[Substitution with thyroid hormones in the elderly : Goals and risks]. / Substitution mit Schilddrüsenhormonen im höheren Lebensalter : Ziele und Gefahren.

Substitution with thyroid hormones is indicated in elderly patients with overt hypothyroidism, especially, when they present with typical symptoms of hypothyroidism. In light of the current study situation, the use of levothyroxine to treat clinical hypothyroidism in elderly patients is still controversial. In a recent double-blind, randomized, placebo-controlled study, levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. The impact of levothyroxine therapy in patients with subclinical hypothyroidism on cardiovascular risk is not completely clear. Levothyroxine treatment is safe and free of side effects, when the thyroid-stimulating hormone (TSH) levels remain within the normal range. Prescription of levothyroxine in patients with only slightly elevated TSH levels often leads to overtreatment, which is associated with an increased risk of fractures, neurological and psychological symptoms, and atrial fibrillation. The recommendations of the European Thyroid Association is to treat elderly patients only when the TSH value is greater than 10 mU/l and the patient is symptomatic or the patient has a high cardiovascular risk. The therapeutic TSH range in elderly patients in the case of levothyroxine treatment should be 1.0-5.0 mU/l. Follow-up of the TSH level is mandatory in order to not oversee a developing overt hypothyroidism and to avoid overtreatment in case of levothyroxine treatment.

Primary adrenal lymphoma: 3 case reports with different outcomes.

Primary adrenal lymphoma (PAL) is an extremely rare entity, with approximately 70 cases reported in the English literature and 120 cases worldwide. Here we report the cases of a 53-year-old and a 62-year-old male patient and a 60-year-old female patient affected by large B-cell non-Hodgkin lymphoma of the adrenal gland. We summarize the diagnostic approaches that confirmed the diagnosis of PAL and describe individual treatment outcomes after therapy. Based on these case reports and a review of the literature patients are usually in the 6th or 7th decade of life and present with B-symptoms or rapidly progressive adrenal insufficiency in case of bilateral involvement. The identification of bilateral adrenal masses often causes a severe diagnostic problem. An etiological approach with assessment of the hormonal profile and detailed diagnostic imaging should be aimed at. Furthermore, if PAL is suspected biopsy of the adrenal mass should be performed after biochemical exclusion of a pheochromocytoma. Once the diagnosis is established further treatment decisions should be made in a multi-disciplinary setting in specialized centers.

Biochemical evidence supporting the Cortina criteria.

Whether acromegaly is inactive or active, respectively cured or not cured depends on the GH suppressibility and the basal IGF-I level. According to the Cortina criteria, GH suppression after oral ingestion of 75 g glucose to <1 microg/l using conventional polyclonal immunoassays and an IGF-I level within the age-matched normal range are regarded as evidence of good control of acromegaly. According to more recent publications, mortality, which is increased in active acromegaly, is normalized when GH and IGF-I levels have become normal as defined above. Morbidity, i.e. typical features of acromegaly like cardiac problems, carpal tunnel syndrome, carbohydrate intolerance, and excessive sweating may also improve though painful arthropathy, and coarse facial features usually remain unaltered even if the biochemistry has been completely normalized. Using more sensitive GH assays, a group of acromegalic patients was shown to have normal IGF-I levels after surgery, with post-glucose levels of GH <1 microg/l but >0.14 microg/l, which is the upper level of normal subjects and of a second group of successfully operated acromegalic patients. The latter group also had slightly lower IGF-I levels, though such levels were normal in both groups. Whether this may indicate that these patients who have higher GH levels after oral glucose measured with the more sensitive immunoradiometric assay (IRMA) will more likely develop recurrences remains to be demonstrated in a larger cohort. According to the criteria put forward in Cortina d'Ampezzo in February 1999, all patients who have post-glucose GH levels <1 microg/l and normal age-matched IGF-I levels have to be regarded as well controlled, i.e. sufficiently treated. Because of lack of evidence, there is at present no reason to change the consensus reached there.

The influence of hyperthyroidism on the hypothalamic-pituitary-gonadal axis.

