Paternal deprivation prior to adolescence and vulnerability to pituitary adenomas.

It has been reported that women with prolactinoma were exposed, early in life, to an environment characterized by an absent or violent father. The present study was designed to evaluate whether paternal absence or violent paternal behavior were more prevalent in patients with pituitary adenomas (prolactinoma, acromegaly, non-secreting adenoma and Cushing's disease) compared to a control population. We conducted an observational case-control multicenter study. We interviewed 395 patients with prolactinoma (296 females and 99 males), 130 with acromegaly (87 females and 43 males), 237 with non-secreting adenoma (144 females and 93 males) and 68 with Cushing's disease (61 females and 7 males) and 365 patients from the same clinics with nodular thyroid disease or lymphocytic thyroiditis with euthyroidism as controls. Violent or absent fathers were significantly more prevalent in patients with prolactinoma or acromegaly than in controls (P = 0.001 and P = 0.002, respectively) but not in patients with non-secreting adenoma or corticotrophinoma. Absent fathers in prolactinoma and acromegaly versus controls: P = 0.001 and P = 0.119. Violent fathers in prolactinoma and acromegaly versus controls: P = 0.069 and P = 0.001. The prevalence of absent or violent fathers was also significantly higher in prolactinoma and acromegaly when compared to non-secreting adenoma (P = 0.039 and P = 0.033, respectively). Paternal deprivation before adolescence may be a risk factor for prolactinoma and acromegaly but not for non-secreting pituitary adenomas or Cushing's disease.

Mapping the gene causing hereditary primary hyperparathyroidism in a Portuguese kindred to chromosome 1q22-q31.

A Portuguese kindred with autosomal dominant isolated primary hyperparathyroidism (HPT) that was associated with parathyroid adenomas and carcinomas was investigated with the aim of determining the chromosomal location of this gene, designated HPTPort. Leukocyte DNA from 9 affected and 16 unaffected members and 7 parathyroid tumors from 4 patients was used in comparative genomic hybridization (CGH), tumor loss of heterozygosity (LOH), and family linkage studies. The CGH studies revealed abnormalities of chromosomes 1 and 13, and the results of LOH studies were consistent with the involvements of tumor suppressor genes from these regions. Family segregation studies mapped HPTPort to chromosome 1q22-q31 by establishing linkage with eight loci (D1S254, D1S222, D1S202, D1S238, D1S428, D1S2877, D1S422, and D1S412) (peak two-point LOD scores = 3. 46-5.14 at 0% recombination), and defined the location of HPT Port to a 21 cM region flanked centromerically by D1S215 and telomerically by D1S306. Thus, HPTPort has been mapped to chromosome 1q22-q31, and a characterization of this gene will help to elucidate further the mechanisms that are involved in the development of parathyroid tumors.

A minimal mathematical model of calcium homeostasis.

A mathematical model of calcium homeostasis is presented in which the controlling factors are the plasma concentrations of calcium, PTH, and calcitriol, and the effector organs are the parathyroids, bone, kidney, and intestine. Other factors can be added as the need arises. The model is aimed at simulating what happens in a single individual, but its parameters and variables were adjusted to the corresponding published average values. Simulations of published observations in humans undergoing the infusion of calcium or its chelators are presented. With a single exception, these simulations provided a good fit to the data. The response of the system to extrinsic perturbations was characterized by simulating chronic infusions of calcium, PTH, and calcitriol. Finally, the steady state response to perturbations in some of its parameters (the secretory mass of the parathyroids and the affinity and/or sensitivity of the calcium, PTH, and calcitriol receptors) and to renal failure were also investigated in an attempt to analyze the pathogenesis of clinical hypo- or hypercalcemias. In its present form the model cannot be used to base clinical decisions in individual cases. However, it requires modest computational resources, and clinicians with a modest mathematical background can manipulate it. It is a useful tool for the analysis of general mechanisms of the diseases of calcium metabolism and for the design of clinical experiments aimed at characterizing these diseases. The model can also be the core of future autoadaptive extensions to be used in individual patients.

Thyroxine toxicosis in patients with iodine induced thyrotoxicosis.

