Prolactin studies in "functionless" pituitary tumours.

Hyperprolactinaemia was found in all 17 women and in one out of six men who presented with hypogonadism and a radiologically enlarged sella turcica but no other clinical endocrine dysfunction. Some of the women also had galactorrhoea. The greater the level of hyperprolactinaemia in these 18 patients the larger their sellae turcica except in two patients with unusual features. The sella turcica was usually asymmetrically enlarged and there was rearly an upward extension of tumour, though the sella floor often showed some erosion on tomography. An oral dose of bromocriptine suppressed the hyperprolactinaemia in mose patients at the same rate as in normal post-partum women. Nine of the 18 patients with hyperprolactinaemia had low basal luteinizing hormone (LH) levels. The LH responsiveness to 100 mug of LH-releasing hormone (LHRH) was tested in 12, and eight showed subnormal values. Of eight biopsy specimens obtained four showed acidophil granules on light microscopy, and in five granules of various sizes were seen on electron microscopy.     

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.     

Management of selected patients with hyperprolactinaemia by partial hypophysectomy.

Results are reported in 35 patients with prolactinomas who underwent pituitary surgery within the past five years. After surgery prolactin concentrations became normal in 26 patients and symptoms were alleviated, and nine normal pregnancies were achieved in seven women, including all those who had complained of infertility. Normal prolactin concentrations were restored in 16 of 17 patients with tumours 5-19 mm in diameter but in only six of 11 with tumours less than or equal to 4 mm and four of seven with tumours greater than or equal to 20 mm. Normal prolactin concentrations were restored in all those with preoperative concentrations below 1000 mU/l but in none of those with concentrations above 10 000 mU/l. Although not all of the patients were followed up for five years, hyperprolactinaemia did not recur in any patient whose prolactin concentration had returned to normal six weeks after surgery. This included 16 patients with macroprolactinomas (greater than 10 mm in diameter), who were followed up for from two to five years. These data contrast strikingly with those reported by others at similar stages of follow up and show clearly that partial hypophysectomy offers an acceptable alternative treatment for selected patients with prolactinomas.     

Development of pituitary adenoma in women with hyperprolactinaemia: clinical,endocrine, and radiological characteristics.

Sixty eight women referred for treatment of hyperprolactinaemia entered a three year follow up study to determine the clinical and endocrine course of the disease and its association with microadenoma of the pituitary. Details recorded before treatment included medical history, gonadotrophin and ovarian hormonal concentrations, and release of prolactin in response to protirelin (thyrotrophin releasing hormone), benserazide, cimetidine, and nomifensine. Sellar tomography was then performed yearly for three years in all women, 54 of them also undergoing computed coronal and sagittal tomography. At baseline evaluation 27 women showed radiological evidence of pituitary adenoma; at the end of the follow up period the number had increased to 41. Amenorrhoea, steady and raised serum prolactin concentrations, a low ratio of luteinising hormone to follicle stimulating hormone, a longer duration of disease, and low serum progesterone concentrations were more common in women with a final diagnosis of pituitary adenoma than in those whose sella remained normal. Tests for release of prolactin had yielded abnormal results from the outset in all 41 women with radiological evidence of pituitary adenoma and in about half of those whose sella had remained radiologically normal. Response to medical treatment (metergoline in 20 patients, bromocriptine in 21) was similar and showed no difference between patients with tumorous and non-tumorous hyperprolactinaemia. These findings suggest that a large proportion of women with hyperprolactinaemia may harbour a prolactin secreting pituitary adenoma which becomes apparent over a relatively short period. Amenorrhoea and steady and raised serum prolactin concentrations are more common in these women. Tests for release of prolactin are of predictive value in identifying women who will develop a pituitary adenoma.     

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.     

Effectiveness of pergolide mesylate in long term treatment of hyperprolactinaemia.

Twenty five patients with hyperprolactinaemia were treated with pergolide mesylate, a new dopamine receptor agonist. Twenty three received treatment for six to 20 months, and in all serum prolactin concentrations were considerably reduced. In most patients prolactin concentrations were maintained in the normal range by a low, once daily dose of pergolide and reversal of associated reproductive disorders was observed. Tumour volume as assessed by computed tomography decreased considerably during treatment in three out of four patients with a pituitary tumour. The drug was well tolerated. Side effects were similar to those of bromocriptine, but four out of eight patients who had been forced to stop taking bromocriptine because of untoward effects were subsequently able to tolerate treatment with pergolide. Pergolide mesylate promises to be a useful addition to the currently available long acting dopamine agonists in the management of hyperprolactinaemia.     

