Coexistent empty sella and prolactin-secreting microadenoma

The empty sella turcica may be found in people with no antecedent history of intracranial disease, as well as in those with known pituitary pathology or following therapy to the pituitary gland. We have evaluated 3 women with galactorrhea and hyperprolactinemia, 2 of whom had amenorrhea. Each had an empty sella. In all cases polytomograms demonstrated asymmetry of the sella floor with focal bony erosion, conventional pneumoencephalography showed intrasellar air, and polytomographic pneumoencephalography confirmed air limited to one side of the pituitary fossa with tumor and/or residual normal tissue on the opposite side. In 2 patients who had extensive endocrine evaluation, pituitary function was normal with the exception of hyperprolactinemia. Transsphenoidal excision of microadenomas resulted in postoperative normalization of the serum prolactin concentration and resumption of regular menses in the previously amenorrheic women.     

Hypothalamic-pituitary function and radiographic evaluation of women with hyperprolactinemia and an "empty" sella turcica.

A primary "empty" sella may be associated with significant hypothalamic-pituitary dysfunction. This report characterizes the endocrinologic and radiographic findings in six patients with hyperprolactinemia (range 34.3 to 1,170 ng/ml) ultimately found to have an enlarged empty sella. Lateral skull x-ray films and thin-section tomograms were suggestive of pituitary tumors in all patients. Four patients underwent transphenoidal sellar exploration after pneumoencephalography (PEG) failed to demonstrate air within the sella. The inability of PEG to demonstrate an empty sella in two patients was explainable on the basis of an intact diaphragma sellae with previous transient intrasellar pathology responsible for the sellar enlargement. Dynamic hypothalamic-pituitary testing yielded no consistent pattern of response. These studies suggest that an empty sella: (1) may be associated with hyperprolactinemia, regardless of etiology, (2) is not diagnosable by dynamic hormonal testing, and (3) may be indistinguishable from a pituitary tumor by current radiographic techniques.     

Galactorrhea and hyperprolactinemia during treatment of polycystic ovary syndrome

The serum concentration of prolactin and the presence of galactorrhea were evaluated systematically in a prospective study of the effect of medroxyprogesterone acetate (MPA) in polycystic ovary syndrome (PCO). In 21 patients, the diagnosis of PCO was made by laparoscopy. Three women presented with galactorrhea and increased prolactin levels, 2 had galactorrhea with normal prolactin levels, and 3 had an isolated elevation in the serum concentration of prolactin. Treatment with MPA induced galactorrhea in 10 additional patients. Elevated levels of prolactin were detected in 18 of the patients during treatment. There was no correlation between the score for galactorrhea and the level of prolactin. Tomograms of the sella turcica were abnormal in 3 of 8 patients with hyperprolactinemia. The authors conclude that galactorrhea and/or hyperprolactinemia are important side effects of MPA in patients with PCO.     

A practical approach for the evaluation of women with abnormal polytomography or elevated prolactin levels

Based upon the experience gained in the evaluation of 60 patients with abnormal polytomography and/or elevated prolactin levels, the following observations can be made: Patients with amenorrhea, amenorrhea and galactorrhea, galactorrhea alone, or anovulatory cycles and infertility may or may not have pituitary tumors. Clinical symptoms do not always correlate with the prolactin level, and patients with normal prolactins may have pituitary tumors. The incidence of empty sella is significant (15.8% in this series). Visual field examination is not a useful screening procedure, but evaluation of thyroid function is important to detect the occasional patient with hypothyroidism (3.5% in this series). The insulin tolerance test is not helpful in detecting the presence of pituitary tumors or in guiding management decisions, and the CT scan contributes little and should be omitted from the evaluation process. A straightforward, economical, and efficient approach to this clinical problem is presented.     

Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.     

