Long-term Treatment of Galactorrhoea and Hypogonadism with Bromocriptine

Seventeen women and four men with galactorrhoea and associated hypogonadism have been treated with bromocriptine for 2 to 28 months. In 18 patients the gonadal status became normal as the galactorrhoea improved. The gonadally unresponsive patients had either pituitary tumours or premature menopause. Prolactin levels fell with treatment; withdrawal of the drug was associated with an increase in serum prolactin and a recurrence of the galactorrhoea and hypogonadism. Two patients tried to become pregnant on treatment and both succeeded. Raised prolactin levels appear to block the actions of the gonadotrophins at a gonadal level rather than prevent their synthesis or release; lowering prolactin secretion with bromocriptine allows resumption of normal gonadal function. Bromocriptine appears to be the treatment of choice for inappropriate lactation in association with hypogonadism on a long-term basis.     

Pituitary prolactin and growth hormone levels during different reproductive states in mice with a high or a low lactational performance

The pituitary prolactin and growth hormone (GH) levels were determined by disc electrophoresis on 10% polyacrylamide gel during the virginal and pregnant stages and on Day 12 of lactation, using C3H/He and C57BL/6 mice. The former had been shown to be superior to the latter in both mammary development and lactational performance. The pituitary prolactin levels were significantly higher in C3H/He mice than in C57BL/6 mice during the virginal and pregnant stages. However, no strain differences existed in the prolactin levels on Day 12 of lactation. Little difference in the prolactin levels was found between estrus and diestrus, and the levels declined gradually with the advance of pregnancy in both strains. The levels decreased after 1 hr of suckling preceded by 8-hr removal of young on Day 12 of lactation in both strains, but the difference between before and after suckling was statistically significant only in C3H/He mice. Both pituitary GH content and concentration were significantly higher in C3H/He mice than in C57BL/6 mice during the virginal stage and the content was also higher in C3H/He mice during the pregnant stage. However, there existed no strain difference in the levels on Day 12 of lactation. Little change in the pituitary GH levels was observed during the different reproductive states in both strains.     

Prolactin and schizophrenia: clinical consequences of hyperprolactinaemia

Prolactin is a polypeptide hormone that is synthesized and secreted from specialised cells of the anterior pituitary gland, known as lactotrophs. The hormone was given it's name because extracts from the bovine pituitary gland caused growth of the crop sac and stimulated the elaboration of crop milk in pigeons, and promoted lactation in rabbits. Although prolactin is best known for the multiple effects it exerts on the mammary gland, it has over 300 separate biological activities not represented by its name. It sub serves multiple roles in reproduction other than lactation and is an important modulator of homeostasis in the mammalian organism. Hence Bern and Nicoll suggested renaming it "omnipotin or versatilin". Schizophrenia is a severe psychiatric disorder that affects approximately one percent of the population worldwide. It is well established that traditional typical anti-psychotics elevate prolactin levels. It is also agreed that the serum prolactin concentration is not elevated in patients with schizophrenia who are not receiving anti-psychotic medication. Hyperprolactinaemia has direct effects on the brain and on other organs. Direct consequences include galactorrhoea. Indirect consequences of hyperprolactinaemia include oligomenorrhoea and amenorrhoea, erratic or absent ovulation, sexual dysfunction, reduced bone mineral density and cardiovascular disease. With the advent of prolactin sparing anti-psychotics, ample consideration needs to be given to the physiological consequences of hyperprolactinaemia in schizophrenic patients. In this paper we will examine molecular biology, secretion and physiology of prolactin. The consequences of hyperprolactinaemia in humans including effects on fertility, sexual dysfunction, bone mineral density, cardiovascular disease, changes in psychopathology and movement disorders will be reviewed. The literature on the association between schizophrenia, anti-psychotic medication and hyperprolactinaemia and more specifically on the consequences of this hyperprolactinaemia in schizophrenic patients will also be reviewed.     

CT abnormalities of the pituitary in hyperprolactinaemic women with normal or equivocal sellae radiologically.

