27. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000; 356: 1789-1794. 28. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003; 41: 1690-1696.
All batches of Met-hGH examined stimulated statural growth to approximately the same extent. The growth rates measured partly exceeded the results obtained in previous studies with pituitary preparations in the same dosage. Under treatment with SI, i.e. the preparation with the highest amount of ECP, high antibody titres with high binding capacity against GH and ECP were found. With SII all antibody determinations showed much lower titres. With Somatonorm (SIII), in the large majority of cases no antibodies were detectable. The titres registered in a few children were low and the binding capacities were negligible. The biologically determined somatomedin activity was initially pathologically low. During treatment it rose to supraphysiological levels. Also the radioimmunologically assayed somatomedin and the alkaline phosphatase increased significantly. At the start of the first series, two patients showed allergic skin reactions which turned out to be caused by the insufficiently purified preparations. Therapy with extractive preparations was free of such side-effects and fully successful. Both of the patients were atopic. A third child who was also allergic developed after 6-9 months the highest antibody titres seen, combined with a high binding capacity. Also, with this boy, treatment was switched over to pit-hGH, with very good results. Two children with pituitary dwarfism already developed in utero high antibody titres against Met-hGH but not against ECP. For this response, neither the Somatonorm nor its impurities can be implicated. Rather, it is the reaction to GH generally, which the organism recognizes as a foreign protein and thus as an antigen. One of the patients stopped growing after nine months. Likewise, pituitary GH did not lead to any further improvement.
A decade ago diabetics with uraemia were excluded from dialysis because of the uniformly poor outcome of dialysis and transplantation, and the progressive deterioration of vision. By 1978, however, owing to technical advances in haemodialysis and reduction of complications, survival among chronically haemodialysed diabetics improved considerably. During the past five years, continuous ambulatory peritoneal dialysis (CAPO) has established itself as a viable alternative to haemodialysis in the diabetic patient with end-stage renal disease (ESRD). Thus, the uraemic diabetic patient today has several options once the decision is made to start dialysis. The therapy of each diabetic renal failure patient accepted for renal replacement needs to be tailored to the severity of the illness and adapted to the personal and family situation. Unless there is some contraindication every potentially rehabilitable uraemic diabetic, younger than 55 years, should first be offered a kidney transplantation. For others the choice of transplantation, peritoneal dialysis or haemodialysis depends on the individual medical condition and socioeconomic situation. Both peritoneal dialysis and haemodialysis have specific advantages and disadvantages (Table 1). Because of the widespread use of haemodialysis in the past two decades, this treatment is readily available in the majority of centres in most countries. However, about 25% of the patients so treated fail to thrive and the mortality rate on haemodialysis is equivalent to that of cadaver kidney transplant. Also, retinopathy continues to progress and only a small percentage of patients are fully rehabilitated. CAPO is indicated especially for those capable of self-care at home and those with an unstable cardiovascular system because CAPO gives excellent haemodynamic control. Furthermore intraperitoneal insulin administration allows good control of blood sugar and the control of blood pressure is excellent on CAPO. Its principle disadvantages are recurrent peritonitis, progression of
Many women experience emotional or physical side effects when taking oral contraceptives (OCs). Despite the potential impact on women's health and well-being, there are no valid methods to screen women for their risk of OC side effects. The present paper presents the results of two studies where anthropometric indicators of androgen exposure, 2D:4D and middle-phalangeal hair, were examined for their potential as predictors of OC side effects. In study 1, 2D:4D was associated with women's reports of a history of: (a) negative mood side effects; (b) discontinuation due to negative mood side effects; (c) specific mood side effects (i.e., crying, sadness, and altered trust in one's partners) and (d) specific physical side effects (i.e., headaches, fatigue, and decreased sex drive). In study 2, 2D:4D and/or middle-phalangeal hair was/were associated with a reported history of: (a) discontinuation due to negative mood side effects; (b) specific mood-related side effects (i.e., negative mood, disrupted sleep, increased aggression, and altered trust in one's partner) and (c) specific physical side effects (i.e., headaches, decreased menstrual cramps, and increased sex drive/arousal). The general pattern was that adverse OC side effects were experienced by women with lower 2D:4D and fewer middle-phalangeal hairs. Almost all relationships remained significant when response bias was controlled. These results suggest a possible role for prenatal testosterone exposure and both androgen action and sensitivity in women's experience of OC side effects. Furthermore, these two digit measures may be useful predictors of hormonal contraceptive side effects in women.
