Directed forgetting of emotionally toned items and mental health: a meta-analytic review.

Item- and list-method directed forgetting paradigms have been used to study forgetting of emotionally toned items in clinical and control group populations for several decades. Meta-analysis of item-method studies found that clinical populations retained more remember- than forget-cued items of each valence. These effects were comparable to that shown by control populations for positive and negative items, but less than that shown by controls on neutral items. Encoding deficits may underlie clinical populations' item-method directed forgetting since those populations retained fewer remember-cued items of each valence compared to control populations. Moderator analysis indicated larger effect size variability for some clinical populations (e.g., anxiety disorders) than other populations (e.g., PTSD, schizophrenia). Meta-analysis of list-method directed forgetting among clinical populations revealed only List 1 forgetting or costs for neutral items; i.e., better memory for to-be-remembered than forgotten List 1 neutral items, but no List 2 enhancements or benefits; i.e., better memory for List 2 items among those told to forget than remember List 1 items, for any item valence. Control populations showed costs and benefits for all item valences. Results from both paradigms are discussed in terms of clinical-control population differences in executive processes. Limitations of the meta-analyses and suggestions for future research are presented.

The natural history of the pituitary incidentaloma.

BACKGROUND: The wide availability of computed tomography and magnetic resonance imaging has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (incidentalomas). Because the natural history of this entity is not known, the approach to the pituitary incidentaloma has not been established. OBJECTIVE: To determine the natural history of untreated pituitary incidentaloma, recognizing that this includes lesions of various causes. METHODS: Thirty-one adults with incidentalomas were prospectively followed up conservatively for a mean of 6.4 years (range, 3 to 11 years). Clinical and biochemical assessment, computed tomography or magnetic resonance imaging of the pituitary, and visual field testing by Goldmann perimetry at baseline, 6 months, and yearly thereafter were the outcomes assessed. RESULTS: Only patients with pituitary incidentalomas greater than 10 mm in greatest diameter developed tumor enlargement or complications. Three patients developed asymptomatic tumor enlargement. In four patients, masses decreased in size. Only two patients developed complications. One required subsequent surgery. The only permanent impairment was panhypopituitarism following surgery in this patient. CONCLUSIONS: Patients with pituitary incidentalomas of unknown causes usually follow a benign course for at least 6 years after discovery. Neurosurgical intervention is not initially required in the management of is not initially required in the management of pituitary incidentalomas, particularly those less than 10 mm, as long as clinical observation can be continued.

Recurrent hypoglycemia secondary to drug-dispensing error.

We present three patients who developed hypoglycemia due to inadvertent dispensing of sulfonylurea drugs. Each patient had a similar clinical course characterized by hypoglycemia that remitted during hospitalization and recurred after discharge. The cause of the hypoglycemia was determined only after close inspection of the patients' medications, not the label on the container. Our experience suggests that hypoglycemia due to drug-dispensing error may be more common than is generally recognized.

Bedside assessment of skin-fold thickness. A useful measurement for distinguishing Cushing's disease from other causes of hirsutism and oligomenorrhea.

BACKGROUND: The known catabolic effects of glucocorticoid excess on protein metabolism prompted us to devise a method to assess this measure in reproductive-aged females with Cushing's disease. Since collagen protein is a major component of skin, decreased abundance of this protein should cause a reduction in skin-fold thickness. To determine whether skin-fold thickness is useful as an added tool in the diagnosis of Cushing's disease, we compared this value in female patients with Cushing's disease with those who presented with a similar set of symptoms. METHODS: This open prospective study was conducted in an endocrinology clinic at a tertiary care center. The study population consisted of 88 females in the reproductive age group who presented to the clinic with hirsutism, oligomenorrhea, and/or obesity. Measurement of skin-fold thickness, body mass index, Ferriman-Gallwey index, and serum testosterone were performed in all patients. RESULTS: Skin-fold thickness in the patients with Cushing's disease was 1.5 +/- 0.2 mm (range, 1.0 to 1.8 mm). This value was significantly (P < .01) lower than that in controls or subjects with other disorders that have a similar set of presenting symptoms. CONCLUSIONS: Bedside assessment of skin-fold thickness is an easy, low-cost, and noninvasive test for distinguishing Cushing's disease from disorders with similar presenting symptoms in females of reproductive age. Assessment of skin-fold thickness should be used as an adjunct to current physical and biochemical study of patients with symptoms suggestive of Cushing's disease.