Sixteen young women with hyperprolactinaemia and normal or equivocal sella in radiographs underwent computed tomography using a Siemens Somatom II. In all but one case an abnormality was found. The sella was full in seven and partially empty in nine. A tumour was visible in six of the full and in four of the partially empty sellae. All but one of the 10 tumours was unilateral, and in seven the pituitary stalk was deviated away from the tumour. After administration of intravenous contrast (Urografin) four tumours showed diffuse enhancement, four ring enhancement, and two enhanced less than adjacent normal pituitary tissue. Two of the tumours have been subsequently shown histologically to be prolactinomas. Prolactin response to thyrotrophin-releasing hormone predicted a tumour in seven out of eight with visible tumours but also in three out of four without visible tumours; using metoclopramide, a tumour was predicted in six out of seven with tumours, but again in three out of four without visible tumours. Such results question the value of dynamic tests for the discrimination of tumours. We conclude that practically all women with sustained hyperprolactinaemia and a normal or equivocal sella radiologically have pituitary disease.     

Hyperprolactinemia in nonpregnant women due to pituitary tumors

The human prolactin molecule has been isolated and its structure characterized. This anterior pituitary hormone plays an important function in the induction and maintenance of lactation in the post-partum nursing mother. Prolactin-producing tumors cause inappropriate lactation in the nonpregnant woman. Bromocriptine, an ergot derivative, mimics the action of dopamine in the anterior pituitary gland and does not cure the underlying pathology. Prior to the development of bromocriptine, there was no effective treatment for the symptoms of amenorrhea and galactorrhea. Although the methods of therapy are more sophisticated today, there remain a number of unanswered questions. The unknown long-term risks of bromocriptine therapy must be balanced against the potential risk of osteopenia.     

Bromocriptine in management of large pituitary tumours.

Bromocriptine has an accepted place in the management of small pituitary tumours that secrete either prolactin or growth hormone. The treatment of large tumours with extrasellar extensions is more difficult, however: though surgery is the standard treatment, it is often unsuccessful in returning excessive hormone secretion to normal and may cause hypopituitarism. A prospective trial was undertaken to assess the frequency with which changes in pituitary function and size of large tumours occurs. Nineteen patients were studied before and during treatment with bromocriptine (7.5 to 60 ml/day) for three to 22 months, using contrast radiology and a detailed assessment of pituitary function. Eighteen patients had hyperprolactinaemia and two of these also had raised concentrations of growth hormones; one patient had an apparently non-functioning tumour. In 12 patients (63%) tumour size decreased with bromocriptine and no tumour enlarged. Nine patients had visual-field defects, which improved in seven, becoming normal in five. Pituitary function improved in nine patients (47%) becoming entirely normal in three. Bromocriptine should be the treatment of choice in patients with large pituitary tumours with extrasellar extensions, provided close supervision is maintained.     

Acromegaly with 'normal' serum growth hormone levels. Clinical features, diagnosis and results of transsphenoidal microsurgery.

Among 216 consecutive patients with growth hormone secreting pituitary adenomas who underwent primary neurosurgical treatment at the University of Erlangen-Nürnberg, 8 cases of acromegaly with 'normal' basal growth hormone levels (less than or equal to 5 ng/ml) were seen. They all had the typical clinical features of acromegaly, exhibited an abnormal growth hormone secretion following an oral glucose load, and had markedly elevated somatomedin C levels. The GRH- and TRH/GnRH-tests were not found helpful in establishing the diagnosis. Neuroradiology could demonstrate a pituitary adenoma in all of the patients. Following transsphenoidal microsurgical resection of the tumours, growth hormone secretion during oral glucose tolerance testing was normalised in 7 of the 8 patients. Immunohistology and explant culture studies documented growth hormone secreting pituitary adenomas in all cases. The authors conclude that even the finding of repetitive 'normal' (less than or equal to 5 ng/ml) serum GH levels does not exclude active acromegaly and when the clinical diagnosis of acromegaly is suspected, dynamic endocrine testing may reveal abnormal secretion patterns of GH in these cases. Transsphenoidal microsurgical resection of a pituitary adenoma offers a good chance of clinical and endocrinological remission in these cases.     

Ectopic production of ACTH and corticotropin-releasing hormone (CRH).

