Sex Hormone Binding Globulin Binding Capacity Research Articles

Testostérone libre ou biodisponible : dosages ou calculs. Comparaison critique de différents modes d'approche

The aim of the study is to find the most reliable practical approach to the estimation of free or bioavailable serum testosterone. We compare assayed values of bioavailable testosterone (T Bio), Free testosterone DPC (Free T DPC), total testosterone (Ttot) and calculated Free Androgen Index FAI = [Ttot/SHBG] × 100, calculated Free Testosterone using the equation derived from the law of mass action for the model: two binding proteins (SHBG, Albumin) and two ligands (T,E 2) (FTc II Södergaard) or one ligand (T) (Ftc I Kaufman and Fiers). Serum SHBG, Albumin, E 2 are determined exprimentally in every sample. The bioavailable (or non-SHBG bound) T correlates well with Free T by ultrafiltration ( r = 0.96; P < 0.01), is easy to perform, reliable and sensitive if a particular care is ensured in the purification of the tracer. Assayed women values of T Bio agreed well with calculated values for FTc II or FTc I ( r = 0.93; P < 0.01) using the laws of mass action. In contrast, the ratios of FTc II/T Bio and FTc I/T Bio (which should be constant if indexes reflect T Bio) remain negatively SHBG dependent for women and positively SHBG dependent for men confirming that the assumptions of the model are too simplified and the association constants Ka values too approximative. Calculated FTc is an acceptable substitute for an estimation of bioavailable T if we presume women with standard SHBG binding conditions and sera free of significant amounts of substances or steroids that could occupy the binding sites in the SHBG moiety and invalidate the calculation. Although showing a good correlation ( r = 0.89; P < 0.01) with T Bio, FAI is not a useful index: the FAI/T Bio ratio is negatively correlated ( r = –0.86 P < 0.001) with SHBG and overestimate strongly the SHBG binding capacity contribution for a reliable quantification of the non-SHBG bound T. The Free T DPC is inaccurate, not sufficiently sensitive, not free of proteins effects and less correlated with T Bio ( r = 0.49; P < 0.05) than Ttot ( r = 0.64; P < 0.01) for women!

The shbg Gene and Hormone Dependence of Breast Cancer: A Novel Mechanism of Hormone Dependence of MCF-7 Human Breast Cancer Cells Based upon SHBG.

BACKGROUND: SHBG (sex hormone binding globulin) is a 45 kDa glycoprotein thatbinds sex steroid with high specificity and affinity. SHBG is produced in various tissues including breast, liver, endometrium, and prostate via activated ER alpha and is secreted into plasma. SHBG regulates the activity of bioavailable sex steroid in plasma and in cells and also modulates cell growth regulation. METHODS: The predictive value of SHBG on the efficacy of hormone therapy against human breast cancer was determined. To evaluate the role of shbg gene expression in estrogen-dependent cell growth of MCF-7 breast cancer, cDNA cloning and determination of the expression of the shbg gene of MCF-7 cells was performed using PCR, RT-PCR Southern blotting. RESULTS: The SHBG titer (17 beta -estradiol binding capacity of SHBG) showed high predictability for the hormone dependence of breast cancer. Tumors of patientswith high SHBG titers showed a 91.8% response rate (N = 49). In contrast, tumors of patients with low SHBG titers showed only an 8.2% response rate (N = 61). >From our experimental results using MCF-7 cells, it is suggested that the SHBG titer includes SHBG secreted from liver and breast cancer cells. MCF-7 cells showed high expression of the wild type shbg gene, hybridized with Hammond's SHBG probe, which represents the 3'portion of SHBG-cDNA cloned from hepatocytes. E2 (17 beta-estradiol) induced the expression of the wild type shbg gene. However, the exon VII splicing variant of the shbg gene did not respond to E2 induction. CONCLUSIONS: From our results and the reports of other investigators, it is suggested that loss of hormone dependence in breast cancer may be caused by the loss of wild type shbg gene and the appearance of the exon VII splicing variant.The shbg-E2 complex binds to SHBG receptor (SHBGR) in cell membrane and internalizes through SHBGR mediated endocytosis causing the production of intracellularcAMP and E2-responsive second messenger. SHBG functions as a nuclear protein. From these data, we prepared a model of a novel mechanism of hormone dependence of breast cancer based upon SHBG and the shbg gene.

