EFFECTS OF NORGESTREL AND ETHINYLOESTRADIOL INGESTION ON SERUM LEVELS OF SEX HORMONES AND GONADOTROPHINS IN MEN

DL-norgestrel and ethinyloestradiol were ingested separately and in combination by six healthy men. Serum levels of testosterone, 5α-dihydrotestosterone, oestradiol, FSH, LH and prolactin were measured before (basal), during and after ingestion of the combined drugs. Ethinyloestradiol 50 μg and DL-norgestrel 500 μg for nine days lowered the levels of testosterone to 8% (1·25 nmol/l = 0·36 ng/ml), 5α-dihydrotestosterone to 22% (0·39 nmol= 106 pg/ml), oestradiol to 46%(0·025 nmol/l = 6·88 pg/ml), FSH to 31% (0·55 U/l)and LH to 61% (2·37 U/l) of the basal values. All levels had risen on the third day after stopping the drugs and had recovered to pretreatment values within a week. Prolactin values did not show any definite trend of change during the treatment. In three men ethinyloestradiol alone, 50 μg daily for 5 days, reduced serum levels of all three sex hormones to approximately 80% of basal levels and FSH to 70% but left LH and prolactin levels unchanged. In three men DL-norgestrel alone, 525 ug daily for 4 days, reduced the androgen levels to below 40% of the basal levels, but had little effect on oestradiol levels. FSH, LH and prolactin levels were reduced to 63%, 70% and 65% respectively by the 4 days of DL-norgestrel treatment. The 26 h effects of DL-norgestrel were studied in three men who ingested 1050 ug of the drug in one dose. Serum testosterone and 5α-dihydrotestosterone levels had their greatest depression (30% and 60% respectively) at 12 to 14 h after the ingestion, whereas serum levels of DL-norgestrel peaked at 2 h after the ingestion. In this study serum FSH levels showed a clear depression in two men but LH and prolactin levels did not change. The results show a powerful effect of DL-norgestrel in reducing serum androgen levels in men, an effect which may be partly mediated through the concurrent suppression of the pituitary gonadotrophins.     

DOSAGE-RELATED EFFECTS OF DANAZOL ON SEX HORMONE BINDING GLOBULIN AND FREE AND TOTAL ANDROGEN LEVELS

Danazol is known to cause marked suppression of sex hormone binding globulin (SHBG) levels in plasma and to increase the proportion of plasma testosterone unbound to protein but the effect on the concentration of total and free testosterone is unclear. Twenty-five patients with endometriosis were treated daily for 6 months with doses of danazol ranging from 50 to 600 mg. The fall in SHBG and rise in percent free testosterone was dose-related during the early part of treatment. Suppression of total testosterone and 5 alpha-dihydrotestosterone levels occurred and was probably due to increases in metabolic clearance rates. The observed fall in androstenedione levels was related to the incidence of menstrual abnormality, suggesting that this might be due to reduced ovarian activity. The concentration of free testosterone increased by a factor of two in the first week but subsequently returned to levels of between 25 and 50% above pretreatment levels. This pattern of changes may be due to the rise in metabolic clearance rates being dependent on induction of enzymes of androgen metabolism.     

OESTROGEN-RELATED CHANGES IN SEX HORMONE BINDING GLOBULIN LEVELS DURING NORMAL AND GONADOTROPHIN-STIMULATED MENSTRUAL CYCLES

Previous studies have identified no consistent change in sex hormone binding globulin (SHBG) levels during normal menstrual cycles. This is despite marked cyclical changes in plasma oestradiol concentration, and the observation that SHBG level increases in pregnancy, and after administration of exogenous gonadotrophin or synthetic oestrogens. The level of SHBG was measured in 19 normal females at 2 d intervals from day -8 to +10 where the preovulatory peak of oestradiol was designated as occurring on day 0. SHBG levels increased by a mean 15% +/- 4 (SEM) between the follicular and luteal phases (P less than 0.001) and this was due entirely to an increment between day 0 and +2. The change in SHBG levels was correlated with the change in oestradiol levels between days -8 and 0 (P less than 0.001). Fifty-six infertile patients were also studied. Twenty-seven received Pergonal alone whilst the other 29 received Pergonal after a preceding 5 d on Clomid. In both groups peak preovulatory oestradiol levels were greater than 3 times higher than in normal cycles. SHBG levels showed no change in the follicular phase but rose markedly during the luteal phase. These increases were significantly correlated with peak preovulatory oestradiol concentration but showed no relationship with mid-luteal progesterone concentration. We conclude that supranormal levels of oestradiol cause marked increases in SHBG binding capacity and increases in SHBG level of a lower order occur shortly after the preovulatory peak of oestradiol in the normal menstrual cycle.     

