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Biomedical subjects

J W Honour

Publications and source records attributed to J W Honour.

At least 19 recordsLinked to original sources
PubMed1995

Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21-hydroxylase deficiency. PATIENTS AND DESIGN: All 21 female patients with classic CAH attending the adult endocrinology clinics at The Middlesex Hospital were reviewed. Their ages at menarche and menstrual pattern were recorded and blood samples were taken in the follicular phase of the menstrual cycle when on their usual maintenance therapy. MEASUREMENTS: Measurements of serum LH, FSH, progesterone, 17 alpha-hydroxyprogesterone, testosterone, androstenedione and plasma renin activity were recorded. Urinary steroid profiles were obtained by gas chromatography and mass spectrometry. Molecular genetic analysis of the 21-hydroxylase gene was performed on leucocyte DNA. RESULTS: In the 18 patients who had spontaneous menarche the degree of menstrual disturbance and progesterone excess was related to the effectiveness of adrenal suppressive therapy. Three out of 21 patients, however, failed to experience menarche on standard medical therapy. These patients with primary amenorrhoea were characterized by reduced endometrial thickening, by non-suppressible serum progesterone concentrations despite suppression of 17 alpha-hydroxyprogesterone levels and by the presence of progesterone metabolites in urinary steroid profiles. Molecular genetic analysis did not differentiate between patients with raised progesterone concentrations and those without. CONCLUSION: A subgroup of women with congenital adrenal hyperplasia have the triad of non-suppressible serum progesterone of adrenal origin, primary amenorrhoea and infertility due to failure of endometrial thickening. The characteristic urinary steroid profile best distinguishes this subgroup of women from others with congenital adrenal hyperplasia and menstrual disturbance due to inadequate adrenal suppression.

17-alpha-Hydroxyprogesterone↗
PubMed1995

Megestrol-induced Cushing's syndrome.

This case describes the first report of a patient developing Cushing's syndrome whilst being treated with the synthetic progestogen, megestrol acetate (Megace). Drugs are the commonest cause of Cushing's syndrome. Some synthetic progestogens are known to have glucocorticoid activity at high doses. On structural grounds neither megestrol nor its major metabolites would be expected to interact with the glucocorticoid receptor, through the manufacturers report that it may have 'weak glucocorticoid activity'.

Adenocarcinoma↗
PubMed1995

Low adrenal androgens in men with HIV infection and the acquired immunodeficiency syndrome.

Using gas chromatography and mass spectrometry we have studied the ratios of steroid metabolites and 24-hour urinary steroid excretion rates in 37 men of whom 14 where positive for the human immunodeficiency virus (HIV; group A), while 9 had acquired immunodeficiency syndrome (AIDS; group B). Controls were sick non-AIDS patients admitted to an intensive care unit (ICU) and healthy volunteers. In groups A and B and the ICU controls, there was a reduction in the excretion of adrenal androgen metabolites and a reduced ratio of 5 alpha to 5 beta androgen metabolites. These data suggest that adrenal androgens are removed in HIV and AIDS in a similar manner to other systemic illnesses. In group B patients and the sick controls, the ratios of cortisol to cortisone metabolites were raised compared with controls. Daily, total cortisol metabolite excretion rates in AIDS were similar to those in patients in the ICU. The selective loss of adrenal androgens may be mediated by cytokines and influence components of the immune system. The progression of HIV to AIDS may be due in part to an imbalance between androgens and glucocorticoids.

Acquired Immunodeficiency Syndrome↗
PubMed1995

11 beta-Hydroxysteroid dehydrogenase and its inhibitors in hypertensive pregnancy.

Preeclampsia is accompanied by amplification of the sodium retention that is a feature of normal pregnancy. Recent evidence suggests that mineralocorticoid receptor activation is increased in preeclampsia, but classic mineralocorticoids (aldosterone, 11-deoxycorticosterone) are not present in excess. Cortisol can act as a mineralocorticoid receptor agonist only when its renal inactivation to cortisone by 11 beta-hydroxy-steroid dehydrogenase is impaired, for example, in congenital enzyme deficiency and after administration of exogenous inhibitors (eg, licorice). Endogenous inhibitors of this enzyme have been detected in human urine and are increased in pregnancy. To establish whether cortisol causes mineralocorticoid excess in hypertensive pregnancy and whether endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase are responsible, we studied 25 hypertensive pregnant patients (13 with preeclampsia and 12 with gestational hypertension), 16 normotensive pregnant subjects, and 13 nonpregnant control subjects. Concentrations of plasma renin and aldosterone were increased in pregnancy, but less so in hypertensive pregnancy. Plasma potassium and urinary electrolytes were not different between the groups. Plasma cortisol was increased in pregnancy but not different in hypertensive pregnancy, and urinary cortisol, plasma and urinary cortisone, and urinary tetrahydrocortisol and tetrahydrocortisone were not different between the groups. Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase were more active in urine from pregnant women but were not increased further in hypertensive pregnancy. There were no differences in these parameters between patients with preeclampsia and gestational hypertension. We conclude that deficient inactivation of cortisol to cortisone does not contribute to the sodium retention of normotensive or hypertensive pregnancy and that endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase have no evident pathophysiological significance in pregnancy.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

Adrenal cortex, tumor, and peripheral production of deoxycorticosterone.

