Familial pattern of corticosteroids and their metabolism in adult human subjects--the Scottish Adult Twin Study

Corticosteroids are important in the regulation of normal physiology and are key factors in regulating cardiovascular physiology and disease, the development of which is known to have a genetic component. However, there is little information on the extent to which plasma and urine steroid levels are determined by familial and genetic factors. We have examined basal and ACTH-stimulated plasma steroid levels and 24-h corticosteroid metabolite excretion rates in 146 pairs of adult twins [75 monozygotic (MZ); 71 dizygotic (DZ)]. Intraclass correlation coefficients were measured for all variables; several plasma steroid measurements were strongly related in both (MZ) and (DZ) twins, consistent with a familial pattern. These included basal levels of 11-deoxycortisol and aldosterone. ACTH-stimulated plasma aldosterone levels were also significantly correlated, to a significant degree, in both MZ and DZ twins. The index of 11beta-hydroxysteroid dehydrogenase activity (tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) and of the more specific index of activity of the type 2 isoform of this enzyme (urine free cortisol/cortisone) also correlated, to a similar degree, in DZ and MZ twins. In contrast, for the basal and ACTH-stimulated plasma concentrations and 24-h urine excretion rates of several corticosteroids, there was evidence of significant heritability (H2), in that correlation in MZ twins was greater than in DZ. For example, basal plasma corticosterone concentrations (B) (H2 = 0.44), basal and stimulated 11-deoxycorticosterone concentrations (DOC) (H2 = 0.44 and 0.41, respectively), stimulated 11-deoxycortisol concentrations (H2 = 0.53), and the index of 11beta-hydroxylase activity DOC/B (H2 = 0.49) were all significantly heritable. For the urinary variables, 24-h tetrahydrodeoxycortisol (H2 = 0.59) and free aldosterone (H2 = 0.56) were significantly heritable. Our data provide the first evidence that plasma and urine levels of important glucocorticoids and mineralocorticoids show a strong familial pattern, and in some instances, there is evidence of a genetic component to this. This suggests that corticosteroids have a plausible role in essential hypertension that has a similar heritable component.     

Heritability of plasma adiponectin levels and body mass index in twins

CONTEXT: Adiponectin is suspected to exert antiatherogenic, antiinflammatory, and insulin-sensitizing effects. However, the relative importance of the genetic and environmental factors in influencing plasma adiponectin levels (ADPN) remains unclear. OBJECTIVE: The aim of the study was to investigate whether ADPN and body mass index (BMI) are genetically determined. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: In a series of 60 pairs of healthy twins, we estimated genetic variance and heritability of ADPN and BMI using both ANOVA and path analysis methods. Twins were genotyped at two biallelic single nucleotide polymorphisms (SNPs) at the gene encoding adiponectin: the +45 T/G (on exon 2) and the -11377 G/C (on the promoter). RESULTS: A total of 30 pairs of twins were Monozygotic (MZ), and 30 were dizygotic (DZ). The mean ADPN (+/-SD) was 10.6 +/- 5.7 in MZ and 11.1 +/- 4.5 in DZ twins (nonsignificant). Three tests of heritability (within pair = 1.13, P < 0.0001; among components = 1.62, P = 0.005; and intraclass correlation 1.34, P < 0.0001) consistently showed ADPN heritability. The preferred model of a likelihood-based analysis included an additive genetic influence and an individually unique environmental influence for ADPN, accounting for 88% and 12% of ADPN variance, respectively. We found a significantly higher within-pair difference of ADPN in DZ than in MZ pairs, and in +45 T/G SNP discordant compared with concordant DZ twins, indicating a significant effect of this adiponectin gene SNP on ADPN. CONCLUSIONS: ADPN shows significant genetic variance and heritability, which is independent of BMI and partly accounted for by the +45 T/G, but not the -11377 G/C adiponectin gene SNP.     

Hormone blood levels and their inter-relationships in normal men and men with benign prostatic hyperplasia (BPH).

