Search

Gigantomastia is characterised by excessive breast growth and can occur as a rare, drug-induced adverse event. D-penicillamine is the most frequent cause of drug-induced gigantomastia. Only one case of gigantomastia due to bucillamine, an analogue of D-penicillamine, has been reported so far. We herein report a case of bucillamine-induced gigantomastia presenting with acute enlargement of the bilateral breasts and accessory breast tissue in the axillae 7 months after the start of bucillamine therapy. Awareness about this rare adverse event is important since bucillamine is still widely used in Japan and Korea.

Pituitary adenomas are usually benign tumours arising from the hormone-secreting cells of the anterior pituitary gland, resulting in excess hormone secretion and the development of characteristic syndromes, such as Cushing’s disease, acromegaly and hyperprolactinaemia, and/or mass effects on surrounding vital structures causing for example visual disturbances and pituitary hormone deficiencies. In children and young people under 19 years (CYP), the management of pituitary adenomas is particularly challenging given their extreme rarity, more aggressive phenotype and likely genetic predisposition, as well as the lack of age- and pituitary-specific multidisciplinary teams in current decision-making and service provision. Hence, the UK sought to create national, high-quality, multi-professional guidance using AGREE II methodology under the auspices of the UK paediatric endocrine (BSPED), paediatric oncology (CCLG) and paediatric (RCPCH) societies. Twenty geographically diverse experts in adult and paediatric endocrinology, neuroradiology, clinical oncology, neurosurgery, paediatric neuropathology, and neuro-ophthalmology constituted the guideline development group and formulated 155 clinical questions. Following a systematic literature review of 409 identified papers dating from 1990 to 2016, the group made 56 evidence-based recommendations for biochemical, radiological, cytological, genetic, and ophthalmic assessment of suspected pituitary adenomas as well as surgical and oncological treatment, and follow-up. A further 55 recommendations were made based on group expert opinion and were reviewed by two rounds of an international Delphi expert consensus process. This guideline should facilitate improved clinical care and outcomes in CYP with pituitary adenomas.

BackgroundCabergoline is a dopamine agonist that may be used as primary or adjunctive therapy for acromegaly. Although one study suggested biochemical control may be achieved in a substantial proportion of patients, it is still commonly perceived to be a relatively ineffective treatment.Design and methodA prospective audit was performed of 15 consecutive acromegalic patients (eight males, seven females, median age 55, range 31–92 at presentation) treated with cabergoline to determine the effective dose and tolerability. All had normal anterior pituitary function; two patients had hyperprolactinaemia. Magnetic resonance imaging revealed nine adenomata, two partially empty sellae and four structurally normal pituitary glands. Nine patients had undergone transsphenoidal surgery 1–12 months, and one patient had received pituitary radiotherapy 18 years, prior to commencement of cabergoline. All patients had biochemical GH excess; median serum IGF1 471 ng/ml, range 239–746 ng/ml. The calculated mean of a series of GH measurements ranged from 2.7–45.8 mIU/l, median 9.7 mIU/l.ResultsOn a median weekly dose of cabergoline of 1.75 mg (range 0.5–7 mg) normalisation of both IGF1 and GH occurred in 4 out of the 15 patients (27%). Out of the 15 patients (33%), 5 achieved a serum IGF1 within the reference range with notable reductions seen in a further five patients. Nine patients (60%) achieved a mean serum GH level of less than 5 mIU/l. Duration of treatment was 2–52 months and was well tolerated in 14 patients.ConclusionCabergoline can be an effective and well tolerated primary or adjunctive therapy for acromegaly and useful clinical responses are noted even with modest doses.

BACKGROUND: the impact of hyperprolactinaemia on endometrial function, along with embryo implantation, has been the subject of discussion. This article examines whether experimental hyperprolactinaemia can affect mouse ovarian function, endometrial pinopodes and embryo implantation. METHODS: for pinopode analysis, 60 female mice were randomly divided into two groups: control (vehicle) and experimental [metoclopramide (MCP) 200 mu g per day]. Injections were given subcutaneously for 50 days, and then, normally cycling females were housed with male mice for copulation during proestrus. the animals were killed on the fifth day following coitus when the antimesometrium portions of the uterine horns were removed for endometrial analysis. Blood was collected for prolactin (PRL) determination. in the second experiment, 60 female mice were used to evaluate the ovarian function by measuring estrogen and progesterone levels and counting luteal bodies and oocytes in the oviduct and uterus during estrus. RESULTS: the highest pregnancy rates and the largest population of pinopodes were both found in the vehicle group (P < 0.01). Estrogen and progesterone levels in MCP-treated mice were lower than those in control mice (P < 0.05). Also, the number of implantations was significantly lower in the MCP-treated group compared with the vehicle group after embryo transfer (P < 0.001). CONCLUSION: PRL seems to have suppressive effects on ovarian function and the number of pinopodes; conceivably, hyperprolactinaemia has a negative effect on mouse embryo implantation. Universidade Federal de São Paulo, Dept Gynecol, São Paulo, Brazil Universidade Federal de São Paulo, Dept Morphol, São Paulo, Brazil Universidade Federal de São Paulo, CEDEME, São Paulo, Brazil Universidade Federal de São Paulo, Dept Gynecol, São Paulo, Brazil Universidade Federal de São Paulo, Dept Morphol, São Paulo, Brazil Universidade Federal de São Paulo, CEDEME, São Paulo, Brazil Web of Science

Hyperprolactinaemia is characterised by gonadal dysfunction, including infertility and reduced libido and, if left untreated, is associated with an increased risk of long-term complications, such as osteoporosis. The first-line therapy for patients with hyperprolactinaemia is pharmacological intervention with a dopamine agonist. Currently, there are three dopamine agonists available for hyperprolactinaemia therapy: bromocriptine, quinagolide and cabergoline. Bromocriptine has a long history of use; however, a range of 5–18% of patients are reported to show bromocriptine resistance, with only partial lowering of plasma prolactin levels and an absence of tumour shrinkage. The newer dopamine agonists, quinagolide and cabergoline, offer improved efficacy over bromocriptine, with a lower incidence of adverse events. Quinagolide and cabergoline have also demonstrated efficacy in many patients intolerant or resistant to bromocriptine. Thus, the selection of dopamine agonists available provides more than one option for pharmacological intervention of hyperprolactinaemia. This review discusses the clinical use of quinagolide in comparison to other dopamine agonists for hyperprolactinaemia therapy. Quinagolide may improve patient compliance to treatment owing to its reduced side effect profile, simple and rapid titration over just 7 days, once-daily dosing regimen and easy to use starter pack (available in some countries). Quinagolide offers an additional benefit for patients wishing to become pregnant, as it can be used until the point of confirmation of pregnancy. Therefore, as a well tolerated and effective therapy, with a simple dosing regimen, quinagolide should be considered as a first-line therapy in the treatment of hyperprolactinaemia.