A method is reported for the measurement of the urine excretion rates of tetrahydro-11-deoxycorticosterone (3 alpha,5 beta-THDOC), an important metabolite of 11-deoxycorticosterone (DOC). Quantification using gas chromatography/mass spectrometry (GC/MS) was achieved by comparing the ion fragment response for the molecular ion (m/z 507) of the analyte (as methyloxime trimethylsilyl ether derivative) to that of a fixed amount of an isomer of THDOC added to urine as internal standard. To improve the specificity of measuring THDOC in clinical samples, an additional Sephadex LH-20 chromatography step was introduced to separate 11-deoxycortisol and some progesterone metabolites. In the luteal phase of the menstrual cycle, THDOC excretion was higher than in the follicular phase; it was also higher than in women taking oral contraceptives. The correlation of THDOC with progesterone production, independent of a constant cortisol output, supports an ovarian or peripheral conversion of progesterone to DOC. The assay proved useful (1) in monitoring for the recurrence of a mineralocorticoid-secreting tumor and (2) when adrenal production of DOC was not fully suppressed in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Under the latter circumstances, the renin-angiotensin system seemed to be an important regulator of DOC production.

Adrenal Cortex↗
PubMed1992

Genetic analysis of the steroid 21-hydroxylase gene following in vitro amplification of genomic DNA.

The 5' end of the steroid 21-hydroxylase B gene encompassing putative control regions and the first 3 exons, has been selectively amplified in vitro from a number of patients with congenital adrenal hyperplasia caused by a deficiency of this enzyme. Sequence analysis has revealed a number of isolated instances of gene conversion to the 21-hydroxylase A sequence. One mutation, a C to G transversion at the 3' end of the second intron, thought to lead to incorrect splicing of the mRNA, was found in 11 subjects all with the classical form of the disease.

Adrenal Hyperplasia, Congenital↗
PubMed1992

Studies to confirm the source of 11 beta-hydroxyandrostenedione.

In a longitudinal study of 82 children we found a gradual rise in median plasma concentrations of 11 beta-hydroxyandrostenedione (11 beta-OH-A4) from 2.5 to 6.4 nmol/l during childhood which was similar in both sexes. This could reflect changes in adrenal function during the adrenarche and sexual maturation. Plasma concentrations of 11 beta-OH-A4 in adults follow the patterns of cortisol secretion. In patients with diseases of the adrenal cortex, the plasma concentrations of 11 beta-OH-A4 were consistent with the pathology of each condition. In women with polycystic ovaries (PCO) undergoing gonadotrophic stimulation for in vitro fertilization and embryo transfer, 11 beta-OH-A4 (median = 3.8 nmol/l), testosterone and androstenedione, were raised when compared to women with normal ovaries (11 beta-OH-A4 median = 2.6 nmol/l). Follicular fluid has concentrations of 11 beta-OH-A4 six to twelve times greater than plasma levels and in women with PCO, 11 beta-OH-A4 concentrations were lower than in women with normal ovaries, which is consistent with an inhibition of ovarian 11 beta-hydroxylase. Granulosa cells in vitro demonstrated the production of 11 beta-OH-A4 by side chain cleavage of cortisol. These data support an adrenal source for 11 beta-OH-A4 but the raised plasma concentrations in women with polycystic ovary syndrome (PCOS) may reflect the excess androgen output from the ovary. 11 beta-OH-A4 may therefore be an additional marker for ovarian dysfunction.

Adult↗
PubMed1992

11 beta-hydroxyandrostenedione in plasma, follicular fluid, and granulosa cells of women with normal and polycystic ovaries.

