-RH stimulation was also found. A CT scan of the sella showed no adenoma. The patient responded to prednisolone and thyroxine replacement therapy. When, a few months later, the dose of thyroxine was reduced to a suboptimal level, the hyperprolactinemia recurred.
Elevated blood levels of prolactin increase the synthesis, turnover, and release of 3,4-dihydroxyphenylethylamine (dopamine) from the tuberoinfundibular dopaminergic neurons, which project to the median eminence. The present study examined whether hyperprolactinemia also increases local cerebral glucose utilization, as determined by the 2-deoxy-D-[1-14C]glucose method, in the median eminence and other brain structures. Adult male rats were given ovine prolactin (4 mg/kg) subcutaneously every 8 h for 48 h. This treatment exerted an autoregulatory feedback effect on endogenous rat prolactin secretion, as evidenced by decreased circulating levels of rat prolactin. Ovine prolactin treatment also decreased plasma glucose concentrations. However, in both partially immobilized and free-ranging rats, glucose utilization in brain structures containing tuberoinfundibular dopaminergic cell bodies (the arcuate nucleus) and terminals (the median eminence) was not affected by ovine prolactin treatment. Hyperprolactinemia was, however, associated with decreased glucose utilization in the medial forebrain bundle and the CA subfield of the dorsal hippocampus. The lack of a significant effect of prolactin treatment on glucose utilization in the median eminence indicates that the resolution of the deoxyglucose technique, as used here, is not adequate to detect the ovine prolactin-induced increase in tuberoinfundibular dopaminergic neuronal activity, that the median eminence does not utilize glucose as its primary energy substrate, or that ovine prolactin treatment causes a counterbalancing decrease in the activity of other neurons projecting to the median eminence.
Information about the effects of pituitary hyperprolactinemia on endometrium, especially in levels coexisting with absence of amenorrhea in women, is scarce. The interference of high prolactin levels on endometrial morphology was thus investigated in young post-pubertal and adult mice rendered hyperprolactinemic by long-term treatment with metoclopramide (MC). No remarkable differences have been noticed upon light microscopy examination of the endometria comparing young to adult cycling MC-treated mice, except on the max/min diameter ratio, which in young animals was lower than in adults (ANOVA, p < 0.01). Both young and adult MC-treated mice presented an increased number of endometrial glands than their respective controls (ANOVA, p < 0.01). However, young MC-treated animals showed the highest values of endometrial thickness index compared to other groups (ANOVA, p < 0.01). Our results indicate that MC-induced hyperprolactinemia causes mouse endometrium proliferation, mainly in young animals.
Therapeutic doses of phenothiazines increased serum levels of prolactin, resulting in a number of side effects. Bromocriptine, a potent dopamine agonist, appears to effectively reduce the serum prolactin level. In this open pilot study, bromocriptine mesylate (Parlodel, Sandoz) was administered in an escalating dose schedule to 11 stabilized psychiatric outpatients with hyperprolactinemia resulting from thioridazine HCl (Mellaril, Sandoz) treatment. 6 of 9 patients showed decreases. Overall global psychiatric evaluations were unchanged over the course of combined therapy for all but 1 patient, who showed improvement. The trend of decreased prolactin serum levels indicates that bromocriptine mesylate may prove a useful adjunct to reduce the side effects of hyperprolactinemia.