Serum concentrations of thyroxine (T4) and triiodothyronine (T3) were measured in 74 untreated hyperthyroid patients. Of these, 47 had Graves' disease, 12 had toxic nodular goiter and 15 had iodine induced thyrotoxicosis (IIT). The average serum T4 concentrations were, respectively, 13.5 microgram/100 ml and 13.3 microgram/100 ml (normal 4.5-10.3 microgram/100 ml). The average serum T3 concentrations were in the same order 732 ng/100 ml, 505 ng/100 ml and 378 ng/100 ml )normal 116-288 ng/100 ml). Of the 15 patients with IIT 5 had a pattern of T4-toxicosis (T4 larger than or equal to 10.5 microgram/100 ml; T3 less than 290 ng/100 ml). This pattern was not found in any of the patients from the other two groups. In IIT the ratio between the serum concentrations of serum T4 and T3 is similar to the one observed in normal individuals from non endemic areas. In patients with Graves' disease and toxic nodular goiter the increase in serum T3 is twice as high as the increase in serum T4. It is concluded that in IIT the serum concentrations of T3 and T4 increase in parallel while in the other two groups there is a preferential secretion of T3. As a consequence, a pattern of T4 toxicosis is a likely event in IIT and, when present, may constitute a biochemical characteristic of the condition.

Some forms of big big prolactin behave as a complex of monomeric prolactin with an immunoglobulin G in patients with macroprolactinemia or prolactinoma.

The purpose of this study was to characterize the structure of big big PRL (bb-PRL) in patients with macroprolactinemia or prolactinomas. Serum samples from these patients were fractionated by Sephadex G-100 chromatography, and PRL was measured in the eluate by an immunoradiometric assay. The fractions containing bb-PRL were subjected to affinity chromatography with an antihuman immunoglobulin G (IgG) agarose column. PRL and IgG were assayed in the fractions obtained after affinity chromatography by immunoradiometric assay and radial immunodiffusion, respectively. bb-PRL was also immunoprecipitated with an antihuman PRL antibody, followed by polyacrylamide gel electrophoresis and Western blotting. We found that an average of 60% (range, 27-87%) of bb-PRL from patients with macroprolactinemia was retained by the agarose, indicating that this form of PRL contains an IgG. In one of the patients with prolactinoma, the big big form constituted 76% of the total PRL immunoreactivity. Most (75%) of the bb-PRL from this patient behaved as an IgG after affinity chromatography. In the two other patients with prolactinoma, we found that 22% and 25% of the bb-PRL, which represented only 2% and 3% of the total PRL in the serum, reacted as an IgG. In both groups of patients, the 23-kilodalton form of PRL was detected after the immunoprecipitation of bb-PRL. These results show that bb-PRL is in part a complex of 23-kilodalton PRL with an IgG and not an antibody mimicking the actions of PRL, as has been demonstrated for some large forms of growth-hormone.

A possible role for D8/PSF-A-like sequences in lactotroph versus somatotroph expression of the human prolactin gene.

The transcription factor GHF-1/Pit-1 is essential for the expression of GH and prolactin (PRL) by somatotrophs and lactotrophs respectively. However, PRL is not expressed in mature somatotrophs despite the presence of GHF-1/Pit-1. A possible mechanism is the presence of a somatotroph-specific repressor in the 5'-flanking sequences of the PRL gene. The region -3500/-1750 of the human (h) PRL gene is associated with negative regulatory activity and contains an element, designated D8, that resembles repressor PSF-A sequences which are located in the distal upstream region of placental members of the human GH family. An internal deletion of D8 sequences resulted in a significant stimulation of promoter activity in somatotroph GC (P < 0.005) and somatolactotroph-like GH3 and GH4C1 cells (P < 0.05), but not lactotroph-like 235-1 cells after gene transfer. However, D8 binding was observed by nuclease protection with lactotroph- as well as somatotroph-like cell nuclear protein. Although proteins that bind to the D8 element appear ubiquitous, this element does yield tissue-specific complexes in mobility shift assays. Further, competition studies do not suggest an interaction between GHF-1/Pit-1 and D8 proteins. The hPRL D8 element was inserted upstream of a thymidine kinase promoter and used to transfect pituitary and non-pituitary HeLa cells, to assess intrinsic repressor activity and/or promoter specificity. Although no repression was observed, a significant ninefold increase in expression was observed in HeLa cells (P < 0.001) which was at least twofold greater than observed in any of the pituitary cell lines tested. These results implicate D8 in the somatotroph-specific repression of hPRL; however, they also suggest that D8 can act as a stimulator as well as a repressor, depending on the interaction of a ubiquitous D8 factor forming promoter and cell-specific complexes with other elements/factors.

Medullary thyroid carcinoma: an accurate pre-operative diagnosis by reverse transcription-PCR.