SEX HORMONE BINDING GLOBULIN IN SALIVA

Measurement of salivary steroid hormone concentrations has frequently been advocated as a convenient alternative to plasma measurements. This is partly due to the belief that salivary steroid concentrations are a reliable reflection of the plasma free hormone level, a belief reinforced by earlier inability to demonstrate the presence of significant quantities of steroid binding proteins. Recent reports confirm that such quantities of these proteins are present in saliva and that they retain their steroid binding activity. We have measured sex hormone binding globulin (SHBG) and albumin in saliva from 14 men, 21 non-pregnant women and 36 pregnant women. No differences in the concentration of salivary albumin was evident in any of the groups studied whereas a significant difference in the concentration of SHBG was evident between men and non-pregnant women, and non-pregnant and pregnant individuals. Although much lower, salivary SHBG and albumin concentrations broadly reflect those found in plasma. Furthermore, a highly significant correlation existed between salivary SHBG and albumin concentrations in all groups studied. It now seems generally accepted that the albumin present in saliva arises from contamination by either traces of blood or gingival fluids. The close relationship between the concentrations of albumin and SHBG in saliva suggests that they both gain entry by a similar route. Furthermore, their presence may significantly influence the concentration of certain steroids in saliva, and this may explain the occasional failure of salivary steroid concentrations to accurately reflect the plasma free hormone levels.     

A COMPARISON OF THE EFFECTS OF DANAZOL AND GESTRINONE ON TESTOSTERONE BINDING TO SEX HORMONE BINDING GLOBULIN IN VITRO AND IN VIVO

Danazol and gestrinone are both effective agents in the treatment of endometriosis. Their mechanism of action is unknown but may be related to their androgenic activity, which is at least partly dependent on increases in the proportion of testosterone which circulates unbound to plasma protein. We have quantified these increases in patients on treatment, and by experimentation in vitro have demonstrated the relative importance of the reduction of sex hormone binding globulin (SHBG) binding capacity and competition with testosterone for SHBG binding sites by the drugs and some of their metabolites. The mean SHBG binding capacity in patients treated with danazol (400 mg/d, n = 7) and gestrinone (5 mg/week, n = 7) fell from 66.9 and 56.4 nmol/l to 36.1 and 28.1 nmol/l, after 1 week's treatment and to 11.1 and 7.1 nmol/l after 4 weeks respectively. Despite the similarity between the falls in SHBG binding capacity there was a significantly greater increase in % free testosterone in plasma samples from patients treated with danazol than in those from patients treated with gestrinone at 1 week. Experiments in vitro suggest that this was largely due to ethisterone (a major metabolite of danazol) competing with testosterone for SHBG binding sites. After 4 weeks on treatment there was a similar, near maximal reduction in SHBG binding of testosterone in both treatment groups. At the low levels of SHBG binding capacity reached by this time the extra effect of any competition for binding sites was much reduced.     

DEMONSTRATION OF SEX HORMONE BINDING GLOBULIN IN HUMAN CEREBROSPINAL FLUID

This study demonstrates the existence of sex hormone binding globulin (SHBG) in human cerebrospinal fluid (CSF) by means of a highly sensitive radioligand saturation assay that has been recently described by us for measurement of SHBG in human plasma. The molecular similarity of this 5 alpha-dihydrotestosterone binding protein with plasma-SHBG was substantiated by a number of experiments in which the CSF-protein displayed the same properties as plasma-SHBG with respect to thermolability, affinity, specificity and sedimentation rate. SHBG levels in the CSF of normal women were found to be 0.139 +/- 0.04 nmol/l (mean +/- standard deviation), and in normal men to be 0.083 +/- 0.03 nmol/l respectively. CSF-SHBG in patients with a variety of neurological diseases associated with different degrees of a blood-CSF barrier disturbance, showed a good correlation with commonly determined parameters such as CSF-albumin and CSF-IgG that are known to be of plasma origin. The concept of CSF-SHBG originating from plasma by restricted diffusion is strongly supported by the finding that the CSF/plasma ratio of SHBG is independent of the plasma-SHBG concentration in the entire physiological range. Possible diagnostic and pathophysiological implications of this so far undetected CSF-constituent are discussed with regard to neurological and endocrine abnormalities.     