Background Little is known about the influence of high exposure to bisphenol A on recurrent miscarriage and immunoendocrine abnormalities. Methods Serum bisphenol A, antiphospholipid antibodies (aPLs), antinuclear antibodies (ANAs), natural killer cell (NK) activity, prolactin, progesterone, thyroid-stimulating hormone (TSH) and free T4 were examined in 45 patients with a history of three or more (3-11) consecutive first-trimester miscarriages and 32 healthy women with no history of live birth and infertility. Subsequent pregnancy outcome and embryonic karyotype of abortuses were examined prospectively. Results The mean+/-SD values for bisphenol A in patients were 2.59+/-5.23 ng/ml, significantly higher than the 0.77+/-0.38 ng/ml found for control women (P=0.024). High exposure to bisphenol A was associated with the presence of ANAs but not hypothyroidism, hyperprolactinaemia, luteal phase defects, NK cell activity or aPLs. A high level of bisphenol A in itself did not predict subsequent miscarriage. Conclusion Exposure to bisphenol A is associated with recurrent miscarriage.

Clinician choice of an atypical antipsychotic may depend on a number of factors such as perceived efficacy, tolerability and cost. It is also important that the choice of treatment takes into consideration the previous response to treatment, experience of side-effects and personal clinical characteristics. The receptor-affinity profiles of the atypical antipsychotics differ; with the exception of amisulpride, a selective D2/D3 antagonist, all the atypical antipsychotics exhibit a greater affinity for the serotonin-2A receptors than dopamine receptors. However, there is no evidence that the variation in receptor affinities is relevant to efficacy. Indeed, the crucial factor may be fast dissociation from low affinity for the D2 receptor. Tolerability also varies between the atypical antipsychotics and the side-effect profile may be related to the receptor-affinity profile of the individual drugs. Extrapyramidal side-effects are generally less of a problem with most atypical drugs than with conventional drugs, but weight gain, loss of glycaemic control, sedation and hyperprolactinaemia remain problematic in some patients. Amisulpride is effective for the treatment of both positive and negative symptoms, and is well tolerated with regard to weight gain, glucose tolerance and sedation. In two clinical trials, the AMIRIS and SOLIANOL studies, amisulpride demonstrated clear advantages over some other atypical antipsychotics with respect to negative symptoms, depressive symptoms and weight gain.

BACKGROUND: Renal transplantation (RT) is the most common solid organ transplant procedure. Several studies have reported on gonadal function in male and female RT recipients with controversial results. METHODS: Forty consecutive patients (20 male, 20 female) with a fully functioning allograft (serum creatinine 0.8-1.3 mg/dl) for at least 15 months after RT were included in the study. Their ages ranged from 23 to 44 years (median 38) and their post-RT follow-up lasted 15-86 months (median 23). FSH, LH, prolactin, 17-beta-estradiol, testosterone, androstenedione and dehydroepiandrostrone were determined in all patients and compared with a group of 80 healthy subjects. Pelvic ultrasonography was performed in all participants. RESULTS: Testosterone was below the normal range in 70% of male patients and within the lowest third in the remainder; a lack of LH increase indicated an inhibition of the reproductive axis. Male testosterone values were negatively influenced by calcineurine inhibitors treatment (P < 0.005), but positively influenced by a better graft function (P < 0.0001). Testicular and prostate volumes were reduced with respect to controls, with the latter related to circulating testosterone levels. Ten of the women (50%) had menstrual cycle disorders after RT, three being affected by transient, and three by persistent, amenorrhea. Another two patients had had transient polymenorrhea. In four women (20%), a premature ovarian failure was diagnosed. No relationship was found between female reproductive function and age, graft function or duration of the post-transplant period. Prolactin was lower in patients on calcineurin inhibitors (P < 0.01). CONCLUSIONS: Abnormalities of the reproductive system were frequent after successful RT in both genders.

OBJECTIVES: Patients with prolactinomas and patients with acromegaly often have heterogenous adenomas. In this study we have focused on patients with prolactinomas who developed acromegaly and acromegalic patients with hyperprolactinaemia. Our hypothesis is that some patients with hyperprolactinaemia may develop clinical acromegaly. METHODS: We have included patients examined at department M, Odense University Hospital between 1996 and 2001. Seventy-eight patients with prolactinomas, 65 females and 13 males, with a median age (range) of 30 Years (14-74) and 47 Years (20-66), respectively, were included in the study. RESULTS: In females and males the median prolactin (PRL) levels were 90 microg/l (27-4700; normal values (NV)

Treatment of psychotic symptoms has traditionally involved conventional antipsychotics. While efficacious, their side-effects have been problematic and the approval by the Food and Drug Administration of the newer antipsychotics with improved side-effects profiles heralded important advances in treating psychoses. Prolactin elevation has been associated with all classical and some atypical antipsychotics. We present cases where elevation of prolactin concentrations secondary to antipsychotic treatment was associated with delusions of pregnancy. Risperidone was the antipsychotic employed and elevation of prolactin concentrations were noted each time. The delusions abated and prolactin concentrations decreased when the drug was discontinued. Rechallenge with risperidone resulted in re-elevation of prolactin levels along with recurrent delusions. Substituting risperidone with another antipsychotic (either olanzapine or quetiapine) also led to abatement of the delusions and lowering of prolactin. Although no direct psychotogenic effects of prolactin are known, it is contended that delusions of pregnancy reported during antipsychotic treatment might be associated with rising prolactin concentrations.

Objectives. Hyperprolactinaemia has been associated with the active phase of human systemic lupus erythematosus and rheumatoid arthritis. In the present study, we investigated the role of prolactin (PRL) in relation to the number of typical symptoms and serum markers of systemic inflammation in patients with polymyalgia rheumatica (PMR). Methods. One hundred and two PMR patients presented with typical symptoms such as adynamia, bilateral muscular pain in shoulders, upper arms or neck, bilateral muscular pain in the pelvic girdle, headache, morning stiffness, arthralgia, symptoms of depression, fever, initial weight loss (>4 kg month), and transient visual symptoms. If one of the mentioned symptoms was present, the corresponding item was scored with one point (maximum unweighted item points = 10). PRL, interleukin-2 (IL-2) IL-6, IL-I receptor antagonist (IL-Ira), tumour necrosis factor (TNF), soluble IL-2 receptor (sIL-2R), and soluble vascular cell adhesion molecule (sVCAM) were measured by enzyme-linked immunosorbent assay in patients and 31 age-matched healthy controls. Results. Fifteen PMR patients with elevated PRL had a higher number of symptoms as compared with patients with normal levels (P = 0.003). PRL was correlated with the number of symptoms (all PMR patients: r rank = + 0.380, P < 0.001) and duration of morning stiffness (all PMR patients: r rank = + 0.335, P = 0.002) irrespective of prior corticosteroid treatment. However, PRL did not correlate with markers of systemic inflammation such as erythrocyte sedimentation rate, C-reactive protein, serum IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM. Conclusion. The number of symptoms in PMR patients was positively correlated with PRL, but PRL was not correlated with serum markers of inflammation. This indicates that PRL is not a pro-inflammatory stimulus in patients with PMR. The inter-relationship between PRL and symptoms or duration of morning stiffness may be more a sign of central nervous system involvement, as it can be observed in people with depressed mood or under psychological stress.

