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PubMed1993

A nonsecreting pheochromocytoma presenting as an incidental adrenal mass. Report on a case.

A 25 year old women presented an incidental adrenal mass which was diagnosed to be a pheochromocytoma before surgery by means of a positive 131-I-MIBG scintigraphy. Urinary vanilmandelic acid resulted repeatedly normal as well as basal plasma norepinephrine (NE), epinephrine (E) and dopamine (DA). Urinary homovannilic acid resulted in the normal range. Stimulation tests with iv glucagone, tyramine and metoclopramide evoked normal NE and E responses while a slight increase in plasma DA was observed after metoclopramide. Oral clonidine suppressed plasma catecholamines (CA) normally. Histologic and immunohistochemical studies confirmed that the tumor was a pheochromocytoma showing positivity for tyrosine hydroxylase but not for dopamine-beta-hydroxylase activity. This case is the first report on a completely asymptomatic pheochromocytoma presenting as an incidental adrenal mass which was investigated with repeated biochemical tests before surgery and demonstrates that, among the extremely variable functional attitudes of pheochromocytomas, a defect in CA synthesis and secretion is also to be included.

Adrenal Gland Neoplasms↗
PubMed2004

Type 2 Diabetes Mellitus and Insulin Resistance: Stroke Prevention and Management.

Clinically recognized disorders of glucose metabolism include impaired fasting glucose, impaired glucose tolerance (both termed prediabetes), and diabetes mellitus. Type 2 diabetes mellitus affects 6% to 13% of adults in the United States. Among patients with recent stroke, 70% will have known diabetes, occult diabetes (detectable on an oral glucose tolerance test), or prediabetes. Type 2 diabetes mellitus is associated with a two- to six-fold increased risk for first or recurrent ischemic stroke. The mechanisms for the association are myriad and include the effects of hyperglycemia on vascular tissues and coagulation, and aberrations in blood pressure regulation, lipid metabolism, endothelial function, vascular inflammation, lipid metabolism, smooth muscle cell proliferation, and fibrinolysis. The most effective strategies to prevent stroke among people with diabetes include blood pressure control, antiplatelet therapy, and statin therapy. Tight glycemic control is recommended to prevent microvascular disease, but the effect on macrovascular disease, including stroke, has not been proven. Target blood pressure should be less than 130/80. Antiplatelet therapy may be accomplished with 81 to 325 mg of aspirin daily or 75 mg of clopidogrel daily. Statins should be given in dosages effective to reduce low-density lipoprotein cholesterol to less than 100 mg/dL. For glycemic control, first line therapy for most patients is metformin, starting at 500 mg daily. With time, most patients will need two or three oral medications from different classes and many eventually will require insulin therapy. Prevention of diabetes may be best accomplished by identifying those at risk and modifying diet, weight, and exercise habits. Screening for prediabetes and diabetes is appropriate for men and women older than 45 years and all individuals with vascular disease. Insulin resistance and impaired insulin secretion is the major underlying defect in type 2 diabetes mellitus. It also affects 50% of nondiabetic subjects with a recent ischemic stroke. Emerging evidence has linked insulin resistance to the pathophysiologic derangements in type 2 diabetes mellitus that accelerate atherosclerosis. Treatment of insulin resistance with weight loss, exercise, or medication can correct these derangements, and represents a promising approach to stroke prevention.

Journal Article↗
PubMed1981

Influence of the LH-RH analogue buserelin on cyclic ovarian function and on endometrium. A new approach to fertility control?

The long-acting stimulatory luteinizing hormone - releasing hormone analogue D-Ser(TBU)6-EA10-LH-RH (buserelin) was administered intranasally once daily in a dose of 400 mcg to 24 normally ovulating women and to 4 women with pre-existing endocrine dysregulation. Ovulation was inhibited in 136 out of 156 treatment months. In 20 treatment months, progesterone values temporarily increased indicating luteinization of follicles or ovulation with defective corpus luteum function. Estradiol secretion showed a tendency to lower values as treatment progressed but individually indicated follicle maturation until the end of the observed medication period. Bleeding pattern ranged from menses-like bleeding in regular as well as irregular intervals to amenorrhea. The morphological findings of 31 endometrial biopsies of 20 volunteers ranged from atrophy (n = 4) to proliferation (n = 25) with early signs of hyperplasia as well as early secretory transformation (n = 2). The morphological alterations indicate that unopposed estrogen stimulation of the endometrium is the main problem of long-term contraception with the dose schedule of buserelin used.

Adolescent↗
PubMed1982

Hormonal control of glucose homeostasis during development and ageing in mice.

