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.     

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.     

The incidence of complications during pregnancy after treatment of hyperprolactinemia with bromocriptine in patients with radiologically evident pituitary tumors.

The course of pregnancy achieved after bromocriptine therapy is described in nine patients with radiologically evident prolactin-secreting pituitary tumors. In six patients no complications occurred. No changes in sellar size or secondary endocrine deficiencies developed. In three patients, however, complications developed between the 22nd and 24th weeks of pregnancy. Despite prior external pituitary irradiation, one patient developed transient bitemporal hemianopsia and one patient had apoplexy of the pituitary tumor with transient paresis of the left abducens nerve. A third patient developed parasellar expansion of the pituitary tumor with bone destruction and paresis of the right abducens and oculomotor nerves. After transsphenoidal surgery the paresis of both nerves disappeared. Microscopically, the tissue removed at surgery was a chromophobe adenoma with focal fibrosis and calcifications without recent hemorrhages. In the course of more than 100 pregnancies achieved in The Netherlands after bromocriptine therapy, five patients reportedly developed complications of the pituitary tumor. At present, patients in whom complications can be expected cannot be predicted by the size or configuration of the sella turicica or the magnitude of elevation of the plasma prolactin level. In two patients external pituitary irradiation did not prevent complications during pregnancy.     

Prolactin-secreting pituitary microadenoma: detection and evaluation

Eleven women with secondary amenorrhea associated with hyperprolactinemia were studied. Base line evaluations, visual field determinations, and routine sella turcica x-rays were normal. Prolactin-secreting pituitary microadenomas were found in all of the patients only after further diagnostic studies were carried out. These studies included polytomography of the sella turcica; dynamic pituitary testing of growth hormone reserve, adrenocorticotropic hormone reserve, and gonadotropin reserve; and prolactin suppression with L-dopa. The early diagnosis of a small prolactin-secreting adenoma may be possible if several diagnostic criteria are utilized. The most sensitive diagnostic indices available are (1) polytomography, (2) the magnitude of the plasma prolactin elevation, and (3) the failure to suppress prolactin secretion with L-dopa. Our findings emphasize the importance of an extensive evaluation of all women with amenorrhea associated with hyperprolactinemia.     

Evaluation and treatment of patients with prolactin-secreting pituitary tumors

Six women with secondary amenorrhea and hyperprolactinemia, four of whom had associated galactorrhea, were studied. Four were found to have prolactin-secreting pituitary microadenomas and two had macroadenomas. Suppression of prolactin secretion and stimulation of prolactin, serum growth hormone and thyroid-stimulating hormone secretion were studied, and gonadotropin and adrenocorticotropic hormone reserves were evaluated. The most sensitive techniques available for the diagnosis of pituitary adenomas in patients with amenorrhea and hyperprolactinemia appear to be the measurement of the magnitude of plasma prolactin elevation and hypocycloidal tomography of the sella turcica. The dynamic function tests proved to be of little diagnostic, but of great prognostic, value for patients with small pituitary tumors.     

Prolactin response to perphenazine. A sensitive and specific test for pituitary tumor in hyperprolactinemic women

A simple biochemical screening test for prolactin-secreting pituitary tumors is needed because computed tomography is expensive and may be insensitive in the detection of microadenomas. We compared serial prolactin levels following perphenazine stimulation in 20 women with histologically documented tumors to those in 22 normal controls. In addition, seven women who were diagnosed as having functional (nontumor) hyperprolactinemia were tested. All subjects were given perphenazine, 8 mg orally. Baseline and hourly serum prolactins for six hours were compared. A 200% or greater response occurred in all control patients and functional hyperprolactinemic subjects within six hours following medication. Without exception, tumor patients exhibited a markedly blunted or absent response. This markedly diminished response pattern was compatible with the presence of a pituitary adenoma and suggests that the presence of a tumor interferes with normal pituitary secretory responsiveness.     

