Effects of mitotane treatment on human steroid metabolism: implications for patient management.

Mitotane (o,p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6ß-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography-mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14-20 mg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6ß-hydroxycortisol and 6ß-hydroxy-20-dihydrocortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35-52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5α-/5ß- and 20ß-/20α-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females - mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5α- relative to 5ß-reduced metabolites were similar to those of patients with 5α-reductase 2 deficiency or on treatment with the 5α-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5α-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6ß-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20ß-reduction.

The sweating apparatus in growth hormone deficiency, following treatment with r-hGH and in acromegaly.

Adult growth hormone deficient patients are known to exhibit reduced sweating and their ability to thermoregulate is diminished. Treatment of these patients with recombinant human growth hormone (r-hGH) is claimed to reverse these abnormalities. We have investigated this claim, as well as the mechanism underlying these altered sweating responses in GH-deficient patients as part of a placebo-controlled study on the effects of 6-12 months r-hGH therapy. Skin biopsies were obtained from these subjects and changes in morphology and innervation parameters for the eccrine sweat glands were examined. These included histochemistry for acetylcholinesterase (AChE) and immunohistochemistry for the neuropeptide vasoactive intestinal polypeptide (VIP) and for PGP9.5, a general neuronal marker. Sweat gland acinar size and periacinar innervation were measured by computerised image analysis. The patients underwent pilocarpine iontophoresis sweat rate tests and their serum insulin-like growth factor 1 (IGF-1) levels were assessed. Since active acromegaly involves excess GH secretion and hyperhidrosis, skin biopsies and sweat tests were also carried out on a group of these patients, as well as on control subjects. We have demonstrated a sweating defect in adult GH-deficiency which is accompanied by a reduction in AChE and VIP levels in the nerve supply to sweat glands. Following r-hGH therapy, an increase in AChE and VIP staining is seen in the sudomotor nerves accompanied by restoration of sweat rates and serum IGF-1 levels. Hence, normalization of sweat gland function includes recovery of sudomotor synapse constituents. A trophic effect of GH on sweat gland epithelium and/or on the associated nerves is proposed, supported by the observation that in acromegaly the size of sweat gland acini and the density of innervation to the sweat glands was greater than in controls.

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.

Management and treatment of patients with acromegaly.

Untreated acromegaly causes substantial morbidity and mortality, and results in a marked reduction in quality of life. For this reason, the treatment goals need to be well defined and therapy optimised. This article describes the clinical approach to acromegaly, including: Pathophysiology of growth hormone secretion; Clinical features; Biochemical and radiological diagnosis; Treatment goals and therapeutic options; Prognosis.

Changes in growth hormone, insulin, insulinlike growth factors (IGFs), and IGF-binding protein-1 in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by severe physical and mental fatigue of central origin. Similar clinical features may occur in disorders of the hypothalamopituitary axis. The aim of the study was to determine whether patients with CFS have abnormalities of the growth hormone/insulinlike growth factor (GH-IGF) axis basally or following hypothalamic stimulation with insulin-induced hypoglycemia. We compared levels of GH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), insulin, and C-peptide in nondepressed CFS patients and normal controls. We found attenuated basal levels of IGF-I (214 +/- 17 vs. 263.4 +/- 13.4 micrograms/L, p = .036) and IGF-II (420 +/- 19.8 vs. 536 +/- 24.3 micrograms/L, p = .02) in CFS patients and a reduced GH response to hypoglycemia (peak GH; 41.9 +/- 11.5 vs. 106.0 +/- 25.6 mU/L, p = .017). Insulin levels were higher (7.6 +/- 1.0 vs. 4.3 +/- 0.8 mU/L, p = .02) and IGFBP-1 levels were lower (19.7 +/- 4.6 vs. 43.2 +/- 2.7 mg/L, p = .004) in CFS patients compared with controls. This study provides preliminary data abnormalities of the GH-IGF axis in CFS. It is not apparent whether these changes are components of a primary pathological process or are acquired secondary to behavioral aspects of CFS such as reduced physical activity.

Characteristics of the eating disorder in Prader-Willi syndrome: implications for treatment.