OBJECTIVE: To study the expression of calcitonin (CT) and thyroglobulin mRNA in samples of leftover cells in needles used for fine-needle aspiration biopsy either from thyroid tumours or cervical lymph nodes. PATIENTS AND METHODS: Specimens were analysed using reverse transcription-polymerase chain reaction; 12 samples from 11 patients were included and molecular diagnosis was compared with cytological or histological diagnosis and serum CT measurements. RESULTS: Transcripts of the CT gene were detected in all six patients with medullary thyroid carcinoma (MTC) but in none of the other patients. CONCLUSIONS: Present data reinforce this technique as a reliable and alternative tool to establish the pre-operative diagnosis of MTC, especially when cytological examination is not conclusive or when cytological information is not in agreement with clinical data. Furthermore, it may be clinically useful to identify those conditions in which increased serum CT in the presence of a thyroid nodule is not due to MTC.

Somatic trinucleotide change encompassing codons 882 and 883 of the RET proto-oncogene in a patient with sporadic medullary thyroid carcinoma.

OBJECTIVE: Restriction analysis is a straightforward procedure for mutational analysis. It is commonly used for screening RET mutations. Incomplete digestion is a well-known cause of false results. Herein, we report another limitation of the method. DESIGN AND METHODS: Screening for somatic mutations in RET exons 16, 13 and 15 was performed in a patient with a sporadic medullary thyroid carcinoma. Genetic study was carried out by both restriction analysis and direct sequencing. RESULTS: A somatic trinucleotide change encompassing codons 882 and 883 of the RET proto-oncogene (GTA GCT to GTT TTT) was documented. Particular to this case is the silent mutation (GTA-->GTT) at codon 882. Independently, both the novel silent mutation and the missense mutation at codon 883 may disrupt the same AluI restriction site. Based on the restriction pattern we were able to say that both mutations occurred in the same allele. CONCLUSIONS: Restriction analysis is an easy approach for screening RET mutations; however, it is not enough to assign a final diagnosis.

An unusual case of papillary carcinoma of the thyroid with cutaneous and breast metastases only.

Cutaneous metastases of thyroid carcinoma are infrequent and, when present, are usually located in the vicinity of a widespread primary tumor. Breast metastases from these tumors are even less common. We report the case of a 64-year-old female with a toxic multinodular goiter in whom a fine-needle biopsy, performed in 1985 at the age of 52, was suggestive of papillary carcinoma of the thyroid. Total thyroidectomy for a papillary carcinoma, follicular variant, was performed in 1988. Four months after surgery, a cutaneous metastasis was discovered in the right thigh. Surgical excision of the lesion followed by treatment with radioactive iodine decreased serum Tg levels from 7495 to 3.3 micrograms/l. Under suppressive therapy with L-thyroxine, serum Tg remained undetectable for the next 4 years. Then, serum Tg levels rose to 3.9-5.6 micrograms/l and a second cutaneous metastasis was removed from the abdominal wall. The patient was again treated with radioactive iodine and the post-treatment whole-body scan did not show any area of increased uptake of the radionuclide. However, serum Tg levels under suppression with L-thyroxine remained elevated at 4-20 micrograms/l for the next 2 years. In August 1995, a 1.5 cm nodule was found in the right breast. Cytological examination was suggestive of a breast metastasis from thyroid carcinoma and the lesion was removed by enucleation. This proved to be a metastasis from a papillary carcinoma of the thyroid. Elevated (19-44 micrograms/l) serum Tg levels persisted postoperatively. A third cutaneous metastasis was revealed by 131I scintigraphy in the right buttock and surgically removed in December 1996. Serum Tg levels have remained undetectable since then. To the best of our knowledge, this is a unique case of a papillary carcinoma of the thyroid with a propensity to metastasize only to the skin and breast during a follow-up of 11 years.

ACTH-producing carcinoma of the pituitary with haematogenic metastases.

The case report is presented of a 47-year-old white woman with Cushing's disease treated by bilateral adrenalectomy in June 1981. A first computed tomography (CT) scan in September 1984 showed a voluminous pituitary adenoma with invasion of the sphenoid sinus and left parasellar extension. The tumour increased progressively in size, a suprasellar extension developed and the optic chiasm was eventually affected. In March 1988 and June 1989 the patient underwent two surgeries for the pituitary tumour, the second followed by radiotherapy. During this period, the ACTH values varied between 100 pmol/l and 403 pmol/l (normal: < 13 pmol/l). After radiotherapy, a progressive shrinking of the tumour was observed and the ACTH concentrations decreased to a lowest value of 27.5 pmol/l. The patient was clinically well until September 1993 when, suddenly, the plasma ACTH concentration increased to very high levels (greater than 965 pmol/l). There was no evidence of tumour growth on the sellar CT scan. In January 1995, an ACTH-producing pituitary carcinoma was diagnosed, based on the presence of bone metastases. The patient died in May 1995.