Studies were conducted to determine if the inhibitory effects of chronic hyperprolactinemia on sexual behavior in male rats occur through reduced sexual arousal as opposed to reduced erectile function. Pituitary-grafted (hyperprolactinemic) and sham-operated, gonadally intact male rats were given standard tests of copulatory behavior, mounting behavior tests after genital anesthetization and penile reflex tests while restrained in a supine position. Beginning 7 days after pituitary transplantation, the number of erections displayed in penile reflex tests was significantly reduced in the pituitary-grafted animals. Increased intromission latencies and reduced intromission rates in tests of copulatory behavior were also observed at this time. Beginning 3-4 weeks after surgery, mounting rates were inhibited in hyperprolactinemic animals in both the copulatory behavior tests and tests of mounting behavior after genital anesthetization. Prolactin levels were significantly elevated in the pituitary-grafted animals, but serum testosterone levels were unaffected. To determine if the effects of hyperprolactinemia on erectile function occurred through changes in supraspinal input to neurons in the spinal cord controlling erectile function, pituitary-grafted and sham-operated male rats were subjected to spinal transection (between vertebral levels T6 and T9). Beginning 7 days later, penile reflex performance was re-examined. Hyperprolactinemic animals displayed significantly fewer erections during the initial test, but not in tests performed 10 and 13 days after spinal transection. The pituitary-grafted animals also showed a significant reduction in latency to the first erection with each successive test, suggesting a delayed recovery from increased supraspinal inhibitory input.(ABSTRACT TRUNCATED AT 250 WORDS)
Prolactin-secreting pituitary tumors can be induced in young rats through prolonged estrogen treatment. Recent evidence suggests that such tumors are associated with a degeneration of tuberoinfundibular dopaminergic (TI-DA) neurons, which normally inhibit prolactin secretion by the anterior pituitary's lactrophs. For this study, chronic hyperprolactinemia was induced in young, ovariectomized Fisher 344 rats through Silastic capsule implants of 17 beta-estradiol, placed subcutaneously for 1 month prior to removal. Rats with such estrogen-induced hyperprolactinemia then received transplants of neonatal arcuate-median eminence (ME) tissue (containing TI-DA neurons) or amygdala (control) tissue, placed either within the third ventricle or bilaterally within the hypothalamus. Blood samples were obtained 1 month after transplantation and prolactin concentrations measured by radioimmunoassay. Two of 4 animals receiving ventricularly-placed arcuate-ME transplants and 4 of 7 animals receiving bilateral arcuate-ME transplants showed substantial reductions in plasma prolactin levels compared to mean values in control animals. Follow-up catecholamine (CA) histochemistry indicated a bright fluorescence intensity in the median eminence of animals remaining hyperprolactinemic with ineffective transplants. Furthermore, in sharp contrast to the very low, nonpulsatile LH levels found during a second bleeding in recipients bearing ineffective transplants, recipients with effective arcuate-ME transplants had the high, pulsatile levels of LH characteristic of normal, ovariectomized rats. These data suggest that developing TI-DA neurons, within effective arcuate-ME transplants, became functional to reinstate or accentuate DA inhibition of prolactin secretion and, in so doing, indirectly normalized LH secretion as well.
Hyperprolactinemia adversely affects reproductive functions, presumably through an effect at the hypothalamic level. Given the numerous published reports linking hypothalamic serotonin (5-hydroxytryptamine, 5HT) mechanisms to the regulation of gonadotrophin secretion, we sought to determine the effects of experimentally induced hyperprolactinemia on ovarian steroid-induced increases in serum LH levels and region-specific hypothalamic 5HT synthesis in ovariectomized rats. In the first study, bilaterally ovariectomized Sprague-Dawley rats either received two pituitary homografts implanted beneath the left kidney capsule or were sham-grafted. Both groups of rats were injected subcutaneously with 5 micrograms/100 g of estradiol benzoate (E2) in corn oil vehicle at 08.00 h, 1 and 2 days before serum collection and 5 mg/100 g of progesterone (P) in corn oil vehicle at 07.00 h on the day of serum collection. Blood samples were collected via chronic indwelling jugular cannulae from each rat at 10.00, 12.00, 13.00, 14.00, 16.00 and 18.00 h. A statistically significant elevation in serum LH levels was detected at 13.00, 14.00 and 16.00 h. This increase in serum LH levels was significantly attenuated in rats bearing pituitary homografts, an effect attributed to the high serum PRL levels measured in these animals. In the second study, bilaterally ovariectomized Sprague-Dawley rats were divided into three experimental groups: (1) rats bearing two pituitary homografts and injected with E2 and P on the schedule and at the dosages previously described, (2) sham-grafted rats injected with E2 and P on the schedule and at dosages previously described and (3) sham-grafted rats injected with corn oil vehicle only.(ABSTRACT TRUNCATED AT 250 WORDS)
An increase in plasma luteinizing hormone levels which occurs in the male rat in response to the presence of a receptive female was associated with increased norepinephrine metabolism in several regions of the hypothalamus and reduced norepinephrine metabolism in preoptic area and olfactory bulbs. Hyperprolactinemia induced by grafting three anterior pituitary glands beneath the kidney capsule blocked female-induced changes in norepinephrine metabolism and attenuated the increase in luteinizing hormone release. These results suggest that endocrine and behavioral responses of male rats to the presence of a female are mediated by changes in catecholamine metabolism in several brain regions. The ability of hyperprolactinemia to induce deficits in male sexual behavior may be due to the blockade of these CNS responses to exteroceptive stimuli originating from the female.