Over-eating and resultant obesity is well recognized as a central feature of the Prader-Willi Syndrome (PWS). The eating behaviour of 13 subjects with PWS was been studied retrospectively over a 28-day period and also by direct observation when given free access to food. Changing cognitions normally associated with food intake (e.g. changes in hunger) were assessed using visual analogue scales (VAS) and by asking subjects to rate photographs of particular foods. Eight out of 13 subjects (61%) with PWS had to have their access to food severely restricted. Ten (77%) ate excessive amounts when given free access to food, and although feelings of 'hunger', 'desire to eat' and 'fullness' changed in the expected direction, these changes were delayed, compared to a control group, and only occurred after eating a significantly greater amount of food. Ratings of 'hunger' and 'fullness' started to return to pre-meal levels sooner than in the controls. The present authors consider that PWS is an example of genetic obesity secondary to an impaired satiety response. These observations have important implications for treatment.

Evidence for 5-hydroxytryptamine1A receptor involvement in the control of prolactin secretion in man.

The effects of pindolol pretreatment (2 days) on prolactin and cortisol responses to a single dose of (+)-fenfluramine (30 mg po) were examined in nine healthy male volunteers. Pindolol pretreatment attenuated the (+)-fenfluramine-induced increase in prolactin concentrations but failed to affect the (+)-fenfluramine-induced cortisol increase. These data provide evidence in support of 5-HT1A receptor involvement in the regulation of prolactin secretion but question its importance in the regulation of cortisol secretion in man.

Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a disorder characterized by severe physical and mental fatigue and fatiguability of central rather than peripheral origin. We hypothesized that CFS is mediated by changes in hypothalamopituitary function and so measured the adrenocorticotrophic hormone (ACTH), cortisol, growth hormone, and prolactin responses to insulin-induced hypoglycemia, and the ACTH, cortisol, and prolactin responses to serotoninergic stimulation with dexfenfluramine in nondepressed CFS patients and normal controls. We have shown attenuated prolactin responses to hypoglycemia in CFS. There was also a greater ACTH response and higher peak ACTH concentrations (36.44 +/- 4.45 versus 25.60 +/- 2.78 pg ml), whereas cortisol responses did not differ, findings that are compatible with impaired adrenal cortical function. This study provided evidence for both pituitary and adrenal cortical impairment in CFS and further studies are merited to both confirm and determine more precisely their neurobiological basis so that rational treatments can be evolved.

Measurement of excessive appetite and metabolic changes in Prader-Willi syndrome.

The behavioural, cognitive and metabolic response to food intake was studied in 13 adults with the Prader-Willi syndrome (PWS) and compared to ten age-matched controls. Rates of eating were observed during one hour's access to food and feelings of hunger were assessed using a visual analogue scale. Blood was taken for estimation of glucose, insulin, cholecystokinin (CCK), prolactin, growth hormone (GH) and cortisol every 20 min for a total period of 100 min. Ten (76%) of the subjects with PWS ate steadily for the whole hour that food was available and on average consumed three times more calories than the control group. The median ratings for feelings of hunger in the PWS group changed in the expected direction but these changes were delayed compared to the control group and only reached the same level as the controls after the PWS subjects had eaten a significantly greater amount of food. In the PWS group, in contrast to the control group, feelings of hunger started to re-emerge shortly after food was removed. There were marked differences between individuals with PWS in the extent of the changes in serum prolactin levels. Increases in plasma glucose levels were inversely correlated with changes in hunger ratings in the PWS group, but not the control group. There was a significantly greater increase in serum CCK levels during the meal in the PWS group than in the control group indicating that in PWS failure of peripheral release of CCK in response to food intake was not the explanation for the impaired satiety response.

Assessment of gall bladder dynamics, cholecystokinin release and the development of gallstones during octreotide therapy for acromegaly.