The effect of hyperprolactinaemia, induced by two or four pituitary homografts under the kidney capsule, on gastric and duodenal ulcers has been studied. The acute gastric ulcer models used were pylorus ligation, indometacin-induced and ethanol-induced gastric ulcers. Chronic gastric ulcers were induced using acetic acid and duodenal ulcers by mercaptamine hydrochloride. After pylorus ligation, there was an approximate 30–40% increase in gastric secretion, a significant increase in total acidity (P < 0.01) and in the ulcer index (P < 0.01) in rats bearing pituitary homografts under the kidney capsule when compared with the sham-operated control. Hyperprolactinaemia did not affect the formation of ethanol-induced gastric ulcers but showed a 40% reduction in the development of indometacin-induced gastric ulcers. It also produced a 20% increase in the ulcer index in acetic acid-induced chronic gastric ulcers and a 30% increase in ulcer area in mercaptamine-induced duodenal ulcers. Our results showed that hyperprolactinaemia induced gastric acid secretion and thereby aggravated gastric and duodenal ulcers in rats. Hyperprolactinaemia did not affect gastric cytoprotection.

Women with polycystic ovary syndrome (PCOS) typically have abnormal gonadotropin secretion and, in 30% of cases, mild and transient hyperprolactinemia. Elevated prolactin (PRL) is found in the late follicular and luteal phases of natural as well as stimulated cycles. Increased levels of both PRL and luteinizing hormone (LH) conceivably reflect a reduced dopamine inhibitory effect. To clarify the influence of dopaminergic control in PCOS, the investigators retrospectively examined the effects of cabergoline, a potent dopamine agonist that inhibits PRL secretion, on the ovarian response to stimulation with recombinant follicle-stimulating hormone (FSH). Enrolled in the study were 44 couples in which the women were diagnosed as having PCOS, in part because of anovulatory infertility and/or oligomenorrhea or amenorrhea. Eighteen women (group A) whose mean serum PRL was 32. 8 ng/ml received 0.25 mg of cabergoline (Dostinex) per week before and during ovarian stimulation. The remaining 26 women (group B), with a mean PRL of 31.3 ng/ml, received no treatment for hyperprolactinemia. For ovarian stimulation investigators used Triptorelin, a gonadotropin-releasing hormone agonist; FSH in an individualized dose; and human chorionic gonadotropin (hCG). The two groups were similar demographically and clinically. The total of 107 ovulatory-stimulated cycles available for study represented approximately 2 ½ per participant. Cabergoline reduced the mean serum prolactin to 12.5 ng/ml at the time stimulation began. Women not given cabergoline received significantly less recombinant FSH per cycle and were stimulated for a shorter time before hCG was given. Their peak serum estradiol levels were significantly higher than in group A women. Serum progesterone levels on the day of hCG treatment did not differ significantly in the two groups. Ultrasonography showed that hyperprolactinemic women developed significantly more follicles of all sizes on the day hCG was given than did those given cabergoline. Mild ovarian hyperstimulation syndrome (OHSS) developed in 6.2% of group B women and 2.4% of those in group A; all these cycles were canceled. There were 8 pregnancies in group A, 3 of them multiple, and 11 in group B, 5 of them multiple; the differences were not significant. These findings agree with the existence of a dopaminergic component in the regulation of LH release in women with PCOS. Pretreatment with the dopamine agonist cabergoline seems to reduce the ovarian response to recombinant FSH without altering the pregnancy rate or the risk of multiple pregnancy. This might be a helpful means of limiting the risk of OHSS.

BACKGROUND Impaired sexual function is an important cause of depression in uraemic females. Hyperprolactinaemia is frequent, and often associated with decreased serum oestradiol concentration, which can significantly contribute to accelerated bone loss. The aim of the study was to evaluate the effect of hormone replacement therapy (HRT) on sexual function, serum 17beta-oestradiol and prolactin, and bone mineral density (BMD) in pre-menopausal women undergoing haemodialysis. METHODS Among 63 women on haemodialysis, aged 18-45 years, 23 with secondary amenorrhoea and serum oestradiol < 30 pg/ml were enrolled into the 1 year study. They were divided into: group I (n = 13) treated with transdermal oestradiol with cyclic addition of noretisterone acetate, and control group II (n = 10). BMD was measured with dual energy X-ray absorptiometry (DEXA). RESULTS No important changes in sexual function and hormonal profile were observed in the control group, whereas in all women from group I the treatment induced regular menses and a marked improvement of libido and sexual activity. Serum 17beta-oestradiol increased after the first month from 20.5 +/- 11.7 to 46.8 +/- 13.6 pg/ml (P < 0.001) and remained at that level until the end of the study, accompanied by a decrease of serum prolactin (from 1457 +/- 1045 to 691 +/- 116 mIU/ml after 12 months; P < 0.001). In group I, the treatment induced an increase in BMD, although significant only in L2-L4 (P < 0.05), whereas in group II a mild insignificant decrease was observed. However, a comparison of BMD values after 12 months in both groups revealed marked (P < 0.01-P < 0.05) differences at all studied sites. CONCLUSIONS Transdermal HRT allows sustained physiological serum oestradiol concentrations in pre-menopausal women with oestrogen deficiency on haemodialysis, with the restoration of regular menses and a marked improvement in their sexual function. The treatment inhibits bone demineralization and can play an important role in the prevention of early osteoporosis in this group of patients.

ObjectiveTreatment with dopamine agonists has been associated with cardiopulmonary fibrotic reactions, predominantly in patients treated for Parkinson's disease. To our knowledge, these reactions have previously not been associated with low-dose cabergoline treatment for hyperprolactinaemia.MethodA case of constrictive pericarditis in a patient treated with cabergoline for hyperprolactinaemia is presented. The patient has been treated at a county hospital and a university hospital in southern Sweden.ResultsA 20-year-old woman with a 3-year history of amenorrhoea was referred to the department in 1992. From 2001 to 2005, she was given cabergoline, 0.5–1.5 mg/week. In 2005 a pericardectomy was performed due to fibrotic, constrictive pericarditis.ConclusionsOur present case suggests that constrictive pericarditis may develop even on low-dose cabergoline, which might indicate that this reaction, as opposed to valvular fibrosis, is not mediated by a 5-HT2B agonistic mechanism.

OBJECTIVE: The stimulatory and inhibitory effects of N-methyl-D-aspartic acid (NMDA) and kainic acid on prolactin (PRL) secretion have been correlated with the serum prolactin concentrations before drug administration. In the present experiments, we analysed the role of NMDA and kainic acid in PRL secretion in females with different serum concentrations of PRL. METHODS: Hypoprolactinaemic females were obtained by ovariectomy or after administration of diethyldithiocarbamate (an inhibitor of dopamine-beta-hydroxylase). Chronic hyperprolactinaemia was induced by neonatal administration of testosterone or oestradiol and acute hyperprolactinaemia was induced either by administration of alpha-methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) or by ether exposure. To analyse the role of dopamine in the effects of NMDA, we measured pituitary concentrations of dopamine after NMDA treatment and the effects of pretreatment with domperidone. RESULTS: (1) NMDA, but not kainic acid, stimulated PRL release in cyclic females. This effect was independent of serum PRL concentrations and was not accompanied by a decrease in pituitary concentrations of dopamine. (2) NMDA did not change PRL secretion in neonatally androgenized females, whereas NMDA and kainic acid inhibited PRL release in neonatally oestrogenized females. The inhibitory effects of NMDA and kainic acid were blocked by domperidone. (3) Kainic acid inhibited PRL secretion in prepubertal hyper- and hypoprolactinaemic rats. (4) Hyperprolactinaemia induced by ether stress was counteracted by administration of NMDA and kainic acid. CONCLUSIONS: (a) NMDA has a dual effect on prolactin secretion that is independent of prior prolactin concentrations and of dopamine activity, but kainic acid is only inhibitory. (b) The stimulatory or inhibitory effects of NMDA and kainic acid on PRL secretion were not strictly related to basal PRL concentrations and necessarily involved a change in the secretion of prolactin releasing factors, as no correlations were observed between changes in pituitary concentrations of dopamine and serum PRL concentrations. (c) Females rendered hyperprolactinaemic by neonatal administration of testosterone or oestradiol responded differently after NMDA administration. (d) NMDA and kainic acid blocked the mechanisms involved in stress-induced PRL secretion.