Rapid weight gain, at least in some women, is an expression of a neuroendocrine state characterized by reduced hypothalamic dopaminergic tone.

A group of 17 consecutive regularly menstruating women who gained at least 5 kg the previous year (Group 1) was compared with a control group of similar age, parity and social class (Group 2). Galactorrhea was observed in 6/17 women from group 1 and in 1/16 women from group 2 (chi 2 4.571; p < .05). Average morning prolactin levels were higher in group 1 (8.15 +/- 4.92 micrograms/l) than in group 2 (5.29 +/- 2.48 micrograms/l; p < .05). The two groups were similar in their morning thyroxin, triiodothyronine, TSH, estradiol, cortisol, gastrin, cholecystokinin, somatostatin, oxytocin, insulin and IGF-1 levels. Leptin levels were significantly higher in group 1 than in group 2 (18.85 +/- 10.63 micrograms/l vs. 10.15 +/- 6.38 micrograms/l; p < .02) but this difference could be attributed exclusively to the higher body mass index (BMI) of group 1 (MANCOVA). Analysis of the distribution of basal prolactin levels in group 1 revealed a skewed distribution due to the presence of six outliers (Barnett and Lewis test associated with Mahalanobis distance) whose values were higher than the highest value found in group 2. These outliers were henceforth considered as subgroup 1a, and the remnant patients in group 1 as subgroup 1b. Besides the expected difference in basal prolactin levels between subgroups 1a and 1b (13.72 +/- 3.69 and 5.12 +/- 1.81 micrograms/l, respectively) and the higher frequency of galactorrhea in group 1a (4/6 vs. 2/11; p < .05) no other differences were observed in clinical or basal biochemical parameters. Following domperidone (10 mg, i.v.) the percentual increase in prolactin (delta Prl 20'/Prl 0') was significantly lower in group 1 than in group 2 (23.9 + 15.2 vs. 37.0 +/- 21.2; p < .05). In absolute values, the prolactin rise in subgroup 1a (100.7 +/- 45.5 micrograms/l) was significantly lower (p < .02) than that of subgroup 1b (157.3 +/- 50.3 micrograms/l) and group 2 (152.7 +/- 34.5 micrograms/l). Group 1 (and each one of its two sub-groups) also differed from group 2 in a higher incidence of meaningful life-events the year preceding the study. This study confirms previous observations that recent weight gain in women is preceded by important life-events and is associated with galactorrhea and increased prolactin levels in a number of them. Besides, it provides evidence that the increased prolactin levels are due to reduced hypothalamic dopaminergic tone.

Cortisol, prolactin, growth hormone and neurovegetative responses to emotions elicited during an hypnoidal state.