Maintenance of serum calcium by parathyroid hormone-related peptide during lactation in a hypoparathyroid patient.

We describe the changes in calcium homeostasis seen in a hypoparathyroid woman during the third trimester and with lactation following her second pregnancy. During lactation her need for supplemental calcium and calcitriol abated, and in fact she was transiently hypercalcemic and hypophosphatemic. This change was associated with a rise of serum parathyroid hormone-related peptide (PTHrP) released systemically during lactation. This is the first documentation of the time course of serum PTHrP levels from the late third trimester throughout lactation in a hypoparathyroid woman. In this context PTHrP may have sufficient biological activity to compensate for parathyroid hormone deficiency.

Normal endothelial function despite insulin resistance in healthy women with the polycystic ovary syndrome.

Women with the polycystic ovarian syndrome (PCOS) carry a number of cardiovascular risk factors, including insulin resistance, lipid abnormalities, and an altered pattern of sex steroid exposure. Noninvasive measurements of endothelial function, which can demonstrate abnormalities well in advance of clinically apparent disease, have not been previously reported in this patient group. We undertook a cross-sectional evaluation of endothelium-dependent and -independent vascular function using brachial artery ultrasound. We studied healthy women with clinical and laboratory evidence of PCOS (n = 18) and age-matched controls (n = 19), not taking any antihypertensive, cholesterol-lowering, or hormonal therapies. Laboratory parameters of insulin resistance, glycemia, cholesterol status, and hormone levels were also measured. Despite marked differences in glucose/insulin ratio [6.1 +/- 1.1 mmol/pmol (PCOS) vs. 9.9 +/- 0.6 (controls)] and free androgen index [11.9 +/- 2.3 (PCOS) vs. 3.7 +/- 0.6 (controls); normal, <5], we did not find evidence of impaired endothelial function in our patients with PCOS. Both endothelium-dependent (8.7 +/- 3.1%) and endothelium-independent (23.2 +/- 3.4%) vascular responses were normal, and practically identical to the responses seen in the control group (endothelium-dependent, 9.0 +/- 0.7; endothelium-independent, 23.0 +/- 1.2%). The PCOS women were more obese, but baseline brachial arterial diameters were not different between groups. There was no correlation between degree of insulin resistance or hyperandrogenism and the brachial response. This group of healthy obese young women with insulin resistance and hyperandrogenism due to PCOS had normal endothelium-dependent and -independent vascular responses compared to age-matched controls. The factors resulting in preservation of these response are unclear and warrant further investigation.

Human mixed somatotrophic and lactotrophic pituitary adenomas.

Six patients with acromegaly at examination were found to have pituitary adenomas composed of cells that secreted GH and PRL. This was demonstrated by the elevated serum hormone concentrations, by immunoperoxidase staining of 5 specimens, and by electron microscopic examination of 4. Ultrastructural characteristics, described in detail, suggest that these adenomas were mixed adenomas consisting of 2 well-defined, distinct cell types, each secreting one hormone. By immunoperoxidase staining some cells were found to contain immunoreactive growth hormone, other cells immunoreactive prolactin. No cells were detected exhibiting immunostaining for both growth hormone and prolactin. Eelctron microscopy, consistent with the results of immunostaining, revealed the presence of two distinct cell types, distinguishable from each other by their characteristic fine structural features. No intermediate forms were noted. Thus there was no evidence to suggest that one cell type might transform to the other. Present findings seem to indicate that mixed adenomas secreting growth hormone as well as prolactin and consisting of somatotrophs as well as lactotrophs do occur in the human pituitary gland. Although all the results obtained so far suggest that these tumors are composed of two distinct cell types and thus can be interpreted as representing real mixed adenomas, further work is required to establish whether or not they derive from one common progenitor.

Idiopathic, sustained, inappropriate secretion of ADH with associated hypertension and thirst.