The development of gallstones is a well recognized complication of therapy with the long-acting somatostatin analogue, octreotide in patients with acromegaly. A group of nine acromegalic patients was treated with octreotide at doses of 300-600 micrograms daily for 8 months and the changes in fasting and post-prandial cholecystokinin release, and gall bladder motor function (determined by a radiosotopic technique) were assessed at regular intervals. In addition the development of any gallstones was determined by serial ultrasonography. Fasting cholecystokinin levels showed no significant change over 6 months, whereas the post-prandial levels demonstrated a significant decrease (p less than 0.01) during therapy, yet remained significantly higher than fasting levels. Twenty-four hours after commencing therapy gall bladder ejection fraction was decreased by 57 +/- 23 per cent and gall bladder ejection rate decreased by 63 +/- 19 per cent compared to the pretreatment values, whereas after 6 months' therapy a marked reduction in gall bladder ejection fraction (greater than 35 per cent) and gall bladder ejection rate (greater than 40 per cent) persisted in only four of nine patients. Three of these four patients with persistently impaired gall bladder motor function were subsequently shown to have developed either gallstones or biliary sludge during the course of therapy. We conclude that treatment with octreotide is associated with an impaired post-prandial release of cholecystokinin in all acromegalic patients, but gallstones only develop in those patients who, in addition, have evidence of a persistently impaired gall bladder motor response to cholecystokinin.

Endocrine function, psychiatric and clinical consequences in patients with macroprolactinomas after long-term treatment with the new non-ergot dopamine agonist CV205-502.

Although bromocriptine is the mainstay of treatment of macroprolactinomas, its therapeutic usefulness may be limited by poor tolerance, lack of consistent reduction in serum prolactin levels and tumour size, and the necessity for multiple dosing. Consequently new dopamine agonists have been developed, including the long acting non-ergot agonist CV205-502 which has been shown to date to be consistently effective in reducing serum PRL levels and causing tumour shrinkage. Twelve patients were treated for periods of up to 24 months with CV205-502 in doses ranging from 0.075 mg to 1.65 mg once daily. Clinical and psychiatric assessments, biochemical parameters, tumour size determination, and anterior pituitary function tests were performed regularly. Tumour shrinkage was noted in all patients, and varied from 11 per cent reduction to complete disappearance of tumour. Prolactin levels became normal in seven patients and were reduced by more than 90 per cent in the remaining five. Normal menstruation resumed in six of the eight women, one of whom conceived after one year of therapy; libido returned in all patients. Psychiatric complications occurred in three patients necessitating withdrawal of therapy in one. Significant weight loss was noted in 11 of 12 patients. Triglyceride concentrations fell from 1.5 +/- 0.1 to 1.0 +/- 0.1 mmol/l at 12 months (p = 0.006), and cholesterol fell from 6.3 +/- 0.4 to 5.3 +/- 0.3 mmol/l (p = 0.04). The mean TSH response 20 min following TRH injection fell from 14.3 +/- 2.9 to 8.7 +/- 1.3 mU/l at 2 months (p = 0.027). There was a significant increase in the peak growth hormone response to the insulin stress test from basal median (25th-75th centiles) values of 15 (4.4-25.5) mU/l to 24.5 (9-37) mU/l at 2 months (p less than 0.01) and 31 (19.3-63.5) at 12 months (p less than 0.005). CV205-502 is highly effective in the medical management of patients with macroprolactinomas, reducing prolactin levels and tumour size and restoring normal anterior pituitary function. It is, however, associated with the important side effects of weight loss and psychiatric complications which should be drawn to the attention of clinicians.

CV205-502, a new non-ergot dopamine agonist, reduces prolactinoma size in man.

Seven patients with large prolactin-secreting pituitary adenomas were treated for 8 weeks with once-daily doses of the new, potent, non-ergot, long-acting dopamine agonist CV205-502. In five patients previous treatment with bromocriptine had failed to control their disease or been poorly tolerated and had therefore ceased. In all seven patients serum prolactin levels fell over the 8-week period of CV205-502 treatment with the decrease ranging from 33 to 99%. Associated with this decline in prolactin all patients showed symptomatic improvement with two of the five women beginning to menstruate and the two patients with visual field impairment showing marked improvement. Tolerance of the drug, with doses at 8 weeks ranging from 0.075 to 0.3 mg, was excellent with only minimal and transient side-effects being noted in three patients in none of whom was discontinuation of therapy necessary. In one patient noncompliance after 6 weeks of therapy was associated with a rapid return of her serum prolactin towards pretreatment levels. In all seven patients the clinical and biochemical improvement was accompanied by a marked reduction in tumour size.