Empty sella in control subjects and patients with hypopituitarism

The frequency and distribution of various degrees of empty sellae have been examined in subjects without any pituitary disorder and in patients with hypopituitarism. Among them none had sellar enlargement. Sellar computed tomography (CT) with contiguous 2 mm slices (thickness in the axial projection) was performed in 56 control subjects. The CT findings on sella turcica were graded into 4 groups (0, 1+, 2+, and 3+), and grades 2+ and 3+ indicated moderate and marked empty sellae. Thirty-nine percent of the control subjects had empty sellae of grade 2+ or 3+. Sellar CT scans with contiguous 2 mm slices were also performed in 11 patients with hypopituitarism. The sellar volume ranged from 224 to 715 mm3. CT scan was carried out more than 2 years after the onset of hypopituitarism in 10 of 11 patients, and showed typical empty sellae of grade 3+ in all 10 patients. There was no empty sella in a patient with hypopituitarism whose CT scan was carried out 3 months after the massive postpartum hemorrhage. Our results indicate that moderate empty sella of grade 2+ can be seen in subjects without any pituitary disorder, and that a typical empty sella of grade 3+ is present in hypopituitarism with a normal sized sella turcica. An empty sella associated with hypopituitarism may be due to shrinkage of the pituitary gland related to its hypofunction.     

Empty sella following spontaneous resolution of a pituitary macroadenoma

BACKGROUND/AIM: Empty sella is a radiological finding characterized by the presence of arachnoid herniation into the sella, resulting in compression of the pituitary against the sella wall. The objective of this case presentation is to discuss secondary empty sella in a patient with spontaneous resolution of a pituitary macroadenoma. METHODS: A case of empty sella syndrome is presented. Static and dynamic testing was performed. Etiology, pituitary function, and imaging are discussed. RESULTS: A 69-year-old African-American woman was referred by her primary care physician for evaluation and treatment of 'hypothyroidisim'. Thyroid tests were performed because of muscle and joint tenderness and revealed low free thyroxine and normal thyroid-stimulating hormone levels. The diagnosis of secondary hypothyroidism was made, and magnetic resonance imaging (MRI) of the pituitary revealed an empty sella turcica. In retrospect, the patient had presented 11 years earlier with tinnitus, and an MRI of her auditory canals demonstrated an 'incidental' 1.5-cm pituitary tumor. No endocrine evaluation was done at that time, and neurosurgical follow-up of the pituitary tumor by serial MRIs demonstrated the genesis into empty sella. CONCLUSIONS: In our patient the natural history of her pituitary tumor was that it involuted and resulted in an empty sella. Although oftentimes speculated as a cause of empty sella, tumor involution has rarely been shown to be causative. In this instance, empty sella was associated with hypopituitarism. This case illustrates the importance of endocrine evaluation of patients with this radiological finding.     

Coexisting acromegaly and primary empty sella syndrome

The normal functions of the pituitary gland may be suppressed when the gland is compressed onto the sella floor by arachnoid tissue extending through an impaired sella diaphragm. Interestingly, pituitary hormone hypo- and hypersecretion, including acromegaly, have been observed in patients with an 'empty sella'(1-4). This 'empty sella syndrome' has been classified into a primary form, in which no inciting factor (pituitary irradiation or surgery for a pituitary tumor) is present, and a secondary form, in which the empty sella occurs after pituitary procedures. In this report we describe a patient who presented with clinical and biochemical features of acromegaly and who had an empty sella on pituitary magnetic resonance imaging (MRI).     

Results of dynamic endocrine testing of hypothalamic pituitary function in patients with a primary "empty" sella syndrome

A total of 52 patients (38 women, 14 men) with a primary "empty" sella syndrome underwent dynamic endocrine testing consisting of insulin-induced hypoglycaemia and a combined anterior pituitary stimulation test utilizing GnRH and TRH. The diagnosis of an "empty" sella turcica was made on the basis of thin collimation CT reconstructions and in addition either metrizamide cisternography or magnetic resonance (MR) imaging. Only 16 of the patients presented with endocrine problems. Hyperprolactinaemia was the most common endocrine disturbance detected, and was found in 17 individuals. Panhypopituitarism was found in 3 patients. Nine other patients had some degree of partial pituitary insufficiency, but only two of them required replacement therapy. However, 31 patients had no evidence of endocrine dysfunction.     

Treatment of presumed prolactinoma by transsphenoidal operation: early and late results.

