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PubMed2005

Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease.

Malnutrition is defined as abnormalities caused by an inadequate diet, but this term is often used inappropriately to describe the syndrome of loss of body weight with muscle mass being replaced by fatty tissue and declining serum proteins present in adults and children with chronic kidney disease (CKD). This syndrome is more accurately described as cachexia, and manifests as growth failure in children with CKD. Cachexia is common and is an important risk factor for poor quality of life and increased mortality and morbidity in both adults and children with CKD. Anorexia, acidosis and inflammation are important causes of cachexia, but the underlying molecular mechanism is not well understood. Dietary intake is often poor and resting metabolic rate is increased in CKD. The energy cost of growth is increased in experimental CKD. Circulating concentrations of cytokines, such as leptin, tumor necrosis factor-alpha and interleukins 1 and 6 are increased in patients with CKD and correlate with the degree of cachexia in these individuals. We hypothesize that cytokines signal through orexigenic neuropetides such as agouti-related peptide and neuropeptide Y (NPY), and anorexigenic neuropetides such as proopiomelanocortin and alpha-melanocyte-stimulating hormone in the arcuate nucleus in the hypothalamus. This signaling system also involves the NPY receptor and the melanocortin receptors and controls appetite and metabolic rate in health and disease. Furthermore, the first order neurons of this system are located outside the blood-brain barrier and can therefore sense the circulating levels of cytokines, as well as long-term satiety hormones such as leptin and insulin and short-term satiety hormones such as ghrelin and peptide (P) YY. There is experimental evidence that this hypothalamic neuropeptide signaling system may have an important role in the pathogenesis of cachexia in CKD. Understanding the molecular mechanism of cachexia in CKD may lead to novel therapeutic strategies.

Cachexia↗
PubMed1996

From laboratory to bedside: new strategies in the treatment of malnutrition in cancer patients.

The objective of this review is to present and discuss the current and the possible future perspectives of artificial nutrition in preventing and treating cancer cachexia. English-language studies published in the last 25 years were retrieved using MEDLINE, bibliographies and consultation with experts. MEDLINE search terms included "cancer," "malnutrition," and "nutritional support." In vivo and in vitro controlled studies were selected, and data from each study were independently abstracted by the authors. Data obtained indicate that cancer cachexia is a common manifestation of advanced malignant disease, characterized by marasmus due to impaired nutrient metabolism, weight loss, and anemia. In patients, the presence of cachexia increases morbidity and mortality, delays or impedes the delivery of the adequate treatment, reduces the efficacy of anti-neoplastic therapy, and impairs patient's quality of life. Indirect evidence indicates that cancer cachexia is mediated by circulating cytokines, produced by the host in response to the presence of the malignancy. In the past two decades, nutritional support was used to counteract the detrimental effect of cancer cachexia on the host, but with limited success. More recently, the better understanding of the mechanisms of cancer cachexia and the identification of pharmacologic effects provided by specific nutrients, has formed the rationale for a "new" mode of nutrition therapy/nutritional support, adding pharmacotherapy to adjunctive initial care.

Cachexia↗
PubMed2005

Cancer-associated malnutrition.

Malnutrition is a common problem among patients with cancer, affecting up to 85% of patients with certain cancers (e.g. pancreas). In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterised by loss of lean body mass, muscle wasting, and impaired immune, physical and mental function. Cancer cachexia is also associated with poor response to therapy, increased susceptibility to treatment-related adverse events, as well as poor outcome and quality of life. Cancer cachexia is a complex, multifactorial syndrome, which is thought to result from the actions of both host- and tumour-derived factors, including cytokines involved in a systemic inflammatory response to the tumour. Early intervention with nutritional supplementation has been shown to halt malnutrition, and may improve outcome in some patients. However, increasing nutritional intake is insufficient to prevent the development of cachexia, reflecting the complex pathogenesis of this condition. Nutritional supplements containing anti-inflammatory agents, for example the polyunsaturated fatty acid (PUFA) eicosapentanoic acid (EPA), have been shown to be more beneficial to malnourished patients than nutritional supplementation alone. EPA has been shown to interfere with multiple mechanisms implicated in the pathogenesis of cancer cachexia, and in clinical studies, has been associated with reversal of cachexia and improved survival.