In 128 non-hospitalized men (age range 36-65 years) rectal palpation revealed in 54 cases an enlargement of the prostate (group II), which was very distinct in 20 cases (group III). The measurement of testosterone (T), 5alpha-dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) oestradiol (Oe2), sex-hormone-binding-globulin binding capacity (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (Prl) in the blood of normal men (group I) and those with BPH (group II or III) demonstrated no significant differences between the three groups when respective age ranges were compared. A significant increase of FSH and decrease of 3alpha-diol with age was seen in the normal group (I), which was similar but less pronounced in BPH (groups II and III). A distinct increase of DHT with age was found in BPH (group II), which was not so dominant in normal men (group I). From these data it is concluded that the conversion of DHT to 3alpha-diol might be reduced in older males independent from the occurrence of BPH and that the hyperplastic prostate possibly secretes significant amounts of DHT into the circulation. These results are discussed with respect to their possible role in the pathogenesis of BPH.     

Widespread pain among 11-year-old Finnish twin pairs

OBJECTIVE: To examine the prevalence of widespread musculoskeletal pain (WSP) symptoms in 11-year-old Finnish twins and to determine the relative role of genetic and environmental factors in the etiology of WSP. METHODS: Data on current pain items were collected from 1995 to 1998 from a national sample of Finnish families with 11-year-old twins born between 1984 and 1987. The presence of WSP was determined using a validated questionnaire method. Pairwise similarity was computed for 583 monozygotic (MZ) pairs, 588 same-sex dizygotic (DZ) pairs, and 618 opposite-sex DZ twin pairs. Variance components for genetic and environmental factors were estimated using biometric structural equation modeling techniques. RESULTS: The prevalence of WSP was 9.9%, with no sex difference. The majority of twin pairs with WSP were discordant. The tetrachoric correlations for male MZ (r = 0.38), male DZ (r = 0.37), female MZ (r = 0.59), female DZ (r = 0.54), and opposite-sex pairs (r = 0.43) showed little difference by zygosity. Female pairs were more concordant than male pairs among both MZ and DZ twins. Biometric model-fitting indicated that genetic factors did not account for the pattern of twin similarity. Among boys 35%, and among girls 56%, of the variation in liability to WSP could be attributed to shared familial environmental effects. The remainder was attributed to unshared environmental effects. CONCLUSION: Genetic factors seem to play at most a minor role in WSP in 11-year-old twins, and environmental factors shared by family members account for a substantial proportion of the variability in WSP.     

Studies on the feedback regulation of gonadotropin concentrations in male rats. (III). The effects of testosterone and its metabolites on gonadotropin secretion from rat pituitary cells in culture

To determine whether dihydrotestosterone (DHT) or estradiol (E2) exerts negative or positive feedback effects on rat pituitary gland, Testosterone (T) metabolite (T, DHT, 5 alpha-androstane-3 alpha, 17 beta-diol:3 alpha-diol or E2) was added to the cultured pituitary cells. Anterior pituitary glands were obtained from 6-week-old male rats. Pituitary cells were prepared by trypsin digestion and incubated with various concentrations of steroid hormones for 72 h to determine the effects of steroid hormones on basal secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) after 48 h preculture without steroids. Then 10 nM luteinizing hormone-releasing hormone (LH-RH) with appropriate concentrations of these steroid hormones was added to the pituitary cells in culture and incubated for another 6h to determine the effects of steroid hormones on LH-RH induced gonadotropin release. After the incubation, pituitary cells were lysed with 0.1% Triton X100 to measure the intracellular gonadotropin content. The concentration of LH and FSH was determined by radioimmunoassay. T, DHT and 3 alpha-diol stimulated basal FSH but not basal LH secretion, and inhibited both the release of FSH and LH from cultured pituitary cells during incubations with LH-RH in a dose-dependent fashion. Intracellular content of both FSH and LH were increased, and total FSH and not LH was also increased by the addition of DHT in a dose-dependent manner. E2 did not exert any of such effects on pituitary cells in culture. These studies suggest that 5 alpha-reduced metabolites but not aromatized metabolite of T play an important role on feedback regulation of gonadotropin secretion at pituitary level. DHT directly acts on pituitary gland not only to stimulate the production of FSH but also to suppress FSH and LH secretion induced by LH-RH.     

The NHLBI Twin Study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a).