The hypothesis was tested that corticotropin-releasing factor (CRF) is involved in the inhibition of gonadotropin secretion during chronic hyperprolactinemia. Two models of hyperprolactinemia were used, namely inoculation with the prolactin (PRL)-secreting tumor 7315b and implantation of isogenic pituitary glands. Gonadectomized, adrenalectomized male rats received a testosterone capsule and a corticosterone pellet and were inoculated subcutaneously with tumor 7315b. Similar rats without tumor served as controls. The rats were studied 3-4 weeks later while anesthetized with urethane. Plasma testosterone and corticosterone were similar in the two groups of rats. Compared to controls, the tumor-bearing rats had significantly higher plasma levels of PRL (100-fold increase) and adrenocorticotropin (ACTH; 3-fold increase), whereas plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) had significantly decreased to 15 and 40%, respectively. CRF release into hypophysial stalk plasma was higher in rats with tumor 7315b than in controls (298 +/- 23 vs. 197 +/- 28 pg/h), and hypothalamic CRF content had increased from 3.0 +/- 0.3 to 4.3 +/- 0.3 ng. Male rats received 3 pituitary glands under the kidney capsule. Sham-operated rats served as controls. They were studied 5-7 weeks later while anesthetized with urethane. Compared to controls, pituitary-grafted rats had larger adrenals (49 +/- 4 vs. 34 +/- 2 mg), higher plasma PRL (156 +/- 18 vs. 52 +/- 8 ng/ml), ACTH (0.46 +/- 0.05 vs. 0.22 +/- 0.02 ng/ml) and corticosterone (455 +/- 39 vs. 268 +/- 14 ng/ml), and lower plasma levels of LH (21 +/- 2 vs. 41 +/- 6 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
Since high concentrations of prolactin (PRL) enhance the hypothalamic release of corticotropin-releasing factor (CRF), and CRF decreases the hypothalamic secretion of luteinizing hormone (LH)-releasing hormone (LHRH), it could be that CRF is involved in the suppressed secretion of LH during hyperprolactinemia. The aim of this study was to explore this possibility in hyperprolactinemic male rats. Hyperprolactinemia, induced by insertion of 3 pituitary glands under the kidney capsule, decreased plasma LH levels by 68% and caused a 2-fold increase in plasma corticosterone. Intracisternal administration of the CRF antagonist alpha-helical CRF(9-41) induced both in pituitary-grafted rats and in normoprolactinemic controls a 2 to 3-fold increase of LH in the plasma sample taken 1 h after injection of alpha-helical CRF(9-41). Plasma levels of LH in pituitary-grafted rats were 2-3 times higher during intracerebroventricular infusion for 7 days with CRF antiserum than during saline infusion. Furthermore, after infusion of CRF antiserum for 7 days into the lateral brain ventricle plasma LH levels had increased by 270% in normoprolactinemic male rats. These results indicate that hypothalamic CRF is involved in the control of LH release in male rats. To further investigate whether CRF is involved in the effect of PRL on LH secretion, we infused PRL, alone or together with CRF antiserum, for 7 days into the lateral brain ventricle of normoprolactinemic male rats. After 7 days of PRL infusion, LH levels had decreased by 45%, whereas plasma corticosterone was 150% higher. This action of PRL on LH and corticosterone was prevented when besides PRL also CRF antiserum was infused.(ABSTRACT TRUNCATED AT 250 WORDS)
Progressively increasing plasma prolactin (PRL) concentrations are currently associated with menstrual disturbances, anovulation and cessation of cyclic activity. Galactorrhea-amenorrhea in the presence of normal plasma PRL is rare, but the favorable response to bromocriptine confirms its lactogen dependency. The concept of "transient hyperprolactinemia' is analyzed and alternative explanations for the positive results of dopamine agonist therapy in this particular condition are proposed. Moderate hyperprolactinemia can be associated with luteal inadequacy and infertility. Inhibition of PRL secretion with bromocriptine can normalize luteal function and restore the ability to conceive.