Anti-Inflammatory Agents↗
PubMedDate not supplied

Leptin serum levels in cachectic heart failure patients. Relationship with tumor necrosis factor-alpha system.

Cachexia is a strong predictor for mortality in patients with congestive heart failure. To investigate the role of leptin and regulators of apoptosis in cardiac cachexia we compared leptin concentrations and their relation to the TNF system, interleukin 1-beta (IL-1b), and soluble Fas in patients with heart failure with and without cachexia. Patients with cardiac cachexia have increased levels of interleukin-1b compared to non-cachectic heart failure patients [mean(S.E.)=1.11(0.62) vs. 0.02(0.02), P=0.01] and decreased concentrations of leptin [10.79(3.93) vs. 23.24 (8.35), P=0.1]. Leptin levels correlate with TNF-RI in cachectic heart failure patients (r=0.58, P=0.018). The TNF-RI levels were also correlated with Fas, both in all the patients taken together (r=0.5, P=0.006) and in those with cachexia (r=0.52, P=0.036). Our data indicate that more prospective studies are needed to clarify the role of leptin in the pathophysiology of heart failure cachexia.

Aged↗
PubMed1996

Characterization of a cancer cachectic factor.

Cancer cachexia is a syndrome of progressive wasting which has been suggested to be mediated by tumour-necrosis factor-alpha, interleukins 1 and 6, interferon-gamma and leukaemia-inhibitory factor. It has proved difficult to correlate levels of tumour-necrosis factor-alpha and interleukin-6 with cancer cachexia, and the weight loss induced by leukaemia-inhibitory factor may be due to toxicity. In the murine adenocarcinoma MAC16, cachexia is mediated by circulatory catabolic factors, which we have now isolated using an antibody cloned from splenocytes of mice transplanted with the MAC16 tumour, with a delayed cachexia. The material is a proteoglycan of relative molecular mass 24K which produces cachexia in vivo by inducing catabolism of skeletal muscle. The 24K material was also present in urine of cachectic cancer patients, but was absent from normal subjects, patients with weight loss due to trauma, and cancer patients with little or no weight loss. This suggests that cachexia in mice and humans may be produced by the same material.

Adenocarcinoma↗
PubMed2002

Peripheral mechanisms involved with catabolism.

PURPOSE OF REVIEW: This review summarizes recent developments concerning the mechanisms of skeletal muscle and adipose tissue breakdown, which are a hallmark of cachexia during many diseases. Current knowledge on the hypermetabolism which often contributes to cachexia is also considered. RECENT FINDINGS: Recent studies have identified interactions between Ca2+, proinflammatory cytokines (in particular tumor necrosis factor-alpha) and the activation of transcription factors (e.g. nuclear factor-kappaB) in the stimulation of major proteolytic pathways in cachexia. Progress has also been made in explaining the inhibiting effects of several drugs on protein breakdown. Advances in our understanding of the mechanisms of adipose tissue catabolism in cachexia include demonstrations that (1) tumor necrosis factor-alpha, in addition to its direct lipolytic effect, promotes adipose tissue breakdown by inhibiting adipocyte differentiation and increasing adipocyte apoptosis, (2) interleukin-6 has a lipolytic effect, and (3) chemokines are expressed by adipocytes and interact with tumor necrosis factor-alpha to cause lipolysis. Concerning the hypermetabolism in cachexia, new evidence supports previous theories that uncoupling protein-2 and 3 are primarily involved in the generation of reactive oxygen species and in the control of fatty acid flux across the mitochondrial membrane, respectively. Furthermore, the cytokine-induced transcriptional coactivator-1 for the peroxysome proliferator-activated receptor-gamma was recently identified as a contributor to hypermetabolism. SUMMARY: These new insights into major catabolic pathways during cachexia provide a focus for future studies in this area and may help to develop promising therapeutic approaches.

Adipose Tissue↗
PubMed1991

Dependence of a human squamous carcinoma and associated paraneoplastic syndromes on the epidermal growth factor receptor pathway in nude mice.