Seventy seven patients who were presumed to have a prolactinoma on the basis of biochemical findings underwent transsphenoidal operation between October 1977 and September 1983. Sixty one patients were found to have a microadenoma, and hyperprolactinaemia was cured in 46 of these, amenorrhoea in 39 (80% of those with the symptom), galactorrhoea in 32 (80%), and infertility in 31 (82%). Four of eight patients found to have a macroadenoma were also satisfactorily treated with surgery. Two patients had a lesion other than a prolactinoma, and in six a tumour could not be found at operation; four of these last eight patients had a normal serum prolactin concentration after operation. Recurrent hyperprolactinaemia was rare, occurring in only three patients in the series overall; among the 32 patients followed up for more than five years only two of the 22 whose operation had initially been successful developed recurrent hyperprolactinaemia.     

Effects of bromocriptine on pituitary tumour size.

In a prospective study designed to assess the influence of bromocriptine on pituitary tumour size 12 patients with pituitary tumours, eight of whom had suprasellar extensions, were treated for three months with 20 mg of bromocriptine daily after a gradual increase to this dose. The group comprised eight women and four men, five with prolactin-secreting adenomas, four with acromegaly, two with functionless adenomas, and one with Nelson''s syndrome. All five patients with prolactin-secreting adenomas showed a reduction in pituitary tumour size as assessed by computerised tomography and metrizamide cisternography accompanied by a fall in prolactin concentrations and clinical and biochemical improvement in their hypopituitarism. One patient in this group had a visual-field defect before treatment, and this resolved. There was no radiological evidence of reduction in tumour size in the remaining seven patients, though this might refect the fairly short duration of treatment, particularly in view of the ancillary evidence of clinical, biochemical, and visual-field improvement in some of the patients. These results emphasise the potential value of bromocriptine in treating patients with large prolactinomas or recurrences of such tumours after previous chiasmal decompression and conventional external megavoltage irradiation on the pituitary.     

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.     

May primary empty sella turcica be a cause of isolated ACTH deficiency? A case report and the review of related literature

Isolated ACTH deficiency is an uncommon cause of secondary adrenocortical insufficiency and accompaniment with primary empty sella has been reported in several cases. We present a case of isolated ACTH deficiency associated with empty sella. A sixty-two year old woman was admitted to our endocrine clinic with complaints of weakness, fatigue, weight loss, nausea, vomiting, and lack of appetite for about one month. Physical examination indicated orthostatic hypotension and epigastric tenderness. Laboratory investigations revealed hypoglycemia, hyponatremia and anemia, in addition low plasma cortisole and ACTH levels. Serum cortisole responses to short and prolonged ACTH stimulation were tested and partial and accurate responses were obtained, respectively. Plasma ACTH and serum cortisole levels failed to respond after intravenous injection of human corticotropin releasing hormone. Other hypophysial hormone levels were within the normal reference ranges. Although cranial and abdominal computerized tomography images were evaluated as normal, cranial magnetic resonance imaging of the pituitary gland revealed 'primary empty sella turcica'. Replacement therapy with methylprednisolon resulted in the improvement of hypoglycemia, hyponatremia and clinical symptoms. Based on these results, the patient was diagnosed as isolated ACTH deficiency and was scheduled for follow up by our outpatient clinic. Our report is consistent with other reports pointing out that primary empty sella may be responsible for pathogenesis of isolated ACTH deficiency.     

Primary empty sella with isolated ACTH deficiency and microprolactinoma

The empty sella turcica is defined as the herniation of the subarachnoid space within the sella with displacement of the pituitary towards the posteroinferior wall. By autopsy studies, the incidence in the general population is around 20%. The association of prolactinoma and empty sella has been coincidental & infrequently reported. As such for microadenoma, visual field testing and screening for hypopituitarism is not needed, but if it is associated with empty sella, both visual field testing and screening for hypopituitarism is necessary.     

Treatment of Nelson's syndrome by pituitary implantation of yttrium-90 or gold-198.

Eight patients with Nelson''s syndrome were treated with a pituitary implant of yttrium-90 or gold-198 four to 16 years after adrenal surgery. All had considerable pigmentation. One already had cranial nerve abnormalities and visual field defects and had had both a craniotomy and deep x-ray treatment. Radiographs showed that the pituitary fossa was abnormal in seven patients. A biopsy performed in six cases showed mucoid (or basophil) adenoma in all. In the four specimens examined ACTH was identified by electron microscopy or immunofluorescence, or both. Patients were followed up after pituitary implantation for three months to 12 years. All showed decreased pigmentation, and six became normal. Four patients regained normal ACTH levels and the other two studied had decreased levels. In no case did new cranial nerve disease or further sellar expansion develop since operation, and two patients showed remodelling of the sella. Complications were temporary leakage of cerebrospinal fluid and diabetes insipidus in one patient and gonadotrophin deficiency in another.     