A 21-year-old goitrous hypothyroid Chinese woman had elevated serum iodotyrosines with a monoiodotyrosine level of 85.9 nmol/l (normal 0.49-0.89 nmol/l) and a diiodotyrosine level of 25.3 nmol/l (normal 0.023-0.53 nmol/l). She was amenorrheic with low luteinizing hormone and follicle-stimulating hormone levels at 5.8 and 2.8 U/l, respectively. The hypogonadotropic hypogonadism was due to an elevated prolactin level of 8.8 nmol/l. She also had a low potassium level of 3.2 mmol/l, and a high urinary aldosterone level of 158 nmol/day. The hyperprolactinemia, hypogonadotropic hypogonadism, hyperaldosteronism and hypokalemia subsided with the administration of bromocriptine 5 mg/day. However, bromocriptine accentuated the hyperiodotyrosinemia, and the patient remained hypothyroid. Levothyroxine therapy lowered the monoiodotyrosine and diiodotyrosine levels, ameliorated all her endocrinopathies, started her periods, and shrank the goiter. She probably had a deiodinase defect which permitted the discharge of accumulated iodotyrosines from the thyroid gland. Since iodotyrosines are tyrosine hydroxylase inhibitors, the hyperiodotyrosinemia causes dopamine synthesis inhibition, and induces the hyperprolactinemia and hyperaldosteronism.
In order to investigate the possible relationship of hyperprolactinemia to psychological distress in patients undergoing chronic hemodialysis, 19 uremic women were evaluated by a semistructured interview and administered the Kellner Symptom Questionnaire. Group A (10 uremic women with hyperprolactinemia) did not differ significantly in anxiety, depression, somatization and hostility from group B (9 normoprolactinemic uremic women). Both groups rated themselves more depressed and hostile than a normal control group of 10 women, and hyperprolactinemic patients were also significantly more anxious than the normal controls.
Six women with primary hyperprolactinemia (mean prolactin level, 50 ng/ml) were matched with six normal women on eight factors influencing life style. Observers blind to endocrine status followed the subjects weekly for 10 weeks. Patients took bromocriptine, 2.5 mg twice daily, or placebo in a randomized double-blind sequence with crossover at 5 weeks. The mean Hamilton score for the patients was compatible with mild depression and higher than that for normal subjects during placebo but not during bromocriptine treatment. Libido was similar in both groups during placebo and bromocriptine. The mean number of orgasms reported per day was lower in patients than in normal subjects during both treatment conditions, although one patient reported orgasms during drug treatment only. Hyperprolactinemia in women may be associated with mild depression and a decrease in orgasmic frequency.