Increased levels of epidermal growth factor receptor (EGFR) have been shown on squamous cell carcinomas. Recently, we described a squamous cell carcinoma (MH-85) derived from the oral cavity which was associated with several paraneoplastic syndromes including hypercalcemia and cachexia. This tumor induced the same paraneoplastic syndromes in nude mice (BALB/c, nu/nu, male, 4-6 weeks old). Scatchard analysis revealed that there are two classes of EGFR in MH-85. The dissociation constant and number of binding sites for the high affinity receptors were 38 pM and 5 x 10(4)/cell, respectively, and 2.2 nM and 6 x 10(5) cell, respectively, for the low affinity receptors. Growth of MH-85 in culture was stimulated by epidermal growth factor (EGF) and inhibited by monoclonal antibody 108 to human EGFR, which recognizes the extracellular domain of the EGF receptor. Surgical removal of submandibular glands from male nude mice resulted in a dramatic decrease in plasma EGF levels and a significant reduction of tumor growth, hypercalcemia, and cachexia. When EGF (5 micrograms/mouse, every 2 days for 6 weeks, i.p.) was administered to these sialoadenectomized animals, tumor growth increased, with a parallel increase in hypercalcemia. When monoclonal antibody 108 (1 mg/mouse, i.p.) was given 1, 5, and 10 days after MH-85 tumor implantation, tumor formation was retarded, which resulted in delayed onset of hypercalcemia and cachexia. Moreover, when the antibody was injected 6 times in nude mice exhibiting large tumors and profound hypercalcemia and cachexia, there was a striking decrease in tumor growth, which was accompanied with a reversal of hypercalcemia and cachexia. These results indicate that growth of the human squamous cell carcinoma MH-85 is dependent on the EGFR pathway and that subsequent development of hypercalcemia and cachexia is dependent on tumor growth. They also suggest that agents which interfere with the EGFR pathway may have therapeutic potential as anticancer agents in some human tumors.

Animals↗
PubMed1997

[Current views on use of megestrol acetate in oncology practice].

Anorexia of tumourous origin associated with cachexia is a frequent clinical problem which has a substantial impact on the therapeutic results and patient survival. It is encountered in as many as 90% patients in the stage of palliative care. Tumourous cachexia is thus a difficult problem in oncological practice. Hormonal therapy of malignant breast disease is an integral part of adjuvant as well as palliative treatment in postmenopausal as well as premenopausal patients. Both oncological problems, tumourous cachexia and hormonal therapy interfere by their consequences with the quality of life of oncological patients, i.e. a situation which is becoming the pillar of care of oncological patients. The author reviewed the contemporary available literature pertaining to tumourous cachexia and hormonal therapy of breast cancer. He emphasizes the mechanism which participates in tumourous cachexia and discusses possibilities to influence it by therapy. Megestrol acetate (Megace, Bristol-Myers Squibb Co.) proves so far the most effective pharmacological preparation which improves anorexia and cachexia in severely ill patients. In the review of the literature the author presents examples of the use of megestrol acetate in the hormonal strategy of treatment of breast cancer and mentions some problems which deserve further study. The objective of the submitted review is to draw attention of the medical community to a drug which is a stimulant in the comprehensive, pretentions strategy of treatment of malignant diseases and which leads by its basic action also to improvement of the quality of life of these patients.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

Clinical characteristics of preoperative hypoalbuminemia predict outcome of cardiovascular surgery.