Background. Erythropoietin (rHuEpo) therapy has been shown to improve sexual function in the male dialysis population, with several studies suggesting a direct effect upon endocrine function, as well as correction of anaemia. Nevertheless many male dialysis patients receiving rHuEpo continue to complain of sexual dysfunction. Methods. At a dedicated renal impotence clinic, 65 male dialysis patients were screened for endocrine disturbances. Baseline serum sex hormones were compared between those receiving and not receiving rHuEpo, using either the two-sample t test or the Mann-Whitney U test, after assessing for normality. Results from four patients were excluded on account of either medications (antiemetic phenothiazines), hepatic dysfunction, or carcinomatosis. Results. Twenty-five patients (41.0%) were receiving rHuEpo, the recipients and non-recipients being well matched for haemoglobin (10.19±0.29 vs 10.55±0.25 g/dl, n.s.), age (51.1±1.9 vs 53.6±2.1 years, n.s.) and duration of sexual dysfunction (median, 3.0 vs 3.0 years, n.s.). The rHuEpo recipients had a higher median creatinine (1090 vs 972 μmol/l, P

Hyperprolactinaemia is seen during and after treatment with classical antipsychotics such as haloperidol (Goodnick et al., 2002). Whereas in women, elevated values of prolactin have been associated with a variety of diverse side-effects including galactorrhoea, sexual dysfunction, breast engorgement, and long-term osteoporosis, hyperprolactinaemia in men leads to impotence, loss of libido, and hypospermatogenesis (Petty, 1999). Since these adverse events may have a negative impact on compliance, they are of particular concern to the treating psychiatrist. Prolactin is secreted by the anterior pituitary gland and is under the inhibitory control of dopamine, released from tubero-infundibular neurons. Current concepts consider elevated prolactin levels to be due to an antipsychotic D2 blockade on the tubero-infundibular tract. This effect was shown to outlast acute haloperidol administration (Nordstrom et al., 1992). Clozapine, however, does not seem to be associated with hyperprolactinaemia since PET data showed a lack of dopamine blockade in the tubero-infundibular tract (Farde et al., 1994). Other reports, however, consider the clozapine-induced D2-blockade, to be present in some degree. In contrast to classical antipsychotics, this blockade did not follow a curvilinear relationship between serum drug concentration and receptor occupancy (Nordstrom et al., 1995). Preclinical data, however, suggest that clozapine, which with the exception quetiapine, is the most benign antipsychotic in sparing central D2 receptors, may transiently induce prolactin elevations (Turrone et al., 2002). Kapur and Seeman (2001) generated the hypothesis, of a fast dissociation from D2 receptors in comparison to older compounds like haloperidol, which in contrast induce a sustained D2 blockade.

Recent clinical studies performed with the novel long acting dopamine agonist cabergoline in the inhibition and suppression of puerperal lactation and in the treatment of hyperprolactinaemic disorders are reviewed. Inhibition of puerperal lactation is achieved with a single 1.0 mg oral administration of the drug, with better efficacy and tolerability results in comparison with bromocriptine, 2.5 mg twice daily for 14 days; 1.0 mg cabergoline (given as 0.25 mg twice daily for 2 days to minimize adverse events) is also effective and well tolerated for the suppression of established lactation. In the treatment of hyperprolactinaemic amenorrhoea, 1-2 mg weekly doses of cabergoline (given on a twice weekly schedule) compare favourably with 5-10 mg daily bromocriptine (given on a twice daily schedule) both for biochemical (normalization of serum prolactin concentrations) and clinical efficacy (resumption of ovulatory cycles) as well as for tolerability. The results of these double-blind, reference therapy-controlled studies have been confirmed by several open studies, that also showed tumour shrinkage in most patients with macroprolactinomas and many patients with microprolactinomas. Persistence of normal or at least lower than pretreatment serum prolactin concentrations for several months after cabergoline withdrawal, together with persistence of cyclic ovulatory menses, has been also demonstrated. It is therefore suggested that cabergoline should become the drug of choice when inhibition or suppression of puerperal lactation is required and for the treatment of hyperprolactinaemic disorders.

A non-isotopic in situ hybridization method with digoxigenin-labelled probes was used to examine growth hormone (GH), prolactin (PRL) and human β-chorionic gonadotropin (β-hCG(LH)) gene expression in 63 pituitary tumours in acromegaly and 20 adenomas in hyperprolactinaemia. hCG and LH were detected simultaneously because of the extensive homology (more than 90%) of their mRNA sequences (1). A comparison with former results obtained with 35S-labelled probes shows the value of the easier and faster non-isotopic method. Additionally, immunohistochemical data are included to give even more evidence for the synthesis of the respective hormones by the tumour cells. In all 63 adenomas in acromegaly, GH mRNA was revealed in 59 PRL mRNA and in 36 β-hCG(LH) mRNA. A positive immunostaining for GH was found in all, for PRL in 40, and for β-hCG(LH) in 34 adenomas. The comparison of the two in situ hybridization methods revealed no differences concerning GH mRNA detection, but not all tumours positive after non-isotopic PRL and β-hCG(LH) mRNA detection showed signals with the radioactive method. Referring to the 20 PRL-secreting adenomas, PRL gene expression was demonstrable in all, GH mRNA in 12, and β-hCG(LH) mRNA in 2 cases. Comparing the positive results of immunohistochemistry with those of in situ hybridization, correspondence was found in 19 cases for PRL, in 5 cases for GH and in no case for β-hCG(LH).

Studies of 6-h hormone pulse patterns distinguished patients with polycystic ovarian disease (PCOD) from those with hyperprolactinaemia or hypothyroidism associated with ultrasonically diagnosed polycystic ovaries (PCO). No specific derangement in the gonadotrophin pulse pattern was responsible for these changes, as shown in patients with and without PCO in the latter two groups. These changes may reflect an abnormal ovarian response to normal or abnormal gonadotrophic drive. Out of 26 patients with PCO and elevated dehydroepiandrosterone sulphate (DHEA-S) levels, only three patients (11.5%) proved to have adrenal 21-hydroxylase deficiency. Ultrasonic visualization of polycystic ovaries must be supplemented with an endocrine biochemical assessment. Moreover, mild elevation of DHEA-S, without a concurrently high 17 alpha-hydroxyprogesterone level was not diagnostic of adrenal hyperplasia.

