Triple Pituitary Adenoma in Cushing's Disease: Case Report

Summary A case of a triple pituitary adenoma identified in a surgically removed pituitary gland from a 52-year-old woman operated on for Cushing's disease is presented. The histology revealed 3 distinctly separate microadenomas, 1 corticotroph and 2 immunoreactive for prolactin (PRL). The latter were apparently silent, since the serum PRL levels were within normal range. The problems associated with the inability to identify multiple adenomas pre-operatively and the possible failure of selective transsphenoidal adenomectomy in case of multiple adenomas are emphasised.     

A recurrent case of TSH-PRL secreting microadenoma following hypothyroidism

A thirty-seven-year-old housewife whose chief complaints were recurrence of galactorrhea and amenorrhea three years after having a selective adenomectomy. Hormonal examination done as a result of the continuation of the endocrinism revealed a hyperprolactinemia and high level of TRH due to hypothyroidism. Serum prolactin responded to neither TSH stimulation nor L-Dopa suppression tests. In addition, serum TSH did not react to TRH test. Contrast enhancement CT showed an intrasellar enhancing mass the size of which was less than 1 cm in diameter. A unilateral septal transsphenoidal operation was performed; and a soft white-yellowish mass 7 X 5 X 5 mm in size was found in the left inferolateral aspect of the pituitary gland. Histological studies of frozen sections of this revealed it to be a pituitary adenoma, with the border between tumor and normal tissue being quite distinct. Immunocytochemical diagnosis further confirmed it to be both PRL and TSH producing adenoma. Electron microscopy showed more than three different hormone-producing cells. The PRL cells contained large, and the TSH cells had small hormone granules; but some tumor cells contained secretory granules of both sizes suggesting production of both PRL and TSH in the cytoplasm. It is necessary in the management of patients like this, during the post-operative period, to adequately institute a thyroid hormone replacement therapy so as to prevent recurrence.     

The effect of successful renal transplantation on hormonal status of female recipients

The pituitary, thyroid, and ovarian hormone levels were measured by enzyme and fluorescence polarization immunoassays in 18 women with successful renal transplants (recipients): 10 menstruating, mean age 34.7 years, mean time after transplantation (Tx) 112.00 months, mean SCr 130.60 mumol/L; and 8 menopausal, mean age 52.7 years, mean time after Tx 61.00 months, and mean SCr 119.00 mumol/L. Five women of the menstruating group conceived 7 times and gave birth to 4 healthy infants. The findings were compared to 30 age-matched healthy subjects (controls) and to 13 women under chronic hemodialysis (hemodialyzed patients): 2 menstruating, 24 and 36 years old, and 11 menopausal, mean age 59.4 years. Serum prolactin (PRL) showed a highly significant increase in hemodialyzed patients (p less than .0001) compared to controls. In recipients, PRL levels were significantly lower than in hemodialyzed patients, but higher than in controls (p less than .0001). LH and FSH were elevated in menstruating hemodialyzed patients (p less than .0001, p less than .02, respectively) and significantly high in menopausal hemodialyzed patients (p less than .02, p less than .01, respectively). In menstruating recipients, LH was also highly elevated (p less than .001), while FSH showed no significant difference from controls. In menopausal recipients the increase of LH was less prominent (p less than .02) but FSH was highly increased (p less than .001). T3, T4, and FTI were absolutely normal in recipients, while they were significantly lower than normal (p less than .0001) in hemodialyzed patients. Estradiol showed no significant difference in both groups of recipients, as well as in menopausal hemodialyzed patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

尿毒症透析患者的卵巢功能

为了解女性尿毒症患者卵巢功能障碍的发病情况,明确发病部位,探索其发病机理。方法 应用酶免疫法(EIA)检测了25例更年期前尿毒症透析患者的泌乳素(PRL)、促卵泡素(FSH)、促黄体素(LH)、雌二醇(E_2)及孕酮(P)的基础水平,并观察了部分患者服用克罗米酚(CC)及溴隐停后以上激素的变化。结果 与近龄健康妇女相比RPL明显升高,FSH、LH亦升高,而孕酮值显著下降。闭经者服用CC后,血LH、FSH和E_2水平上升,谓之CC试验结果阳性。虽PRL广泛升高,用嗅隐停可使之暂时下降,但效果很不稳定,排卵率亦很低。结论 (1)尿毒症女性普遍的月经无周期和缺乏E_2、LH峰,以及孕酮值低下,证实了存在下丘脑-垂体-卵巢轴损害;(2)尿毒症女性CC刺激试验阳性,说明垂体-卵巢轴是正常的,损伤部位在下丘脑;(3)尿毒症女性PRL显著升高,主要是垂体泌乳细胞分泌增加,溴隐停治疗,效果不稳定;(4)尿毒症女性月经紊乱应给对症处理,但无需促排卵治疗,而成功肾移植是最好的治疗方法。     