OBJECTIVE: To define the clinical characteristics and outcome of preoperative hypoalbuminemia in adult cardiovascular surgery. STUDY: Inception cohort. SETTING: Adult cardiovascular intensive care unit (CVICU). PATIENTS: Admissions to CVICU between January 1 and December 31, 1993. INTERVENTION: Preoperative hypoalbuminemia (serum albumin < or = 3.5 g/dL) was classified by the presence of malnutrition cachexia (body mass index of < or = 20 kg/m2), liver insufficiency (serum bilirubin > or = 2.0 mg/dL), history of congestive heart failure, or hypoalbuminemia alone. Demographics, chronic diseases, systemic hemodynamics, and laboratory data were obtained at preoperative and later on admission and during the stay in the CVICU. OUTCOME MEASURES: Postoperative organ dysfunction, nosocomial infections, length of mechanical ventilation, hospitalization and death. RESULTS: A total of 2,743 patients (91%) of 3,025 patients who were admitted to the CVICU were enrolled in the study. Preoperative hypoalbuminemia was found in 325 patients (12%): hypoalbuminemia and cachexia in 21 patients (6%), hypoalbuminemia and liver insufficiency in 26 patients (8%), hypoalbuminemia and history of congestive heart failure in 102 patients (31%), and hypoalbuminemia alone in 176 patients (54%). Clinical features of preoperative hypoalbuminemia were age > or = 75 years, female gender, left ventricular ejection fraction < or = 35%, hematocrit < or = 34%, serum creatinine > or = 1.9 mg/dL, systemic oxygen delivery < or = 350 mL/min.m2, acute stressful conditions (eg, infective endocarditis, acute myocardial infarction, or emergency surgery) and chronic obstructive pulmonary airway disease. Redo operations, combined valve and coronary artery bypass graft, mitral valve replacement, and thoracic aortic surgery were the commonest types of surgery performed in these patients. All types of hypoalbuminemia except for malnutrition cachexia increased the likelihood of postoperative organ dysfunction (cardiac, pulmonary, renal, hepatic, and neurologic), gastrointestinal bleeding, nosocomial infections, length of mechanical ventilation, stay in the CVICU, and hospital death. Cachectic hypoalbuminemia increased the requirement for postoperative parenteral nutrition and prolonged the length of stay in hospital. CONCLUSION: Preoperative hypoalbuminemia was attributed to malnutrition cachexia, liver insufficiency or congestive heart failure in < 50% of cardiac patients undergoing cardiovascular surgery. All types of hypoalbuminemia except for malnutrition cachexia increased the likelihood of postoperative organ dysfunction, nosocomial infections, prolonged mechanical ventilation, and death. The morbidity and mortality attributed to hypoalbuminemia could be explained by the underlying clinical characteristics rather than malnutrition cachexia in cardiac patients.

Aged↗
PubMed1989

Nutritional concerns in cancer patients.

One of the prime nutritional concerns in cancer patients is cachexia and deteriorating nutritional status. Cachexia can occur as a result of either treatment or the tumor itself. The progressive malnutrition ultimately affects performance status and organ function. Tolerance to treatment may thus be decreased, which, in turn, may adversely affect toxicity and response. In addition, the deleterious effects of malnutrition on the immune system can increase susceptibility to infection. The weakness and fatigue related to muscle wasting and changes in metabolism affect physical appearance, leading to a loss of self-esteem. Thus, the vicious cycle of cachexia severely impacts on every aspect of daily life. Providing nutritional support and effective treatment may reverse the cachexia. Studies involving caloric supplements alone have not been encouraging. Conversely, studies using megestrol acetate have shown that cancer patients gain weight and that their sense of well-being improves. However, the mechanisms of weight gain remain unknown, and further studies are needed to determine the mechanisms by which appetite is stimulated or catabolism is inhibited or both. Nursing interventions to stimulate appetite and promote greater food intake, coupled with the use of agents that alter metabolism, such as megestrol acetate, may reverse the trend of cachexia and thus provide an increased sense of well-being and improved quality of life.

Antineoplastic Agents↗
PubMed1997

Effects of lentinan on abnormal ingestive behaviors induced by tumor necrosis factor.

Lentinan (LNT), a beta-glucan derived from Lentinus edodes (Berk.) Sign., is known to work positively against cachexia in patients with malignant tumors. Because the cachectin/tumor necrosis factor (TNF) is supposed to be one of the factors that mediate cancer cachexia, we tested the effects of LNT on TNF-induced cachexia in rats. First, we analyzed in detail the cachectic actions of TNF (0.2 mg/kg/day, 5 days, IV) on food and water intake, body weight, and locomotor activity. The day after the first administration of TNF (acute phase), food and water intake, as well as body weight, of all rats decreased. However, over the next few days of treatment (chronic phase), the rats gradually developed a tolerance to the cachectic actions of TNF. Specifically, after the third administration, the rats treated with TNF had a higher amount of water intake than the control rats. This was mainly due to an increase in daytime water intake. We also analyzed the effects of LNT (0.1 or 1.0 mg/kg, twice/wk. IV) on TNF-induced cachexia, and compared the data with those from the rats treated with TNF alone. The higher dosage of LNT significantly suppressed TNF-induced daytime polydipsia and increased the amount of nighttime water intake, as well as the meal size of nighttime food intake. These results suggest that LNT partially normalizes TNF-induced cachexia in rats.