Since its clinical description in the last century, much progress has been made in our understanding of acromegaly. From an initial description of pituitary enlargement as just another manifestation of generalized visceromegaly, the pituitary abnormality has come to be recognized, in most instances, as the underlying aetiological factor. Gigantism and acromegaly are manifestations of disordered pituitary physiology, but the lesion responsible may be hypothalamic, adenohypophyseal or ectopic in location. The best known pathological hypothalamic basis for acromegaly is represented by a neuronal malformation or 'gangliocytoma'. It usually takes the form of an intrasellar gangliocytoma or, more rarely, a hypothalamic hamartoma. The neuronal elaboration of GHRH may play a role in the development of a growth hormone adenoma; the pituitary process may pass through an intermediate stage of somatotropic hyperplasia. When acromegaly has its basis in a pituitary abnormality, the lesion is almost exclusively an adenoma; the non-tumorous adenohypophysis shows no evidence of coexistent hyperplasia. Surprisingly, such tumours are more often engaged in the formation of multiple hormones rather than GH alone. They frequently produce not only GH and prolactin, the products characteristics of cells of the acidophil line, but also glycoprotein hormones, usually TSH. The spectrum of adenomas also varies in its degree of differentiation from a histogenetically primitive lesion, the acidophil stem cell adenoma, to well-differentiated tumours of varying cellular composition and hormone content. Each adenoma type has its clinicopathological, histochemical, immunocytological and ultrastructural characteristics. The isolation and characterization of GHRH has permitted the identification of neuroendocrine tumours, most of foregut origin, elaborating this releasing hormone. Such functional tumours induce hyperplasia of pituitary somatotrophs and may, on occasion, result in the formation of growth hormone adenomas. Resection of these GHRH-producing neoplasms results in reversal of endocrinological and sellar abnormalities. Future efforts should be directed toward the elucidation of the aetiology of pituitary adenomas, specifically whether they represent a proliferative process having its origin in endocrinological imbalance, presumably a hypothalamic abnormality, or whether it has a 'de novo' origin in the 'usual process of neoplastic transformation'.
Polypeptide growth factors form a class of regulatory molecules which exert their effects by binding to specific receptors present on the cell surface. Most of the time the exact role of these factors in the healthy body is unknown. Some, like PDGF and TGF beta, seem to be involved in wound healing. Others, like EGF, promote epithelial cell growth and differentiation. The site of synthesis of most polypeptide growth factors is unknown. Their target can be identified by detecting the cells which present the specific receptors at their surface. It is though that polypeptide growth factors have a paracrine mode of action. Many different cancerous cells produce polypeptide growth factors and the appropriate receptors. Thus, they are able to stimulate their own growth in an autocrine fashion. Recently, some polypeptide growth factors and receptor genes or cDNAs have been molecularly cloned. Growth factor genes and messengers are much more complex than would be expected from the size of the polypeptide. Some cDNAs have been introduced into bacterial expression vectors and large amounts of the factors have been produced by bacteria. New tools, such as molecular probes and specific antibodies, are thus now available to investigate the production of the growth factors and their receptors. The same tools will facilitate the identification and understanding of the molecular mechanism whereby cancerous cells produce the growth factors and the appropriate receptors simultaneously. The importance of growth factors and receptors in cancer is stressed by the finding that three oncogenes are in fact the genes coding for one growth factor and two receptors. Finally, the molecular probes and the specific antibodies raised against these molecules can be used to identify precisely the growth factor(s) and receptor(s) produced abnormally in cancers. Antibodies that inhibit specifically the interaction of this very growth factor with its receptor could then be developed, thus allowing human tumour cell growth to be controlled.