Age-related changes in the hormonal control of glucose homeostasis were examined in immature (5-wk-old), young adult (10-wk-old) and older adult (30 and 60-wk-old mice). In immature mice, basal plasma glucose and insulin concentrations were higher than young adult mice. Glucose tolerance was impaired in immature mice, although the plasma insulin response to glucose and other secretagogues (arginine and glucagon) was well developed, and the hypoglycaemic effect of exogenous insulin was not impaired. Glucagon and epinephrine evoked a greater acute hyperglycaemia in immature mice, suggesting that these hormones exert a stronger rapid glucose-raising effect in preadult life. Basal plasma glucose and insulin concentrations were lowest in young adult mice, and increased with advancing adult age. Glucose tolerance was best in young adult mice and deteriorated with age, while plasma insulin concentrations after administration of glucose, arginine and glucagon were lowest in young adult mice and increased with age. However, in response to these secretagogues, the percentage increase in plasma insulin above basal was reduced in older adult mice. This indicates a defect of stimulus-recognition-secretion-coupling in the B-cells of older adult mice. The raised plasma glucose concentrations of older adult mice could not be attributed to an increase in the acute hyperglycaemic action of glucagon or epinephrine. The hypoglycaemic response to exogenous insulin decreased with age, suggesting that tissue sensitivity to insulin was impaired. Treatment with growth hormone and cortisone for 5 days produced a greater antagonism of insulin in older mice than young adult or immature mice. Growth hormone impaired glucose tolerance at each age, but only produced a marked hyperinsulinaemia in older adult mice. In contrast, cortisone produced a marked hyperinsulinaemia at each age, but only impaired glucose tolerance in older adult mice.

Aging↗
PubMedDate not supplied

Evaluation of hypoglycemic counterregulation using a modification of the Andres glucose clamp.

The glucose clamp, developed by Andres for the quantification of insulin action and secretion, was modified to study counterregulatory mechanisms against hypoglycemia, thereby overcoming the technical difficulties in producing a standardized, reproducible hypoglycemic stimulus. Normal subjects are exquisitely sensitive to small decrements in glucose; levels within the normal range cause suppression of endogenous insulin (approximately 4.0 mM) and activation of glucagon and epinephrine (approximately 3.5 mM) secretion. The glucose threshold for hormone release is modified by multiple factors, including age, gender, and the level of insulin per se. If glucose continues to fall toward 3.0 mM, the hormonal response is intensified and symptoms appear. The window between the appearance of symptoms triggering carbohydrate ingestion and the earliest signs of neuroglycopenia are surprisingly narrow. Subtle neuroelectrophysiological changes in cortical and brain stem function are evident at 2.9 mM. Insulin-dependent diabetes mellitus (IDDM) patients must rely heavily on their ability to secrete epinephrine to overcome a defective glucagon response. Unfortunately, this defense mechanism may diminish as disease duration increases, and may become further impaired by iatrogenic hypoglycemia accompanying insulin treatment. Commonly, the glucose level triggering adrenergic responses is shifted downward during intensive insulin therapy of IDDM. This may help explain why such patients release epinephrine and experience symptoms of hypoglycemia at a lower glucose level.

Adolescent↗
PubMed1992

Management of recurrent gallstones.

The risk of gallstone recurrence following non-surgical treatment has been overestimated in the past for two reasons: (1) diagnosis of primary gallstone dissolution was based on oral cholecystography; and (2) gallstone recurrence was expressed as a cumulative recurrence rate. Results based on better methodologies for diagnosis of gallstones (ultrasonography) and for calculation of results (life-table analysis) have indicated that gallstones recur in about 50% of patients, and that the risk of recurrence is confined mainly to the first 5 years after dissolution. Pretreatment gallstone characteristics, but not patient characteristics, are important risk factors for gallstone recurrence. Multiple stones are more likely to recur than solitary stones, a phenomenon attributable to the presence of a potent pronucleating factor in the bile of patients with multiple stones. This observation, and the finding that NSAID administration may reduce gallstone recurrence via inhibition of mucin secretion, suggests that the nucleation defect might be a key factor in the pathogenesis of recurrent gallstones. Prophylaxis with low-dose CDCA or UDCA has proven ineffective for preventing gallstone recurrence, although it may reduce it. Since the majority of recurrent gallstones are small when first seen because of regular ultrasonographic follow-up, multiple, radiolucent and in functioning gallbladders, they are amenable to bile acid retreatment, and intermittent bile acid therapy is probably a viable strategy for long-term management of cholesterol cholelithiasis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation.

Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca(2+) influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.