The incidence of ultrasonically diagnosed polycystic ovaries (PCO) was studied in 389 Arab patients with different types of menstrual dysfunction and 100 normal women with regular menstruation. Two-hundred-and-forty-six patients (63.2%) were found to have PCO but only 206 (53.0%) were confirmed as cases of polycystic ovarian disease (PCOD) on endocrine grounds. Polycystic ovaries were diagnosed in 50% of patients with hyperprolactinaemia, 36.4% with hypothyroidism, 23.7% with hypothalamic dysfunction, 100% with adrenal 21-hydroxylase deficiency and in 16.0% of normal women. More women with PCOD presented with oligomenorrhoea or dysfunctional uterine bleeding (77.7%) and hirsutism (72.3%) but obesity had no discriminating value between the groups with different diagnoses. Ultrasonic diagnosis of PCO should be supplemented with an endocrine biochemical assessment to prevent overdiagnosis of PCOD and to exclude other endocrine dysfunctions.

Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid hyperplasia, pancreatic endocrine tumours and pituitary adenomas. Here, we report a patient with a history of insulinoma who developed secondary infertility as a further symptom of the disease. When he was first examined at the age of 36 years, he complained of weakness, reduced libido and impotence. Laboratory evaluation revealed non-obstructive azoospermia and hyperprolactinaemia. In contrast to sexual activity and serum prolactin, semen quality did not significantly respond to bromocriptine therapy. During follow-up, a growing pituitary adenoma caused acromegaly with elevated serum concentrations of growth hormone, insulin-like growth factor 1 (IGF-1), and prolactin. After microsurgery of the tumour at the age of 44 years, sperm concentration persistently increased up to 5.6 x 10(6)/ml. In accordance with the clinical diagnosis of MEN1, DNA sequencing revealed a mutation in exon 2 of the menin gene which results in a truncated, inactive protein product. In conclusion, MEN1 with pituitary lesions may cause severe hypogonadism and infertility. Both hyperprolactinaemia and overproduction of growth hormone and IGF-1 seem to be involved in testicular dysfunction in the present case. The possible role of menin in the testis, however, remains to be elucidated.

Summary The association between hyperostosis frontalis interna (HFI), acromegaly and hyperprolactinaemia was investigated. Thirty six acromegalic patients, of whom 19 had hyperprolactinaemia, were compared with 36 randomly-selected, age-sex matched controls. There was a higher prevalence of HFI in the skull X-rays of the acromegalic cohort (P = 0.0002) when compared to the control group. This difference was apparent in both men (P = 0.01) and women (P = 0.01). Acromegalic patients with hyperprolactinaemia also expressed HFI in a higher proportion of individuals than the control group (P = 0.0001). Intra- and interobserver variability was assessed and concordance with 100% and 97% in the moderate and severe HFI sub-groups. The following sub-group analysis was undertaken: acromegalics and those acromegalics with hyperprolactinaemia were compared with the controls and a highly significant distinction was confirmed (P = 0.0007 and P = 0.00001 respectively). A relationship between HFI severity and the patient's age was noted in both male and female acromegalics. Also, the severity of HFI appeared related to disease duration in female acromegalics. The cause of HFI remains unknown but appears to be strongly associated with acromegaly, particularly in the presence of co-existent hyperprolactinaemia. The association may have symptomatic significance and the presence of HFI should be confirmed or refuted in all patients with acromegaly.

Transient hyperprolactinaemia has been shown to accompany the procedure of oocyte retrieval under laparoscopic control. This study was concerned with establishing whether transvaginal oocyte retrieval was also associated with hyperprolactinaemia and whether the hyperprolactinaemic response was dependent on the method of anaesthesia/analgesia employed. Two distinct patterns were recorded. Oocyte retrieval under general anaesthesia was accompanied by a rapid rise in prolactin levels, which peaked after 40 min. Oocyte retrieval under intravenous sedation was associated with a slow rise in circulating prolactin concentrations. Significant differences in the prolactin rise between the general anaesthesia and sedation groups appeared within 10 min of the start of the procedure. It is concluded that although the surgical stress of oocyte recovery is associated with mild transient hyperprolactinaemia, most of the hyperprolactinaemic response is due to the anaesthetic.

We describe a young man who developed extensive hypothalamic dysfunction including diabetes insipidus, adipsia, hyperprolactinaemia, and poikiliothermia together with central sleep apnoea following exposure to toluene.

The effects of cranial irradiation on hypothalamic-pituitary function were studied over a 5-year period in 31 adult patients with nasopharyngeal carcinoma. The estimated radiotherapy doses to the hypothalamus and pituitary were 3979 +/- 78 (+/- SD) and 6167 +/- 122 cGy, respectively. Within 2 years of radiotherapy, significant impairment in the secretion of growth hormone, gonadotrophins, corticotrophin and thyrotrophin were evident and 14 per cent of patients developed hyperprolactinaemia. Using life table analysis, the cumulative probability of endocrine dysfunction was estimated to be 62 per cent after 5 years with deficiencies in growth hormone, gonadotrophins, corticotrophin and thyrotrophin found in 63.5, 30.7, 26.7 and 14.9 per cent of patients, respectively. Growth hormone deficiency was the earliest endocrine dysfunction observed. Hyperprolactinaemia was uncommon in the male patients but occurred in five of eight women within 3 years of cranial irradiation. The alterations in gonadotrophin secretion suggest a defect in the pulsatile release of gonadotrophin releasing hormone. Twenty-eight patients developed a hypothalamic pattern of delayed thyrotrophin response to thyrotrophin releasing hormone one year after radiotherapy--four subsequently became hypothyroid. Patients who received radiotherapy for cervical lymph nodes were at greater risk of developing hypothyroidism. Thus, in these patients with no pre-existing disease in the hypothalamic-pituitary region, progressive impairment in hypothalamic pituitary function leading to endocrine dysfunction requiring treatment occurs in 50 per cent of patients 5 years after cranial irradiation. Regular endocrine assessment should be performed in all patients following cranial irradiation.

Risperidone is a potent antagonist of both dopamine (D2) and serotonin (5-HT2) receptors, demonstrating improvement of both positive and negative symptoms and a lower propensity for inducing extrapyramidal symptoms (EPS) than typical neuroleptics. Its most common side-effects, found in the Canadian multi-centre trial (Chouinard et al., 1993), were agitation, anxiety, insomnia, EPS, headache and nausea, in order of frequency. With regard to endocrine effects, risperidone causes an increase in prolactin levels similar to that of other neuroleptics (Claus et al., 1992). In open clinical trials (De Cuyper, 1991), the overall incidence of risperidone-induced endocrine side-effects was quite low: 2.9 % for amenorrhoea and 1-2% for galactorrhoea. However, it is assumed that the incidence can vary depending upon the characteristics of patients and the drug regimen, i.e. dosage and titration schedule. In our experience, hyperolactinaemia is likely to occur when prescribing risperidone to female or first-onset psychotic patients: we are reporting 5 cases of risperidone-induced hyperprolactinaemia with these characteristics.