We have investigated the function of the hypothalamic-pituitary-gonadal (H-P-G)-axis in patients with severe, untreated Graves' disease. We studied 7 male and 6 female healthy volunteers, and 7 male and 7 female patients with Graves' disease. Hormone profiles were developed by blood sampling every 10 min for an 8 hour period. In women this was done in the early follicular phase of menstrual cycle. LH-, FSH-, and PRL levels were measured using immunoradiometric assays and testosterone (T), estradiol (E2), sex-hormone binding globulin (SHBG), and progesterone (P) were measured with standard assays. The pulsatility of LH, FSH and PRL was calculated using the programmes Pulsar, Cluster and Desade. The temporal relationship of plasma LH, FSH, and PRL pulses was also investigated using specific concordance analysis. Data were evaluated by means of non-parametric statistics. LH-secretion was increased in all hyperthyroid patients, while FSH-secretion was increased in hyperthyroid men only. Pulsatile characteristics of LH- and FSH-secretion (frequency, peak shape) in patients were not different from controls. No change in PRL-secretion was shown. Significant copulsatility occurred between LH and FSH, and LH and PRL. This was more pronounced in hyperthyroid than in healthy study subjects. Plasma levels of steroid hormones and sex-hormone-binding globulin were significantly (p<0.005) increased in hyperthyroid men. Free Androgen Index was significantly (p<0.005) decreased in hyperthyroid males. No other auto immune diseases were noticed. Our results indicate that the function of the H-P-G axis is not impaired in hyperthyroid patients, but gonadotropin levels are increased. Hyperthyroid men show relative primary gonadal insufficiency that may be due to exaggerated SHBG levels. The copulsatility of LH and FSH, and of LH and PRL was confirmed both in patients and controls.

Criteria for cure of acromegaly: a consensus statement.

In February 1999, a workshop was held in Cortina, Italy to develop a consensus defining the criteria for cure of acromegaly. The workshop was sponsored by the University of Brescia and hosted by the Italian Society of Endocrinology. Invited international participants included endocrinologists, neurosurgeons, and radiotherapists skilled in the management of acromegaly. This statement summarizes the consensus achieved in these discussions.

The somatopause is no indication for growth hormone therapy.

Growth hormone (GH) secretion in the elderly is generally diminished although there are marked individual differences ranging from normal GH secretion and normal levels of insulin-like growth factor (IGF)-I through low GH and subnormal IGF-I. It is assumed that the reduced central cholinergic activity leading to unrestrained somatostatin release leads to impaired GH secretion. The somatopause, if it occurs at all, is, in contrast to the menopause, a subtly developing physiological event. The menopause often causes severe symptoms that justify hormone replacement therapy, but the somatopause is a physiological event at the end of the lifespan with no acute symptoms that can be attributed to GH deficiency with certainty. Whether the non-specific symptoms of old age, i.e. truncal obesity, muscle atrophy, decreasing energy, and mental disorders, can be--even partially--blamed on decreased GH secretion is unclear. Thus, GH therapy in elderly patients, in the absence of pituitary disease cannot be recommended. In addition, the following has to be considered: 1) GH has to be given by subcutaneous injection, which may be technically difficult in elderly patients. 2) It is difficult to find the right individual dosage of GH since elderly patients may show increased sensitivity to GH therapy (compared with children) or may be GH-resistant. 3) Manifestation of diabetes mellitus may be enhanced in elderly patients. 4) The elevation of IGF-I levels may enhance the progression of malignant disease; it has been shown that the concentration of IGF-I in the circulation correlates to the frequency of prostatic cancer. Furthermore, acromegalic patients have a higher frequency of colonic polyps and gastrointestinal malignancies. 5) Even if problems such as dosage, mode of application and the questions of safety are resolved, the present costs of GH therapy will not allow to advocate GH treatment of all elderly patients with low levels of IGF-I. However, since some patients seem to benefit from GH therapy in senescence, further studies are needed. There may be a subset of elderly patients in whom GH treatment is useful. However, unless these patients are included in a study protocol, GH treatment should not be given to elderly patients in the absence of pituitary disease.

Prolactin-producing pituitary adenoma and carcinoma with neuronal components--a metaplastic lesion.