The effect of multiparity on intrasellar prolactinomas

A complete reassessment of ovulation, pituitary reserve and function, and sella turcica anatomy was carried out in nine multiparous patients with intrasellar prolactinomas to determine whether long-term bromocriptine therapy was required and to document the natural history of the disease after two or more pregnancies. After the last pregnancy, bromocriptine was discontinued and pituitary function and anatomy and prolactinoma activity were reassessed with documentation of ovulation (basal body temperature graphs and menstrual history), search for fat droplet-positive galactorrhea, pituitary fossa tomography, computerized tomographic scan, triple-bolus testing, and visual fields. These data were compared with a similar workup carried out prior to the first pregnancy. Three groups of eventual outcomes were identified radiologically. Anterior pituitary gland function and reserve remained normal in all, and no neurological sequelae were noted. Four patients did not require long-term treatment. A hypothesis of autoinfarction of the adenoma is raised, since three patients were shown to have empty sellae.     

Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea

Over a period of two and a half years, 34 women with galactorrhea or amenorrhea, all with an abnormal sellar polytomogram, underwent transsphenoidal microsurgical exploration of the sella. Eighteen women and microadenomas (less than or equal to 1 cm. in diameter), seven had macroadenomas (greater than than 1 cm. in diameter), and five had unidentified lesions. Only one women had a normal pituitary gland. Three women had cryosurgery without biopsy. Preoperatively, hyperprolactinemia occurred in 24 of 25 women with adenomas and two of five with nonadenomatous lesions. There were no operative deaths. Significant morbidity occurred in only three patients, none of whom had microadenomas. Postoperatively, menses resumed in 16 of the 17 women with microadenomas and in two of the seven with macroadenomas who presented with amenorrhea. Galactorrhea disappeared in 15 of the 17 women with microadenomas and in four of the seven with macroadenomas who presented with galactorrhea. In five patients with unidentified lesions, a return of menses occurred in two of four with previous amenorrhea, and galactorrhea abated in two of three who presented with lactation. We conclude that sellar polytomography in women with hyperprolactinemia is a useful technique technique for the diagnosis of pituitary adenomas, a lesion which may occur more frequently than previously realized. In addition, transsphenoidal microresection of microadenomas is safe and effective.     

Hyperprolactinemia and polycystic ovarian syndrome.

Prolactin and pituitary gonadotropin levels were studied in eight patients with polycystic ovarian syndrome. All women were of reproductive age and had had menstrual disorders since menarche. Three patients had hyperprolactinemia with or without galactorrhea and tomograms of the sella turcica revealed pituitary microadenomas. The remaining five patients with normal baseline prolactin levels had a prolactin stimulation test which used 25 mg of thorazine per os, and a prolactin suppression test using l-dopa 500 mg per os. Analysis of the results of these tests and a comparison with tests performed in five normal individuals used as controls showed significantly different responses in the two groups of women. The preliminary information obtained indicates that an abnormal prolactin secretion status may exist in the polycystic ovarian syndrome.     

Dissociation of serum prolactin response to sequential thyrotropin-releasing hormone and chlorpromazine stimulation in patients with primary empty sella syndrome

The presence of galactorrhea and/or hyperprolactinemia in patients with the primary empty sella syndrome (PESS) has been proposed to be of hypothalamic etiology. To further elucidate this possible mechanism, sequential testing of 19 subjects with PESS with 500 micrograms thyrotropin-releasing hormone (TRH), followed by the injection of 0.7 mg/kg chlorpromazine (CPZ) 150 minutes later, was compared with results obtained in 6 patients with idiopathic galactorrhea (IG) and 3 normal adult women in the early follicular phase of the menstrual cycle. The thyroid-stimulating hormone and prolactin (PRL) response to TRH was similar in all three groups. The mean maximal increase of serum PRL following CPZ, however, was 16.1 +/- 18.5 ng/ml (standard deviation) in the PESS group, whereas the mean maximal PRL response was 68.6 +/- 40.9 ng/ml in subjects with IG and 67.7 +/- 48.1 ng/ml in the seven normal women. The impaired responsiveness of CPZ in the PESS group was significant (P less than 0.05) when compared with the normal CPZ response in the other two groups. The results of this study suggest that patients with PESS may have hypothalamic dysfunction, and that sequential testing of subjects with TRH and CPZ may be of value in differentiating patients with PESS from those with IG.     