A 15 year old girl presented with excessive thirst and hypertension (170/110 mm Hg). Biochemical investigations revealed serum sodium 118 meq/liter, serum osmolality 238 mosmol/liter, urine sodium 90 meq/liter, urine osmolality 700 mosmol/liter, persistenly elevated serum antidiuretic hormone (ADH) levels (5.8 to 11.9 pg/ml) and no obvious cause for the hypertension. The hypertension is, at least in part, volume-related, diminishing with fluid restriction. Features of gross water intoxication (e.g., confusion, coma) have not occurred. The etiology of the inappropriate secretion of ADH is not obvious but is not thought to be due to "resetting of osmoreceptors" as evidenced by failure to maximally dilute urine following a water load test and persistently elevated serum ADH levels. A similar patient described by Epstein and associates in 1962 is presently well with persistent features of inappropriate secretion of ADH.

Hormonal side effects in women: typical versus atypical antipsychotic treatment.

Neuroleptic-induced hyperprolactinemia can cause menstrual disorders, impaired fertility, galactorrhea, and sexual dysfunction, as well as hypoestrogenism secondary to disruption of the hypothalamic-pituitary-ovarian axis. The development of the prolactin-sparing atypical antipsychotic drugs offers prevention and resolution of these adverse reactions. Thus far, this property of the new medications has received insufficient clinical attention. The authors use case vignettes to discuss assessment and management of clinical situations that arise as a result of antipsychotic-induced endocrine changes.

Localization of prolactin in chromophobe pituitary adenomas: study of human necropsy material by immunoperoxidase technique.

In order to identify prolactin-producing tumours in human pituitary glands, 45 chromophobe adenomas, obtained from unselected necropsies, have been studied by various staining procedures including the immunoperoxidase technique for the demonstration of prolactin. The presence of immunoreactive prolactin was revealed in the cytoplasm of the tumour cells in six cases (13%), indicating that the occurrence of prolactin-producing adenomas is not rare. No correlations were established between tumours and clinical history. Two adenomas were detected in female and four in male patients. The age of the patients at necropsy ranged from 28 to 75 years. Three adenomas were associated with disseminated carcinoma, two with fatal liver disease, and one with diabetes mellitus, atherosclerosis, and pyelonephritis. Manifest endocrine symptoms were not disclosed, and endocrine investigations, including measurements of blood prolactin levels, were not undertaken. Thus, direct evidence is lacking as to whether or not these tumours were actively secreting prolactin. In the non-tumorous parts of the anterior lobes the number of prolactin cells was decreased in two cases, suggesting that prolactin released from the adenoma cells suppressed prolactin production in the non-tumorous pituitary. However, the number of prolactin cells of the non-tumorous adenohypophysis seemed to be unchanged in two and increased in another two cases. The present findings conclusively proved the existence of the prolactin-producing adenomas as a distinct entity. These tumours do not stain with acid or basic dyes, they are PAS or thionin negative, and do not contain immunoreactive growth hormone. Thus, by conventional staining procedures they are indistinguishable from other chromophobe adenoma types. Herlant's erythrosin and Brookes' carmoisine methods, claimed spedifically to stain prolactin cells, failed to provide reliable results, hence their use cannot be recommended in tumour identification. Immunoperoxidase staining of prolactin is the only technique which conclusively reveals the presence of immunoreactive prolactin in the cytoplasm of the tumour cells and permits diagnosis. It is proposed that this technique be introduced in pituitary morphological studies. Its application may lead to a better understanding of problems related to prolactin-producing tumours and their secretory activity.

Prolactin hypersecretion and short luteal phase defects.

The short luteal phase is commonly found in ovulating women presenting with infertility, or in amenorrheic women induced to ovulate with clomiphene. When the short luteal phase defect is accompanied by the discovery of galactorrhea, the two abnormalities may share a common underlying cause. Two cases are presented to demonstrate the short luteal phase defect as one early manifestation that may occur during the development of the amenorrhea-galactorrhea syndrome. Antiprolactin therapy may cause this menstrual disorder to revert to normal, allowing normal fertility and terminating the galactorrhea.