BIOACTIVE LUTEINIZING HORMONE IN PLASMA OF URAEMIC MEN AND MEN WITH PRIMARY TESTICULAR DAMAGE

Elevation of immunoreactive LH and reduced testosterone production are consistent features of Leydig cell dysfunction in uraemic hypogonadism. To investigate further Leydig cell regulation in uraemia, we measured plasma bioactive LH (B-LH) and immunoreactive LH (I-LH), as well as FSH, testosterone, creatinine, urea and albumin in seven uraemic men before and after haemodialysis and compared them to levels both in eugonadal controls (n = 10) and in men with primary testicular damage (n = 10). Plasma B-LH was increased in uraemic men compared with both nonuraemic control groups. Plasma I-LH and FSH were increased and testosterone decreased in uraemic men compared to eugonadal controls. In comparison with nonuraemic men with primary testicular damage, plasma I-LH levels were similar but FSH and testosterone lower in uraemic men. As a consequence, the ratio of B-LH to I-LH (LH:B/I ratio) was decreased in men with primary testicular damage but normal in uraemic men. A single session of haemodialysis decreased creatinine (50.5%) and urea (58.5%) and increased B-LH (47.7%), I-LH (32.9%), FSH (24.4%), testosterone (15.8%) and albumin (17.8%) levels, but the LH:B/I ratio was unchanged. Increases in gonadotrophin levels were greater than could be accounted for by haemoconcentration suggesting that dialysis may also ameliorate uraemic suppression of the hypothalamus and pituitary. Ultrafiltrates of human uraemic plasma (mol wt less than 25 000) had no inhibitory effect on in-vitro steroidogenesis by isolated rat Leydig cells making circulating uraemic 'middle-molecule'-type toxins unlikely to be involved in causing lowered testosterone levels in uraemic men.(ABSTRACT TRUNCATED AT 250 WORDS)     

SEX HORMONE BINDING GLOBULIN IN WOMEN WITH ANOREXIA NERVOSA

In 29 women with anorexia nervosa, on a blood sample withdrawn at 0900 h before and during weight gain, the binding parameters of serum sex hormone binding globulin (SHBG) were measured by a solid phase method and the levels of testosterone, oestradiol and thyroid hormones were measured by radioimmunoassay. The binding capacity of SHBG was higher than the upper limit for normally menstruating women in 23 patients whilst its affinity for binding testosterone at 37 degrees C was normal (0.32-0.53 X 10(-9) mol/l). The mean levels of testosterone, oestradiol and free thyroxine were normal and the mean level of triiodothyronine was significantly (P less than 0.005) decreased. The binding capacity of SHBG did not correlate significantly with body mass index, percent weight lost, thyroid hormone or sex hormone levels. In 9 patients, an i.v. infusion providing 1200-1400 calories daily was given for 1 week. In these patients a significant decrease (P less than 0.005) in the binding capacity of SHBG (from 74.7 +/- 26.7 to 52.9 +/- 21.8 nmol/l) and a significant increase (P less than 0.001) in T3 levels (from 0.69 +/- 0.21 to 0.95 +/- 0.13 nmol/l) was observed. In 14 patients, when a weight gain of at least 5% was obtained, the binding capacity of SHBG fell into the normal range (25.6-62.9 nmol/l) while T3 levels rose to normal (0.85-2.30 nmol/l). These findings suggested that variations of calorie intake and/or body weight may influence the binding capacity of SHBG in the human.     

NORMAL NEONATAL SURGE OF GONADOTROPHINS AND SEX STEROIDS IN INFANTS OF MEN WITH ISOLATED HYPOGONADOTROPHIC HYPOGONADISM

The inheritance of isolated hypogonadotrophic hypogonadism (IHH) is not fully determined. Although men with this diagnosis can be treated to induce fertility, it is not known whether their offspring will inherit the hormonal deficiency. We evaluated the hypothalamic-pituitary-gonadal axis in nine children (born to men with IHH) during the first few months of life. This axis normally shows activation in infancy similar to that which occurs at puberty. Luteinizing hormone (LH) releasing hormone stimulated a peak LH response in excess of prepubertal levels (39.0 +/- 11 mIU/ml [mean +/- SD]). Testosterone in males (6.2 +/- 2.8 nmol/l and oestradiol in two of the females (320 and 100 pmol/l) were also in excess of prepubertal levels. These infants of men with IHH showed no evidence of inheriting hypogonadotrophic hypogonadism. While further studies will be conducted at the usual age of puberty to confirm spontaneous activation of the hypothalamic-pituitary-gonadal axis, our studies suggest that it may be possible to assess the integrity of this axis at a much younger age.     