The most common ectopic production of a pituitary hormone is the one of ACTH leading to Cushing's syndrome. Ectopic ACTH-hypersecretion is the cause of Cushing's syndrome in 10-15% of all cases. The ACTH-secreting tumours are often oat-cell carcinomas of the lung, less frequently pancreatic cancers, hypernephromas, or C-cell carcinomas of the thyroid. Some of these tumours may be benign or semi-benign as the rare carcinoid tumours and cause great problems in the differential diagnosis of ACTH-dependent hypercortisolism. Out of 173 of our patients with Cushing's syndrome observed in the last 12 years 21 were caused by ectopic ACTH-production. Of these 21 patients 13 have a small cell carcinoma of the lung. The ectopic ACTH-syndrome often has typical clinical features caused by the levels of ACTH and cortisol leading to hypocalcemic alkalosis with muscle weakness and wasting, carbohydrate intolerance, and hypertension with oedema. The survival time in many of these patients is not long enough to allow them to develop typical signs of Cushing's syndrome though they are often highly pigmented. These patients are easily diagnosed. However, patients with small tumours which do not cause very elevated ACTH-levels and who have the more typical clinical signs of full-blown Cushing's syndrome are difficult to recognize. For the differential diagnosis of ACTH-dependent Cushing's syndrome the corticotropin-releasing hormone (CRH) stimulation test and dexamethasone suppression test with high doses are helpful. In special cases the venous sampling procedure for ACTH-measurements is necessary, also CT or NMR is helpful. Ectopic CRH-production is a rare cause of ACTH-dependent Cushing's syndrome. Patients with ectopic CRH-production and consecutive ACTH-hypersecretion from the pituitary have not been studied extensively. There are especially no well documented results of the use of the CRH-stimulation test in vivo in this group of patients with Cushing's syndrome. On the other hand, in the documented cases, not only CRH-, but also ACTH-production was found in the tumours. So far, this rare cause of ACTH-dependent Cushing's syndrome has to be excluded or confirmed by the measurement of endogenous CRH-levels. But until now we have not been able to detect one single case of ectopic CRH-production using a sensitive homologous CRH-radioimmunoassay over a period of more than 8 years in which we have seen nearly 120 newly diagnosed patients with ACTH-dependent Cushing's syndrome. Only in the plasma and tumour tissue of two patients of other groups have we found high CRH-levels.     

Amenorrhoea,Galactorrhoea, and Primary Hypothyroidism with High Circulating Levels of Prolactin

A 22-year-old woman with primary hypothyroidism developed amenorrhoea and galactorrhoea during oral contraceptive therapy. Investigation showed high levels of circulating prolactin which rose in response to insulin-induced hypoglycaemia and were suppressed by an oral glucose load. After treatment with thyroxine normal periods returned, the galactorrhoea improved, and the prolactin levels fell to undetectable levels. The results of the prolactin and human growth hormone assays confirm that it is possible to distinguish between human growth hormone and human prolactin.     

New long-acting bromocriptine (Parlodel MR and Parlodel LAR) in the treatment of pituitary tumours with hyperprolactinemia.

In order to assess the efficacy and tolerability of new long acting bromocriptine: Parlodel MR (oral form) and Parlodel LAR (injectable form suitable for repeatable administration) 40 patients (29 women and 11 men) with pituitary tumours with hyperprolactinemia (PRL 70 micrograms/l) were investigated in a double blind study. Patients were divided into 2 groups of 20. In the first group Parlodel R or Parlodel MR in equivalent doses was given, the other group was administered Parlodel R or Parlodel LAR. During the next 6 months 20 patients were treated with Parlodel MR and the other 20 with Parlodel LAR. In all patients pituitary and peripheral hormones, CT scan and visual fields were examined before and after 28 days of bromocriptine treatment. During the next six months 20 patients were treated with Parlodel MR while the other 20 with Parlodel LAR. Serum PRL fell in all patients and values in the normal range were obtained in 36 patients. In 30 out of 35 patients with signs of pituitary tumour in CT scan, a significant tumour shrinkage was observed. Most patients achieved considerable clinical improvement: disappearance of galactorrhoea, resumed menses in women, increased potency in men. There were no difference in efficacy in Parlodel R, Parlodel MR and Parlodel LAR, but in the case of Parlodel LAR the least number of side effects was found. Treatment with long acting bromocriptine-Parlodel MR and LAR of patients with pituitary tumours with hyperprolactinemia is an efficacious, safe and better tolerated method than Parlodel R treatment.     