Evaluation of the pituitary. Patients with suspected prolactin-producing tumors

We have reviewed our experience in the radiographic and ophthalmologic evaluation of 1001 patients with symptoms suggesting the presence of a pituitary, prolactin-secreting adenoma. Twenty-seven patients had abnormal or suspicious radiographic examination of the sella turcica. Twenty-two of those had hyperprolactinemia. In only one instance was an abnormality noted on polytomography that was not seen on a conventional four-view study of the skull. Based on these findings, a four-view plain conventional radiographic assessment of the skull suffices as a screening procedure in patients with amenorrhea, galactorrhea, or both. Thin section tomography should be reserved to more thoroughly evaluate those patients with elevated serum prolactin concentrations and/or abnormal conventional radiographs. We found visual field testing to be of little value as an initial screening procedure in these patients.     

Serum prolactin levels in galactorrhea.

Some patients with galactorrhea will have normal serum prolactin levels but many will have elevated serum prolactin levels. The galactorrhea may be due to drug ingestion, nipple afferent nerve stimulation, nonneoplastic disease or injury, and intracranial tumors. Serum prolactin levels were measured by radioimmunoassay in 17 women with galactorrhea. Levels 5 and 6 times normal values were found in two women who had proved pituitary adenomas. The latter conditions must be strongly considered and functional tests may help in diagnosis prior to enlargement of a prolactin-secreting tumor to the size where changes in the sella are seen on x-ray or visual field changes occur. If galactorrhea persists when no evidence of tumor can be found, the patient must be periodically re-evaluated, as the tumor may have been too small for detection at the time of the previous examination.     

Clinical response to CB-154 and the pituitary response to thyrotropin-releasing hormone-gonadotropin-releasing hormone in patients with galactorrhea-amenorrhea.

Ten patients with galactorrhea and amenorrhea were treated with 2-bromo-alpha-ergocryptine (CB-154). All patients had normal anteroposterior and lateral x-rays of the sella turcica and normal or low gonadotropin levels. Before treatment, serum prolactin (PRL) levels were between 80 and 1575 ng/ml. Prior to initiating therapy, six patients were further evaluated by the intravenous administration of thyrotropin-releasing of a pituitary etiology in all patients. During treatment, PRL levels were measured at monthly intervals. After 1 month, serum PRL concentrations were reduced between 13% and 99%. In eight subjects there was complete cessation of galactorrhea. During treatment, nine patients resumed ovulatory menstrual cycles and three patients conceived. After discontinuing therapy, five of seven subjects had a recurrence of galactorrhea, amenorrhea, and hyperprolactinemia.     

Spontaneous regression of prolactin-producing pituitary adenomas

Two women evaluated for amenorrhea, galactorrhea, and hyperprolactinemia had radiographic changes of the sella turcica (localized erosion on trispiral tomography) suggestive of a pituitary tumor. Both patients experienced spontaneous regression of apparent prolactin-secreting adenomas with a marked decrease in the quantity of galactorrhea and a reduction of serum prolactin concentrations to the normal range. One patient noted a marked improvement of headaches and spontaneous menses resumed in the other patient.     

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.     

Computed tomography of the brain in patients with serum prolactin levels over 200 ng/ml.