Animals↗
PubMed1998

New cachexic factors.

Patients with pancreatic cancer show evidence of cachexia at the time of diagnosis, involving not only loss of adipose tissue, but also lean body mass. The shorter survival time of men than women with non-small cell lung cancer has been attributed to their enhanced rate of weight loss. From studies in animal models, various cytokines have been proposed as mediators of the cachectic process, although evidence from human studies is generally lacking. Only serum levels of IL-6 have been found to correlate with the clinical development of cachexia, but this may be a marker for the process rather than the actual mediator, because the direct administration of this cytokine to experimental animals failed to induce cachexia, despite the induction of an acute-phase response. Ciliary neurotrophic factor, a member of the IL-6 superfamily, has, however, been shown to produce loss of muscle mass in experimental animals, although it failed to exert a direct catabolic effect on muscle in vitro. A sulphated glycoprotein found in the urine of patients with cancer cachexia is capable of directly inducing protein catabolism in skeletal muscle by a process involving an increase in prostaglandin E2. Agents capable of attenuating this effect, e.g. eicosapentaenoic acid and ibuprofen, have been shown to stabilize body weight loss in cachectic cancer patients. This pharmacological approach to the treatment of cachexia appears to be more successful than nutritional manipulation.

Animals↗
PubMed2001

Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice.

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C(6)H(12)CIN(3)O(4)S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower (P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (-38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (~-54 to -69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (-80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

Adenocarcinoma↗
PubMed2002

Anticancer drugs that induce cancer-associated cachectic syndromes.

Cachexia--a wasting condition--seriously impairs the quality of life of patients with advanced cancer. Previous studies have shown that several inflammatory cytokines mediate the development of cancer-associated cachexia. Experimentally, cachexia-like symptoms can be induced in tumor-bearing mice and treatment of such mice with chemotherapeutic agents reverses cachexia as a result of its therapeutic action. Nonetheless, cancer chemotherapy occasionally induces anorexia as an adverse reaction. For example, treatment with antitubulin taxanes reduces body weight in tumor-bearing mice more than healthy mice, even when the agents significantly reduce tumor growth. However, the complex relationship between cancer cachexia and the effects of anticancer drugs remains to be elucidated. This review outlines what is known about the development of cachectic reactions, especially in tumor-bearing mice, that occur during treatment with anticancer agents and highlights the clinical relevance of the information.

Animals↗
PubMed1989

Cachectin activity in the serum of cachectic, tumor-bearing rats.

Cachectin/tumor necrosis factor has been postulated to be a possible mediator of cancer cachexia. Using a sensitive bioassay, we attempted to detect circulating cachectin activity in the serum of sarcoma-bearing rats and to correlate levels with measurements of cachexia and the extent of disease. In addition, we resected the tumor to determine the time course of reversal of cachexia and the disappearance of cachectin activity in the serum. Circulating cachectin activity was not detectable in the serum of non-tumor-bearing rats or in tumor-bearing rats until 28 days after implantation. With evidence of food intake and body weight decline, cachectin activity became detectable in the serum and levels increased as cachexia and tumor burden increased. Serum cachectin activity levels correlated directly with tumor burden and inversely with food intake and body weight change. After resection of the tumor, food intake and body weight increased and serum cachectin activity became undetectable. Serum triglyceride levels were higher in cachectic tumor-bearing rats than in pair-fed non-tumor-bearing controls, and levels decreased after tumor resection as cachectin activity decreased. The results suggest that cachectin is a humoral mediator of cachexia in this rat-tumor model.

Animals↗
PubMed1993

Mechanisms of paraneoplastic syndromes of colon-26: involvement of interleukin 6 in hypercalcemia.