Changes in prolactin in peripheral plasma during lactation in the brushtail possum Trichosurus vulpecula

A heterologous double-antibody radioimmunoassay has been validated for prolactin in plasma and pituitary preparations of T. vulpecula. Serial dilutions of crude pituitary homogenates and plasmas from several marsupials and purified prolactin from the tammar, Macropus eugenii, showed parallel dose response curves. In both male and female possums plasma prolactin concentrations increased in response to a single intravenous injection of thyrotrophin releasing hormone. Plasma prolactin concentrations were measured in six lactating females (June-November) and in four non-lactating females (July-October). In the following year prolactin levels were also measured in 11 possums with young less than 50 days old and in 24 possums with young aged between 100 and 145 days. In early lactation prolactin concentrations were low (less than 8 ng/ml) but increased to high levels (greater than 30 ng/ml) by 120 days and remained high until about 160 days of lactation. Thereafter concentrations declined although the young continued to take milk from the mother for a further 30-50 days. The changes in plasma prolactin concentrations throughout lactation are very similar to those described for the tammar, and this unusual pattern appears to be common to marsupials. Non-lactating possums showed no consistent changes in plasma prolactin concentrations between July and October.     

Studies on ovarian quiescence in the lactating bonnet monkey (Macaca radiata)

Lactating bonnet monkeys were used as a model to understand the mechanism of ovarian quiescence during lactation. The ovary of the bonnet monkey in the 3rd month of lactation responds well to exogenous pregnant mare serum gonadotropin stimulation with serum estrogen values reaching maximal levels by day 3 of the gonadotropin injection. The adminstration of ovine prolactin to such monkeys significantly inhibited the ovarian responsiveness to exogenous gonadotropin. The responsiveness of the pituitary of the lactating monkey (in the 3rd month of lactation) to luteinizing hormone releasing hormone injection was suppressed and supplementation with exogenous prolactin further accentuating this effect. The relative ability of chlorpromazine given intravenously/intramuscularly/intranasally to enhance endogenous prolactin levels was assessed. During the first 5 months of lactation when the basal prolactin levels were high, the luteinizing hormone levels were low. As the suckling stimulus reduces and prolactin levels fall, luteinizing hormone levels increase, the first post-parturient mensus occurring by 218 ± 4 days. This event was postponed by 3 months on increasing endogenous prolactin levels by administering chlorpromazine (250 μg/day by intranasal mode) over a 5 day period every month starting from the 3rd month of lactation.     

Bone mineral content in normally menstruating women with hyperprolactinaemia

Decreased bone density has been reported in women with hyperprolactinaemia due to pituitary tumours. We identified a number of seemingly healthy women with hyperprolactinaemia, i.e. a serum prolactin concentration exceeding 500 mU/l (25 micrograms/l) on three occasions, during a study in 1980/1981 of a representative population sample of greater than 1,400 women in seven different age strata (range 26-72 years). We compared vertebral bone mineral content and bone mineral areal content in 5 hyperprolactinaemic normally menstruating 50-year-old women with that of 6 controls matched for age and menstrual status but found no difference. Since the degree of prolactin elevation was similar in our study group to that previously reported for hyperprolactinaemic subjects with pituitary tumours and the time of exposure to raised hormone concentration appears to be of the same magnitude, other hormonal changes than hyperprolactinaemia per se seem to be the cause of low bone mineral content in women with hyperprolactinaemia and amenorrhoea.     

Neuroendocrine actions and regulation of hypothalamic neuropeptide Y during lactation

The expression of neuropeptide Y (NPY) and its co-messenger, agouti-related peptide (AgRP), in arcuate neurons of the hypothalamus is increased during lactation in rats. Our research has been addressing the questions of the physiological actions of these peptides during lactation and the physiological signals associated with lactation that result in increased expression of their genes. Our studies indicate that NPY and AgRP exert pleiotropic actions during lactation that help integrate neuroendocrine regulation of energy balance with controls over anterior and posterior pituitary hormone secretion. Further, reciprocal signaling to the NPY/AgRP system by leptin and ghrelin is responsible for the changes in expression of these hypothalamic peptides in lactating animals, and thus, may contribute to regulation of food intake and the various neuroendocrine adaptations of lactation.     