The value of pituitary magnetic resonance imaging in men with hypogonadism

PURPOSE: We assessed the usefulness of magnetic resonance imaging (MRI) of the brain in the evaluation of hypogonadal men with a variety of endocrine patterns. MATERIALS AND METHODS: A total of 51 men with low levels of total testosterone (TT) or free testosterone (FT) underwent MRI. Erectile dysfunction and/or decreased libido were present in 43 (84.3%) of cases and infertility in 8 (15.7%). Serum prolactin (PRL) was obtained in all cases. Low levels of TT and FT were defined as less than 300 and 1.5 ng/dl, respectively. Markedly low levels of TT were defined as less than 200 ng/dl. RESULTS: In 38 of 51 (74.5%) men the MRI was normal. A small pituitary gland (the partially empty sella syndrome) was noted in 9 (17.6%) cases and microadenoma was noted in 4 (7.8%). Prolactin levels were greater than twice the upper limit of normal in 3 of 4 (75%) cases of adenoma, and low FT was noted in all 4 cases. An additional case of adenoma was identified in a man with markedly decreased TT and normal PRL. All men with adenoma presented with the combination of erectile dysfunction and decreased libido. Among men without adenomas the highest PRL value was always less than twice the upper limit of normal. Overall, only 1 of 17 men with markedly decreased TT (less than 200 ng/dl) demonstrated adenoma. None of the 17 men with low luteinizing hormone with low TT or FT had an adenoma or pituitary/hypothalamic mass. CONCLUSIONS: The likelihood of identifying pituitary adenoma by MRI is high if PRL levels are more than twice the upper limit of normal. Medically significant abnormalities are identified in only a small percentage of hypogonadal men with low luteinizing hormone or if TT levels are markedly decreased. The decision to obtain MRI in these latter cases should be based on individual circumstances.     

Fertility in prolactinomas--considerations concerning some clinical cases

Prolactinoma is a frequent endocrine cause of infertility in both man and women. The aim of this study was to evaluate female fertility in association with hyperprolactinemia. The study is a retrospective one, based on the cases monitored in the Endocrinology Department of Ia?i. From the 113 cases of prolactinoma in women we have selected 83 women aged between 18-45 years (fertile age). The diagnosis was suspected on clinical bases: endocrine (amenorrhea-galactorrhea, associated or isolated, spaniomenorrhea, infertility), and tumoral (headache, visual disturbances) syndromes and confirmed by biological (PRL dosage) and morphological (pituitary CT) tests. We classified the found associations between prolactinoma and fertility in: no correlation (previous pregnancies with no desire for another child--76 patients = 75.2%); prolactinoma diagnosed immediately after a pregnancy by persistency of galactorrhea, lack of menses reapparition, headache (16 cases = 15.8%); prolactinoma diagnosed before pregnancy, which was obtained thanks to the hyperprolactinemia treatment (9 patients = 8.9%). All 9 patients of the last group were in remission at the moment of pregnancy apparition and had a normal pregnancy, giving birth to normal children. Infertility associated with prolactinoma is reversible with treatment. Lowering of prolactin levels to normal is often necessary to permit ovulation. Bromocriptine used by pregnant women appears to be safe for the developing fetus, at least in our study where the treatment was interrupted in most cases in the first trimester of pregnancy.     