PSAs, with few exceptions, consist of a piliary and a sebaceous component. In androgen-sensitive areas, each has the capacity to develop into either a terminal hair follicle or a sebaceous follicle depending upon its location. Without androgen, there is no development of the sexual hair follicle or sebaceous gland. Androgens appear to promote sexual hair growth by recruiting a population of PSAs that have preset genetic sensitivity to initiate the production of terminal hairs. The site of action of androgens within the PSA is unclear. There are indications that androgens may act at more than one site in a system that requires two-way reciprocal interaction between dermal and epithelial cells for the generation of hair growth. Growth hormone appears to exert an important synergism with androgen in affecting the PSA, seemingly through the mediation of insulin-like growth factors. Hirsutism is due to an increased density of growing terminal hairs. The majority of cases of moderately severe hirsutism in women are due to hyperandrogenaemia, as are half the cases of mild hirsutism and about one-quarter of the cases of mild acne vulgaris. We advocate reserving the term idiopathic hirsutism or idiopathic acne for those patients in whom excessive growth of terminal hair or acne is not explained by androgen excess. We believe that highly variable sensitivity to androgen within the population explains both idiopathic hirsutism and cryptic hyperandrogenaemia; that is, these disorders lie at opposite ends of the normal spectrum of sensitivity to androgen. The biological basis for the variations in responsiveness of PSAs to androgens is unknown. The regression of hirsutism induced by antiandrogen treatment is characterized by the growth of hairs that are more vellus in character, i.e. smaller and less medullated.
Many of the diabetic neuropathic syndromes are characterized by painful symptoms with a sensation of burning and associated with troublesome hyperaesthesia. It is important to distinguish between the acute and chronic forms of peripheral sensory neuropathy; while the former carries an excellent prognosis for symptomatic improvement within one year, the latter may cause persistent symptoms for many years. In contrast to the acute form, in which symptoms are particularly severe but abnormal neurological signs are minimal, patchy stocking and glove sensory loss together with peripheral small muscle wasting are often present in chronic sensorimotor neuropathy. Peripheral polyneuropathies are more common in patients with poor metabolic control, although recent evidence implicates blood glucose flux as a possible contributory factor to neuropathic pain. It is possible that blood glucose flux or altered peripheral blood flow leads to increased spontaneous activity in nociceptive afferent fibres which are present in the axonal sprouts that characterize small fibre neuropathy. In the diagnosis of the neuropathies, exclusion of other aetiological factors is of paramount importance as there is no specific diagnostic test for diabetic nerve damage. If there is no symptomatic improvement after a period of stable and optimal metabolic control together with simple analgesics, then the tricyclic drugs should be regarded as first line therapy. The rapid effect of these drugs suggests a peripheral rather than central mode of action.
This review discusses androgen status in male and female obesity, according to their specific phenotype, and the main mechanisms responsible.Published data in the literature of the last 20 years represented the basis of most of the data and concepts incorporated in the review.Obesity is associated with profound alterations in androgen secretion, transport, metabolism, and action, according to a dichotomous behavior depending on sex. Obese men are characterized by a progressive decrease of testosterone levels with increasing body weight, whereas obese women, particularly those with the abdominal phenotype, tend to develop a condition of functional hyperandrogenism. Reduced sex hormone–binding globulin synthesis and circulating blood levels represent the sole common mechanism which is responsible in both sexes. Among other still partially undefined factors, mechanisms potentially responsible for the sex dichotomy in androgen levels involve specific alterations of gonadotropin secretion, estrogens, the hypothalamic-pituitary-adrenal axis, leptin, androgen receptors, specific steroidogenic enzymes in the peripheral tissues, and, possibly, ghrelin. In both sexes, androgens play an important role in determining the sex-dependent pattern of body fat distribution. Moreover there are theoretical possibilities that low testosterone in men and high free testosterone fraction in women may play a role in the development of the metabolic syndrome. This is exemplified by the well defined association between obesity and other features of the metabolic syndrome in women with polycystic ovary syndrome and in hypogonadal men. The effects of androgen and antiandrogens in obese men and women also represent arguments in favor of this association.Given the fundamental role of sex hormones in the regulation of body composition, fuel homeostasis, and reproduction in humans, more emphasis should be placed on the potential role of androgen dysregulation in the pathophysiology of different obesity phenotypes and the metabolic syndrome.
Summary In this brief review, we have attempted to highlight developments indicating that paracrine communications between germ cells and Sertoli cells exist and probably play a role in male reproduction. In addition to paracrine testicular commu- nication, autocrine and juxtacrine inter- actions are also probably very impor- tant. As an example of autocrine testicular communications, both IGF-I and its receptor have been localized to Sertoli cells, where IGF-I has been shown to stimulate cell proliferation, lactate pro- duction, and plasminogen activator se- cretion (Spiteri-Grech and Nieschlag 1992) and to alter IGF BP-3 clearance (Smith et al. 1992). The strongest sup- port forjuxtacrine testicular interactions comes from preliminary data suggesting that a membrane-bound form of stem cell factor may be needed for normal germ cell maturation, Although much progress is being made in identifying new growth and differenti- ating factors in testis, we still know little about how they function to modulate the complex process of spermatogenesis. For example, how does the Sertoli cell trans- late signals from outside of the seminif- erous tubules into the tubular compart- ment? Do all factors that result in activating the same Sertoli cell intracel- lular signaling pathways regulate identi- cal gene products, leading to similar effects on spermatogenesis? Do the mul- titude of factors that are produced within testis exist simply to provide redundancy for a few select testicular functions, or do they each function in a unique way to finely tune a wide range of actions? Not until these and other questions can be answered will we have a comprehensive understanding of the physiologic pro- cesses that control male reproduction.
