Decrease In Sex Hormone Binding Globulin Research Articles

Abstract A10: Insulin resistance's effect on PSA level for prostate cancer screening

Abstract Introduction: Previous studies showed that BMI decreased serum PSA level. Insulin resistance in obesity is suggested one of reasons. The negative association between BMI and PSA level may be partially due to low testosterone concentration caused by obesity-related hormonal disturbances (decrease of sex-hormone binding globulin and increase of aromatase and IR) Objective: To examine the effect of homeostasis model assessment of insulin resistance (HOMA) index on PSA level after adjusting prostate volume(PV) effect in a screening population. Design: We performed multivariate linear regression and ANOVA to assess potential influencing factors in a cross-sectional study of 30- to 80-year-old Korean men who underwent routine checkups from 2004–2008 (n=3,320). Main Outcome Measures: Associations between factor variables (BMI, HOMA Index, PV) and PSA level assessed by trends tests by multivariate linear regression and/or ANOVA. Results: PSA level was negatively associated with BMI before (P for trend <.01) and after (P for trend by quartile <.05 for all) PV stratification, but not associated with HOMA index before (P for trend >.05) and after (P for trend by quartile >.05 for all) PV stratification. Conclusions: BMI has negative effect on PSA level irrespective of PV stratification, but IR had no association. Hemodilutional effect by obesity may be main cause of BMI's negative association on PSA level. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A10.

Age modulates effects of thyroid dysfunction on sex hormone binding globulin (SHBG) levels.

Symptoms of thyroid dysfunction are difficult to detect in elderly people and TSH is sometimes unreliable. We therefore tested the value of SHBG as a marker of thyroid hormone action on the liver to determine the thyroid status of elderly people. Aging euthyroid men and women have a significant increase in SHBG (p > 0.0001). In aging women the decrease in SHBG with hypothyroidism and increase with hyperthyroidism are highly significant (p < 0.0001 and p < 0.0005 respectively). No significant variation in SHBG was observed in men with thyroid dysfunction. SHBG can help to determine the thyroid status of aging women.

Applicability of the SHBG androgen sensitivity test in the differential diagnosis of 46,XY gonadal dysgenesis, true hermaphroditism, and androgen insensitivity syndrome.

The sex hormone-binding globulin (SHBG) androgen sensitivity test has been used as a simple method to assess androgen receptor function in vivo. After a short term oral administration of the anabolic-androgenic steroid stanozolol the mean nadir serum concentration of SHBG is used as a measure of androgen response. We performed this test in order to evaluate its applicability in 16 patients with intersexual genital status: eleven with 46,XY gonadal dysgenesis and three with true hermaphroditism (group I), and in two patients with androgen insensitivity syndrome (AIS, group II). Ten healthy adult volunteers served as controls. In the two patients with AIS (group II) we found a diminished decrease of serum SHBG to 80.1 % and 80.7 %, respectively, indicating slight residual androgen responsiveness. In eleven patients of group I who were not on hormone replacement therapy, a mean nadir level of 51.7 +/- 8.7 % was found. In the controls the mean nadir serum SHBG level was significantly higher (62.7 +/- 5.2 %), probably due to interference of endogenous androgens and contraceptive medication with the stanozolol-induced SHBG decrease. In three gonadectomised patients who were on hormone replacement therapy the initial SHBG concentration was increased (513.5 +/- 239.1 nmol/l); the mean nadir SHBG concentration of 45.6 +/- 9.8 % of the initial level indicates an increased sensitivity of the test in patients in whom the counteracting ovarian androgens are absent. Our findings confirm that under standard test conditions the SHBG androgen sensitivity test is a simple diagnostic tool for the detection of androgen receptor malfunction.