Testicular Function and Prolactin Responsiveness to TRH and Cimetidine After Renal Transplantation

The hypothalamic-pituitary-testicular axis and the regulation of prolactin secretion were investigated in eleven male renal transplant recipients. Mean serum levels of testosterone and estrone were normal, whereas those of androstenedione and estradiol were low. Mean basal luteinizing hormone (LH) levels were slightly elevated, but the peak responses to 50 micrograms i.v. gonadotropin-releasing hormone (GnRH) were not dissimilar from controls. Both basal and GnRH-stimulated follicle-stimulating hormone (FSH) levels were elevated (p less than 0.02-0.05) and also positively correlated with the time spent on hemodialysis (p less than 0.005-0.002). Basal prolactin (PRL) levels were normal, in all subjects. Nine out of 11 patients had a normal PRL response to Thyrotropin-releasing Hormone (TRH). However only six out of 11 had a normal response to 200 mg i.v. Cimetidine (Cim). Three subjects normally responding to TRH failed to respond to Cim. Uremic primary hypogonadism is not fully reversed by renal transplantation: a slight defect in the pituitary LH release may persist and the impairment of the tubular testicular function is left unchanged. While uremic hyperprolactinemia is corrected, the responsiveness to PRL-stimulating agents, particularly Cim, is not restored to normal, reflecting a derangement at the pituitary as well as the hypothalamic level.     

Hypothalamic-pituitary dysfunction in respiratory hypoxia.

Eight hypoxic male patients with stable chronic obstructive airways disease were submitted for combined anterior pituitary function testing. All subjects showed normal growth hormone and essentially normal cortisol responses to adequate hypoglycaemia, two subjects showed delayed responses of thyroid stimulating hormone to administered thyrotrophin releasing hormone and all had basal prolactin levels within normal limits. Basal levels of luteinising hormone were significantly lower than in the group of age-matched controls (p less than 0.02) but there was a normal increment after the injection of gonadotrophin releasing hormone. Basal levels of follicle stimulating hormone were significantly lower than in the controls (p less than 0.01), and there was also a reduced response from the pituitary after injection of gonadotrophin releasing hormone (p less than 0.01). Resting levels of the thyroid hormones thyroxine and tri-iodothyronine were normal while the expected subnormal testosterone level was observed (p less than 0.05). These results show that hypoxia can produce abnormalities of hypothalamic-pituitary function and that these are primarily located in the hypothalamic-pituitary-testicular axis.     

Transsphenoidal microsurgery for pituitary tumors associated with hyperprolactinemia.

The results of transsphenoidal microsurgery in treating 37 patients (30 women and seven men) with pituitary tumors associated with hyperprolactinemia are presented. Immediate (10-day) postoperative fasting prolactin levels were normal (less than 25 ng/ml) in 19 of 26 patients whose preoperative prolactin level was less than 200 ng/ml, and in only three of 11 patients in whom preoperative prolactin was greater than 200 ng/ml. Twelve of 13 patients with normal preoperative pituitary-target organ function maintained normal axes postoperatively. Thirteen other patients had preoperative deficiencies in one or more pituitary-target organ axes. Postoperatively, in these latter 13 patients, a pituitary-target organ axis that was deficient preoperatively returned to normal in six cases; there was no change in five, and there was impairment in another axis in four instances. Although gross total tumor removal was believed to be complete in 35 of 37 patients, serial postoperative prolactin determinations in four of these 35 patients indicate tumor regrowth. The authors conclude that transsphenoidal microsurgery is currently the operative procedure of choice for the majority of pituitary tumors associated with hyperprolactinemia.     

A prospective analysis of testicular androgenic function in recipients of a renal allograft

Eighteen adult males with end stage renal disease (ESRD) were studied to determine the serum levels of gonadotropins (LH and FSH), prolactin (PRL) and testosterone. All of the patients were studied longitudinally while undergoing maintenance hemodialysis (HD) and six months after renal transplantation. Prior to transplantation, significantly high levels of gonadotropins and PRL were observed. During HD the serum testosterone levels tended to be subnormal in most of the uremic patients and low normal in some of the subjects. Renal transplantation led to a significant improvement (P < 0.05) in serum testosterone. Elevated gonadotropin and PRL levels observed in patients on HD returned to the normal range in most of the patients after successful renal transplantation.     

Hypophyseal function in the operative and postoperative phases after removal of pituitary tumours

Summary In 47 patients with various pituitary tumours plasma cortisol, LH, FSH, prolactin, and GH were measured by radioimmunoassays to investigate anterior pituitary function. In 14 subjects LH-RH and TRH stimulation tests were performed to assess pituitary reserve before, during, and after surgical therapy. The mean cortisol levels were raised during and after the operative procedures until the 14th postoperative days. In patients with functionless tumours the other hormone concentrations remained nearly unchanged and in the normal ranges. After the removal of the tumour a rapid decrease in hormone levels, as might be expected, was rare, with the exception of the GH and prolactin levels in patients with hypersecretion. The postoperative stimulation tests showed a maintained secretory pituitary reserve due to active tissue left behind after operative removal of the tumour.     