Radiation-induced growth hormone deficiency

Deficiency of one or more anterior pituitary hormones may follow treatment with external irradiation when the hypothalamic-pituitary axis falls within the fields of irradiation. Hypopituitarism occurs in patients who receive radiation therapy for pituitary tumours, nasopharyngeal cancer and primary brain tumours, as well as in children who undergo prophylactic cranial irradiation for acute lymphoblastic leukaemia, or total body irradiation for a variety of tumours and other diseases. The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus, after lower radiation doses isolated growth hormone deficiency ensues, whilst higher doses may produce hypopituitarism. The timing of onset of the radiation-induced pituitary hormone deficit is also dose-dependent. The main site of radiation damage is the hypothalamus rather than the pituitary, although the latter may be affected directly.     

Prolactin Synthesis in Primates

THERE is compelling physiological evidence that prolactin and growth hormone in primates are separate proteins, but no conclusive chemical evidence has been obtained in support of this¹. Indeed the close similarity in the primary structure of human pituitary growth hormone (HGH) and ovine pituitary lactogenic hormone² has reinforced the view that perhaps, in the human, lactation and growth are controlled by a single pituitary protein. Histological and immunofluorescence studies using antiserum to ovine prolactin (AOP)³ have shown, however, that there is a substance in primate pituitaries which is immunochemically related to ovine prolactin (OP) and distinguishable from growth hormone.     

Independent actions of gonadotropin releasing hormone upon cyclic GMP production and luteinizing hormone release

Gonadotropin releasing hormone (GnRH) and its potent analog [D-Ser(tBu)6]des-Gly10-GnRH N-ethylamide elevate pituitary cyclic GMP levels while stimulating gonadotropin release in cultured pituitary cells. Addition of mycophenolic acid to pituitary cell cultures decreased basal and GnRH-induced cGMP production to undetectable levels, but did not reduce basal or GnRH-stimulated luteinizing hormone (LH) release. Elevation of endogenous cGMP levels by sodium nitroprusside, or addition of cGMP or its potent derivatives, was also without effect on basal or GnRH-stimulated LH release. These findings demonstrate that the elevation of intracellular cGMP during GnRH action does not mediate the release of LH by pituitary cells.     

Neonatal low-protein diet changes deiodinase activities and pituitary TSH response to TRH in adult rats

Protein malnutrition during neonatal programs for a lower body weight and hyperthyroidism in the adult offspring were analyzed. Liver deiodinase is increased in such animals, contributing to the high serum triiodothyronine (T3) levels. The level of deiodinase activities in other tissues is unknown. We analyzed the effect of maternal protein restriction during lactation on thyroid, skeletal muscle, and pituitary deiodinase activities in the adult offspring. For pituitary evaluation, we studied the in vitro, thyrotropin-releasing hormone (TRH)-stimulated thyroid-stimulating hormone (TSH) secretion. Lactating Wistar rats and their pups were divided into a control (C) group, fed a normal diet (23% protein), and a protein-restricted (PR) group, fed a diet containing 8% protein. At weaning, pups in both groups were fed a normal diet until 180 days old. The pituitary gland was incubated before and after TRH stimulation, and released TSH was measured by radioimmunoassay. Deiodinase activities (D1 and D2) were determined by release of (125)I from [(125)I]reverse triiodothyronine (rT3). Maternal protein malnutrition during lactation programs the adult offspring for lower muscle D2 (-43%, P<0.05) and higher muscle D1 (+83%, P<0.05) activities without changes in thyroidal deiodinase activities, higher pituitary D2 activity (1.5 times, P<0.05), and lower TSH response to in vitro TRH (-56%, P<0.05). The evaluations showed that the lower in vivo TSH detected in adult PR hyperthyroid offspring, programmed by neonatal undernutrition, may be caused by an increment of pituitary deiodination. As described for liver, higher skeletal muscle D1 activity suggests a hyperthyroid status. Our data broaden the knowledge about the adaptive changes to malnutrition during lactation and reinforce the concept of neonatal programming of the thyroid function.