The present study describes the responses of cortisol, prolactin and growth hormone (GH) to emotions elicited during sessions in which an hypnoidal state was induced. The purpose of the study was to provide answers for the following questions: 1) Do sessions with an emotional content have more hormonal surges than baseline, relaxation-only, sessions? 2) Does the induction of a fantasy of pregnancy and nursing elicit a prolactin response? 3) Are there any associations between surges of different hormones? 4) Are hormonal responses related to the intensity, type, or mode of expression of the emotions? For this purpose, thirteen volunteers and twelve patients with minor emotional difficulties were studied during sessions under hypnosis. The period of observation lasted for about three hours. Heart rate (HR), skin conductance (SC) and vagal tone (VT) were monitored. Serum cortisol, prolactin and growth hormone were sampled every 15 minutes. The volunteers had three types of sessions- "blank", consisting of relaxation only (12 sessions), "breast feeding", in which a fantasy of pregnancy and breast feeding was induced (12 sessions) and "free associations" in which the subjects were encouraged to evoke experiences or feelings (17 sessions). The patients had only sessions of free associations (38 sessions). Sessions of free associations had more hormonal surges than "blank" and "breast feeding" sessions. This was true for cortisol (8/17 v.3/24; p < 0.03), prolactin (7/17 v. 3/24; p < 0.05) and GH (9/17 v. 4/24; p < 0.02). During the 55 sessions of free associations (volunteers plus patients) there were 32 surges of cortisol, 18 of prolactin and 28 of GH. Cortisol and prolactin surges were negatively correlated (p < 0.03). GH had no significant association with either cortisol or prolactin. Visible emotions were positively associated with GH surges (p < 0.05). but not with cortisol or prolactin. Cortisol surges were correlated positively with evocations of real events (p < 0.01) and negatively with evocations containing defensive elements (p < 0.01). Cortisol correlated positively with shock and intimidation (p < 0.02) and negatively with rage (p < 0.04). The AUC of the cortisol peaks during shock and intimidation was significantly higher than that of the pool of all other cortisol peaks (12.4 micromol x min x l(-1) v. 7.1 micromol x min x l(-1); p < 0.005). Rage had a marginally significant positive association with prolactin surges (p=0.07). The distribution of GH surges did not show any significant association with types of emotions. The present study provides evidence that cortisol, prolactin and GH respond to psychological stress in humans. However, they are regulated differently from one another. Cortisol and prolactin surges appear to be alternative forms of response to specific emotions. GH surges depend on the intensity of the emotion, probably as a consequence of the associated muscular activity. The current paradigm of stress, implying corticotrophin-releasing hormone (CRH) as the initial step of a cascade of events, is insufficient to account for the diversity of hormonal changes observed in psychological stress in humans.

Endocrine and psychological evaluation of women with recent weight gain.

A group of 13 consecutive regularly menstruating women who gained at least 5 kg the previous year (Group I) was compared to a control group of similar age, parity, and social class (Group II). The two groups were similar in estimated and observed food intakes; pre- and postprandial gastrin levels; hourly 24-h profiles of cortisol and insulin; urinary cortisol and 17-hydroxycorticosteroids. Group I had higher serum prolactin concentrations at all times than Group II (mean values 14.60 micrograms/l vs. 8.84 micrograms/l; p = .0121). Galactorrhea was observed in 5 women from Group I and in none of the women from Group II (p < .05). Group I also differed from Group II in a higher incidence of meaningful life-events the year preceding the study, higher prevalence of sexual dysfunction (9/13 vs. 4/13; p < .01) and higher indexes (p < .05) of several parameters in the MMPI and SCL 90. Median serum cortisol and prolactin concentrations were negatively correlated, both in Group I (R = -.669; p = .012) and in the whole sample (R = -.453; p = .0298). It is suggested that the rapid weight gain is part of a neuroendocrine response to environmental stimuli also characterized by hyperprolactinemia. The significant negative correlation between serum prolactin and cortisol indicates that this response differs from, and is possibly an alternative to, the sympathoadrenal "stress" response.

Proceedings of the workshop, "Practical approaches to the diagnosis and treatment of acromegaly".

Practical approaches to the management of acromegaly are discussed. The roles of surgery, radiotherapy, and medical treatment with oral dopamine agonists such as bromocriptine or the long-acting somatostatin analogue octreotide given subcutaneously are reviewed. Most cases need surgery, but cure is rare in patients with macroadenomas, although common with microadenomas. Radiotherapy should be considered in surgical failures, but takes several years to be effective. Medical treatment with octreotide is effective in the majority, for whom it represents a major advance, but it needs to be administered subcutaneously and the development of gallstones and gastritis in long-term treatment are problems. Bromocriptine is usually less effective, but occasionally still plays a role in the therapeutic program. Combinations of the different modalities are usually required in the management of acromegalic patients.

Psychosomatic factors in patients with hyperprolactinemia and/or galactorrhea.

A biographic and clinical investigation of 101 patients with hyperprolactinemia and/or galactorrhea is reported. Fifty-one patients were reared without their fathers and 18 with an alcoholic, violent one. These situations were uncommon in the control population, and the differences were statistically significant. There was a high frequency of complaints of obesity, headaches, frigidity, lightheadedness, and fullness of the abdomen, limbs, or face. There was a significant temporal correlation of external events in the natural history with onset or worsening of the symptoms. It is concluded that exposure during childhood to an environment characterized by an absent or alcoholic, violent father conditions some women to develop hyperprolactinemia and/or galactorrhea later in life as a response to specific environmental changes. These conclusions apply similarly to patients with prolactinoma, idiopathic hyperprolactinemia, and euprolactinemic galactorrhea, suggesting a close relationship among the 3 entities.