OBJECTIVE: To investigate the role of 11 beta-hydroxylase/11 beta-hydroxyandrostenedione (11-OHA) in the ovarian metabolism of androgens in women with polycystic ovaries (PCO) and its associated syndrome (PCOS). DESIGN: Prospective observational study examining the plasma and follicular fluid (FF) concentrations of 11-OHA, testosterone (T), androstenedione (A), and cortisol from women with PCOS and normal women in spontaneous and stimulated cycles. SETTING: The study was carried out in an infertility department and an endocrine research laboratory of a university hospital. PATIENTS: Five groups of women were studied. Blood was taken from 53 women with PCOS and 13 normal controls. Follicular fluid and blood was obtained from 51 women with stimulated cycles undergoing in vitro fertilization embryo-transfer (IVF-ET), 27 of whom had PCO and 24 had normal ovaries. Follicular fluid alone was also taken from 13 women with normal ovaries undergoing laparoscopies. INTERVENTIONS: Clear FF was obtained for analysis during oocyte collection. Granulosa cells (GCs) were obtained from seven women with PCO undergoing IVF-ET and were incubated with radiolabeled substrates. RESULTS: Circulating concentrations of T and 11-OHA were higher in women with PCOS compared with women with normal ovaries. In women with PCO receiving exogenous gonadotropin, only 11-OHA concentrations were higher. Concentrations of all steroids measured were higher in FF than plasma, with plasma 11-OHA concentrations 4 to 12 times higher in FF. Significantly lower concentrations of 11-OHA were found in the FF of women with PCO compared with women with normal ovaries. There was no evidence of 11 beta-hydroxylation of A by GCs. CONCLUSIONS: Although the raised plasma concentrations of 11-OHA may reflect hyperandrogenism in PCOS and lower 11-OHA concentrations in FF in women with PCO suggest abnormal androgen metabolism, neither can be regarded as a marker for this syndrome.

Androstenedione↗
PubMed1991

The determination of 11 beta-hydroxyandrostenedione in human follicular fluid and plasma.

The development of a chromatographic/immunoassay method is presented for the measurement of 11 beta-hydroxyandrostenedione (11 beta-OH-A4) in ovarian follicular fluid (FFL) and plasma from women undergoing embryo transfer for in vitro fertilization. This method incorporates high-performance liquid chromatography (HPLC) and permits the simultaneous measurement of other steroids from a single sample in order to assess the intraovarian environment. Authenticity of 11 beta-OH-A4 in follicular fluid was confirmed using selected ion monitoring (SIM) gas chromatography/mass spectrometry (GC/MS). Our results demonstrate a mean concentration of 18.6 nmol/l in follicular fluid compared with 3.2 nmol/l in plasma. The origin of 11 beta-OH-A4 in follicular fluid requires further investigation but these findings supports the hypothesis of ovarian 11 beta-hydroxylase activity on C19 steroids.

Adrenal Glands↗
PubMed1991

Urine steroid excretion rates in childhood reflect growth and activity of the adrenal cortex.

Normal ranges for daily urine steroid excretion rates in childhood are reported for the first time by gas chromatographic analysis using capillary columns and flame ionisation detector. Longitudinal data came from a study over 3 years of 127 normal boys (aged 7.5-15.6 years) studied on 5 occasions and 14 pubertal girls studied over 2 years. Cross-sectional data were collected from 115 hospitalized patients (58 males, 57 females) aged 2.9 to 14 years with normal adrenal function. The excretion rate of cortisol metabolites was constant for body size, whereas androgen metabolite excretion rates rose sharply in childhood to approach adult levels at the end of puberty. The new data will enable better interpretation of pediatric patient data.

Adolescent↗
PubMed1991

The use of low doses of ACTH in the investigation of adrenal function in man.

We have investigated the adrenal response, in eight healthy adult men, to low doses of ACTH(1-24) in order to define a dose which will elicit a response similar to that obtained with the short Synacthen test. The studies were performed at 14.00 h and blood samples were withdrawn at 5-min intervals after an i.v. bolus injection of ACTH(1-24). The sampling interval was crucial in determining the timing of the peak response. Using sampling times of 0, 10, 15, 20, 25 and 30 min ensured detection of 47 out of 48 peaks. A dose-dependent rise in plasma cortisol concentration was observed with bolus injections of ACTH(1-24) between 30 and 250 ng/1.73 m2 body surface area. Increasing the dose to 500 ng/1.73m2 (500 times less than that used in the short Synacthen test) elicited an increment of plasma cortisol concentration of 200 nmol/l or greater in all subjects. Pretreatment with dexamethasone (1 mg) did not alter the timing of the peak cortisol concentration but blunted the increase (pretreatment: median, 159 nmol/l; range 83-239; on dexamethasone; median 62 nmol/l; range 21-207; P = 0.04). These data suggest that a dose of ACTH(1-24) of 500 ng/1.73 m2 satisfies the criteria of the short Synacthen test and may provide a useful method of investigating adrenal function.

Adrenal Glands↗
PubMed1990

Synthesis of [11,11,12,12-2H4]progesterone for mass spectral investigations of peripheral metabolism.