The hormonal activity of androgens is mediated in target cells, particularly in human skin, by two kinds of proteins: the androgen receptor and the enzyme 5 alpha-reductase. In well differentiated androgen target cells, 5 alpha-reductase achieves the transformation of testosterone (T) into dihydrotestosterone (DHT), a more active androgen than T, because of its higher affinity for the receptor. In other words, 5 alpha-reductase acts as an amplifier of the androgen signal but is not absolutely required for androgen action. Regarding the regulation of the androgen receptor, minimal information is available. However, in genital skin, the receptor seems to be predominantly localized in the cytosolic compartment before puberty in males and in the nuclear compartment after puberty. In hirsute patients, recent data on genital skin fibroblasts do not show significant differences between the binding capacity of fibroblasts from normal and hirsute women whereas there is no difference between normal men and women. 5 alpha-Reductase activity seems to be a very important step in the processes involved in androgen action. While 5 alpha-reductase activity present in the skin of external genitalia does not seem to be androgen dependent, this is not the case for the enzyme located in pubic skin. In this area, a sex difference between males and females may be observed both in skin homogenates and in cultured fibroblasts. In addition DHT added to a medium of pubic skin fibroblasts is capable of increasing 5 alpha-reductase activity. This increase is not observed when cyproterone acetate is added to the medium and in patients with testicular feminization syndrome without receptors. Pubic 5 alpha-reductase activity is an androgen receptor mediated phenomenon. In patients with hirsutism, and particularly idiopathic hirsutism, 5 alpha-reductase activity is high without an increase in circulating androgens. This may be observed both in pubic skin homogenates and in cultured fibroblasts. Thus, an excess of skin 5 alpha-reductase activity may be considered as a cause of hirsutism but both the exact level of the abnormality in the regulation of the enzyme and its genetic control remain to be elucidated.
Human growth hormone releasing hormone (GHRH) was originally extracted from two pancreatic tumours in patients with acromegaly, and is now known to consist of a 44 residue amidated peptide or its C-terminal-shortened derivatives. The sequence of rat GHRH has also been determined; this 43 residue peptide shows approximately 70% homology with human GHRH, and is located mainly in the arcuate nucleus of the hypothalamus. Pulsatile GH release in the rat is principally a consequence of the pulsatile release of hypothalamic GHRH, although this appears to be associated with a transient suppression of somatostatin release. Exogenous GHRH specifically increases circulating GH in many species, and in the long term may increase growth.
Hirsutism is the excessive growth of terminal hair in a male pattern in a female. In most hirsute women, hirsutism is caused by increased androgens. However, not all women with hirsutism actually show elevated levels of circulating androgens with standard laboratory tests, in which case we speak of idiopathic hirsutism (IH).The aim of this paper is to investigate whether there are biochemical markers that can be used to unravel the cause in IH.An electronic search through the PubMed database was conducted to find studies describing potential biomarkers for IH.The majority of included studies claimed an increased 5α-reductase (5α–RD) activity in women with IH by means of increased DHT metabolite levels. Studies investigating abnormalities of the androgen receptor (AR) and serum levels of indirect markers showed no significant differences.Our literature search showed that polymorphisms of the AR as well as indirect markers seem to be nonspecific, but that the dihydrotestosterone-reduced metabolite 5α-androstane-3α,17β-diol glucuronide is markedly enhanced in women with IH, suggesting an increased 5α–RD activity in these women. Further studies need to be performed to determine the clinical usefulness of 3α-diol G as a biomarker for IH.
Taken together, the studies reviewed here suggest that although gonadotropins are necessary for follicular growth, they are insufficient by themselves to explain the dynamics of folliculogenesis. Indeed, the role of gonadotropins in follicular maturation must necessarily be permissive: that is LH and FSH initiate a synchronized cascade of follicular events directly mediated by paracrine and autocrine factors.