COMPARISON OF THE EFFECT OF APOMORPHINE AND l-DOPA ON SERUM GROWTH HORMONE LEVELS IN NORMAL MEN

Apomorphine hydrochloride (0.75 mg s.c.) has been compared with L-dopa (500 mg p.o.) in their effects on growth hormone secretion in a double blind cross-over study involving nine healthy men. Apomorphine increased serum GH levels above 10 ng/ml in all nine subjects 30-60 min after injection. In contrast, only six of these subjects showed a similar elevation with L-DOPA and in only three had the level increased above 6 ng/ml by 60 min. One subject failed to respond to L-dopa and in two others the peak was less than 6 ng/ml. GH levels were significantly higher at 30, 45 and 60 min following apomorphine than following L-dopa. Apomorphine-induced GH release was not related to changes in serum cortisol or blood sugar. Benztropine mesylate (1 mg i.m.) had no effect on apomorphine-induced GH release. These results suggest: (a) apomorphine may have advantages over L-dopa as a provocative agent to assess GH secretory capacity; (b) a dopaminergic mechanism subserves GH secretion; (c) cholinergic mechanisms do not antagonize dopaminergic-related GH release.     

MEASUREMENT OF SEX HORMONE BINDING GLOBULIN IN HUMAN AMNIOTIC FLUID: ITS RELATIONSHIP TO PROTEIN AND TESTOSTERONE CONCENTRATIONS, AND FETAL SEX

Sex hormone binding globulin (SHBG) has been identified and quantified in human amniotic fluid. Identification was based on its electrophoretic mobility on polyacrylamide gels and its steroid binding characteristics, which were identical to those attributed to SHBG in pregnancy serum. Amniotic fluid SHBG binding capacity was measured by competitive saturation analysis using [³H]-5α-dihydrotestosterone as the labelled ligand, after removal of endogenous steroids with dextran-coated charcoal. Similar amniotic fluid SHBG binding capacities were found in samples taken during early (13–20 weeks, 8.5 ± 5.1 (SD) nmol/l, n= 10) and late (36–37 weeks, 8.7 ± 3.0 nmol/l, n= 28) pregnancy. In comparison with pregnancy serum SHBG levels (390 ± 140 nmol/l, n= 5), amniotic fluid SHBG was not enriched in relation to the relative concentrations of total proteins, albumin or transferrin. Amniotic fluid is therefore not a better source for the purification of SHBG than pregnancy serum. There were no differences in amniotic fluid SHBG levels with respect to fetal sex, but positive correlations were observed between SHBG binding capacities and testosterone concentrations in amniotic fluid from both male (r= 0.68, P < 0.001) and female (r= 0.53, P < 0.05) fetuses. It is suggested that SHBG may sequester free testosterone in amniotic fluid, and that measurements of SHBG in amniotic fluid may help to more accurately identify fetal sex in cases where borderline amniotic fluid testosterone concentrations are found.     

男性心肌梗塞患者血浆性激素与红细胞胰岛素受体关系的临床及实验研究

本文对２０例男性心肌梗塞患者及与之配对的２０例正常人红细胞胰岛素受体进行检测，并根据Ｓｃａｔｃｈａｒｄ曲线计算受体的高、低亲和力位点数（Ｑ１、Ｑ２）及亲和力常数（Ｋ１、Ｋ２），同时测定了血浆性激素及胰岛素水平；并采用离体竞争结合的方法，研究性激素对胰岛素结合离体红细胞的影响。结果显示，心肌梗塞组Ｋ１、Ｑ２、Ｋ２低于正常对照组；直线相关分析发现，血浆睾酮与Ｋ１呈负相关，与Ｑ２呈正相关，胰岛素与Ｑ２呈负相关；竞争结合实验发现睾酮能减低胰岛素与受体的结合，而雌二醇未见影响。这提示，心肌梗塞患者的胰岛素抵抗可能与胰岛素受体数目减低及亲和力改变有关，睾酮可降低红细胞胰岛素受体的结合。     