Spontaneous pregnancy after a pregnancy induced by treatment in hyperprolactinemic women

The relationship between spontaneous pregnancy of hyperprolactinemic patients after a first pregnancy induced by treatment and their serum prolactin levels was examined. Of the 100 patients with hyperprolactinemia studied, 74 became pregnant after treatment; namely, 20 transsphenoidal adenomoidectomy for pituitary prolactinoma (group 1), 26 on treatment with bromocriptine for pituitary prolactinoma (group 2), and 28 on treatment with bromocriptine for hyperprolactinemia without prolactinoma (group 3). After delivery in the first pregnancy, the rates of menstrual restoration and subsequent spontaneous pregnancy in group 1 (72.2% and 75.0%) were significantly (p less than 0.05) higher than those in group 2 (32.0% and 25%) and group 3 (13.6% and 18.2%). The serum levels of prolactin after the first pregnancy and weaning were significantly (p less than 0.05) lower in patients with subsequent spontaneous pregnancy than in patients without spontaneous pregnancy in each group, and the levels in patients with spontaneous pregnancy were significantly (p less than 0.05) lower in group 1 (15.2 +/- 8.8 ng/ml) than in group 2 (46.6 +/- 2.9 ng/ml). These data suggest that the transsphenoidal adenomoidectomy for pituitary prolactinoma may be better than bromocriptine treatment for recovery of reproductive function.     

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.     

Diagnosis of prolactin-secreting pituitary microadenoma.

Four women with secondary amenorrhea associated with hyperprolactinemia were studied. Baseline hormonal evaluation, including serum FSH, serum LH, TSH, T3, T4, and plasma cortisols were normal. Plain sella turcia x-rays were also normal. Prolactin-secreting pituitary microadenomas were found in all of the patients only after further diagnostic studies were done. These studies included polytomography of the sella turcia, dynamic pituitary testing of growth hormone reserve, ACTH reserve, gonadotropin reserve, and prolactin suppression with L-dopa. The early diagnosis of a small prolactin-secreting adenoma may be possible if several diagnostic criteria are ulilized. The most sensitive techniques available are: (1) polytomography, (2) the magnitude of plasma prolactin evaluation, and (3) the failure of suppression of prolactin secretion with L-dopa. Our findings emphasize the importance of an extensive evaluation of all women with amenorrhea associated with hyperprolactinemia.     

Hypothalamic-pituitary function following bromocriptine therapy in patients with prolactinomas

Bromocriptine in a dose of 5 mg daily was given to 18 patients with prolactinomas to promote resumption of menses, to overcome infertility and as a primary treatment for the tumor. Serum prolactin levels fell to within the normal range in 95% of the patients by 12 weeks of therapy. The prolactin response to TRH stimulation was significantly less than before treatment; however, the percent maximum increment was significantly higher. There was no significant change in pituitary reserve of the other hormones. Seven pregnancies occurred during treatment. All the pregnancies have been progressing normally. All patients have already been delivered of healthy babies, including one set of twins. It is suggested that follow-up studies of the various pituitary hormones be conducted on patients on maintenance bromocriptine treatment. In addition, bromocriptine treatment might be used to promote fertility in patients with prolactin-secreting microadenomas.     

Pregnancies in women with hyperprolactinaemia: clinical course and obstetric complications of 41 pregnancies in 27 women.

Observations are reported on 41 pregnancies in 27 patients who initially had infertility and raised serum prolactin concentrations. Associated symptoms were secondary amenorrhoea (81 per cent) and galactorrhoea (81 per cent). All patients were at risk of pituitary expansion during pregnancy, especially these 19 (70 per cent) with radiological evidence of pituitary tumours. Fifteen patients had 21 pregnancies after pituitary implantation with 90yttrium; 14 patients had 20 pregnancies without prior pituitary implantation or any other attempt to prevent tumour expansion. During pregnancies, tumour enlargement as shown by diminished visual acuity, visual field defects, severe headaches, diabetes insipidus and radiological changes occurred only in 3 of the 14 patients who had not had implants. Two patients who became pregnant both before and after pituitary implantation suffered tumour expansion in their pregnancies before implantation, but not when pregnant after the operation. The induction and Cesarean section rates were about 30 per cent in 32 term pregnancies in 25 patients. Details of how pregnancy was achieved and the associated obstetric problems are given.     