Functional evaluation of the adenohypophysis with metoclopramide in hyperprolactinemic-amenorrheic women in relation to radiological findings on the sella turcica

The responses of the adenohypophyseal hormones to metoclopramide (MCP) were evaluated in hyperprolactinemic women with various radiological findings on the sella turcica. Serum PRL concentrations significantly increased after MCP administration in normal women, hyperprolactinemic patients with normal sella and patients with microadenoma, but not in macroadenoma patients with and without suprasellar expansion (SSE). The PRL response to MCP administration was significantly lower in hyperprolactinemic patients than in normal women. Serum TSH concentrations significantly increased after MCP administration in each group of subjects. The TSH response to MCP was significantly higher in patients with normal sella and patients with microadenoma than in normal women. However, the responses of PRL and TSH to MCP were not significantly different between patients with normal sella and patients with microadenoma. Therefore, they were not considered useful in distinguishing tumorous from nontumorous hyperprolactinemia. Serum LH concentrations significantly increased after MCP administration in patients with normal sella, patients with microadenoma and macroadenoma patients without SSE, but not in normal women or macroadenoma patients with SSE. The LH response to MCP was significantly higher in patients with microadenoma than in patients with normal sella. Serum FSH concentrations significantly increased after MCP administration only in patients with microadenoma. The different responses of the adenohypophyseal hormones to MCP in hyperprolactinemic women with various radiological findings on the sella turcica may be explained by the difference in the hypothalamic dopamine activity and in the impairment of the hypothalamic-pituitary system due to pituitary tumor.     

Male hypothalamic hypogonadism: induction of spermatogenesis by subcutaneous pulsatile gonadotrophin-releasing hormone

Six male patients (aged 21-34 years) with isolated hypothalamic hypogonadism were given subcutaneous pulses of gonadotrophin-releasing hormone every 90 min for 14-74 weeks. The therapy produced an increase in testicular volume (4 patients) and a rise in serum luteinizing hormone, follicle-stimulating hormone, and testosterone levels in every patient. Motile sperm developed in 3 patients after a mean of 17 weeks, but were not seen in other patients who were less sexually developed after a mean of 31 weeks of therapy. Computerized tomography scans of the pituitary fossa revealed an empty sella in 4 patients and a partially empty sella in 2. Subcutaneous pulsing of gonadotrophin-releasing hormone is a simple and safe way of inducing spermatogenesis, but it is more likely to be successful in patients whose pubertal development is otherwise near completion. Previous human chorionic gonadotrophin and/or testosterone treatment does not interfere with and may benefit subsequent gonadotrophin-releasing hormone therapy.     

Asymptomatic primary empty sella in a 14-year-old girl: comparison of computer tomography and nuclear magnetic resonance imaging

An enlarged, balloon-shaped sella was detected by chance in a completely asymptomatic 14-year-old girl, who presented with tall stature. While all endocrine functions were found to be normal, metrizamide cisternography with computer tomography revealed a flattened pituitary at the bottom of an empty sella. This could be compared later with nuclear magnetic resonance tomography, thus avoiding intrathecal contrast material and radiation exposure for the patient. The new technique depicts the sellar contents very well.     

Pregnancy in patients presenting with hyperprolactinaemia.

Ninety-two pregnancies occurred in 76 hyperprolactinaemic patients treated with bromocriptine. Half conceived within three months of attempted conception. There was no evidence of an increased rate of spontaneous abortion, fetal abnormality, or multiple pregnancy; the three twin pregnancies occurred in women who were additionally treated with clomiphene and human chorionic gonadotrophin. Thirty-one patients had radiological evidence of a pituitary tumour; 14 with major radiograph changes in the pituitary fossa or serum prolactin concentrations greater than 100 ng/ml received pituitary irradiation before conception. None of the latter showed evidence of enlargement of the tumour during pregnancy. In contrast two of the four patients with similar tumours but who were not irradiated developed visual field defects, one with gross destruction of the pituitary fossa. Prophylactic treatment to limit subsequent tumour expansion during pregnancy in patients with prolactinomas is indicated, and pituitary irradiation before conception appears to be a safe and effective method to achieve this goal.