Hyperprolactinaemia is a well-recognized neuroendocrine response to antipsychotics (Grunder et al., 1999). Both typical and ‘atypical’ antipsychotics have the potential to elevate serum prolactin levels due to their dopamine D2 receptor antagonism (Turrone et al., 2002) ‘Atypical’ antipsychotics with higher dopamine D2 receptor affinities such as risperidone (David et al., 2000) are associated with more pronounced elevation of serum prolactin than those with intermediate or lower affinity such as olanzapine, clozapine, and quetiapine (David et al., 2000). Substituted benzamide antipsychotics such as amisulpride belong to the class of drugs with the strongest potency for prolactin elevation. On the other hand, the partial agonist antipsychotic, aripiprazole, has been shown to lower serum prolactin below placebo levels when it is used as a single agent (Keck et al., 2003).

The plasma Prl response to 200 μg TRH iv was evaluated in 6 hyperprolactinaemic women without radiological evidence of a pituitary tumour (group I), in 15 hyperprolactinaemic women with dubious (group II) and in 17 normo- or hyperprolactinaemic women with clear (group III) radiological abnormalities, in 18 normoor hyperprolactinaemic men with clear radiological abnormalities (group IV), and in 4 women and 3 men with hyperprolactinaemia and sellar destruction who had been treated in the past for pituitary adenoma (group V). The responses were compared with those obtained in a control group of 83 (42 women, 41 men) normoprolactinaemic healthy individuals. The Prl response was defined as a ratio (R2): the 20 min value minus the 0 min value, divided by the 0 min value. The median R2 values were: female controls 5.1, male controls 3.1, group I 0.1, group II 0.2, group III 0.3, group IV 0.55, group V females 0.45 and males 0. It is concluded that 1) subjects suspected of harbouring a microprolactinoma (groups I and II) demonstrate absent or attenuated responses similar to those found in patients with definite prolactinomas and 2) a value of plasma Prl 20 min after 200 μg TRH iv greater than 3.5 times the basal level (R2 > 2.5) rules out the presence of a prolactinoma.

To evaluate the prevalence of hyperprolactinaemia in PCO patients and its possible correlation with a steroid pattern, we studied prolactin secretion (basal and after TRH stimulation) in 40 women affected by typical PCO. LH, FSH, testosterone, oestradiol, oestrone, DHEA-s and 17-OHP serum levels were also evaluated. Twenty-one patients had prolactin (Prl) values in the normal range both in baseline conditions and after TRH stimulation; 10 patients had normal basal values of Prl but an exaggerated response to TRH stimulation; 9 patients had high Prl basal values and an exaggerated response to TRH. The presence of hyperprolactinaemia was associated with increased serum levels of oestrone (P < 0.01), DHEA-s (P < 0.01) and 17-OHP (P < 0.05). In conclusion, hyperprolactinaemia is as relatively frequent condition which affects almost half the patients suffering from PCO and is probably related to an increase of serum oestrogens, mostly oestrone. Moreover, in patients with PCO and hyperprolactinaemia, the production of some other steroids is also affected.

Bromocriptine treatment results in clinical improvement and inhibition of plasma GH levels in only part of the acromegalic patients. The possible role of the simultaneous presence of Prl and GH in GH-secreting pituitary adenomas was investigated with regard to the inhibitory action of bromocriptine on GH secretion and the paradoxical increase of GH release in reaction to TRH. Surgically obtained pituitary tumour tissue from 35 consecutive acromegalic patients was studied immunohistochemically. In 21 patients no Prl was present in the tumour tissue. These patients had normal plasma Prl levels. In the other 14 patients Prl was present in the tumour tissue. Hyperprolactinaemia was found in 10 of these 14 patients. Plasma GH levels from 2 till 10 h after the administration of 2.5 mg bromocriptine measured before operation were significantly more suppressed in the patients with mixed GH/Prl-containing than in those with pure GH-containing pituitary adenomas, being 38 ± 4% and 65 ± 4% of basal values, respectively (P< 0.01). The response of GH to TRH, however, did not differ significantly between the two groups. Conclusions: 1. In about 70% of patients with 'mixed' GH/Prl containing adenomas, hyperprolactinaemia is present. 2. The simultaneous presence of Prl and GH in a GH-secreting pituitary tumour increases the sensitivity of GH secretion to bromocriptine. 3. The plasma Prl level is of value to predict which patients with acromegaly are likely to respond to bromocriptine with an inhibition of GH secretion.

Two novel dopaminergic drugs, designated CV 205-502 and CQP 201-403 have recently been developed by Sandoz Pharmaceuticals Ltd (Basle, Switzerland). The effects of these drugs on PRL and GH secretion by normal rat and tumorous human pituitary cells in vitro have been investigated. Low doses of both CV 205-502 and CQP 201-403 immediately and profoundly suppressed PRL secretion, which failed to recover up to 7 h after removal of the drugs. Similarly, CQP 201-403 significantly suppressed basal GH secretion by human pituitary somatotropic tumours in culture, and both drugs significantly reduced the stimulatory effect of GHRH. These effects are more potent and longer acting than the previously described in vitro effects of bromocriptine. It is concluded that CV 205502 and CQP 201-403 hold potential for the treatment of patients with hyperprolactinaemia and, possibly, also in patients with acromegaly.

We evaluated the clinical applicability of a 2-h test in which the prolactin (Prl) responses to thyrotrophin releasing hormone (TRH) (200 μg iv) and the dopamine antagonist, metoclopramide (MC; 10 mg iv) were studied successively, 1 h apart. Nine healthy women were studied with TRH-MC test and with another test in which MC alone was used or the drugs were given in opposite order. The preceding TRH injection did not affect the Prl responses to MC, nor did preceding MC affect the Prl response to TRH. With the TRH-MC test, Prl responses to TRH and MC were significantly lowered in amenorrhoea (N = 8) and hyperprolactinaemia (N = 15) regardless of whether or not treated with bromocriptine, and to MC only in oligomenorrhoea (n = 11). In normoprolactinaemic galactorrhoea (N = 7) the responses were similar as in healthy women. The ratio between Prl responses to TRH and MC was significantly higher in women with bromocriptine-treated hyperprolactinaemia (1.06 ± 0.8, so) than in healthy controls (0.34 ± 0.13). The capacity of pituitary lactotrophs to secrete Prl in response TRH and MC can be evaluated with a 2-h test which has potential for investigation of pituitary Prl dynamics in gynaecological endocrine disorders, particularly in amenorrhoea and hyperprolactinaemia.

Single doses of carbidopa and benserazide, two inhibitors of aromatic aminoacids decarboxylase, have been given orally to healthy women and men aged 19 to 32 years. Serum prolactin levels increased in respect to baseline levels when 80, 125 or 250 mg of carbidopa and 10, 20, 30, 50, 80 or 125 mg of benserazide were given. The carbidopa doses of 20 and 50 mg were ineffective. Carbidopa induced the enhancement of serum prolactin at a later time and over a longer time span than benserazide. The effect on serum prolactin is dose dependent for both drugs. The hyperprolactinaemia obtained with 250 mg of carbidopa and with 125 mg of benserazide is significantly larger in women than in age matched men. The observed prolactin increase fits with the hypothesis that a diminution of the inhibitory effect of dopamine at the pituitary and/or at the median eminence levels may occur in connection to the pharmacologically impaired monoamine synthesis. An effect of serotonin cannot, however, be excluded.

