Treatment with oral piperazine oestrone sulphate for genuine stress incontinence in postmenopausal women.

The use of oestrogens in the treatment of genuine stress incontinence was assessed by a double-blind prospective trial in 36 postmenopausal women with genuine stress incontinence who received 3 months of cyclical treatment with either piperazine oestrone sulphate or a matching placebo. Patients were assessed subjectively and objectively before and after treatment by 7-day bladder charts, urethral pressure profiles (UPP), the Urilos nappy test, vaginal cytology and hormone assays (plasma oestrogens and gonadotrophins). There was no statistical difference in the subjective response to treatment between the two groups. After 6 weeks of treatment there was a greater reduction in the number of pad changes/24 h in the oestrogen-treated patients that approached statistical significance but, because of a marked response in the placebo group, this difference was not significant after 3 months of treatment. There were also no significant differences between the two groups with respect to the UPP or Urilos measurements but the vaginal cytology and hormone profiles were significantly affected by oestrogens. In view of the possible risks of oestrogen therapy its use in genuine stress incontinence is limited.

Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone.

Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.

Study of the effect of estradiol on gonadotrophin levels in untreated male-to-female transsexuals.

This project was an attempt to test Dörner's theory that aspects of gender identity and sexual behavior depend on a defect in a normal imprinting mechanism of testicular testosterone (T) on the male hypothalamus. It has been suggested that such an action by T is incomplete in male-to-female transsexuals and that in this disorder the hypothalamus retains a cyclic pattern of gonadotrophin secretion and a positive feedback response to estrogens, such as is seen in the normal female. Five untreated male-to-female transsexuals and five normal male controls were each given 2 mg IM of estradiol, and T, estradiol, LH, and FSH globulin was measured serially over the following five days. No significant differences were found in the gonadotrophin or any of the other hormone responses in the transsexuals compared to normal controls. If there is a defect in imprinting of the hypothalamus in transsexual men, it does not seem to affect the basal levels of gonadotrophins or the pattern of their response to estrogen, at least in the intact male.

High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor.

We describe the clinical and biochemical features of six men with male pseudohermaphroditism due to androgen resistance. Each of the subjects had male-gender behavior but incomplete virilization. The underlying defects in androgen metabolism were defined by studies of the 5 alpha-reductase enzyme and the androgen receptor in fibroblasts cultured from biopsies of genital skin. Four of the six have 5 alpha-reductase deficiency, and two have defects of the androgen receptor (the Reifenstein syndrome). The responses of these men to androgen treatment were assessed by monitoring nitrogen balance, plasma luteinizing hormone (LH) values, and clinical parameters of virilization including penile growth, potency and ejaculatory volume, muscle bulk, and growth of body and facial hair. In all of the subjects with 5 alpha-reductase deficiency and one man with the Reifenstein syndrome significant response occurred, as evidence by nitrogen retention, lowered plasma LH levels, and improved virilization, with doses of parenteral testosterone esters that raised plasma testosterone levels above the normal male range and brought plasma dihydrotestosterone levels into the normal male range. The subject who did not respond with clinical virilization nevertheless showed nitrogen retention in response to acute testosterone administration. This patient had a profound deficiency of the androgen receptor, whereas the man with a receptor defect who did respond clinically to therapy had normal amounts of a qualitatively abnormal receptor. We conclude that high dose androgen therapy may be of benefit in improving virilization, self-image, and sexual performance in subjects with 5 alpha-reductase deficiency who have male-gender behavior and in some subjects with defects of the androgen receptor.

Development of a specific radioimmunoassay for cortisol 17-butyrate.

We describe the development and validation of an assay for cortisol 17-butyrate in blood in which there is no significant cross reaction with endogenous corticosteroids at levels encountered normally in man. Preliminary data on blood levels of the drug in absorption studies are presented.

Experience with trilostane in the treatment of Cushing's syndrome.

Five patients with pituitary dependent Cushing's syndrome and two with adrenal carcinoma were treated with increasing doses of trilostane (up to 1440 mg daily). There was no consistent fall in serum cortisol levels. In addition there was no rise in the levels of precursors immediately preceding the proposed site of action of trilostane. These results suggest that trilostane does not effectively block the enzyme 3 beta-hydroxysteroid dehydrogenase delta 4,delta 5 isomerase in patients with Cushing's syndrome and that it should no longer be recommended for their treatment.

Endocrine abnormalities in idiopathic haemochromatosis.

Anterior pituitary functions and sex steroid levels were measured in 12 patients with idiopathic haemochromatosis (eight males, four postmenopausal females) and age-matched controls, 12 with diabetes mellitus and five with hepatic cirrhosis. In idiopathic haemochromatosis gonadotrophin deficiency was present in seven of 12 patients including six of seven patients who had clinical evidence of hypogonadism. Basal prolactin levels were significantly lower in the patients with idiopathic haemochromatosis compared with either of the control groups (p less than 0.02). Nine patients with idiopathic haemochromatosis exhibited subnormal prolactin responses to thyrotrophin releasing hormone. Thyroid and adrenocortical functions were normal in all patients with idiopathic haemochromatosis. Testosterone values were subnormal in five of eight males with idiopathic haemochromatosis; females with idiopathic haemochromatosis had significantly lower testosterone values compared with the diabetic females (p less than 0.05). Oestradiol values in both sexes and sex hormone binding globulin values in the males were not significantly different in patients with idiopathic haemochromatosis compared with the controls. Sex hormone binding globulin levels were significantly higher in females with idiopathic haemochromatosis compared with either diabetic or cirrhotic females (p less than 0.05). Impairment of anterior pituitary function occurs in idiopathic haemochromatosis but is selective; gonadotrophin and prolactin deficiencies are common. Clinical hypogonadism is usually hypogonadotrophic in origin.