Pituitary prolactinoma associated with polycystic ovary--case report.

A 25-year-old female presented with pituitary prolactinoma associated with polycystic ovarian disease and amenorrhea. After trans-sphenoidal adenomectomy, the serum prolactin level returned to normal. Postoperative ultrasonography revealed resolution of the polycystic ovary. Regular menses recommenced 2 months after surgery. Our experience suggests that pituitary prolactinoma may be a cause of polycystic ovarian disease.     

Elevated serum prolactin level in the Zollinger-Ellison syndrome

To estimate the prevalence of prolactinoma in the Zollinger-Ellison syndrome (ZES), serum prolactin (PRL) levels were measured by radioimmunoassay in 36 patients with ZES. Eight patients had elevated PRL levels; however, in one patient the finding was attributed to primary hypothyroidism rather than a prolactinoma. The seven other patients were believed to have previously undiagnosed prolactinomas on the basis of elevated serum PRL levels; the presence of pituitary tumors were confirmed in four by demonstration of sella turcica erosions or enlargement. Serial determinations over three to six years showed a tendency for serum PRL levels to increase modestly in four of six patients. Thus far, two patients have undergone transsphenoidal tumor resections with good results. This study suggests that the prevalence of prolactinoma in patients with ZES is substantial (10% for those with isolated ZES and 54% for those with ZES with multiple endocrine neoplasia, type 1, syndrome), and that early diagnosis is possible with measurement of serum PRL levels. Since levels of PRL tend to increase and clinically significant pituitary tumors can develop, determinations of serial serum PRL levels are recommended for all patients with ZES.     

Diurnal variations of pituitary and testicular hormones in paraplegic men

The effect of the neuro-spinal cord injury upon testicular physiology was evaluated in six adult paraplegic (PPG) men by measuring the circulating levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), androstenedione, testosterone, and dihydrotestosterone every 4 hr throughout a 24-hr period. Three PPG men were studied within the first 3 months (acute period) and the other three patients 39-79 months (stabilized period) after trauma. Hormonal values were compared with eight age-matched normal adult males. Plasma FSH and LH were constantly above normal concentrations regardless of the sampling time and period of observation, whereas prolactin was higher than normal only during the first two months after trauma, returning to normal afterwards. Plasma androgens were consistently below normal during the first 3 months after injury, and returned toward normal thereafter. There may be a direct relationship between the time elapsed after the spinal cord injury and the plasma androgens concentrations. A possible role of PRL in testicular steroidogenesis is suggested.     

Occurrence of pituitary dysfunction following traumatic brain injury

Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.     

Plasma and pituitary content of growth hormone luteinizing hormone, and prolactin in uremic rats. Effects of chronic infusion of insulin

The influence of chronic renal failure on pituitary content and on serum concentrations of growth hormone (GH), prolactin (PRL), and luteinizing hormone (LH) was studied in chronically uremic rats by comparison with control rats fed ad libitum and diet-restricted rats pair-fed with uremic rats. A decrease of pituitary GH content was found in uremic and diet-restricted rats, in association with a normal circulating GH level. A decrease of pituitary PRL and LH content with respectively high and normal serum values was observed in uremic but not in diet-restricted rats. These data strongly suggest that GH disturbances are related to malnutrition, whereas PRL and LH abnormalities are related to the uremic state per se. As hypoinsulinemia was observed in uremic rats, and as insulin is largely implicated in growth, we have investigated the effects of chronic infusion of insulin, using miniosmotic pumps, on pituitary hormone content. In spite of normalization of circulating insulin levels in uremic rats treated with insulin, pituitary GH, LH, and PRL contents were unaffected. Thus, insulin deficiency did not appear to be responsible for the diminished pituitary reserve of these hormones.     