BACKGROUND: The effects of ovarian drilling on the serum levels of gonadotropins and androgens have been studied previously. The aim of this study is to evaluate the effects of ovarian drilling on the serum prolactin levels and its relation to ovulation in women with polycystic ovary syndrome. METHODS: This is a prospective controlled study. Thirty-six women with PCOS underwent ovarian electrocauterization in university hospitals. Control group consisted of 35 ovulatory women with unexplained infertility. Hormonal assessment performed in early follicular phase of spontaneous or induced cycle before operation in the two groups and repeated one week after operation. Hormonal assay was also performed in the early follicular phase of the first post-operative menstruation, folliculometry and progesterone assay were also performed in the same cycle. Data were analyzed by "repeated measurement design, discriminant analysis, correlation coefficient, and Fisher exact test". RESULTS: Six to ten weeks after operation the serum mean +/- SD prolactin levels increased from 284.41 +/- 114.32 mIU/ml to 354.06 +/- 204.42 mIU/ml (P = 0.011). The same values for the control group were 277.73 +/- 114.65 to 277.4 +/- 111.4 (P = 0.981) respectively. Approximately 45% of subjects in PCOS group remained anovulatory in spite of decreased level of LH and testosterone. Prolactin level remained elevated in 73.2% of women who did not ovulate 6-10 weeks after the procedure. CONCLUSION: Hyperprolactinemia after ovarian cauterization may be considered as a possible cause of anovulation in women with polycystic ovaries and improved gonadotropin and androgen levels. The cause of hyperprolactinemia is unknown. Hormonal assay particularly PRL in anovulatory patients after ovarian cauterization is recommended.
The objective of this study was to determine the diagnostic performance of the percentage of serum prolactin (PRL) precipitated with polyethylene glycol (PEG) for the detection of macroprolactinemia in systemic lupus erythematosus (SLE) patients with hyperprolactinemia. Serum samples from SLE patients were examined. Serum PRL was measured by immunoradiometric assay (IRMA) and samples with hyperprolactinemia (> 20 ng/ml) were submitted to PEG precipitation, gel filtration chromatography and affinity chromatography with protein-G sepharose. A comparative survey was used. Among 259 consecutive serum samples from SLE patients, PRL was > 20.1 ng/ml in 43 samples (16.6%). Gel filtration showed a predominant pattern of macroprolactinemia (> 100 kDa) in 14 (32.6%), a predominant pattern of monomeric PRL (23 kDa) in 27 (62.7%), and a variable pattern in two (4.7%). All sera with a predominant pattern of macroprolactinemia displayed anti-PRL autoantibodies by affinity chromatography for IgG. The best cut-off point for percentage of serum PRL precipitated with PEG for detection of macroprolactinemia was > or = 58.4%. Sensitivity and specificity were 100 and 96.6%, respectively. We can conclude that PEG precipitation is a convenient and simple procedure to screen for the presence of macroprolactinemia in sera from SLE patients. Precipitations > or = 58.4% are indicative of the presence of, and those < 50% the absence of, macroprolactinemia. However, samples with precipitations between 50 and 58.3% require gel filtration chromatography to characterize the predominant molecular form of PRL. Therefore, it is important to take these findings into account in future studies that aim to establish a relationship between PRL and disease activity in SLE.
The aim of the study was to evaluate the association between hyperprolactinemia and T lymphocyte activation through the soluble IL-2 receptor (sIL-2R) in systemic lupus erythematosus (SLE) patients. Seventy SLE patients, 18 of them with hyperprolactinemia (HPRL), were compared with 18 normoprolactinemic (NPRL) patients and 10 age-matched healthy blood-bank donor women. Patients were evaluated by means of the SLE activity index (SLEDAI). Total serum IgG and sIL-2R levels were determined by an ELISA assay. Differences between sIL-2R and IgG serum levels in patients and controls were examined by Kruskal-Wallis analysis and a Spearman r correlation to determine the association between sIL-2R, IgG and prolactin (PRL) levels. IgG and sIL-2R serum levels did not differ significantly between HPRL and NPRL patients: 1827.3 (1428-2226) vs 2028.8 (1586-2467) mg/dl and 882.2 (511-1254) vs 740.1 (534-946.4) U/ml, respectively (confidence interval 95%). In the total SLE group, sIL-2R and IgG serum levels were positively associated (P = 0.0009), however, this was not the case for sIL-2R and PRL (P > 0.49). We did not demonstrate an association between HPRL and lymphocyte activation measured through serum sIL-2R in female patients with SLE.