Trilostane in the treatment of advanced breast cancer.

The combination of trilostane 960 mg daily and either dexamethasone 0.5 mg b.d. or hydrocortisone 10 mg b.d. has been used to treat advanced metastatic breast cancer in post-menopausal women. Twenty-three patients had assessable disease and received treatment for a minimum of 8 weeks. Six (26%) showed an objective response and three (13%), stabilisation of previously progressive disease, sustained for at least 3 months. Side-effects were mainly gastrointestinal. Biochemical studies suggest that the mechanism of action may be inhibition of conversion of androstenedione to oestrone.

The effect of pseudopregnancy on glomerular filtration rate and salt and water reabsorption in the rat.

1. Glomerular filtration rate (G.F.R.) and salt and water reabsorption were measured in age-matched virgin rats and rats at different stages of pseudopregnancy and post-pseudopregnancy. 2. Tubular reabsorption and G.F.R. were significantly higher in later pseudopregnancy. Values at mid-pseudopregnancy were intermediate between virgin controls and late-pseudopregnancy. In post-pseudopregnancy G.F.R. and reabsorption had returned to values not different from the virgins. 3. Expansion of extracellular fluid volume (e.c.f.v.) and elongation of proximal tubules were observed during pseudopregnancy. In post-pseudopregnancy increased tubular length was still apparent but e.c.f.v. was not. 4. The remarkable similarity in the changes in e.c.f.v. and renal functions and structure during pseudopregnancy to those in early pregnancy suggests that the feto-placental unit is not necessary for the pregnancy changes. 5. The differences between the time course of change in plasma progesterone and the time courses of changes in e.c.f.v., renal functions and tubular morphology in late pseudopregnancy suggest that progesterone is not directly involved.

The steroid response to controlled adrenal stimulation in congenital adrenal hyperplasia.

Adrenal steroidogenesis has been studied in vivo in eleven patients aged 13-68 years with 21-hydroxylase deficiency, in one patient with 11 beta-hydroxylase deficiency and in ten female control subjects. Serum levels of the delta 5 3 beta-hydroxysteroids, pregnenolone (Pe), 17 alpha-hydroxypregnenolone (17Pe), dehydroepiandrosterone (DHEA) and androstenediol (Adiol) and their delta 4 3-keto counterparts, progesterone (Po), 17 alpha-hydroxyprogesterone (17Po) androstenedione (Adione) and testosterone as well as of 11-deoxycortisol and cortisol were measured during acute adrenal suppression with dexamethasone followed by stimulation with synthetic 1-24 ACTH. In the seven patients with 21-hydroxylase deficiency who were on adequate glucocorticoid therapy, grossly exaggerated responses of 17Po and Po to ACTH were nevertheless preserved. In contrast, there was a grossly subnormal response of 17Pe, DHEA and Adiol to ACTH, and low basal levels of DHEA-sulphate. In the untreated patients the response of 17Pe and DHEA was normal. The Adione response was exaggerated in untreated and normal in treated cases. Similar findings obtained in the patient with 11 beta-hydroxylase deficiency who was studied after 6 weeks without replacement therapy. Our findings demonstrate that production of adrenal steroids that are associated with the adrenarche is not exaggerated in untreated CAH, and is grossly suppressed in treated cases. These findings are compatible with the hypothesis that intra-adrenal cortisol may initiate and/or maintain production of the delta 5 steroids by the zona reticularis that occurs in the human adrenarche.

Heterogeneity in adrenal steroidogenesis in normal men and women.

Adrenal steroidogenesis has been studied in vivo in normal men and women. Serum levels of nine steroids on the biosynthetic pathway (the delta 5 3-beta-hydroxysteroids, pregnenolone (Pe), 17 alpha-hydroxypregnenolone (17Pe), dehydroepiandrosterone (DHEA), androstenediol (Adiol), and their delta 4 3-keto counterparts, progesterone (Po), 17 alpha-hydroxyprogesterone (17Po), androstenedione (Adione), and testosterone (T)) as well as cortisol were measured during adrenal suppression and stimulation. This study demonstrates a marked heterogeneity in adrenal steroid responses between different subjects in the normal population. Thus, in three subjects ACTH stimulation from a dexamethasone-suppressed state resulted in a far greater increment of 17Po than in the other nineteen normal subjects. These three individuals (designated Type 2 responders) may have a partial deficiency of 21-hydroxylase activity. In the remaining nineteen subjects (designated as Type 1 responders) the women had a greater increment of Adiol (P less than 0.05) and a lower increment of Po (P less than 0.01) than the men, suggesting that adrenal 3-beta-hydroxysteroid dehydrogenase/isomerase activity may be slightly lower in women than men.