Sex Hormone-Binding Globulin and Breast Cancer Risk

Epidemiologic evidence supports the hypothesis that a woman's cumulative exposure to premenopausal ovarian steroids, estrogen and progesterone, contributes to the lifetime risk of developing breast cancer. A direct relationship between total endogenous levels of plasma estrogens and the incidence of breast carcinoma has not been demonstrated, however, and no substantial breast cancer risk has been consistently associated with postmenopausal estrogen replacement therapy. This paper summarizes the literature regarding the potential role of sex hormone-binding globulin (SHBG) in modifying breast cancer risk. It has been proposed that circulating levels of bio-available estrogens (ie, not bound to SHBG) might more directly reflect the risk for development of disease. Several studies have detected an association between a decreased percentage of estradiol bound to SHBG, a small increase in free estradiol, and a higher incidence of breast cancer in postmenopausal women. The physiologic significance of this increase in free estradiol, however, especially considered in the context of the relatively lower postmenopausal levels of total estradiol, is not clear. In addition to its carrier function for circulating estradiol, SHBG specifically binds to cells of steroid-responsive tissues, including breast tissue, and decreases the proliferation of some breast cancer cells through activation of cyclic adenosine monophosphate. This suggests that a decrease in the binding capacity of SHBG could potentially diminish SHBG binding to breast cell membranes and increase the rate of cellular proliferation. Oralestrogens increase plasma SHBG levels in postmenopausal women and this increase might mitigate the effect of estrogen replacement therapy on breast cancer epidemiology.

Comparison of a Gonadotropin-Releasing Hormone Agonist and a Low Dose Oral Contraceptive Given Alone or Together in the Treatment of Hirsutism

Heiner, J. S.; Greendale, G. A.; Kawakami, A. K.; Lapolt, P. S.; Fisher, M.; Young, D.; Judd, H. L. Author Information

Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males.

Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was studied in a small group of men (n = 8) with isolated GH deficiency. In nonobese healthy men, age was inversely correlated with serum levels of all androgens studied (although total T levels stayed relatively stable until age 55 yr) as well as with albumin, GH, and IGF-I levels and positively correlated with BMI, insulin levels, and SHBG-binding capacity. Nevertheless, SHBG levels were significantly negatively correlated with insulin levels (P < 0.001) as well as with mean 24-h GH and IGF-I levels. Among possible confounding factors affecting (free) T [(FT)] levels in healthy men, smoking appeared to be accompanied by higher (F)T levels than those in nonsmokers. BMI increased with age, but although BMI was negatively correlated with T, FT, and SHBG, respectively, the age-dependent decrease in T levels persisted after correction for BMI. Data not corrected for BMI may, nevertheless, overestimate the age-associated decrease in T levels. The albumin concentration decreased with age, and if FT is the feedback regulator of plasma T levels, albumin concentration might be a codeterminant (although, evidently, less important than SHBG) of T levels and contribute to the age-associated decrease in T levels. In any case, albumin concentration is a codeterminant of DHEAS concentration. T, DHEA, and DHEAS levels were significantly correlated, but this correlation disappeared after controlling for age; hence, there is no evidence for an adrenal-gonadal interaction in men. In obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI; DHEAS levels were slightly lower than those in the nonobese controls, but no significant correlation between DHEA or DHEAS, and insulin levels was observed. After a weight-reducing, protein-rich diet, resulting in a mean weight loss of +/- 15 kg, SHBG-binding capacity increased to normal values notwithstanding the fact that the subjects were still obese and that the insulin levels remained higher than those in the nonobese controls. Considering that after weight loss, GH and IGF-I levels remained lower than those in the nonobese controls, that adult men with isolated GH deficiency presented with higher SHBG levels than normal controls, which decreased to normal levels during GH substitution, and that elderly men have elevated SHBG levels notwithstanding high insulin levels, we suggest that the low GH and/or IGF-I levels might play a role in the elevated SHBG levels observed in both elderly males and obese men after a weight-reducing diet. As weight loss did not influence DHEAS levels notwithstanding an important decrease in insulin levels, our data do not support a role of insulin in the regulation of plasma DHEAS levels.