Heritability of plasma apolipoprotein (apo) A-I, apo B, and low density lipoprotein (LDL) subclasses and concordance for lipoprotein(a) excess were assessed in 109 monozygotic (MZ) and 113 dizygotic (DZ) twin pairs participating in the third examination of the National Heart, Lung, and Blood Institute Twin Study. The intraclass correlation coefficient for apo A-I was significantly greater in MZ twins (0.56) than in DZ twins (0.37, P less than 0.05); however, apo A-I showed an unequal distribution in the two groups, with significantly greater total variance in DZ twins. Therefore the among-component estimate of genetic variance was applied, and the results indicated no significant heritability for apo A-I (P = 0.59). MZ and DZ twins had equal apo B variance. The intraclass correlation coefficient for apo B in MZ twins (0.71) was significantly higher than in DZ twins (0.25) (P less than 0.0001), indicating significant heritability for apo B. Plasma apo A-I levels were significantly correlated with alcohol intake (P less than 0.0001), body mass index (BMI, P less than 0.0001), and physical activity, while apo B levels were significantly correlated only with BMI (P less than 0.05). After plasma apo A-I and apo B concentrations were adjusted for all of these variables and for cigarette smoking, the analysis of variance and intraclass correlation coefficients remained virtually unchanged. The LDL type intraclass correlation coefficient was higher in MZ twins (0.58) than in DZ twins (0.32, P less than 0.005); however, greater total variance for this parameter in DZ twins was observed and after applying the among component estimate of genetic variance, no significant heritability of LDL type was observed. After adjustment for covariate effects the conclusions were not changed. Only 8.4% of MZ twin pairs, as compared with 26.7% of DZ twin pairs, were discordant for elevated lipoprotein(a) on gradient gels (P less than 0.0001). Our data indicate that there is a strong heritability for plasma apo B and lipoprotein(a), with only weak evidence for heritability of LDL type or plasma apo A-I levels within this population sample.     

Genetic factors and susceptibility to falls in older women

OBJECTIVES: To determine whether genetic influences account for individual differences in susceptibility to falls in older women. DESIGN: Prospective twin cohort study. SETTING: Research laboratory and residential environment. PARTICIPANTS: Ninety-nine monozygotic (MZ) and 114 dizygotic (DZ) female twin pairs aged 63 to 76 from the Finnish Twin Cohort study. MEASUREMENTS: The participants recorded their falls on a calendar for an average+/-standard deviation of 344+/-41 days. Reported falls were verified via telephone interview, and circumstances, causes, and consequences of the fall were asked about. RESULTS: The total number of falls was 434, of which 188 were injurious; 91 participants had two or more falls. Casewise concordance was 0.61 (95% confidence interval (CI)=0.49-0.72) for MZ twins and 0.49 (95% CI=0.37-0.62) for DZ twins for at least one fall, 0.38 (95% CI=0.23-0.53) for MZ and 0.33 (95% CI=0.17-0.50) for DZ twins for at least one injurious fall, and 0.43 (95% CI=0.26-0.60) for MZ and 0.36 (95% CI=0.17-0.55) for DZ twins for recurrent falls. On average, the proportion of familial influences accounting for the individual differences in susceptibility to at least one fall was 30% and to recurrent falls was 40%; nongenetic familial and nonfamilial factors alone accounted for susceptibility to at least one injurious fall. CONCLUSION: In community-dwelling older women, familial factors underlie the risk of falling but not the risk of injurious falls.     

Are genetic influences on peptic ulcer dependent or independent of genetic influences for Helicobacter pylori infection?