The precise mechanisms responsible for increased calcium levels in patients with cancer are not fully understood. In a recent study, the participation of interleukin (IL)-6 as an important mediator of key parameters of cancer cachexia in the colon-26 adenocarcinoma was reported. Here, we show that in addition to cachexia, C-26 tumour bearing mice also develop hypercalcemia. Treatment of these mice with 5' deoxyfluorouridine significantly reduces tumour size and inhibits both hypercalcemia, cachexia, and elevated serum IL-6. Moreover, monoclonal antibody to mouse IL-6 prevents both the cachexia and the hypercalcemia and reduces serum IL-6 levels in C-26 tumour bearing hosts. The administration of a bisphosphonate compound (Clodronate) reverses the hypercalcemia but has no effect on tumour burden, serum IL-6 levels, or wasting. We conclude that tumour-derived IL-6 plays a role in the pathogenesis of the C-26 associated hypercalcemia, and that the increase of serum calcium does not by itself mediate cachexia.

Adenocarcinoma↗
PubMed1985

Nutrition and cancer: physiological interrelationships.

There are many tumors that have paraneoplastic syndromes. Furthermore, location of certain tumors can result in very specific effects on the host, especially tumors in the hypothalamus, the intestinal tract, or the liver. Finally, tumors of the immune system can have significant distant consequences. However, from direct experimental evidence, from model systems, and from the utilization of nutritional manipulation in the treatment of cancer, the data suggest very strongly that there is no unique cancer malnutrition. Early diagnosed cancer does not show malnutrition as a presenting symptom. Furthermore, all metabolic disturbances can be explained on the basis of the metabolic differences of tumor cells and normal cells and are very frequently proportional to the bulk of the tumor. The cachexia that is associated with malignancies is more likely cachexia in cancer patients than it is a specific cancer cachexia, unless the tumor burden is very large. This point was clearly made in a short review of the causes of cachexia in nearly 1500 cancer patients in Russia (145). Brennan also feels that most cases of malnutrition are uncomplicated starvation, and cancer cachexia has many features seen in major injury or sepsis (16). This distinction has great implications in the management of cancer patients.

Adult↗
PubMed1999

Transgenic models to study gonadotropin function: the role of follicle-stimulating hormone in gonadal growth and tumorigenesis.

The role of FSH in gonadal tumorigenesis and, in particular, in human ovarian cancer has been debated. It is also unclear what role the elevated FSH levels in the inhibin-deficient mouse play in the gonadal tumorigenesis. To directly assess the role of FSH in gonadal growth, differentiation, and gonadal tumorigenesis, we have generated both gain-of-function and loss-of-function transgenic mutant mice. In the gain-of-function model, we have generated transgenic mice that ectopically overexpress human FSH from multiple tissues using a mouse metallothionein-1 promoter, achieving levels far exceeding those seen in postmenopausal women. Male transgenic mice are infertile despite normal testicular development and demonstrate enlarged seminal vesicles secondary to elevated serum testosterone levels. Female transgenic mice develop highly hemorrhagic and cystic ovaries, have elevated serum estradiol and progesterone levels, and are infertile, mimicking the features of human ovarian hyperstimulation and polycystic ovarian syndromes. Furthermore, the female transgenic mice develop enlarged and cystic kidneys and die between 6-13 weeks as a result of urinary bladder obstruction. In a complementary loss-of-function approach, we have generated double-homozygous mutant mice that lack both inhibin and FSH by a genetic intercross. In contrast to male mice lacking inhibin alone, 95% of which die of a cancer cachexia-like syndrome by 12 weeks of age, only 30% of the double-mutant male mice lacking both FSH and inhibin die by 1 yr of age. The remaining double-mutant male mice develop slow-growing and less hemorrhagic testicular tumors, which are noted after 12 weeks of age, and have minimal cachexia. Similarly, the double-mutant female mice develop slow-growing, less hemorrhagic ovarian tumors, and 70% of these mice live beyond 17 weeks. The double-mutant mice demonstrate minimal cachexia in contrast to female mice lacking only inhibin, which develop highly hemorrhagic ovarian tumors, leading to cachexia and death by 17 weeks of age in 95% of the cases. The milder cachexia-like symptoms of the inhibin and FSH double-mutant mice are correlated with low levels of serum estradiol and activin A and reduced levels of aromatase mRNA in the gonadal tumors. Based on these and our previous genetic analyses, we conclude that elevated FSH levels do not directly cause gonadal tumors. However, these results suggest FSH is an important trophic modifier factor for gonadal tumorigenesis in inhibin-deficient mice.

Activins↗