A Contraceptive Vaginal Ring Releasing Norethindrone Acetate and Ethinyl Estradiol

A core design contraceptive vaginal ring (CVR) releasing 650 mcg of norethindrone acetate (NA) and 10, 20, 30 or 65 mcg of ethinyl estradiol (EE) daily was developed and tested in 99 women. The CVR inhibited ovulation well with 30 or 65 mcg EE. Vaginal bleeding was better controlled than in 23 control women using NA/EE oral contraceptives. Side effects were comparable to controls for the 20 and 30 mcg EE CVR. The 65 mcg EE CVR resulted in an unacceptably high level of nausea. The 20 and 30 mcg EE CVR caused an increase in serum HDL cholesterol and triglycerides. Total cholesterol was unchanged. Angiotensinogen and sex hormone binding globulin-binding capacity were increased in a subgroup of the 20 and 30 mcg EE CVR subjects, similar to that of 20 controls using EE/gestodene oral contraceptives. This new CVR offers an excellent contraceptive alternative with the best performance provided by the 30 mcg EE dose.

A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol

A core design contraceptive vaginal ring (CVR) releasing 650 mcg of norethindrone acetate (NA) and 10, 20, 30 or 65 mcg of ethinyl estradiol (EE) daily was developed and tested in 99 women. The CVR inhibited ovulation well with 30 or 65 mcg EE. Vaginal bleeding was better controlled than in 23 control women using NA/EE oral contraceptives. Side effects were comparable to controls for the 20 and 30 mcg EE CVR. The 65 mcg EE CVR resulted in an unacceptably high level of nausea. The 20 and 30 mcg EE CVR caused an increase in serum HDL cholesterol and triglycerides. Total cholesterol was unchanged. Angiotensinogen and sex hormone binding globulin-binding capacity were increased in a subgroup of the 20 and 30 mcg EE CVR subjects, similar to that of 20 controls using EE/gestodene oral contraceptives. This new CVR offers an excellent contraceptive alternative with the best performance provided by the 30 mcg EE dose.

Dose-finding study of a contraceptive ring releasing norethindrone acetate/ethinyl estradiol

A core design contraceptive vaginal ring (CVR) with average daily release of 650 mcg of norethindrone acetate (NA) and 30 mcg of ethinyl estradiol (EE) inhibited ovulation and controlled vaginal bleeding well, but caused some nausea. This study was designed to minimally alter the dose of steroid to see if nausea could be reduced without loss of contraceptive efficacy. This 30 650 CVR was compared to a CVR releasing 20 mcg of EE and 1000 mcg of NA ( 20 1000 ) and another releasing 25 mcg of EE and 650 mcg of NA ( 25 650 ) in 69 subjects. Twenty-three subjects using an oral contraceptive containing NA/EE served as controls. Ovulation inhibition was excellent and comparable to the OC for all formulations. The CVR provided better control of vaginal bleeding than did the OC. Side effects were equivalent to the OC with the exception of a slight increase in nausea in CVR users. Lipid changes and globulin increases were comparable to oral contraceptive users. The 20 1000 CVR increased sex hormone binding globulin-binding capacity less than the other two CVRs. The performance of the three CVRs was not significantly different, but the 25 650 showed a trend of reduced performance relative to the other two formulations.

Pathogenesis of the decreased androgen levels in obese men.