THE EFFECT OF HYPOTHALAMIC LUTEINIZING HORMONE RELEASING HORMONE (LH-RH) ON PLASMA GONADOTROPHIN LEVELS IN NORMAL SUBJECTS

The release of gonadotrophin following the injection of synthetic LH-RH (Hoechst) was studied in various physiological and experimental circumstances. In the male, 25 μg of LH-RH led to simultaneous release of FSH and LH prior to and during puberty. In adults, on the other hand, the same dose led only to an increase in LH while FSH levels remained unchanged. At higher doses there was FSH release and an increase in LH proportional to the amount of LH-RH injected. When FSH was released the increase was clearly less than that of LH and often occurred considerably later. In the female, 25 μg of LH-RH led to a clear-cut release of FSH and a small release of LH prior to puberty. After the onset of puberty the degree of response was inverted: the increase in LH was greater than that of FSH. In normally menstruating women the FSH and LH response was greater during the luteal phase than during the preovulatory phase. Treatment with non-sequential hormonal contraceptives blocked FSH and LH release normally produced by the injection of 50 μg of LH-RH. There was no effect when a dose of 100 μg was injected. In post-menopausal women, only LH rose following the administration of 25 μg of LH-RH. After 5 days of treatment with 200 μg ethinyl oestradiol the same dose of LH-RH led to simultaneous release of LH and of FSH. From the above studies it can be concluded that the secretory response of the gonadotrophins to LH-RH is influenced by the endocrine equilibrium and more particularly by the interaction of the gonadal steroids which can alter the synthesis and/or the release of the pituitary gonadotrophins.     

SEX HORMONE BINDING GLOBULIN IN POSTMENOPAUSAL WOMEN: A PREDICTOR OF OSTEOPOROSIS SUPERIOR TO ENDOGENOUS OESTROGENS

To quantify the role of endogenous oestrogen activity in osteoporosis we measured relative metacarpal cortical area (RCA), body mass, serum oestrone, oestradiol, androstenedione, and sex hormone binding globulin (SHBG) in 746 postmenopausal women aged 53 to 76 years, sampled from the general population. The occurrence of fractures and the rate of loss of RCA (delta-RCA) were determined over the previous 9 years. Both RCA and delta-RCA were significantly related to body mass, serum oestrone, oestradiol, and SHBG. The influence of the first three variables appeared to be bone preserving, whereas the latter appeared to be bone wasting. Serum oestradiol, SHBG and body mass proved to have an independent relationship with RCA in multivariate regression analysis. The relationship to delta-RCA was statistically independent for serum SHBG only. Serum androstenedione was unrelated to either RCA or delta-RCA. In the total study population, body mass, serum oestrone, oestradiol and SHBG were not related to the occurrence of fractures over the previous 9 years. In the subgroup of 249 elderly women, aged 65-76 years, SHBG levels were significantly higher for women with type I osteoporotic fractures (vertebral and forearm fractures) as compared to controls. The results suggest a bone wasting influence of SHBG in postmenopausal women, possibly resulting in an increased risk of type I osteoporotic fractures in elderly women.     

RADIOIMMUNOASSAY OF PLASMA DIHYDROTESTOSTERONE IN NORMAL AND HYPOGONODAL MEN

A radioimmunoassay for determination of dihydrotestosterone (DHT) in man is described. After extraction from plasma, DHT is separated by paper chromatography. The radioimmunoassay is performed using an antiserum to dihydrotestosterone-3-oxime-BSA and a charcoal-dextran mixture is used to separate the free from the bound fraction. The reliability criteria of the method in terms of precision, accuracy, sensitivity and specificity have been evaluated. The mean level of DHT in plasma samples from young (age 21-37) and old (age 65-90) normal men is respectively (mean+/-SD) 54-7+/-19 ng/dl (n = 17) and 39-1+/-19 ng/dl (n = 14). The difference is statistically significant (P less than 0-01). The values found in seven patients with Klinefelter's syndrome (21-0+/-6 ng/dl) are significantly lower than normal young subjects (P less than 0-01). Lastly, the DHT levels found in a mixed group of male hypogonadism (azoospermia, due to tubular failure, germinal cell aplasia and anorchia) are reported.     