Twenty women with hyperprolactinaemia secondary to a pituitary adenoma were studied before and after selective transsphenoidal removal of the tumour. Pre-operatively, thyrotrophin-releasing hormone (TRH) (200 μg iv) and metoclopramide (MCP) (10 mg po) did not produce a positive PRL response in the tumour patients. By contrast, 14 post-partum lactating women, who were used as controls, exhibited a positive response to MCP administration. Methergoline (4 mg po) was shown to decrease serum PRL levels in 8 normal subjects, in 6 puerperal women, and 9 of 10 tumour patients. Bromoergocriptine (CB-154, 2.5 mg po) decreased serum PRL levels in 10 tumour patients. Following transsphenoidal removal of the adenoma serum PRL levels were reduced in all patients, and returned to normal in 14 patients. Prognostics for completely normalizing PRL secretion after transsphenoidal surgery is better when initial serum PRL levels are below 200 ng/ml. After surgery all hyperprolactinaemic patients failed to show a positive PRL response to TRH and MCP. Nine normoprolactinaemic patients had a positive response to both stimuli while 3 patients failed to show a positive response immediately following surgery. Long-term studies, however, showed that a positive PRL response was obtained in all patients tested 8–14 months after treatment. A positive PRL response to methergoline and bromocriptine was observed post-operatively in the patients tested regardless of their basal PRL level. Data from this study indicate that surgically proven PRL-secreting adenomas are invariably associated with negative PRL responses to TRH and MCP. The normalization of the prolactin regulation after surgery points toward the intrapituitary localization of the lesion associated with PRL-secreting adenomas.

In order to gain further insight into the role of dopamine (DA) in the control of TSH release and to investigate whether an increased or defective DA inhibition on pituitary thyrotrophs may be considered responsible for the abnormal TSH dynamics in pathological hyperprolactinaemia, we examined the effect of low-dose DA infusion on TRH stimulated TSH secretion in normally cycling women and in patients with pathological hyperprolactinaemia. The effect of long-term bromocriptine therapy on TSH dynamics was also evaluated in a selected group of hyperprolactinaemic women. Fifty-two hyperprolactinaemic patients with no other signs of pituitary or thyroid dysfunction had significantly higher mean TSH serum concentrations and mean TSH peak values after TRH administration than 75 healthy controls. Furthermore, the TSH rises induced by the DA-synthesis inhibitor α-methyl-p-tyrosine (AMPT, 500 mg orally) were enhanced in both prolactinoma and 'idiopathic hyperprolactinaemia' patients as compared with controls. There was a positive correlation between the TRH- and AMPT-induced TSH rises in the hyperprolactinaemic group. Low-dose DA infusion (0.1 μg/kg min) reduced TSH response to TRH in both regularly cycling women and patients with hyperprolactinaemic amenorrhoea. Long-term bromocriptine therapy (2.5 mg tid over 60– 150 days) not only normalized serum Prl levels, but also reduced the TSH response to TRH in 7 hyperprolactinaemic women who had presented exaggerated TSH responses to the basal TRH test. These findings confirm that DA plays a physiological role in the inhibition of TSH release, probably at the level of the anterior pituitary. The fact that both low-dose DA infusion and long-term bromocriptine treatment effectively reduced TSH release in hyperprolactinaemic patients seems to indicate that endogenous DA inhibition of pituitary thyrotrophs is reduced rather than enhanced in pathological hyperprolactinaemia.

Four regularly menstruating volunteers were submitted to an oral treatment, for 3 consecutive cycles and starting on the first day of a cycle, with tiapride at daily doses ranging from 1 × 100 mg to 2 × 100 mg. The first and the last cycle under treatment, as well as a prior control cycle, were thoroughly studied by means of daily measurements of blood concentrations of LH, FSH, prolactin (PRL), oestradiol and progesterone. Tiapride, a benzamide derivative with dopaminergic blocking activity at the level of the lactotrophes, increased mean PRL secretion in each subject but a permanent hyperprolactinaemia above 700 μU/ml was attained only in one subject. Despite these widely fluctuating PRL levels in most subjects, the resulting overall hyperprolactinaemia induced in all cases a progressive deterioration of the function of the corpus luteum: 5 cycles showed luteal phases reduced by 2–5 days, one cycle was characterized by some slight luteinisation but questionable ovulation and the 2 remaining cycles were anovulatory. The interruption of drug intake one week after the onset of menses led thereafter to a cycle with a likely inadequate luteal phase but of normal length. It is concluded that even a non-permanent hyperprolactinaemia can impair the normal function of the hypothalamo-pituitaryovarian axis, as well as exhibit some effects in a cycle consecutive to the normalization of PRL. With the exception of the impaired luteal progesterone secretion, the pooled hormonal data from the short luteal phase cycles under tiaprideinduced hyperprolactinaemia exhibit very little significant differences, as compared to the corresponding values in the control cycles. Some delay in the onset of follicular maturation, however, should be assumed since the follicular phase had been lengthened by 1 to 31 days in 5 of the 6 cycles with luteinisation during treatment. The present results are compatible with a double impact – both at the ovarian and the hypothalamo-pituitary levels – of hyperprolactinaemia in its mechanisms of impaired function of the hypothalamo-pituitary ovarian axis.

The influence of endogenous hyperprolactinaemia on oral glucose tolerance in normal women post-partum was studied. An oral glucose tolerance test (OGTT) was performed 8 weeks after delivery in 23 women, 13 of whom were breastfeeding. The lactating women had significantly higher plasma prolactin values before and during the OGTT than the non-lactating women (P < 0.005). Fasting values of serum FSH, LH, progesterone and plasma glucagon were similar in the two groups. The non-lactating women had higher fasting concentrations of serum oestradiol (P < 0.0005), plasma glucose (P < 0.05) and insulin (P < 0.05) than the lactating women. After oral glucose no differences were found between lactating and non-lactating women in changes in plasma glucose, insulin and glucagon concentrations. It is concluded that lactating women 8 weeks post-partum do not have an impaired OGTT compared to non-lactating women despite elevated plasma prolactin levels.

A 55 year old man with isolated ACTH deficiency is reported. The lesion would appear to be located in the pituitary gland since plasma ACTH and cortisol did not respond to lysine vasopressin and corticotrophin releasing factor (CRF). A fall in T4, a rise in basal values of TSH, prolactin (Prl), LH and FSH, excessive responses of TSH and Prl to TRH, and hyperreactive responses of LH and FSH to LRH were observed. These hormonal changes were examined before and after administration of cortisol. The abnormality in these hormones might be caused by deficiency of long-term glucocorticoid.