In obese men, sex hormone-binding globulin levels (SHBG) as well as total plasma testosterone (T) levels are decreased. Data concerning the levels of nonprotein-bound testosterone (FT) are discordant, with some researchers reporting normal levels, and other reporting decreased levels. The latter imply an impairment of the feedback regulation mechanism of FT levels. We investigated whether an eventual decrease in FT levels and, hence, functional impairment of the gonadostat might occur only at a more severe degree of obesity than that required for a decrease in SHBG and total T levels. We, therefore, determined androgen and precursor levels in three groups of male subjects: nonobese controls [body mass index (BMI), G (kg)/L2 (m) < 26; n = 70]; moderately (BMI, 30-35; n = 18), and severely (BMI, > 40; n = 22) obese men, respectively. In a subgroup of these controls, moderately and severely obese subjects, respectively, we studied LH levels as well as LH pulsatility. Moreover, as a decrease in FT levels might affect the metabolic pattern of the androgens and, more specifically, 5 alpha-reductase activity, we determined the plasma levels of the major 5 alpha-reduced metabolites, androstanediol glucuronide and androsterone glucuronide (AG), as well as the urinary excretion of the major 5 alpha (androsterone glucuronide) and the major 5 beta (etiocholanolone glucuronide) metabolite of the androgens. In moderately obese men, T levels were decreased, which was the consequence of the decreased SHBG-binding capacity. FT levels, however, were normal as were LH levels and both pulse amplitude and frequency of LH pulses, suggesting a normal hypothalamic control of LH secretion. In severely obese men (BMI, > 40), total T, FT, and LH levels as well as LH pulse amplitude were decreased, indicating a functional impairment of the gonadostat. Even in massively obese subjects with decreased FT levels, androgen metabolism and 5 alpha-reductase activity appeared to be normal, as suggested by similar androstanediol glucuronide and AG levels, determined by RIA or calculated from the conversion rates of precursors obtained in nonobese subjects. This was confirmed by the similar AG/eticholanolone glucuronide ratios in obese and nonobese men.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical Pharmacokinetics of Contraceptive Steroids

The present article should be read in conjunction with the original review published in the Journal in 1983. There is no new information of major significance about the pharmacokinetics of levonorgestrel, norethisterone (norethindrone) or ethinylestradiol, although it has been shown that the concentrations of these hormones secreted in breast milk are small and mothers taking combined oral contraceptive steroids may breast-feed safely. Both levonorgestrel and ethinylestradiol can be successfully administered from appropriate vaginal formulations, but no clear advantages over oral administration have been demonstrated. Several new progestogens have been investigated. Desogestrel is a prodrug for its active metabolite 3-keto-desogestrel, gestodene is itself an active progestogen and norgestimate is a prodrug acting by conversion to norgestrel and its metabolites. All 3 compounds have good bioavailability with wide intersubject variation. The newer progestogens, like norethisterone and levonorgestrel, are bound to sex hormone binding globulin (SHBG). This causes their plasma concentrations to increase with time, since SHBG is induced by ethinylestradiol even in doses of 30 micrograms daily. The binding capacity and affinity of SHBG do not increase in direct proportion to its concentration. Further drug interactions with oral contraceptive steroids have been described. Contraceptive steroids may inhibit hepatic microsomal enzyme metabolism and increase the plasma concentration and effect of some tricyclic antidepressants, the hydroxylated benzodiazepines, some beta-blocking drugs, methylxanthines, prednisolone and cyclosporin. There are no significant effects on vitamins. Oral contraceptive steroids induce glucuronidation and hence decrease plasma concentrations of some benzodiazepines, clofibric acid, paracetamol (acetaminophen) and possibly morphine. The plasma concentration of ethinylestradiol may be increased by competitive sulphation with paracetamol. Plasma concentrations of contraceptive steroids are decreased by griseofulvin, which induces their hepatic metabolism. The role of other antibiotics remains controversial but there is probably a group of susceptible women who have lower plasma contraceptive hormone concentrations and experience breakthrough bleeding or pregnancy when given broad spectrum antibiotics. This may relate to interruption of the enterohepatic recirculation of ethinylestradiol. Anticonvulsants, other than valproic acid, all induce contraceptive steroid metabolism and therefore lower plasma hormone concentrations, thus reducing contraceptive effectiveness.

Effects of hyperthyroidism on binding proteins for steroid hormones.

Sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) binding capacities were examined weekly in eight normally cycling women and three women taking birth control pills during a 5-week baseline period and after daily ingestion of 75 micrograms of L-triiodothyronine (T3) for 30 days. The SHBG binding capacity increased whereas the CBG binding capacity decreased after T3 therapy. The binding capacities of proteins for steroid hormones were measured in 18 hyperthyroid subjects (Graves' disease) prior to and after 3 months of antithyroid drug therapy. SHBG binding capacity in hyperthyroid men or women was higher, and CBG binding capacity lower than those in euthyroid subjects. Thus, during hyperthyroidism, binding capacities of sex hormone binding globulin and corticosteroid binding globulin vary in opposite directions. A statistically significant correlation between the ratio of the sex hormone binding globulin to the corticosteroid binding globulin and triiodothyronine levels was found (P less than 0.01). Therefore the ratio of the sex hormone binding globulin to the corticosteroid binding globulin might be potentially useful as a biochemical index of thyroid hormone action in peripheral tissues.

Dietary and hormonal interrelationships in premenopausal women: evidence for a relationship between dietary nutrients and plasma prolactin levels

To investigate possible differences in tissue exposures to reproductive hormones and to determine hormone-nutrient interrelationships, we studied 10 vegetarian and 10 nonvegetarian premenopausal Seventh-day Adventist women. Over 3 d in each of three consecutive menstrual cycles, we collected diet records, fasting midluteal phase blood, and 24-h urine samples. During each study period, we measured plasma and urinary estrogens, plasma free and protein bound-estradiol-17 beta, the binding capacity of sex-hormone-binding globulin (SHBG), androgens, progesterone, and prolactin levels. The omnivores consumed significantly more protein, total and saturated fatty acids, oleic and linoleic acids, and cholesterol than did the vegetarians. Hormonal status and binding capacity of SHBG were similar in both groups. However, for nonvegetarians, prolactin levels were positively correlated with dietary energy, protein, total and saturated fatty acids, and oleic acid. Further study delineating the effects of specific dietary nutrients on the basal level of prolactin secretion is warranted.

An enzyme-linked immunosorbent assay (ELISA) for human sex hormone-binding globulin

An enzyme-linked immunosorbent assay (ELISA) of the “sandwich-type” for sex hormone binding globulin (SHBG) has been developed. A rabbit anti-SHBG antibody (RAb) is immobilized to the microtitre plate. After incubation with standards and samples a second monospecific rabbit anti-SHBG antibody, labelled with alkaline phosphatase is added (RAb ∗). Following further washing substrate is added, colour developed and the plate read at 405 nm wavelength on a standard ELISA plate reader. The assay is not influenced by the presence of steroids at the binding site, and shows good agreement to SHBG binding capacity assay and commercially available IRMA. Its sensitivity, specificity and precision allows its use in the routine laboratory. The SHBG ELISA has been used to measure SHBG concentrations in sera of normal men, women, pregnant women, and women receiving high-dose medroxyprogesterone acetate as a treatment of metastatic breast cancer.

Reproductive hormone responses to resistance exercise

To investigate if changes in circulating testosterone levels during isokinetic resistance exercise in women were similar to those during intense aerobic exercise and to examine concomitant changes in hemoconcentration, specific binding protein (sex hormone binding globulin-binding capacity), non-sex hormone binding globulin bound testosterone, luteinizing hormone, follicle-stimulating hormone, cortisol, and lactate, blood samples were obtained through an indwelling cannula at 30 and 15 min before exercise, after each of six exercises on upper and lower body muscle groups, and at 15 and 30 min after exercise in seven normal menstruating women. Investigations lasting approximately 60 min were performed in the early follicular phase beginning at 3.30 p.m. after two months of training with isokinetic ("Nautilus") equipment. Baseline testosterone and non-sex hormone binding globulin bound testosterone levels were significantly higher in subjects than in a control group. Increased total and non-sex hormone binding globulin bound testosterone was observed immediately prior to exercise with further increases late in exercise, then with proportional increases in cortisol and lactic acid. Sex hormone binding globulin-binding capacity increased before exercise. The testosterone increments exceeded hemoconcentration. Luteinizing hormone and follicle-stimulating hormone levels increased during exercise. The data suggest that origins of the exercise-associated testosterone increment are complex, resulting from hemoconcentration and specific gonadal and adrenal responses.