Animals↗
PubMed2006

The type III flagellar export specificity switch is dependent on FliK ruler and a molecular clock.

Salmonella flagellar hook length is controlled at the level of export substrate specificity of the FlhB component of the type III flagellar export apparatus. FliK is believed to be the hook length sensor and interacts with FlhB to change its export specificity upon hook completion. To find properties of FliK expected of such a molecular ruler, we assayed binding of FliK to the hook and found that the N-terminal domain of FliK (FliK(N)) bound to the hook-capping protein FlgD with high affinity and to the hook protein FlgE with low affinity. To investigate a possible role of FlgE in hook length control, flgE mutants with partially impaired motility were isolated and analyzed. Eight flgE mutants obtained all formed flagellar filaments. The mutants produced significantly shorter hooks while the hook-type substrates such as FlgE, FliK and FlgD were secreted in large amounts, suggesting defective hook assembly with the mutant FlgE proteins. Upon overexpression, mutant FlgEs produced hooks of normal length and wild-type FlgE produced longer hooks. These results suggest that hook length is dependent on the hook polymerization rate and that the start of hook polymerization initiates a "time countdown" for the specificity switch to occur or for significant slow down of rod/hook-type export after hook length reaches around 55 nm for later infrequent FliK(C)-FlhB(C) interaction. We propose that FliK(N) acts as a flexible tape measure, but that hook length is also dependent on the hook elongation rate and a switch timing mechanism.

Bacterial Proteins↗
PubMed2003

Polycystic ovary syndrome: syndrome XX?

Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic and reproductive disorder. It is associated with substantial defects in insulin action and secretion that confer a markedly increased risk for type 2 diabetes mellitus. Insulin resistance modifies reproductive function both by the direct actions of insulin on steroidogenesis and by disruption of insulin signaling pathways in the central nervous system. These insights have led to a new therapy for PCOS with insulin-sensitizing agents. Hyperandrogenemia and insulin resistance cluster in PCOS families, consistent with a genetic susceptibility to these abnormalities. There is evidence for both linkage and association of the hyperandrogenemia phenotype with an allele of a marker locus on chromosome 19, in the region of the gene encoding the insulin receptor.

Adolescent↗
PubMed1990

Visual function improvement in patients with macroprolactinomas treated with bromocriptine.

We studied eight patients who had visual field defects secondary to prolactin-secreting macroadenomas and who had improved visual function with bromocriptine treatment without surgery or radiation. We recommend bromocriptine as a primary treatment for prolactin-secreting macroadenomas. If therapy is effective, continued regular neuro-ophthalmologic, endocrine, and imaging studies are necessary, because treatment with bromocriptine must be continued indefinitely.

Adult↗
PubMed1999

Altered cord serum lipid levels associated with small for gestational age infants.

OBJECTIVE: To determine whether small for gestational age (SGA) infants show changes in lipid metabolism that could distinguish growth-restricted subpopulations. METHODS: Sera from the arterial cord blood from 38 SGA infants were analyzed for apolipoprotein A-I level, total lipid content, and distribution of those lipids as triglycerides, diglycerides, free fatty acids, and phospholipids. Comparisons were made between appropriate for gestational age (AGA) controls (n = 25), SGA infants with a ponderal index below the tenth percentile (SGA I, n = 20), and SGA infants with a ponderal index above the tenth percentile (SGA II, n = 18). RESULTS: Total cord serum lipid content was markedly decreased in all SGA infants compared with AGA infants (2.8 times lower). Although SGA infants showed total lipid concentration decreases, SGA I and SGA II infants showed distinct characteristics. Infants in the SGA I group had higher triglyceride levels (1.8 times higher) and lower free fatty acid levels (1.4 times lower), compared with AGA infants (P < .001). The lipid subclass distribution in SGA II infants was not significantly different from that in AGA infants, with the exception of an increase in triglyceride concentrations (1.3 times higher). Although the 22-kD placenta-derived apolipoprotein A-I was similar in all groups, the level of fetal liver-derived 28-kD apolipoprotein A-I was 6.5 times lower in SGA I infants than in AGA or SGA II infants (P < .001). CONCLUSION: The SGA I infants appeared to have impaired utilization of circulating triglycerides, consistent with peripheral adipose depletion. Diminished fetus-derived apolipoprotein A-I levels with normal levels of placenta-derived apolipoprotein A-I levels might indicate a defect in the production or secretion of apolipoproteins associated with growth restriction.

Fetal Blood↗
PubMed2003

Thrombospondin-1 promotes fibroblast-mediated collagen gel contraction caused by activation of latent transforming growth factor beta-1.