Diabetic retinopathy is a common, and potentially blinding or visually disabling complication of diabetes. Nearly all diabetic subjects will have some degree of retinopathy after 20 years of diabetes, and 50% of those with insulin dependent diabetes will have proliferative retinopathy after 15 years. Macular oedema frequently produces central vision loss and legal blindness, most commonly in non-insulin dependent diabetics. In recent years, several therapeutic modalities have been demonstrated to be effective on the basis of large-scale randomized, controlled clinical trials. These include panretinal photocoagulation (PRP), using the argon laser or xenon arc, for proliferative retinopathy, and focal photocoagulation for macular oedema. Vitrectomy surgery is effective for diabetic vitreous haemorrhage and traction retinal detachment, producing improved vision in most patients, but only a relatively small percentage of patients so treated recover good visual acuity (greater than or equal to 6/12). Other therapeutic modalities, such as hypophysectomy for severe retinopathy, remain controversial, while still others, such as rigorous blood glucose control and aldose reductase inhibitors, are currently under investigation. The primary care physician who deals with diabetic patients should be familiar with the lesions of diabetic retinopathy and with current therapeutic modalities. He should perform an examination of the posterior retina with the direct ophthalmoscope on each diabetic patient at each visit, and should institute prompt referral to an ophthalmologist at the first sign of change. Periodic examination of all diabetic patients by an ophthalmologist should be conducted at the intervals recommended in the previous section. Definitive evaluation and treatment of diabetic retinopathy should be carried out by the ophthalmologist.
Duration of disease is the major susceptibility factor for microangiopathy. Microangiopathy does not occur without the metabolic abnormality of diabetes and there is much circumstantial evidence to implicate poor diabetic control in its pathogenesis. The rate of development and severity of complications, however, are variable even in patients with apparently similar control and about 25% of diabetics will never develop clinical evidence of microangiopathy. Studies of identical twins suggest a genetic component in the pathogenesis of retinopathy in NIDDM, and less so in IDDM, but increased capillary basement membrane thickness does not occur in the non-diabetic identical co-twins of insulin dependent diabetics. There may also be genetic heterogeneity not only of diabetes, but also of its complications, although for a given type of diabetes the prevalence of microangiopathy is often very similar in different racial groups. ]Associations between several different HLA molecules (particularly DR4) and microangiopathy in IDDM have been reported but not consistently confirmed. Recently the finding of an increased frequency of the B3 allotype of the fourth component of complement C4B3 in subjects with retinopathy has suggested that there is an HLA linked association. Both complement and the immunoglobulins are concerned with humoral immunity and the report of an association between a phenotype of the IgG heavy chain markers on chromosome 14 and retinopathy is of particular interest. These associations appear to be additive but independent. These reports need confirmation but provide the best evidence we have for an immunogenetic component (HLA and non-HLA linked) of the aetiology of microangiopathy, at least in IDDM. ]The studies of identical twins, HLA and Gm associations provide good evidence that genetic factors are involved in susceptibility to microangiopathy, at least in some diabetics, although the most relevant genes may not have been identified. Searches for better genetic markers must continue in order to identify those patients at increased risk of developing microangiopathy.
We have provided a brief historical review of developments in our understanding of the endocrine mechanisms underlying the expression of androgen action in women. An alternative to the free hormone concept is considered which proposes that, at least in some target cells, androgens bound to SHBG are the biologically relevant molecules. In nearly every instance, the changes in blood levels of SHBG that have been observed are consistent with this idea. At present there are only bits of direct evidence to support the hypothetical mechanism proposed. As already mentioned, control of androgen action at the level of cellular uptake would provide obvious advantages as well as a potential mechanism to explain the antagonism between androgens and oestrogens which is still a mystery. It is important to note that the proposed mechanism is not obligatory for androgen or other steroid hormone action. Synthetic steroids which do not bind to SHBG or CBG clearly can gain access to target cells by simple diffusion and bind to intracellular receptors. Compounds such as methyltestosterone and dexamethasone are metabolized much more slowly than their natural counterparts and therefore are cleared slowly from the circulation. It is possible that the well-known difficulties in selecting appropriate therapeutic regimens with such compounds is related to the fact that they bypass an important regulatory step in steroid hormone action-modulated entry into target cells. Hopefully, the recent development of powerful new tools of molecular endocrinology will hasten the answer to the question: What is the active androgen in blood?