We reviewed the computed tomographic (CT) findings of the sella turcica in 26 patients with a serum prolactin level of over 200 ng/ml. The interval between the dates of CT examination and checking of the serum prolactin level were within 2 months. There were 24 nonpregnant women with a mean age of 30 years and 2 men with a mean age of 28.5 years. None of them were taking medication known to cause an elevation in serum prolactin levels. Surgery was performed on 8 patients with chromophobe adenomas of the pituitary gland: 6 of them were proven to have prolactin-secreting tumors (prolactinomas) after performing a special stain, and the remaining 2 patients, clinically diagnosed as prolactinomas, showed extremely high serum prolactin levels (3,200 and 2,251 ng/ml, respectively). CT studies showed that the height of the pituitary gland in the coronal sections were more than 7 mm in 15 cases (58%) and more than 10 mm in 13 cases (50%); focal bulging of the diaphragma sellae in 16 cases (62%); erosion of the sellar floor in 20 cases (77%); deviation of the pituitary stalk in 19 cases (73%); and abnormal attenuation or enhancement of the pituitary gland in 18 cases (69%). Three patients (12%) showed no evidence of any abnormal CT finding despite a hyperprolactinemic state of over 200 ng/ml. Six histologically proven cases (23%) of prolactinomas and chromophobe adenomas showed radiologic evidence of cavernous sinus invasion. We conclude that patients with a serum prolactin level higher than 200 ng/ml generally show significant changes in the sella turcica in CT.     

Outcome and long-term effects of pregnancy in women with hyperprolactinaemia.

Twenty-four women with high circulating prolactin became pregnant on 39 occasions, of which 32 ended in delivery. Sixteen patients showed radiological evidence of pituitary tumour, 6 exhibited a normal CT and 2 had an empty sella. The pregnancies were induced in 4 patients after successful pituitary surgery, in 3 after surgery and medical treatment, and in the rest by bromocriptine (16) long-acting repeatable bromocriptine (1) and methergoline (1). No major complications related to hyperprolactinaemia or its treatment were observed during pregnancy in the patients or offspring. Prolactin after pregnancy was lower than before (basal 95 micrograms/l, after 1st pregnancy 38 micrograms/l P < 0.002, after 2nd pregnancy 24 micrograms/l P < 0.005 compared to basal prolactin); this prolactin reduction tended to be greater in the 9 multiparous patients, but did not attain statistical significance, probably because the number of multiparous patients was too small. A new empty sella developed after delivery in 4 women and persisted in another 2, all of which were medically treated; prolactin fell in all 6 cases normalizing in 3; 4 of these patients had undergone two or more pregnancies. The mean period of follow-up from the last pregnancy was 41.6 months (8-101). These data suggest that pregnancy may hasten a tendency to spontaneous improvement of hyperprolactinaemia, and multiparity may be beneficial in this way.     

Macroprolactinomas with suprasellar extension: effect of bromocriptine withdrawal during one or more pregnancies.

OBJECTIVE: To investigate the effects of bromocriptine withdrawal during one or more pregnancies in patients who presented with pituitary macroprolactinomas with suprasellar extension. DESIGN: Four infertile patients presenting with a macroprolactinoma with suprasellar extension conceived during treatment with bromocriptine on 10 occasions resulting in eight full-term normal deliveries. Treatment was withheld shortly after conception in each pregnancy. RESULTS: Serum prolactin (PRL) levels fell initially from a mean of 2,776 (range 1,682 to 4,515) to 27 micrograms/L (range 1 to 71) with the development of a partially empty sella in all patients. Recovery of visual field defects occurred in the only affected individual. In case 1, PRL levels remained within the normal range, after bromocriptine withdrawal in the first pregnancy, with the development of an empty sella. Prolactin levels, however, increased substantially in cases 2 to 4. An asymptomatic suprasellar tumor extension returned in cases 2 and 3. After two or more pregnancies (cases 1, 3, and 4), there was a progressive decline in the serum PRL levels. Although still elevated in cases 3 and 4, the PRL levels were considerably below those obtained at presentation or in the first pregnancy. Tumor regression with the development of an empty sella was observed in both these patients as well in their pregnancy or postpartum period. CONCLUSIONS: Bromocriptine may be safely withdrawn during pregnancy in patients presenting with a macroprolactinoma. With multiple bromocriptine induced pregnancies, PRL levels and tumor size may progressively decrease with the eventual development of an empty sella.     