BACKGROUND: Grafting of cultured epithelium has become a useful technique for the treatment of epithelial defects, since grafted epithelial cells secrete factors promoting wound healing. We identified one such factor produced by cultured oral epithelial cells as thrombospondin-1 (TSP-1). Recently, TSP-1 was reported to act as an activator of transforming growth factor-beta1 (TGF-beta1). OBJECTIVE: The role of TSP-1 in wound healing and its mechanism were investigated in vitro and in vivo. METHODS: The cultured oral epithelial cell-conditioned medium was harvested and applied to Heparin-Sepharose affinity chromatography. Proteins were analyzed by N-Terminal sequencer. TSP-1 and the other factors were applied to fibroblasts-mediated collagen gel contraction assay. The amount of TGF-beta1 (latent TGF-beta1 (LTGF) and active TGF-beta1) in collagen gels was quantified by ELISA and Western blotting analysis. Collagen sponges were soaked with TSP-1 and implanted subcutaneously into rats. RESULTS: A 38 kDa protein secreted from cultured oral epithelial cells was found to be human TSP-1. TSP-1 promoted collagen gel contraction activity, and anti-human TSP-1 and TGF-beta1 antibody inhibited the activity. The diameters of the gels treated with LTGF and TSP-1 were reduced to a greater extent than those of gels treated with either factor alone. Although there were no significant differences in the amounts of total TGF-beta1, which include LTGF, the amount of 25 kDa TGF-beta1 was 3.30-fold greater in TSP-1-treated samples than controls. In vivo, 7 days after implantation, increased numbers of fibroblasts were observed in the sponges treated with TSP-1. CONCLUSION: These findings suggested that TSP-1 causes collagen gel contraction by activation of LTGF. TSP-1 is expected to be especially suitable for regulating wound healing.

Adolescent↗
PubMed1995

Malabsorption of food cobalamin.

Food-cobalamin malabsorption is marked by the inability to release cobalamin from food, which therefore cannot be taken up by intrinsic factor for absorption. The defect is not detectable by classical clinical tests like the Schilling test which are all based on the absorption of free, crystalline cobalamin. Tests of food-cobalamin absorption have been devised, the most popular ones using cobalamin bound to eggs or to chicken serum. The disparity between the abnormal results of these tests and the normal results with the Schilling test defines the disorder of food-cobalamin malabsorption. Release of cobalamin from food requires acid and pepsin, and most food-cobalamin malabsorptive states can be traced to gastric defects. However, other mechanisms may also play a role. The malabsorption is limited to food cobalamin and any free cobalamin, presumably including recycled biliary cobalamin, will be absorbed normally, which may explain its frequently insidious nature. The effect on cobalamin status covers a broad spectrum. At one extreme, some individuals, perhaps in the earliest stages, have normal cobalamin status, while at the other extreme may be found deficiency every bit as severe as in the most florid case of pernicious anaemia. Most often, however, the deficiency is mild, frequently marked by only a low serum cobalamin level, mild evidence of metabolic insufficiency and, sometimes, minimal clinical sequelae. Moreover, in some cases the gastric defect progresses and intrinsic factor secretion is affected, thus transforming into classical pernicious anaemia; this is not inevitable, however, and probably occurs in only a minority of patients. The course of food-cobalamin malabsorption is therefore a varied one. Nevertheless, it may be the most common cause of subtle or mild cobalamin deficiency and it is also sometimes associated with severe deficiency. Its identification and treatment need to be considered more widely in the clinical setting.

Animals↗
PubMed1988

Furosemide pharmacokinetics and pharmacodynamics in renal transplantation.

Furosemide was administered intravenously to four patients who had undergone renal transplantation in the past and four creatinine clearance--matched control subjects. Both patients who had undergone renal transplant and control subjects displayed similar pharmacokinetic and pharmacodynamic behavior, as assessed by drug delivery to the urine and sodium excretion, respectively. Despite similar degrees of natriuresis, patients who had undergone renal transplantation demonstrated a clear defect in urine potassium excretion. This defect in potassium excretion was not related to altered responsiveness of the renin-angiotensin-aldosterone axis because plasma renin activity increased in a normal fashion after furosemide in both control and transplant subjects. Although the plasma aldosterone response to increases in plasma renin activity was sluggish in patients undergoing renal transplantation, normal increases in plasma aldosterone levels were achieved in both groups, suggesting that there may be an intrinsic defect in distal tubular potassium secretion that can be unmasked by furosemide.

Adult↗
PubMed2002

beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.

Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function.

Animals↗
PubMed1997

Impairment of antidiuretic hormone and atrial natriuretic peptide regulation in the obese woman with a swelling syndrome and an increase in capillary permeability to albumin.