Summary We recently investigated two patients with diabetes and elevated serum prolactin levels in whom no cause of hyperprolactinaemia could be found. For this reason we measured fasting serum prolactin levels in 72 diabetic males and compared the results with those of 63 healthy males and 90 nondiabetic males attending an Impotence Clinic. The diabetic group had significantly higher serum prolactin levels (13.1 ± 0.9 ng/ml) than the two control groups (9.9 ± 0.6 ng/ml for normal males and 7.7 ± 0.3 ng/ml for the non-diabetic impotent group). Eighteen percent of the diabetics studied had serum prolactin levels above the normal range for males (> 20 ng/ml). There was no correlation between serum prolactin levels and duration of diabetes, glycosylated haemoglobin level or presence of clinically apparent retinopathy. The correlation between serum prolactin level and fasting plasma glucose was weak though statistically significant (r = 0.26, P < 0.05).

The clinical significance of hyperprolactinaemia in uraemic patients is uncertain and discrepancies between immunoactivity and biological activity of serum hPRL have been reported. We have modified the Nb2 cell bioassay to improve specificity for hPRL and used this assay to measure hPRL bioactivity in sera from 26 uraemic patients and 40 control subjects. Seventeen patients were receiving regular haemodialysis and 9 continuous ambulatory peritoneal dialysis. Levels of hPRL bioactivity were compared with hPRL immunoactivity measured by RIA (PRL-RIA) and by immunoradiometric assay (PRL-IRMA). Serum hPRL levels measured by all three assays were significantly elevated in uraemic patients compared with control subjects (P< 0.001). The immunoradiometric method gave significantly lower results than RIA in control subjects but not in uraemic patients (P< 0.05). There was no significant difference in mean ratio of hPRL bioactivity to PRL-RIA between patients and control subjects (1.18 ± 0.05 vs 1.11 ± 0.03, mean ± sem). The ratio of hPRL bioactivity to PRL-IRMA was slightly decreased in uraemic patients compared with controls (P = 0.05). Serum hPRL bioactivity was closely correlated with immunoactivity in both immunoassays (r ≥ 0.96) in patients and controls. These results confirm that elevated serum hPRL levels in uraemic patients represent biologically active hormone which may contribute to hypogonadism.

The effect of hyperprolactinaemia on the hypothalamo-pituitary axis was assessed by iv injection of 100 μg luteinizing hormone releasing hormone (LRH) in 7 women with prolactinoma before and 3 months after normalization of the Prl level by transsphenoidal surgery. A dose of 20 mg of conjugated oestrogen (Premarin®) was also injected iv into patients with prolactinoma before and 4 months after surgery, and the serum LH levels were determined serially for 120 h after the injection. Surgical treatment caused significant reduction of the mean (± se) serum prolactin (Prl) level from 123.3 ± 7.8 to 19.4 ± 5.6 ng/ml. But the differences in the basal levels of LH (11.3 ± 2.2 to 8.6 ± 1.5 mIU/ml), FSH (8.3 ± 2.4 to 10.6 ± 3.7 mIU/ml) and oestradiol (26.6 ± 8.6 to 37.5 ± 5.5 pg/ml) before and 4 months after surgery were not significant. An exaggerated LH response to LRH in untreated prolactinoma patients was also observed after surgical treatment. After surgical treatment, patients showed LH release with a peak between 48 and 72 h after the injection of Premarin, whereas before treatment they did not show any LH discharge. The mean percent increase in LH between 48 and 72 h was also significantly higher after operation than before operation. These results suggest that the hyperprolactinaemia in prolactinoma patients may cause an impaired positive feedback effect of oestrogen on LH release and that this derangement can be reversed by reduction of the Prl level by adenomectomy.

Hyperprolactinaemia occurred in 40 of 123 unselected patients (33%) with functional secondary amenorrhoea. Galactorrhoea was present only in 15 of these patients (38 %). On the other hand, galactorrhoea was found in 10 of 83 euprolactinaemic patients (12%). The frequency and severity of hyperprolactinaemia and galactorrhoea dissociated in various forms of amenorrhoea. Anorexia nervosa was characterized by euprolactinaemia and the absence of galactorrhoea. Self-induced weight loss resulted in amenorrhoea with a moderate degree of hyperprolactinaemia in 23 % of the cases. Yet, galactorrhoea was uncommon (1.6 %). Amenorrhoea following stress was also associated with moderate hyperprolactinaemia in 31 % of patients and a low frequency of galactorrhoea. By contrast, both hyperprolactinaemia and galactorrhoea occurred more frequently (36 %) and were more severe in patients who had post-pill amenorrhoea, but still 50 % of hyperprolactinaemic patients had no galactorrhoea and 28 % of euprolactinaemic patients had galactorrhoea. This discordance was accentuated in those patients who had been pregnant even if pregnancy did not immediately precede amenorrhoea. Galactorrhoea (63 %) and hyperprolactinaemia (36 %) were common in these patients and very high serum prolactin values were sometimes seen. Our results point to different mechanisms involved in the regulation of hypothalamic pituitary function and breast secretion in various forms of secondary amenorrhoea, and they may help select patients in whom the prolactin assay is likely to identify indication for specific treatment.

This report compares the xeromammographic patterns of 35 patients with hyperprolactinaemia and 70 (age-matched) normoprolactinaemic controls. It is shown that nulliparous patients have less frequent mammary dysplasia and more patterns of involution than the nulliparous controls. The groups of parous patients and parous controls were similar to each other and both had more involutions and less dysplasia than the nulliparous controls. Hyperprolactinaemia in parous women is not associated with any changes in the xeromammographic breast patterns as compared to parous controls. The changes described in hyperprolactinaemic patients can be understood in terms of their low oestrogenic activity.

In order to assess the effect of hyperprolactinaemia on the ovarian response to exogenous gonadotrophin, serum oestrogen levels were determined in 6 normal females. Two hundred and twenty-five IU of human menopausal gonadotrophin (hMG) was im injected daily for 3 days from the 4th day of the menstrual cycle, and the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and oestradiol-17β were determined by radioimmunoassay daily for 7 days starting from the first day of injection (control cycle). After 2 months the same schedule was applied to the previous 6 subjects and in addition sulpiride 100 mg bid was given orally during the course of the study (sulpiride cycle). There was a significant increase in serum FSH and a decline in serum LH during hMG treatment in both groups. The mean (± se) serum levels of PRL in the sulpiride group increased gradually from 24.5 ± 3.8 ng/ml (1st day) to 56.2 ± 3.4 ng/ml (7th day). All these levels were significantly higher than those of the control group. The mean (± se) serum oestradiol increments by hMG stimulation in control and sulpiride groups showed a peak on the 5th day with respective levels of 757.2 ± 202.3 and 845.3 ± 263.3 pg/ml. No significant differences in the mean oestradiol increment were found between the two groups on any day. These results indicate that acute hyperprolactinaemia does not appear to induce ovarian refractoriness to exogenous gonadotrophin in normal cyclic women.

A transsphenoidal operation was performed in a 27 year old man because of a large intrasellar expansion and marked hyperprolactinaemia (33 000 mU/l). The tumour found in the operation bulged into the sphenoidal sinus and was extirpated. On histopathological examination the tumour consisted mainly of congophilic amyloid spherules with intermingled sparse adenoma cells. The adenoma cells were strongly positive for prolactin in immunoperoxidase staining, and in electron microscopy they contained secretory granules. Ultrastructurally the amyloid spherules consisted of masses of concentrical extracellular amyloid filament bundles.