Dimerization of shbg by gelatin and dithiothreitol. Implications for the measurement of SHBG binding capacity in human serum

in individual serum samples, the sex hormone-binding globulin (SHBG) binding capacity for dihydrotestosterone (DHT) was systematically found to be decreased by 30–60% when either gelatin or dithiothreitol (DTT) was present in the assay buffer. The presence of gelatin in the buffer prevented DTT from further decreasing the SHBG binding capacity of serum samples, suggesting a similar mechanism of action on SHBG for both of these substances. This observation led us to compare the molecular forms of SHBG by high performance liquid chromatography on a TSK G 3000 SW column, in the presence or absence of DTT. When undiluted serum previously incubated with [ 3H]DHT was chromatographed, only monomeric SHBG could be detected, independently of the presence or absence of DTT in the elution buffer. When the serum was diluted, incubated and chromatographed with buffer devoid of DTT, a dimeric SHBG peak was progressively observed, as a function of the sample dilution. Furthermore, for a given serum dilution, the relative size of the dimeric SHBG peak was also dependent on the steroid concentration present in the sample. By contrast, when serum was diluted, incubated and chromatographed with DTT-supplemented buffer, only the SHBG dimer peak could be detected. These results suggest that in serum, in vitro at least, SHBG is present in its monomeric form. Serum dilution with buffer devoid of DTT or gelatin induces the progressive dimerization of the protein, resulting in a progressive decrease of its apparent binding capacity. This could explain the great discrepancies of SHBG levels as reported in the literature. Because serum dilution with buffer supplemented with DTT or gelatin induces the complete dimerization of SHBG, independently of the sample dilution, we suggest that these substances be routinely used for the measurement of SHBG binding capacity. The SHBG binding capacity obtained in these latter conditions reflects however half the binding capacity of undiluted serum.

Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome, and other maternal factors: A seroepidemiologic study

Two studies were conducted to assess factors associated with increased risk of hyperemesis gravidarum during pregnancy with data and serum samples collected from participants in the Collaborative Perinatal Study. In the case-control study, 419 pregnant women with hyperemesis gravidarum were matched on medical center, date of study registration, and race with 836 pregnant women who did not vomit during the index pregnancy. Younger age, nulliparity, and high body weight were significantly associated with increased risk of hyperemesis. Women with hyperemesis had significantly reduced risk of fetal loss; however, their infants had higher risk of central nervous system malformations. In the second study, first-trimester pregnancy homones were measured in the serum of 35 women with hyperemesis and 35 control women who were individually matched to cases on age, parity, and medical center. After adjusting for length of gestation, mean levels of total estradiol were 26% higher and mean levels of sex hormone binding-globulin binding capacity were 37% higher in patients with hyperemesis gravidarum than in control subjects. These differences were statistically significant. Although human chorionic gonadotropin concentrations were higher in control pregnancies, the differences were not statistically significant. The average amount of estradiol that was nonprotein bound (adjusted for length of gestation) was also higher in patients than in control subjects. These results are consistent with the hypothesis that elevated estrogen levels are responsible for excessive vomiting in pregnancy.

Adrenal androgens, sex-hormone binding globulin and bone density in osteoporotic menopausal women: is there a relationship?

The relationships among sex steroids, sex hormone binding globulin (SHBG) and vertebral bone density as measured by computerized tomography were studied in 18 post-menopausal women. A significant negative correlation was found between SHBG binding capacity (SHBG-BC) and bone density. Bone density and the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) declined with age, and SHBG-BC was correlated significantly with DHEAS concentrations. The relationship between SHBG-BC and bone density may be affected by adrenal androgen output.