Successful outcome of ergocryptine-induced pregnancies in twenty-one women with prolactin-secreting pituitary adenomas.

The natural history of prolactin-secreting adenomas is not known. For this reason, optimal therapy for women harboring these adenomas who desire to conceive is also unknown. Argument can be found to favor surgical excision, radiation therapy, prolactin-suppressing chemotherapy, and clinical observation. In a large series of women with prolactin-secreting pituitary adenomas, 21 have conceived and delivered healthy infants, all of whom had ergocryptine-induced prolactin suppression as the sole form of therapy. Endocrinologic, neurologic, biochemical, and radiologic assessment failed to demonstrate any obvious growth of the pituitary adenoma, except for slight enlargement of the sella turcica in one patient who delivered twins. The failure to demonstrate any worsening of the clinical state may reflect the fact that no large tumors were included in this series, only small but definite microadenomas found on sellar tomography. All of the various modalities of therapy must be considered with each patient, but this series suggests that ergocryptine treatment with careful clinical follow-up is relatively safe in patients with small pituitary tumors.

Asymptomatic hyperprolactinemia resulting from macroprolactinemia.

Five patients are presented who had moderate hyperprolactinemia as measured by RIA. The patients did not have any symptoms or signs that result from hyperprolactinemia, nor evidence of any underlying cause of hyperprolactinemia. Because of the lack of clinical features, laboratory search for macroprolactinemia was undertaken. In these patients no further investigation or therapy is indicated.

The safety of physiological estrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinemia.

In summary, E- replacement therapy may be administered to women with E deficiency, despite the presence of pathological hyperprolactinemia, with apparently no adverse effect on the underlying disease process. The concern of induction of rapid growth of an underlying pituitary adenoma was not substantiated.

PIP: 38 women aged between 23 and 42 years had secondary amenorrhea and clinical hypoesterogenism as assessed by the failure to have a withdrawal bleed in response to a progestin. All women were initially treated with up to 7.5 mg bromocriptine but it was discontinued because of failure to lower serum prolactin (PRL) or intolerance. Each woman had a basal computerized tomography (CT) scan before estrogen (E) replacement therapy, which was repeated after 6 months, and then yearly. The clinical course was monitored at 3-month intervals for the first year and the yearly. The patients were classified by CT scan as having either idiopathic hyperprolactinemia (19 patients), microadenoma (18 patients), or macroadenoma (1 patient). All patients have been followed with continuous exogenous E therapy for 2 to 6 years. The serum PRL was measured as a single random value by a double antibody homologous radioimmunoassay. 29 received physiological replacement with conjugated E (.625 mg, Premarin) from days 1 to 25 of each month, and added medroxyprogesterone acetate (10 mg, Provera) from days 16 to 25 of each month for 4.0 +or- 1.2 years. There was a significant decrease of serum PRL, and monthly withdrawal bleeding occurred in all women with alleviation of E-deficiency symptoms. 9 patients were treated with OCs for 2.0 +or- .8 years. There was a downward trend in the serum PRL without statistical significance. With abnormal CT scans, 6 patients with microadenomas had a decrease in size, whereas the remainder were unchanged. The patient with the macroadenoma (patient 29) had an onset of headaches after 4 months of therapy, but there was no change in the size of the tumor. The patients with normal CT scans did not show any change. The microadenomas in 2 of 3 women decreased in size. In summary, E-replacement therapy may be given to women with E deficiency, despite the presence of pathological hyperprolactinemia, as the induction of rapid growth of an underlying pituitary adenoma was not confirmed.

A rationale for the use of bromocriptine in patients with amenorrhea and normoprolactinemia.

The return of menses in amenorrheic normoprolactinemic women after treatment with bromocriptine is well documented. To determine whether an increased pituitary prolactin-secreting capacity may be the underlying mechanism, 14 women with amenorrhea were studied. None complained of galactorrhea, but in all 14 it was possible to express a few drops of milk from the nipple. All women were normoprolactinemic and had normal sellar tomography. A standard thyrotropin-releasing hormone (TRH) test was performed and bromocriptine (2.5 mg twice daily) was administered. Within 8 weeks, 9 of 14 patients had return of menses. The second group of five patients did not respond to bromocriptine. The mean prolactin response to TRH was significantly greater in those women who experienced return of menses, although there was individual overlap between both groups. This finding suggests that enhanced prolactin secretory capacity may account for amenorrhea is some apparently normoprolactinemic patients. The TRH test may serve to identify those patients who may benefit from bromocriptine.