Is idiopathic hyperprolactinemia a transitional stage toward prolactinoma?

The basal prolactin (PRL) levels on five different days, the PRL responses to thyrotropin-releasing hormone and to domperidone, and the thyroid-stimulating hormone (TSH) responses to domperidone were studied in 75 regularly menstruating women and 44 patients with moderate hyperprolactinemia. It was found that, for the entire sample, the responses to each of the stimuli could be described by a continuous function of the basal PRL levels. The present work provides evidence for the following conclusions: 1) The PRL responses to thyrotropin-releasing hormone and to domperidone merely bring additional diagnostic information relative to basal PRL levels in the occasional patients with macroprolactinemia; 2) there is a continuous spectrum of lactotroph activities in women, ranging from normal secretors through an intermediate group of hypersecretors (with progressively increased serum PRL levels and decreased responsiveness to stimuli) to full-blown prolactinomas; and 3) idiopathic hyperprolactinemia is a heterogeneous entity that includes the above intermediate group of patients, women with macroprolactinemia, and patients with undiagnosed prolactinomas.

Hyperprolactinemia in women with paternal deprivation during childhood.

It was reported that most females with prolactinoma, idiopathic hyperprolactinemia, or euprolactinemic galactorrhea were reared either without their father or with an alcoholic, violent father. To gain further insight into this association, a group of sisters of patients with prolactinoma (generally exposed to the same environment as the patients') and a control group were studied. Women with paternal deprivation during childhood differed from the women who had normal childhoods in that they had: 1) higher mean serum prolactin concentration (14.7 versus 9.4 ng/mL; P less than .001); 2) higher incidence of hyperprolactinemia (12 of 50 versus three of 59; P less than .005); and 3) higher incidence of galactorrhea (14 of 50 versus seven of 59: P less than .03). These observations support the contention that paternal deprivation during childhood is associated, in a minority of women, with a predisposition to develop hyperprolactinemia and presumably, prolactinoma later in life. A hypothesis on the possible mechanisms of a casual relationship is presented.

The hyperparathyroidism-jaw tumour syndrome in a Portuguese kindred.

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disease characterized by the occurrence of parathyroid tumours and fibro-osseous tumours of the jaw bones. Some HPT-JT patients may also develop renal abnormalities, which include Wilms' tumours, hamartomas and polycystic disease. The HPT-JT gene has been mapped to chromosome 1q25-q31, and we report the clinical and genetic findings in a kindred from central Portugal. HPT-JT was observed in six members from three generations; all had primary hyperparathyroidism (five had parathyroid adenomas, one a parathyroid carcinoma). Ossifying jaw fibromas affecting the maxilla and/or mandible were observed in 5/6. Renal cysts (<2.5 cm) were observed in four. Genetic studies using 18 polymorphic loci from chromosome 1q25-q31, together with leukocyte DNA from 11 family members and tumour DNA from three parathyroids (two adenomas and one carcinoma), revealed loss of tumour heterozygosity in the parathyroid carcinoma only, and the retained haplotype was found to cosegregate with the disease in the six affected members. A new Portuguese kindred with the HPT-JT syndrome that maps to chromosome 1q25-q31 has been identified, and these findings will help in the further characterization of this inherited disorder.

[Combined therapy in non-insulin-dependent diabetes mellitus]. / Terapêutica combinada na diabetes mellitus não insulino-dependente.

In recent years an improved understanding of potential complications associated with hyperinsulinemia has led to a growing interest in alternatives to insulin monotherapy for patients with non-insulin-dependent diabetes mellitus, who have failed on a regimen of diet and sulphonylureas. These patients typically present normal or elevated levels of insulin. This problem which has been attributed to insulin resistance, is superimposed on the peripheral hyperinsulinemia resulting from subcutaneous insulin delivery. A plethora of clinical trials have reported on the efficacy of combining therapy in limiting insulin requirements while achieving better glycemic control. This paper attempts a critical review of the pros and cons with respect to combining therapy and provides guidelines for its practical use.

[Ret proto-oncogene mutations associated with type 2 multiple endocrine neoplasms (MEN 2). Clinical implications]. / Mutações no Ret Proto-oncogene em associação com neoplasias endócrinas múltiplas tipo 2 (MEN 2). Implicações clínicas.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome. Clinical features and diagnostic aspects of this syndrome are reviewed with a focus on progress biochemical screening to genetic analysis of those at risk. The clinical implications resulting from the application of the new methods of molecular biology are discussed.