Contraceptive steroid treatment affects steroid binding proteins and the percentage of free 17β-estradiol and testosterone in the cynomolgus monkey (itmacaca fascicularis)

The levels of steroid binding globulins were characterized in cynomolgus monkeys that were treated with contraceptive steroid preparations delivered either by intravaginal rings (CVR) or orally (OC) in the diet. Levonorgestrel (dNG) was the bioactive progestin and the estrogen was either 17β-estradiol (E 2) in the CVR treatment or ethinyl estradiol (EE) in the OC treatment. Both contraceptive treatments lowered sex hormone binding globulin (SHBG) levels below those observed in males ( P < 0.05) and normal females ( P < 0.01). Corticosteroid binding globulin (CBG) was elevated ( P < 0.01) in the OC treatment, demonstrating the potency of EE. The distribution of E 2 and testosterone (T) between binding to SHBG or albumin and the unbound fraction was calculated after the determination of the percentage of free steroid by centrifugal ultrafiltration. Both contraceptive treatments increased the percentage of free T and E 2 ( P < 0.01) in the subset of monkeys that were evaluated, but the percentage bound to SHBG and albumin were different only for the CVR group ( P < 0.05). Decreased total T concentrations in the treatment groups offset any increase in free T concentrations associated with an increase in the percentage of free T. The differences in the distribution of binding to SHBG associated with these contraceptive steroid treatments was influenced more by the reduction in the binding capacity of SHBG than by the displacement of E 2 and T from SHBG by dNG.

Sex steroid hormone binding globulin levels and free 17β-estradiol and testosterone in cynomolgus monkeys during different reproductive states

The effect of differences in sex hormone binding globulin (SHBG) levels associated with reproductive status on free 17β-estradiol (E 2) and testosterone (T) was characterized in cynomolgus monkeys. Cycling female cynomolgus monkeys had higher SHBG levels than males, pregnant and lactating females ( P < 0.05). Ovariectomized females were not different than control females, suggesting no hypoestrogenic effect. The percentage of free T was elevated in pregnant animals ( P < 0.05) compared to normal males and females, but the percentage of free E 2 was similar between these groups. Although a gender difference in the percentages of free E 2 and T was not detected, there was a gender difference in the free T and E 2 concentrations due to endogenous secretion. Increased free E 2 concentrations during pregnancy were the result of endogenous secretion rather than the decreased binding capacity of SHBG; the increased percentage of free T during pregnancy significantly increased free T concentrations. These data suggest that the gender difference in SHBG levels in cynomolgus monkeys is due to androgenic influences and that estrogens have minimal influence. Furthermore, the decrease in SHBG levels during pregnancy and lactation may not be entirely dependent on these androgenic influences.

Relationships of serum lipoproteins and apoproteins to sex hormones and to the binding capacity of sex hormone binding globulin in healthy finnish men

We have determined the levels of serum sex hormones, the binding capacity of sex hormone binding globulin (SHBG), urinary estrogens, serum lipids, lipoproteins, and apolipoproteins A-I, A-II, and B in 30 healthy middle-aged Finnish men with similar dietary habits. Serum levels of total testosterone, free testosterone, 5α-dihydrotestosterone (5α-DHT), and the binding capacity of SHBG were all positively correlated to high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I) ( r = .43 to .80, P < 0.05 to 0.001). Total testosterone and 5α-DHT showed a positive correlation to the ratio of apo A-I to Apo A-II ( r = .37, P < 0.05 and r = .58, P < 0.01, respectively). Serum estradiol levels were negatively correlated to serum total cholesterol, low density lipoprotein cholesterol (LDL), and Apo B ( r = −.51 to −.56, P < 0.01). Moreover, serum free estradiol was negatively correlated to HDL-C and Apo A-I ( r = −.46 and r = −.50, P < 0.01). In multiple linear regression analysis, 5α-DHT was the most significant independent determinant of HDL-C and apo A-I levels when androgens, luteinizing hormone, estradiol, binding capacity of SHBG, and exogenous factors such as age, body mass index (BMI), smoking, alcohol consumption, and diet were taken into account. Multivariate analysis also demonstrated that both total and free estradiol were inversely related to serum Apo B levels. Our results demonstrate that in healthy men the concentrations of serum lipoprotein cholesterol and apolipoproteins, especially HDL-C and apo A-I, are influenced by the sex hormone status. The metabolic mechanisms and their possible association with the risk of coronary heart disease warrants further study.