Mechanisms of control of prolactin release in response to apprehension stress and anesthesia-surgery stress.

The response of prolactin to stress may not be controlled by a single mechanism. This study was designed to measure the prolactin response in the human female to two reproducible stresses: the apprehension (A) prior to surgery (laparoscopy and hysteroscopy) and the stress of the anesthesia-surgery (AS). Attempts to modify the release of prolactin was made by pharmacologic means. Thirty-eight normally menstruating women served either as controls or received histamine (H1), serotonin, opioid, or dopamine receptor-blocking agents and the prolactin response was measured. The release of prolactin to AS was blunted by higher-dose of opioid and by dopamine antagonists. The A release of prolactin was enhanced by the dopaminergic antagonist and blunted by the other three agents. It was concluded that the mechanism for the stress-induced release of prolactin may vary depending upon the nature of the stress.

Bromocriptine reduction of prolactinoma size.

Eight consecutive patients with large prolactinomas, as assessed by elevated serum prolactin concentrations and suprasellar extension of the visualized pituitary adenoma on computerized tomographic (CT) scanning, were treated with bromocriptine. With prospective evaluation all eight patients demonstrated disappearance of symptoms ascribed to both the hyperprolactinemia and the tumor itself, and all eight showed a decrease in tumor size within 3 months, as assessed by CT scanning. This prospective study demonstrates that the reduction in size of a large prolactinoma by bromocriptine is commonly observed and should be considered as an initial form of therapy for such patients.

Prediction of response to ergocryptine in the galactorrhea-amenorrhea syndrome.

Forty women with secondary amenorrhea and galactorrhea, thirty-six of whom had associated hyperprolactinemia, were studied prior to therapy with ergocryptine. Abnormal sella tomographic findings were present in 23. The findings on sellar tomography, basal serum prolactin concentrations, and pharmacologic stimulation/suppression of the serum prolactin failed to predict subsequent responders and nonresponders to ergocryptine. Pituitary stimulation for hormone responsiveness did differentiate subsequent responders to ergocryptine from nonresponders. The serum growth hormone response to hypoglycemia was the most definitive predictor. Return of apparently ovulatory function occurred in 29 patients, 11 of whom conceived and have delivered healthy infants.

The hyperprolactinemic polycystic ovary syndrome may not be an distinct entity.

Thirteen women with hyperprolactinemia and clinical stigmata of the polycystic ovary syndrome (PCO) had their serum prolactin (PRL) response to thyrotropin-releasing hormon (TRH) compared with two other groups of PCO. One PCO group had an elevated ratio of basal luteinizing hormone (LH) to follicle-stimulating hormone (FSH), and another had a normal ratio of basal LH to FSH. The PRL response to TRH was similar in hyperprolactinemic PCO and elevated LH PCO, and both were significantly greater than normal LH PCO and normal women. This suggests the hyperprolactinemic polycystic ovary (HPCO) is probably produced by similar central and/or peripheral mechanisms that result in the production of an elevated serum LH. These two features are probably associated in a common pathophysiologic mechanism. The HPCO syndrome does not appear to be a distinct entity but clinically must be differentiated from other causes of mild hyperprolactinemia.

Long-term follow-up of hyperprolactinemic women treated with bromocriptine.

Seventy-five women with hyperprolactinemia and demonstrable or suspected prolactinomas were treated with bromocriptine only and followed for 5 to 9 years. Biochemical, radiologic, and clinical responses were generally maintained in the long term, once established in the short term. Underlying mass effects on neurologic and pituitary function tended to improve, and no tumor progression was noted. Hypogonadal symptoms normalized in 68 of 75 women. Bromocriptine responses in long-term follow-up do not demonstrate any cumulative problems not seen in short-term therapy.