BACKGROUND: Genetic factors play a role or roles in the etiology of peptic ulcer disease and the acquisition of Helicobacter pylori infection. OBJECTIVE: To evaluate the relative importance of genetic and environmental influences as well as the importance of H. pylori on peptic ulcer disease. DESIGN: Cross-sectional study on monozygotic (MZ) and dizygotic (DZ) twins, reared apart or together. PARTICIPANTS: Twins of the subregistry of the Swedish Twin Registry included in the Swedish Adoption/Twin Study of Aging. MEASUREMENTS: Peptic ulcer disease and H. pylori status were assessed in MZ and DZ twin pairs reared apart or together. A total of 258 twin pairs had information regarding H. pylori status and history of peptic ulcer. Helicobacter pylori status was assessed as the presence of anti-H. pylori IgG. RESULTS: The intraclass correlations for peptic ulcer disease for MZ twins reared apart and together and DZ twins reared apart and together were 0.67, 0.65, 0.22, and 0.35, respectively, which indicates that genetic effects are important for liability to peptic ulcer. The correlation coefficient for MZ twins reared apart (0.67) provides the best single estimate of the relative importance of genetic effects (heritability) for variation in liability to peptic ulcer disease, and structural model fitting analyses confirmed this result (heritability, 62%). The cross-twin cross-trait correlations for MZ and DZ twins were examined to determine whether genetic effects for peptic ulcer were shared with or independent of genetic influences for H. pylori. The cross-correlations for MZ and DZ twins were almost identical (0.25 and 0.29, respectively), suggesting that familial environmental rather than genetic influences mediate the association between peptic ulcer disease and H. pylori infection. CONCLUSIONS: Genetic influences are of moderate importance for liability to peptic ulcer disease. Genetic influences for peptic ulcer are independent of genetic influences important for acquiring H. pylori infection.     

Dizygotic twinning is not linked to variation at the alpha-inhibin locus on human chromosome 2

Natural multiple pregnancy in women leading to dizygotic (DZ) twins is familial and varies across racial groups, suggesting a genetic predisposition. Mothers of DZ twins have a higher incidence of spontaneous multiple ovulation and elevated FSH concentrations. FSH release is controlled by feedback of inhibin peptides from the ovary, and immunization against inhibin alpha-subunit results in an increased ovulation rate in animals. The inhibin alpha-subunit is therefore a candidate gene for mutations that may increase the frequency of DZ twinning. Restriction digests of a PCR product from exon 1 with the enzyme SpeI detects a C/T polymorphism at bp 128 with two alleles of 447 and 323/124 bp. The polymorphism was typed in 1,125 individuals from 326 pedigrees with 717 mothers of spontaneous DZ twins. The alpha-inhibin locus mapped within 3 centimorgans of D2S164, and linkage with DZ twinning was excluded [decimal log odds ratio (LOD) score, -2.81 at theta = 0]. There was complete exclusion of linkage (LOD, less than -2) of a gene conferring relative risk 1.8 (lambdas, >1.8) across the chromosome, except at the p-terminus region and a small peak (maximum LOD score, 0.6) in the region of D2S151-D2S326. Analysis using either recessive or dominant models excluded linkage with DZ twinning in this population (LOD score, less than -2.5) across chromosome 2. We conclude that dizygotic twinning is not linked to variation in the alpha-inhibin locus. The results also suggest that mutations in other candidates on chromosome 2, including the receptor for FSH and the betaB-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.     

Quantitating genetic and nongenetic factors influencing androgen production and clearance rates in men

Both hereditary and nonhereditary factors have a decided influence on plasma sex steroid concentrations in men. We studied the relative contributions of genetic and nongenetic factors on the production rate (PR) and MCR of testosterone and dihydrotestosterone (DHT) and their conversion ratios to other metabolites in monozygotic (MZ; n = 22) and dizygotic (DZ; n = 24) male twins. Zygosity was determined by measurement of 10 blood proteins and enzymes. The kinetic studies were conducted with isotope dilution techniques. The genetic effect was determined from the equation: 2[rMZ - rDZ], where r is intraclass correlation. A heritability of over 40% was found for the PRs of DHT/body surface area and of testosterone/body surface area. Nongenetic factors accounted for 50% or more of the variation of the conversion ratios for testosterone/3 alpha-androstanediol and DHT/3 alpha-androstanediol. The results suggest that genetic factors markedly influence the PRs of testosterone and DHT, suggesting that the PR of these potent androgens is under genetic control despite the decided influence of environmental factors on their clearance.     

Widespread pain among 11‐year‐old Finnish twin pairs

Objective

To examine the prevalence of widespread musculoskeletal pain (WSP) symptoms in 11‐year‐old Finnish twins and to determine the relative role of genetic and environmental factors in the etiology of WSP.

Methods

Data on current pain items were collected from 1995 to 1998 from a national sample of Finnish families with 11‐year‐old twins born between 1984 and 1987. The presence of WSP was determined using a validated questionnaire method. Pairwise similarity was computed for 583 monozygotic (MZ) pairs, 588 same‐sex dizygotic (DZ) pairs, and 618 opposite‐sex DZ twin pairs. Variance components for genetic and environmental factors were estimated using biometric structural equation modeling techniques.