THE INFLUENCE OF BROMOCRIPTINE ON SERUM LEVELS OF GROWTH HORMONE AND OTHER PITUITARY HORMONES AND ITS METABOLIC EFFECTS IN ACTIVE ACROMEGALY

The effect of treatment with bromocriptine for 12--18 months on serum GH and metabolic responses was studied in sixteen patients with active acromegaly. Of this group ten patients showing a sustained GH reduction of more than 50% during an 8 h bromocriptine test, proved to be responsive to long-term therapy. In the responding patients GH levels decreased to 38% of the pretreatment level after 12 months of therapy. A dose higher than 10 mg did not produce a significantly greater effect. Prolactin and LH levels decreased in all patients, FSH levels showed a significant rise. Testosterone levels in the male patients increased significantly, indicating that the state of hypogonadism can at least be partially reversed. The GH levels became normal in only one patient. We conclude that the role of bromocriptine in acromagaly is limited and selective pituitary operation and/or irradiation is preferred as definitive treatment in most patients.     

DIET-INDUCED CHANGES IN SEX HORMONE BINDING GLOBULIN AND FREE TESTOSTERONE IN WOMEN WITH NORMAL OR POLYCYSTIC OVARIES: CORRELATION WITH SERUM INSULIN AND INSULIN-LIKE GROWTH FACTOR-I

The purpose of this study was to investigate the effect of calorie restriction on serum concentrations of sex hormone binding globulin (SHBG) in women with normal or polycystic ovaries (PCO) and to examine the possible role of insulin and insulin-like growth factor-I (IGF-I) in mediating changes in SHBG levels. Six normal subjects with mean (SD) body mass index (BMI) 25.5 (2.2) and five subjects with PCO (BMI 36.1 (3.7)) were studied before and after 2 or (PCO only) 4 weeks of a very low calorie diet (330 kcal/day; Cambridge Diet). In both normal women and patients with PCO there was a twofold increase in SHBG concentrations after 2 weeks and this was sustained in the PCO subjects for a further 2 weeks. The rise in SHBG was accompanied by a fall in free testosterone concentrations. There were parallel changes in serum insulin and IGF-I concentrations which decreased during the diet and there were significant negative correlations of SHBG with insulin in both normal subjects (r = -0.62) and women with PCO (r = -0.60). In addition, serum concentrations of an insulin-dependent small molecular weight (34 kDa) binding protein for IGF-I (IGF-BPI) increased significantly during dieting in both groups and were negatively correlated with serum insulin (controls, r = -0.56; PCO, r = -0.68) and positively correlated with serum SHBG levels (controls, r = 0.69; PCO, r = 0.63). In summary, these data indicate that in both normal subjects and those subjects with PCO, calorie restriction results in a highly significant increase in SHBG concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

DECREASED SEX HORMONE BINDING GLOBULIN (SHBG) AND INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN (IGFBP-1) IN EXTREME OBESITY

Obesity may be characterized by abnormal sex steroid secretion and reduced sex hormone binding globulin (SHBG) which in turn is related to fat distribution and insulin secretion. Recent in-vitro and in-vivo evidence suggests that insulin is the common mechanism regulating the secretion of SHBG and insulin-like growth factor small binding protein (IGFBP-1). IGFBP-1 appears not only to be a carrier for insulin growth factors (IGFs) but also to play an active role in growth processes, independent of growth hormone secretion. We have examined the possible relationship between fasting insulin, SHBG, testosterone, IGF-1, IGFBP-1 and fat distribution in 25 extremely obese, menstruating women (mean weight 107 +/- 3 kg) with normal glucose tolerance. Fat distribution was assessed from measurements of the waist to hip ratio (W/H). The obese women showed an elevated fasting insulin (mean +/- SEM; 21 +/- 2 mumol/l), a normal IGF-1, but reduced IGFBP-1 (14.6 +/- 2 micrograms/l); in 15 women IGFBP-1 levels were undetectable by the present assay. In addition, SHBG levels were reduced in the obese women (24 +/- 2 nmol/l) but total testosterone values (1.9 +/- 0.1 nmol/l) were normal. The elevated fasting insulin levels were positively correlated with increasing upper segment obesity as expressed by a rising W/H ratio (P less than 0.01, r2 = 0.306) and inversely correlated with SHBG (P less than 0.01, r2 = 0.483). Similarly, reduced SHBG values showed an inverse correlation with increasing W/H ratio (P less than 0.001, r2 = 0.383). No correlation was found between IGFBP-1 and W/H ratio but a strong positive correlation was seen between IGFBP-1 and SHBG (P less than 0.001, r2 = 0.466). Furthermore, an equally significant inverse correlation was found between IGFBP-1 and insulin levels (P less than 0.001, r2 = 0.474).(ABSTRACT TRUNCATED AT 250 WORDS)     