Recent studies indicate that cells of various epithelial tumors are capable of transformation to neurons. Observing both neurons and neuropil in two prolactin-producing adenohypophyseal tumors, one benign and one malignant, we sought to assess their cellular differentiation, the presence of nerve growth factor receptor, and expression of the dopamine receptor gene using immunocytochemistry, electron microscopy, and in situ hybridization. Light and electron microscopy clearly revealed cells morphologically transitional between adenoma/carcinoma cells and neurons. Large neurons lacked proliferative activity. Neurons in varying number showed immunoreactivity for pituitary hormones including prolactin, growth hormone and alpha subunit in the adenoma and prolactin alone in the carcinoma. The distribution of nerve growth factor receptor staining was similar. In both tumors, in situ hybridization showed mRNAs for prolactin and dopamine receptor within adenohypophyseal cells and neurons. Our results indicate that the occurrence of neurons and neuropil in growth hormone and prolactin-producing pituitary tumors appears to be the result of metaplasia. The process is not limited to benign tumors and may be due to the production of tropic substances by the adenohypophysial cells, which by paracrine/autocrine mechanisms result in transformation of adenoma cells to nerve cells.

A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients.

This follow-up study was carried out to validate the effectiveness of cross-gender hormone therapy embedded in a multistep treatment concept for transsexual patients. This therapy described in detail by the authors elsewhere and presented briefly below provides cross-gender hormone substitution to obtain an assimilation of secondary sex characteristics to the desired sex as quickly as possible. Personal and social background data of 46 male-to-female (M-to-F) and 42 female-to-male (F-to-M) patients passing through different stages of the treatment concept were included. In the Endocrinological Outpatient Clinic of the Max-Planck-Institute/Munich the effectiveness of cross-gender hormone replacement therapy as well as frequency and distribution of side effects were examined by follow-up examination of endocrinological parameters. Cross-gender hormones were administered either parenterally or orally. Blood samples were collected routinely after 2 to 6 months depending on the duration of hormone substitution and complication rate. The incidence of hyperprolactinemia in estrogen-treated M-to-F transsexuals lies in the range of studies published before, whereas the number of patients developing galactorrhea is significantly lower in our patients. The incidence of thromboembolic events during the time of cross-gender hormone treatment in our patients is negligible. Changes in hematological parameters are observed under cross-gender hormone therapy. With the cross-gender hormone regimen performed by us it is possible to generate less side effects in the treatment of transsexual patients than described before.

Transsexualism and osteoporosis.

The aim of this study was to investigate whether and to what extent our regime of cross-gender hormone replacement therapy might influence osteoporosis development in transsexual patients. We found that after long-term therapy the bone densities of our cross-gender hormone-treated transsexual groups (10 male-to-female and 10 female-to-male) did not show significant differences compared to those of the corresponding biological sex. Moreover, the bone-density during therapy pointed out very little variability and that independent of the gender-alteration (transsexuality-direction) and the age of the transsexuals. Our results indicate that for transsexual patients treated with cross-gender hormone replacement therapy the risk of developing osteoporosis is low.

[Estrogen treatment for prevention and therapy of osteoporosis]. / Ostrogenbehandlung zur Prophylaxe und Therapie der Osteoporose.

Postmenopausal osteoporosis affects 30% of all women. Major risk factors include hereditary factors, deficiency of calcium and vitamin D in the diet, too little exercise, excessive alcohol consumption and a reduction in the amount or duration of sex hormone secretion (late menarche, early climacterium, etc.). Osteoporosis prophylaxis is of great importance. Since in the early stages, osteoporosis does not produce symptoms, an early diagnostic work-up involving osteodensitometry makes good sense in patients with individual risk factors. In addition to physical activity, basic countermeasures always include adequate calcium and vitamin D supplementation. Replacement therapy with estrogens (usually in combination with gestagens) is an effective and causal treatment of postmenopausal osteoporosis. However, the indication must be established individually on the basis of a benefit-risk consideration.

Somatostatin analogs in ectopic corticotropin production.

Eutopic corticotroph pituitary adenomas and adrenal cortisol-producing adenomas do not usually express somatostatin receptors. However, ectopic corticotropin (ACTH)-producing tumors often express somatostatin receptors. Thus, the octreoscan can detect and localize tumors in 80% of patients with ectopic ACTH syndrome, and so it can be used to differentiate between eutopic and ectopic ACTH-dependent bilateral adrenal hyperplasia. Octreotide therapy can produce a rapid and sustained reduction of ACTH and cortisol levels in patients with ectopic ACTH-dependent Cushing's syndrome and, in some, may be the only long-term therapy possible. Although no large series have been reported, a review of the literature reveals a large number of case reports that have demonstrated the effectiveness of octreotide.