Clinical endocrine investigations in patients with pituitary adenoma (author's transl)]

LH-RH tests of hypothalamo-pituitary gonadotropinfunction were performed in 26 patients with pituitary adenomata before and after prolactin suppression and/or surgical treatment. Various degrees of galactorrhea together with menstrual disorders were the key symptoms in all patients. There was a significant association of elevated prolactin levels with impaired LH-responses. Seven patients have undergone transspenoidal dissection of the pituitary adenoma and in five of them the pituitary LH-response reverted to normal (R2) after surgery. Nine of 15 amenorrhoic patients had a recurrence of menstrual cyclicity, partly biphasic within 3 months and a normalized LH-response after Bromocriptin therapy. 19 of our patients were desirous of pregnancy. Five pregnancies were confirmed within 4 months of treatment.     

Computed tomography versus magnetic resonance imaging for the evaluation of suspected pituitary adenomas

The purpose of this study was to evaluate and compare thin-section magnetic resonance imaging (MRI) and high-resolution computed tomography (CT) in patients with suspected pituitary adenomas. Twenty-two patients (19 women and three men) with hyperprolactinemia (N = 16), increased growth hormone secretion (N = 2), increased corticotropin secretion (N = 1), and nonsecreting adenomas (N = 3) were studied with both contrast-enhanced, high-resolution CT scanning and thin-section MRI. Contrast-enhanced examinations consisted of contiguous 1.5-mm coronal sections during contrast infusion. The MRI examinations consisted of spin-echo T1- and T2-weighted sequences with a 2.5-3.0-mm slice thickness on the coronal and sagittal planes. Fourteen women had similar findings on CT and MRI (four macroadenomas, six microadenomas, one wide stalk, two empty sellas, and one normal study). The remaining eight subjects had conflicting results: CT findings were compatible with a microadenoma in all eight patients, whereas MRI detected one enlarged pituitary, two empty sellas (one with prolapse of the optic chiasm) without evidence of adenoma, and five normal examinations. Thus, both studies detected macroadenomas accurately, but CT was frequently unable to diagnose correctly an empty sella. Because patients with possible microadenomas were not submitted to surgery, the accuracy of either radiologic method cannot be assessed at this time. However, we suggest that MRI is superior to CT because of its inherently greater soft-tissue contrast, which allows clear visualization of the optic chiasm, optic nerves, cavernous sinuses, and carotid arteries.     

Prolactin and placental hormone levels during pregnancy in prolactinomas

Prolactin (PRL) and the placental hormones, estradiol (E2), estriol (E3), progesterone (PG), chorionic gonadotropin (HCG), and placental lactogen (HPL) were serially measured throughout pregnancy and early postpartum in three patients with prolactinomas in whom pregnancy was achieved by one of the three modalities of treatment: bromocriptine administration (patient I), irradiation of the pituitary (patient II), and human gonadotropin administration after excision of the adenoma (patient III). It was found that PRL in patient I reached the high pretreatment levels in the 2nd month of pregnancy and increased to further abnormal concentrations in the last 2 months, but fell at the onset of labor 1 week after an episode of severe headache. The PRL changes in this patient were attributed successively to tumor expansion and apoplexy. In patient II PRL decreased after irradiation, but was not normalized. During pregnancy it remained moderately increased presenting minor fluctuations. The third patient with postoperative GH and TSH pituitary insufficiency had low pretreatment PRL levels which remained practically unchanged throughout pregnancy. The two last patients gave birth to identical twins. The placental hormones were found normal in all three patients but E2 and PG were relatively increased during the last weeks of pregnancy in the twin pregnancies. Amniotic fluid and umbilical cord PRL and E2 concentrations were normal. The patients presented agalactia and suckling did not induce a PRL increase. We conclude that a) serial PRL measurements during pregnancy reflect the changes occurring in the prolactinomas and are essential in monitoring the patients bearing these tumors; b) maternal hyperprolactinemia or failure of PRL to increase during pregnancy do not influence either the secretion of placental hormones or PRL concentration in amniotic fluid and the newborn; and c) hyperprolactinemia during pregnancy is of maternal pituitary origin.     

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.     

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.     