Anorexia nervosa in woman with Turner's syndrome

The authors report a case of anorexia nervosa in woman with Turner's syndrome (45, X). In this case there was a low blood concentration of LH and FSH, and there was a lack of reaction to intravenous administration of 100 micrograms of GnRH. Partial syndrome of "empty sella" was found in a presented case by use of magnetic resonance imaging. There was a connection between the onset of anorexia nervosa and the tragic death of the patient's father. The inconsiderate start with HRT aggravated a course of a anorexia nervosa. The authors considered the plausible existence of relations between "empty sella" and the development of anorexia nervosa.     

Galactorrhea and hyperprolactinemia

Galactorrhea refers to the secretion of a milky fluid from the breast, occurring either spontaneously or with manual expression, in the absence of pregnancy or the postpartum state. The development of a sensitive and specific radioimmunoassay for human prolactin during the last decade along with improved neuroradiologic techniques have greatly expanded understanding of nonpuerperal lactation. Discussion reviews the pevalence of galactorrhea, the etiology of hyperprolactinemia and/or galactorrhea, pituitary tumor, parapituitary lesions, oral contraceptive (OC) associated galactorrhea, drug induced galactorrhea, hypothyroidism, neurogenic stimulation, idiopathic galactorrhea, clinical features of galactorrhea, laboratory evaluation, neuroradiologic evaluation, hypocycloidal tomography, carotid angiography, pneumoencelphalography (PEG), computerized tomography (CT), management, and therapy. The prevalence of galactorrhea in women is reported to range from 0.1-32%. Much of this variability can be attributed to differences in examination techniques, the investigator's definition of galactorrhea, and the patient population studied. Nonpuerperal hyperprolactinemia is an important cause of galactorrhea and is found in 49-77% of cases, but hyperprolactinemia does not appear to be the sole prerequisite for galactorrhea since only 15-68% of patients with excessive prolactin secretion develop galactorrhea. Pituitary tumors are the most important diagnostic consideration have been reported in approximately 20% of cases of galactorrhea and 34% of cases of amenorrhea galactorrhea. Parapituitary lesions, an infrequent but important cause of hyperprolactinema and galactorrhea, can result in excessive prolactin secretion by interfering with either the production or delivery of prolactin inhibitory factor to the lactotrope cells of the anterior pituitary gland. OC associated galactorrhea is a frequent diagnosis in patients with nonpuerperal lactation and has been implicated in 10-14% of cases. OC discontinuation can also produce galactorrhea. Pharmacologic agents are a common cause of hyperprolactinemia and/or galactorrhea. A variety of forms of neurogenic stimulation have been linked to hyperprolactinemia and/or galactorrhea. Idiopathic galactorrhea is a diagnosis of exclusion and is applicable to 40-50% of patients with nonpuerperal lactation. In patients with galactorrhea, the presence of the abnormal, milky breast secretion may be the sole symptom or it may be associated with other pertinent clinical findings. All patients with galactorrhea should have measurements of thyroid stimulating hormone and serum prolactin performed. The optimal management of patients with prolactinomas is somewhat controversial. Surgical resection remains the most definitive form of therapy with the transsphenoidal approach most frequently used. Recent invesitgations show promise for bromocriptine as an alternative therapeutic modality.     

Primary empty sella syndrome and amenorrhea.

The empty sella syndrome is defined anatomically and radiologically. A case report of an amenorrheic patient who was diagnosed as having the primary empty sella syndrome is presented. Its pathogenesis, clinical profile, and endocrine relationships are discussed. Specific reference is directed toward the capability of the empty sella syndrome to produce pituitary impairment and possibly amenorrhea.