Hecogenin has been transformed into [11,11,12,12-2H4]progesterone via base-catalyzed isotope exchange with D2O (at C-11), carbenic decomposition of the 12-tosylhydrazone formed by the use of [N,N,N'-2H3]toluene-p-sulfonylhydrazine, and reduction with [2H2]diimide to give [11,11,12,12-2H4]tigogenin, followed by standard degradation of the spiroketal side chain and dehydrogenation in ring A.

Desoxycorticosterone↗
PubMed1990

Regulation of testicular function by insulin and transforming growth factor-beta.

Hyperinsulinism is associated with disorders of androgen production in humans. We have studied the effects of insulin and insulin-like growth factor-1 on androgen production in vitro using a crude preparation of mouse Leydig cells incubated with luteinizing hormone in a serum-free medium. We found a positive correlation between testosterone production and the luteinizing hormone dose over 3 hours. Exposure of the cells for 1 hour to insulin (1 micrograms/ml) prior to the addition of luteinizing hormone significantly augmented the amount of testosterone produced in response to the gonadotropin when added after this preincubation. In contrast, prior exposure of the cells to proinsulin (30 micrograms/ml), insulin-like growth factor-1 (30 ng/ml), or epidermal growth factor-1 (1 micrograms/ml) did not influence the testosterone response to luteinizing hormone. Transforming growth factor-beta reduced the testosterone response to luteinizing hormone. Transforming growth factor-beta (1,000 pg/ml) blocked the insulin augmentation of luteinizing hormone-stimulated testosterone production. We conclude that insulin has an endocrine effect on testosterone production by mouse Leydig cells in vitro. Furthermore, the Leydig cell response to insulin is itself sensitive to interaction with transforming growth factor-beta which may operate as part of the paracrine control of Leydig cell function.

Aging↗
PubMed1990

Comparative trial of luteinizing hormone-releasing hormone analog/human menopausal gonadotropin and clomiphene citrate/human menopausal gonadotropin in an assisted conception program.

To establish the usefulness of a new drug regimen in an assisted conception program, a trial was performed comparing clomiphene citrate (CC) plus human menopausal gonadotropins (hMG) with a new regimen of intranasal luteinizing hormone-releasing hormone (LH-RH) analog plus hMG. One hundred two patient cycles received treatment with CC and hMG and 118 patient cycles received treatment with LH-RH analog and hMG. Fifteen percent of cycles were canceled in the CC group and 8% in the analog group. Four percent of cycles in the CC group were canceled due to premature ovulation. The number of oocytes collected in the analog group was significantly higher than in the CC group (8.5 versus 5.5), as was the number of mature oocytes (3.5 versus 2.7). However, the percentage of mature oocytes was higher in the CC group (54.2% versus 42.3%). The number of embryos resulting from in vitro fertilization as well as the number of cleaving embryos were significantly higher in the analog group (5.2 versus 2.8 and 4.6 versus 2.3, respectively). The pregnancy rate in the analog group was significantly higher than in the CC group (30.6% versus 16.1%), as was the live birth rate (21% versus 8%). Early pregnancy loss was significantly higher in the CC group than in the analog group (35% versus 9%); and the serum level of LH on the day of human chorionic gonadotropin (hCG) administration was also significantly elevated in the CC group when compared with the analog group (8.1 versus 4.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1990

Virilisation of female preterm infants.

Two cases of hypertrophy of the clitoris in premature girls are reported; this was associated with persistently high concentrations of adrenal fetal zone androgens.

Adrenocorticotropic Hormone↗
PubMed1990

Adrenal function in asthma.

A dose dependent suppression of daily cortisol excretion was shown in 25 children with asthma being treated with beclomethasone dipropionate. Cortisol metabolites tended to occur below the normal range when doses of beclomethasone of more than 400 micrograms/m2/day were given. Androgen excretion below the normal range was apparent in asthmatic children aged 8-13 years regardless of whether they were receiving inhaled steroids. This may be the reason for growth delay often seen in asthmatic children. These side effects of beclomethasone are not enough reason to discourage its prescription for the treatment of asthma, but endocrine assessment is desirable when the dose exceeds 400 micrograms/m2/day.

Adolescent↗
PubMed1990

In vitro gene amplification for prenatal diagnosis of congenital adrenal hyperplasia.

A simple, rapid, non-radioactive method for detecting homozygous deletions/conversions of the steroid 21-hydroxylase gene is described. In our experience this method will be useful for first trimester prenatal diagnosis of congenital adrenal hyperplasia in 17% of families of a child with the salt losing form. This test includes an internal control to monitor the success of amplification.

Adrenal Hyperplasia, Congenital↗