Results

The prevalence of WSP was 9.9%, with no sex difference. The majority of twin pairs with WSP were discordant. The tetrachoric correlations for male MZ (r = 0.38), male DZ (r = 0.37), female MZ (r = 0.59), female DZ (r = 0.54), and opposite‐sex pairs (r = 0.43) showed little difference by zygosity. Female pairs were more concordant than male pairs among both MZ and DZ twins. Biometric model‐fitting indicated that genetic factors did not account for the pattern of twin similarity. Among boys 35%, and among girls 56%, of the variation in liability to WSP could be attributed to shared familial environmental effects. The remainder was attributed to unshared environmental effects.

Conclusion

Genetic factors seem to play at most a minor role in WSP in 11‐year‐old twins, and environmental factors shared by family members account for a substantial proportion of the variability in WSP.

     

Free estradiol, free testosterone, and sex hormone-binding globulin in perimenopausal women

To determine whether menstrual status had an effect on plasma sex hormone-binding globulin (SHBG) capacity and nonprotein-bound estradiol (% free E2) and testosterone (% free T), we measured these as well as plasma FSH, total E2, and T and the MCRs of E2 and T in a group of 78 perimenopausal women. The women were allocated to 4 groups: women with cycles whose plasma FSH level was less than 40 mIU/mL (A; n = 16), women with cycles whose plasma FSH level was greater than 40 mIU/mL (B; n = 19), women who were amenorrheic for less than 1 yr (C; n = 13), and women who were amenorrheic for more than 1 yr (D; n = 30). The mean plasma SHBG values were 51.4 +/- 5.7 (+/- SE), 48.3 +/- 4.3, 45.9 +/- 5.4, and 51.1 +/- 3.7 nM in groups 1-4 respectively, and were not significantly different from one another. The mean % free E2 and % free T values also were not different between the groups. However, the mean total E2 and free E2 (% free E2 X E2/100) concentrations were significantly (P less than 0.05) higher in both groups A and B than in groups C and D. The E2 concentration was also higher in group A than in group B. There were strong correlations between the E2 and free E2 concentrations between the T and free T (% free T X T/100); (P less than 0.0001) concentrations, between SHBG capacity and weight, and between the MCRs of both E2 and T and % free E2 and % free T. In normal women, the menopause is not associated with changes in SHBG or % free steroids. Hence, the measurement of E2 could be used to predict the mass of free E2 in these women.     

Genetic Influences on Insulinemia in Normotensive Twins

The aim of this study was to establish the contribution of genetic factors to the variance of plasma insulin concentration in healthy, normotensive twins. Seventeen pairs of monozygotic (MZ) and 17 pairs of dizygotic (DZ) twins were investigated. The test of genetic variance revealed a significantly larger within-pair variance of fasting plasma insulin (FPI) and a relative insulin resistance (RIR) in the DZ twins, in comparison with the MZ twins. Both FPI and RIR had a higher intraclass correlation coefficient in the MZ twins than in the DZ twins; the corresponding heritability estimates were 0.54 for FPI and 0.66 for RIR. Adjusting for age, gender, and body mass index did not affect heritability estimates for either FPI or RIR. Our data indicate that genetic factors are important determinants of insulinemia in normal subjects, independent of body mass index.     

The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study

OBJECTIVE: To assess the genetic contribution to radiographic hip osteoarthritis (OA) by measuring the distribution of disease features in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A population-based, cross-sectional study was conducted of 135 MZ and 277 DZ healthy female twin pairs, 50 years of age and older, who were recruited into the St. Thomas' UK Adult Twin Registry. Pelvic radiographs were read by a single observer who was blinded to the pairing and zygosity of the twins. The films were assessed for overall OA grade using a modification of the Kellgren and Lawrence scheme, and assessed for individual radiographic features. RESULTS: There was evidence of significant familial clustering for grade I and grade II OA changes, with an excess concordance in MZ twins compared with DZ twins, suggesting a genetic effect. The MZ versus DZ excess was also apparent for those classified as having more severe disease, although the number of pairs with these disease features was small. Familial clustering attributable to genetic factors was evident for joint space narrowing of <2.5 mm. Familial, but not genetic, clustering was seen for subchondral sclerosis. The number of pairs concordant for definite osteophytes in the sample was too low to assess this feature alone. These results translate into a significant heritability of 58% for OA overall and 64% for joint space narrowing. The heritability estimates decreased a little when the potential confounding influences of age, body mass index, and hip bone density were taken into account. CONCLUSION: Genetic factors have a significant contribution to OA at the hip in women and account for approximately 60% of the variation in population liability to the disease.     

Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alpha-reductase activity and androgen receptor content

The intraprostatic concentrations of testosterone (T) and dihydrotestosterone (DHT) have been measured in only a few men. We measured, in prostatic tissue obtained at surgery from seven men with benign prostatic hyperplasia, the effects of 3-month treatment with a long-acting GnRH agonist on 1) the intraprostatic concentrations of T, DHT, and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol); 2) prostatic 5 alpha-reductase activity; and 3) the prostatic content of androgen receptors (AR). Plasma T, DHT, and 3 alpha-diol levels also were measured. Prostatic tissue samples obtained at surgery from a group of untreated men with benign prostatic hyperplasia also were studied. The mean DHT and 3 alpha-diol concentrations in the prostatic tissue of the treated men were about 10% of those in untreated men (n = 19; P less than 0.01 for DHT and P less than 0.05 for 3 alpha-diol), and the mean intraprostatic T concentration in the treated men was about 25% of that in the control group (0.10 greater than P greater than 0.05). The mean in vitro formation of DHT by the prostatic tissue of the treated men was about 50% lower (P less than 0.05) than that by prostatic tissue of the untreated men (n = 9). The mean cytosolic AR content in the prostatic tissue of the treated men was significantly higher (P less than 0.05), whereas the mean nuclear content of both salt-extractable and salt-resistant AR was significantly lower (P less than 0.05) than that in the prostatic tissue of the untreated men (n = 8). The mean plasma T levels in treated men decreased from 4.77 +/- 1.79 (SD) ng/mL (16.5 +/- 6.2 nmol/L) to 0.27 +/- 0.42 ng/mL (0.9 +/- 1.5 nmol/L) after 1 month of therapy and remained in the castrate range thereafter. We conclude that pharmacological castration resulting from 3-month treatment with a long-acting GnRH agonist decreases the intraprostatic T concentration to about one fourth and those of DHT and 3 alpha-diol to about one tenth of the levels in untreated men. Thus, GnRH agonist treatment may not completely abolish intraprostatic androgen concentrations in metastatic prostatic cancer patients. The decrease in prostatic 5 alpha-reductase activity as well as the decrease in nuclear receptors are probably secondary to the decrease in plasma T concentrations.     

Genetic effect in resting and exercise metabolic rates

Two studies dealing with the contribution of the genotype in individual differences for resting metabolic rate (RMR), thermic effect of a 4.2 MJ carbohydrate meal (TEM), and energy cost of submaximal exercise are reported. The genetic effect for RMR and TEM was studied in 31 pairs of parent-child, 21 pairs of dizygotic (DZ) twins, and 37 pairs of monozygotic (MZ) twins, whereas the heritability of the energy cost of submaximal exercise was determined from data on 22 pairs of DZ twins and 31 pairs of MZ twins. The heritability of RMR reached approximately 40% of the variance remaining after adjustment for age, gender, and fat-free mass, (FFM). The genetic effect for TEM was equivalent to at least 40% to 50% of the variation in the energy expended during four hours after the meal test. A highly significant genetic effect was found for fasting plasma glucose (greater than .72), but the results for fasting plasma insulin are unclear. No significant genetic variance was seen for the glucose and insulin response to the carbohydrate meal. Finally, heritability for the metabolic rate during cycle exercise was high (greater than or equal to .46) at low power output, but it became nonsignificant when the energy cost reached about 6 times the RMR.     