Prolonged desensitization pretreatment for in vitro fertilization in women with polycystic ovary

OBJECTIVE: To analyse the outcome of intracytoplasmic sperm injection (ICSI) in women with severe polycystic ovary disease (PCD), stimulated after prolonged pituitary desensitization in comparison with regular long protocol therapy. MATERIALS AND METHODS: The results of controlled ovarian hyperstimulation (COH), fertilization rate, early embryo development parameters and clinical pregnancy rates were compared depending on the duration of pituitary desensitization before gonadotropin administration. A total of 60 patients with severe PCOD were desensitized with GnRH agonist up to 30 days before COH. The results were compared with the group of 213 patients with mild PCOD treated with regular long protocol (control). RESULTS: We observed a slightly higher rate of mature oocytes MII as well as the number of embryos obtained in the control group, however the pregnancy rate in the group with prolonged desensitization was significantly higher (50%) in comparison to the control group (33.8%). CONCLUSION: The prolonged pituitary desensitization before controlled ovarian hyperstimulation gives better chance for obtaining pregnancy in patients with severe PCOD. It could be recommended facing previous treatment failure.     

Visual and neurological disturbances accompanying with pregnancies of hyperprolactinemic patients

Twenty-three hyperprolactinemic infertile cases become pregnant after surgical treatment and/or bromocriptine administration, and 18 of them accomplished normal full-term deliveries. Serial ophthalmological examination which had been performed monthly throughout pregnancy revealed that four cases bearing pituitary adenomas developed visual disturbances which manifested themselves in the latter part of gestational period. The objective signs detected in these cases were bitemporal hemianopsia, temporal and nasal visual defects and the disappearance of central isopter. Another patient with microadenoma complained of headache at 16 weeks of gestation and it became more severe as gestation progressed. Bromocriptine (1.25 mg/day) was effective in diminishing this symptom. Although all these cases recovered from visual disturbances and headache after delivery, two of them were operated on transsphenoidally when radiological evidence of pituitary enlargement was found in the postpartum period. It is generally accepted that nearly 20% of hyperprolactinemic patients have pituitary adenomas. In view of the limited accuracy of techniques used in diagnosing pituitary tumor, it is legitimate to postulate that most hyperprolactinemic infertile patients have microadenoma to some extent. For this reason, a detailed follow up of visual field and neurological signs throughout pregnancy of hyperprolactinemic patients is important in early detection of changes in pituitary size.     

Pituitary response to luteinizing hormone-releasing hormone after induced abortion in the first and second trimesters.

Luteinizing hormone-releasing hormone (LHRH) (100 microng) was administered subcutaneously to healthy female volunteers 2 and 4 weeks after induced abortion in the first trimester (group A) and the midtrimester (group B). Four patients were studied in each group. The response to LHRH was determined in terms of plasma LH and follicle-stimulating hormone levels. Adequate pituitary response occurred in subjects of group A at both 2 and 4 weeks. In group B pituitary unresponsiveness was found at 2 weeks which persisted to some extent at 4 weeks. These data are in accord with the pituitary unresponsiveness observed after termination of pregnancy at term and suggest that the duration of pregnancy has an influence on the development of this unresponsiveness.     

The effects of pregnancy on patients with hyperprolactinemia

Seventy women with amenorrhea with or without galactorrhea associated with high serum prolactin levels and radiologic evidence of pituitary tumors were treated with transsphenoidal tumor resection. The prolactin level was measured in 29 patients before pregnancy, at 3 months post partum or cessation of lactation, and at 6-month intervals thereafter. The results were compared to those of 18 patients who had hyperprolactinemia but no demonstrable radiologic evidence of a pituitary tumor and who responded to bromocriptine and conceived. Our investigations showed that operation resulted in normalization of serum prolactin levels in 74% of patients. Forty of the 49 patients less than 36 years old conceived (80%). Five of 29 patients who were studied before and after operation as well as after delivery showed an increase in serum prolactin levels post partum and persistent amenorrhea suggesting recurrence. Six of the 18 patients who became pregnant after bromocriptine also showed a significant rise in serum prolactin levels above the treatment level. None of the patients in the two groups developed visual changes or symptoms or radiologic changes during pregnancy. These results showed that transsphenoidal operation has a high incidence of success, but some patients may show a rise of serum prolactin levels and persistent amenorrhea after pregnancy or passage of time, suggesting recurrence. Some patients who become pregnant after bromocriptine therapy may have further rises in prolactin greater than pretreatment levels. Follow-up of these patients is indicated.