OBJECTIVE: To study the regulation of antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP) in obese and lean women with a swelling syndrome. PATIENTS: Thirty-four obese women and 12 lean women with a swelling syndrome and an abnormal isotopic test of capillary permeability to albumin were investigated. MEASUREMENTS: After 10 nocturnal hours of fluid restriction, subjects were asked at 8am to ingest a tap water load of 20 ml/kg within 10 min and to remain strictly recumbent until twelve noon on the first day, and to remain standing and to walk around until twelve noon on the second day. Free water clearance and the cGMP/creatinine and albumin/creatinine ratios were determined hourly in the morning. RESULTS: The total 4 h-urinary volume/ingested water volume ratio was significantly lower on the second day both in the lean and the obese patients, the differences being slightly larger in the obese patients. The increase in free water clearance was significantly less on the second day in the obese patients. The increase in cGMP/creatinine ratio was also significantly lower on the second day in the obese patients. The maximum level of the urinary albumin/creatinine ratio was significantly higher on the second day in the obese patients. CONCLUSION: In obese women with a swelling syndrome: (1) The higher increase in the urinary albumin excretion rate after water loading followed by a sustained upright position suggests a widespread alteration in capillary function, which is also indicated by the isotopic test of capillary permeability to albumin. (2) The water load-induced inhibition of ADH secretion and stimulation of ANP secretion or ANP activity, more defective in the upright position than in the recumbent one, is probably another major contributing factor to orthostatic oedema.

Adult↗
PubMed2002

Improvement of interleukin 2 production, clonogenic capability and restoration of stromal cell function in human immunodeficiency virus-type-1 patients after highly active antiretroviral therapy.

Haematological abnormalities frequently occur in patients infected by human immunodeficiency virus-type 1 (HIV-1). Increasing evidence indicates that bone marrow suppression (BM) results from viral infection of accessory cells, with impaired stromal function and alteration of haematopoietic growth factor network. We have investigated the effects of antiretroviral therapy on cytokine and chemokine production by BM cells and stromal cells in a group of HIV-1-infected subjects before and during treatment. Compared with uninfected controls, an altered cytokine and chemokine production by BM cells was observed before treatment, characterized by decreased interleukin 2 (IL-2) and elevated tumour necrosis factor-alpha, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normal T cell-expressed and secreted) levels, along with a defective BM clonogenic activity. Antiretroviral therapy showed increased BM clonogenic capability, associated with normalization of IL-2 production and chemokine receptors expression on CD34+ cells. Pre-therapy, BM accessory cells were represented by macrophage-like cells, in some cases positive for HIV-1 DNA, suggesting that these cells are the main target of HIV-1 infection. During therapy, the stromal cells became predominantly fibroblastoid-like, as observed in normal controls, and were negative for HIV-1 DNA. Controlling HIV-1 replication may produce amelioration of stem cell activity, and restoration of stromal cell pattern and functions, with increased IL-2 production at BM level.

Adult↗
PubMed1999

Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin-releasing hormone.

The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with idiopathic hypogonadotrophic hypogonadism (IHH). There are conflicting reports in the literature as to whether the primary neuroendocrine defect is of hypothalamic GnRH secretion, as with most causes of IHH, or of pituitary resistance to GnRH action. Because of the anatomical inaccessibility of the hypophyseal portal circulation, direct measurement of GnRH levels in human subjects is not possible. Previous investigators have attempted to unravel this problem through the use of GnRH stimulation tests and the limitations of this approach may explain the differing results obtained. We used the more physiological approach of treating a male GHS patient for four weeks with GnRH, 7-10 microg/pulse, delivered subcutaneously at 90 minute frequency via a portable minipump. This therapy failed to induce any rise in plasma gonadotrophin and testosterone concentrations. By contrast, eight weeks treatment with exogenous gonadotrophins maintained physiological plasma testosterone concentrations and induced testicular enlargement with induction of spermatogenesis. The data indicate that the primary endocrinopathy in GHS is of pituitary gonadotrophin secretion and not of hypothalamic GnRH. Moreover, the patient did not harbour any mutation of the GnRH receptor gene. Two clinical observations are consistent with progressive involution of gonadotrophic function, rather than a congenital gonadotrophin deficiency. First, the patient's development was arrested at early mid-puberty at the time of original presentation and, second, effective spermatogenesis was induced extremely rapidly during gonadotrophin treatment, suggesting prior exposure of the testes to FSH. Both spinocerebellar ataxia and pituitary dysfunction might thus have been in evolution since late childhood.

Adult↗