FAILURE OF POSITIVE FEEDBACK IN NORMAL MEN AND SUBJECTS WITH TESTICULAR FEMINIZATION

The abdity of the hypothalamic-pituitary unit to release luteinizing hormone (LH) in response to oestrogen Cpositive feedback) was studied in normal men and women and in subjects with testicular feminization or XY gonadal dysgenesis. Ethinyloestra-diol (200 μg a day for 3 days) given orally to six regularly menstruating women during the early to mid follicular phase of the cycle evoked an LH surge which started between 48 and 72 h after the initiation of treatment. A similar positive feedback effect on the secretion of follicle-stimulating hormone (FSH) could not be demonstrated. In eight normal men there was no evidence for a stimulatory effect of ethinyl-oestradiol (in doses of 200 μg or 500 μg a day for 3 days) on gonadotrophin release even though the levels of plasma ethyloestradiol in men on the higher dosage regime were greater than those found in women. Changes of peripheral LH, but not FSH, in men were inversely related to plasma ethinyloestradiol concentrations. A patient with XY pure gonadal dysgenesis exhibited a female type of LH release in response to ethinyloestradiol administration (200 μg a day for 3 days), but two patients with the syndrome of testicular feminization failed to release LH. The results suggest that normal adults of the two sexes differ in their ability to respond to ethinyloestradiol administration with LH release. The female response in XY gonadal dysgenesis emphasizes the importance of testicular secretions for the suppression of positive feedback whereas the male type of response in cases of testicular feminization indicates that testosterone does not represent the central mediator of this testicular function. The reported observations are compatible with the concept that the organizing action of the testes on positive feedback is mediated through 17β-oestradiol.     

THYROID HORMONE LEVELS AND PROTEIN BINDING IN PATIENTS ON LONG-TERM DIPHENYLHYDANTOIN TREATMENT

The effect of long-term diphenylhydantoin (DPH) treatment on thyroid hormone concentrations and protein binding was determined in a randomized controlled trial. As has been demonstrated previously, total thyroxine (T4) concentrations were significanly depressed in patients on DPH. There was no significant effect on indirect indices of protein binding of thyroid hormones, and the free thyroxine index (FTI) was also significantly depressed. Triiodothyronine (T3) and thyrotrophin (TSH) concentrations were either unaffected, or only very slightly affected by DPH. Significant effects on the FTI were still apparent 4 weeks after discontinuing treatment. It is concluded that the depression of total T4 levels observed in vivo is not due solely to diminished protein binding, but may instead be largely explained by reports suggesting enhanced degradation of T4 following DPH therapy. Since 1961 it has been known that diphenylhydantoin (DPH) has a significant effect on the levels of the circulating thyroid hormones in the plasma (Oppenheimer et al., 1961). It is known that the effect is extrathyroidal (Oppenheimer et al., 1961) and it was initially assumed to be due to an effect on protein binding. This assumption followed the demonstration that DPH decreased the binding of thyroxine (T4) to throxine binding globulin (TBG) in vitro (Oppenheimer & Tavernetti, 1962). However, more recent work (Chin & Schussler, 1968; Larsen et al., 1970; Hansen et al., 1974; Stjernholm et al., 1975) has suggested that there may be a true depression of free T4. Most previous studies have been in epileptic patients for whom the control groups were not totally comparable (Hansen et al., 1974; Chin & Schussler, 1968) or in normal subjects who underwent DPH therapy for only a short time (i.e. 1-2 weeks, Hansen et al., 1974). Moreover, DPH dosage in earlier studies has for the most part been arbitrarily decided upon, or evaluated by clinical signs. It is known that there are extremely variable individual responses to given doses of DPH (Richens & Dunlop, 1975), resulting in variable plasma levels of DPH. This study describes the effects of long-term DPH treatment on thyroid function and thyroid hormone protein binding. A comparable control group was also studied, and DPH concentration in the blood was continually monitored. The same patients were reexamined after discontinuation of therapy, to elucidate the duration of the effect.