Heritability of variation of plasma cortisol levels

Heritability of the variation of the plasma concentrations of total and unbound cortisol, cortisol binding globulin (CBG), and dehydroepiandrosterone sulfate (DHEA-S) was investigated in 20 monozygotic (MZ) and 20 dizygotic (DZ) male twin pairs. Three plasma samples collected between 8 AM and 9:30 AM were pooled for the assays. Heritability was calculated from the intraclass correlation [2(rMZ - rDZ)]. The mean age, total and unbound cortisol, CBG, and DHEA-S were not significantly different between the MZ and DZ groups of twins. The heritability index for variability of the plasma content of steroids was 45.4% (p less than .05) for total cortisol, 50.6% (P less than .05) for unbound plasma cortisol, 57.8% (P less than .05) for DHEA-S, and 32.4% (P greater than .05) for CBG. The data were analyzed by factor analysis, and heritability estimates were corrected for factors including age, smoking, drinking, exercise, and degree of obesity. These factors did not account for the variation in hormone values in twin pairs. Factor analysis of the three quantitative measurements, cortisol, percent free cortisol, and DHEA-S, provides no evidence for shared factors. The correlation coefficients between age and CBG and total and unbound plasma cortisol concentrations were insignificant. The correlation coefficient between total plasma cortisol levels and CBG was 0.57, which indicates that CBG accounts for 32% of the variation of plasma cortisol concentrations. The results suggest that genetic factors have a decided influence on the variation of the concentration of cortisol of DHEA-S in normal adult men.     

THE EFFECT OF ENDOGENOUS PROGESTERONE ON SERUM LEVELS OF 5α-REDUCED ANDROGENS IN HIRSUTE WOMEN

This study was to examine indirectly the effect of endogenous progesterone, a known competitor for 5 alpha-reductase, on androgen metabolism in target organs in hirsute women. Serum levels of progesterone, testosterone (T), androstenedione (A), dihydrotestosterone (DHT) and 5 alpha-androstane 3 alpha 17 beta-diol (3 alpha-diol) and sex hormone binding globulin (SHBG) were assessed serially over a four week period in normal women, six hirsute women with regular menstrual cycles, eight hirsute women with oligomenorrhoea (and presumptive polycystic ovaries) and seven non-hirsute women with oligomenorrhoea. Serum T and A levels were significantly higher than normal in both hirsute and non-hirsute women with oligomenorrhoea, while serum SHBG was significantly lower than normal in the two groups of hirsute women. The calculated free T level was higher than normal in all three groups of patients. DHT levels were not significantly different from normal in any of the three groups of patients. The 3 alpha-diol level showed considerable overlap with normal in all groups of patients and was only significantly higher than normal in hirsute women with oligomenorrhoea (P less than 0.05). There was a small fall in DHT in the late luteal phase of the cycle of those women with a sustained rise in serum progesterone in the second half of the cycle, but no change in serum 3 alpha-diol. These studies suggest that serum 3 alpha-diol may not be as good an indicator of peripheral androgen metabolism in hirsute women as previously reported and that a rise in serum progesterone has only a minimal effect on circulating levels of the active 5 alpha-reduced androgen metabolites. Although in vitro 3 alpha-diol has been shown to be a potent inhibitor of 5 alpha-reductase this casts doubt on its role in this regard in vivo.     

Twin concordance and sibling recurrence rates in multiple sclerosis

Size and ascertainment constraints often limit twin studies to concordance comparisons between identical and fraternal twins. Here we report the final results of a longitudinal, population-based study of twins with multiple sclerosis (MS) in Canada. Bias was demonstrably minimized, and an estimated 75% of all Canadian MS twin pairs were ascertained, giving a sample sufficiently large (n = 370) to permit additional informative comparisons. Twinning was not found to affect prevalence, and twins with MS did not differ from nontwins for DR15 allele frequency nor for MS risk to their siblings. Probandwise concordance rates of 25.3% (SE +/- 4.4) for monozygotic (MZ), 5.4% (+/-2.8) for dizygotic (DZ), and 2.9% (+/-0.6) for their nontwin siblings were found. MZ twin concordance was in excess of DZ twin concordance. The excess concordance in MZ was derived primarily from like-sexed female pairs with a probandwise concordance rate of 34 of 100 (34 +/- 5.7%) compared with 3 of 79 (3.8 +/- 2.8%) for female DZ pairs. We did not demonstrate an MZ/DZ difference in males, although the sample size was small. We observed a 2-fold increase in risk to DZ twins over nontwin siblings of twins, but the difference was not significant.