Long-term effects of radiotherapy and bromocriptine treatment in patients with previous surgery for macroprolactinomas

The long-term effect of radiotherapy and bromocriptine treatment was retrospectively evaluated in 25 patients who had previously undergone transsphenoidal surgery for treatment of macroprolactinomas. Surgery had reduced the median serum prolactin (PRL) value from 613 micrograms/l, a reduction of 53%. Postoperative bromocriptine was administered to 21 of the 25 patients. In 14 of these patients, serum PRL values became normal or almost normal with medication. There were no radiological or ophthalmological signs of progressive tumor growth during bromocriptine treatment. Fourteen patients received postoperative radiotherapy. After withdrawal of bromocriptine in 13 of these patients an average of 7 years after radiotherapy, the median serum PRL value had further decreased by 95%. The PRL reduction was similar for all doses applied, 38 to 52 Gy. After withdrawal of bromocriptine in 8 patients not receiving radiotherapy an average of 7 years after operation, the median serum PRL level had further decreased by 75%. At follow-up, 18 additional instances of pituitary insufficiency had developed in the group receiving radiotherapy, compared with 8 cases of insufficiency in the group not receiving radiotherapy. Thus, because bromocriptine has a long-standing effect on prolactin secretion, and radiotherapy is associated with a notably high incidence of pituitary insufficiency, we propose that photon irradiation should be considered mainly for patients who are not candidates for surgical or medical treatment.     

Hypogonadism of male prolactinomas: Relation to pulsatile secretion of LH: Hypogonadisms des Mannes mit Prolaktinomen: Beziehungen zur pulsatilen LH-Sekretion

In order to investigate whether a hypothalamic disorder cause hypogonadism in male prolactinomas, LH pulsatile secretion was studied in 13 male patients. Serum PRL levels ranged from 186 to 45,000 ng ml-1 before treatment, and all the tumors were macroadenomas. Reduced LH secretion was revealed in 5 of 13 patients, and FSH was reduced in 1 of 13. Serum testosterone (T) levels were lower than the normal limit in all the patients. HCG tests in 3 patients showed good responses, but the peak values of T were lower than those of normal men. LH pulsatilities were examined in 5 hyperprolactinemic patients before treatment, in 4 hyperprolactinemic patients after operation, and in 8 normoprolactinemic patients after operation and/or bromocriptine treatment. There was no significant difference of the mean LH values, the frequencies of LH pulses, and amplitudes among the hyperprolactinemic patients before operation (n = 5), the normoprolactinemic patients after operation (n = 8), and normal men (n = 7). From these results, it was evident that the hypothalamus and pituitary function of male prolactinomas were well preserved, in spite of higher serum PRL levels and larger tumor size than those reported in females. It is suggested that the main cause of hypogonadism in these patients is due to testicular dysfunction resulting from excessive serum PRL.     

Changes of CSF prolactin induced by metoclopramide in man

A sharp increase in serum and CSF prolactin (PRL) values after acute metoclopramide (10 mg i.m.) administration was found in six male patients without endocrine diseases. Peak values occurred simultaneously in serum and in CSF. This finding suggests the possibility that CSF PRL content depends also on the retrograde transport from pituitary gland.     

Cervical sympathectomy affects adrenocorticotropic hormone and thyroid-stimulating hormone in rats

To examine the effects of bilateral cervical sympathectomy on the secretion of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), and prolactin (PRL), 18 male rats were divided into three groups: control (Cont), sham operation (Sham), and bilateral cervical sympathectomy (Symp). All rats were kept under a normal circadian rhythm for 2 weeks. Subsequently, blood was collected and plasma ACTH as well as serum TSH, GH, and PRL levels were measured. The difference in ACTH levels between the Cont and Sham groups was not significant, but ACTH levels in the Symp group were significantly higher than those in the other groups. The difference in TSH levels between the Cont and Sham groups was also not significant, but TSH levels in the Symp group were significantly lower than those in the Cont group. There were no statistically significant differences in GH and PRL levels among these groups. The present results suggest that cervical sympathectomy in the rat increases ACTH secretion and decreases TSH secretion in the pituitary. These effects seem to be due to a mildly increased secretion of melatonin in the pineal body that probably in turn increases corticotropin-releasing factor (CRF) secretion and decreases thyrotropin-releasing hormone (TRH) secretion in the hypothalamus. Extrapolation of these findings to humans suggests that longterm and repeated stellate ganglion block would affect the pituitary secretions of ACTH and TSH.