Biological activity of anastrozole in postmenopausal patients with advanced breast cancer: effects on estrogens and bone metabolism

BackgroundTo study the short-term biological effect of anastrozole on serum estrogens, androgens, 17-hydroxyprogesterone (17OH-PGR), gonadotrophins, sex hormone binding globulin (SHBG) and bone metabolism markers. Materials and methodsThirty-four consecutive patients with advanced breast cancer received anastrozole 1 mg/day. Blood samples were taken before commencement of treatment and at 2, 4, 8and 12 weeks during treatment to measure serum levels of estrogens (E1, E2 and E1-S), androgens [androstenedione (Δ4), dihydrotestosterone (DHT), testosterone (TST), free TST, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S)], 17OH-PGR, SHBG and gonadotrophins. As an indicator of bone resorption, we measured serum levels of C-terminal telopeptide of type I collagen (ICTP) and the cross-linked N-telopeptide of type I collagen (NTx), and for osteoblastic activity, intact osteocalcin (BGP) and bone alkaline phosphatase (BAP). ResultsAfter 2 weeks E1 and E1-S levels decreased on average by 56% (range 23.1–88.8%) and 75.8% (range 52.4–87.2%), respectively; E2 decreased on average by 62% (range 31.4–89.6%). No significant changes were detected in levels of androgens or 17OH-PGR. There was a significant increase in gonadotrophins over time (P = 0.0001 for both luteinizing hormone and follicle-stimulating hormone), and a significant decrease in SHBG (P = 0.0001). A progressive significant increase in bone metabolism serum markers was detected in all patients: BAP, P = 0.039; BGP, P = 0.016; ICTP, P = 0.0021; and NTx, P = 0.0013. In particular, patients with bone metastases had a statistically significant increase of bone resorption markers (ICTP, P = 0.0019; NTx, P = 0.025) and borderline for bone formation markers. In patients without bone disease, BAP, BGP and ICTP remained unchanged, whereas serum NTx significantly increased (P = 0.019). ConclusionsAnastrozole is a selective aromatase inhibitor as it does not modify serum levels of androgens and 17OH-PGR. In our experience no relationship was found in the short-term period between serum estrogen suppression and bone metabolism.

Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study.

The objective was to examine prospectively the association between low testosterone and sex hormone-binding globulin (SHBG) levels and the subsequent development of type 2 diabetes in men. Analyses were conducted on the cohort of the Massachusetts Male Aging Study, a population-based random sample of men aged 40-70. Of the 1,709 men enrolled in 1987-1989 (T1), 1,156 were followed up 7-10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2. After controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and SHBG. The odds ratio for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l), both significant at P < 0.02. Our prospective findings are consistent with previous, mainly cross-sectional reports, suggesting that low levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.

Serum prostate specific antigen, sex hormone binding globulin and free androgen index as markers of pubertal development in boys

Prostate specific antigen (PSA) expression in the prostate gland is regulated by androgens. Serum levels of PSA are undetectable by routine assays in normal boys. Measurable values could serve as a marker for pubertal development. In order to explore this question, we measured serum PSA levels in normal boys throughout puberty and examined the interrelationships with various hormonal and physical developmental changes. Sera from 77 normal boys in Tanner stages I to V (T-I to T-V) were analysed for PSA levels by a sensitive time-resolved fluoro-immunometric assay (sensitivity: 0.012 microgram/l). In addition, sex hormone binding globulin (SHBG), insulin like growth factor I (IGF-I), IGF binding protein 3(IGFBP-3) and testosterone were measured. PSA was detectable in 0% of Stage T-I (n = 16), 33% of T-II (n = 18), 65% of T-III (n = 17) and 100% of T-IV (n = 10) and T-V (n = 16) boys. PSA levels rose significantly according to stage (P < 0.05). Also, there were significant (P < 0.05) increments in serum testosterone, IGF-I and IGFBP-3 levels from stages T-I to T-IV. PSA showed a positive correlation with testosterone (r = 0.86, P < 0.001), IGF-I (r = 0.66, P < 0.001), and IGFBP-3 (r = 0.34, P = 0.004) levels. Both PSA and these analytes, however, showed significant overlap between stages T-I and T-II with only 6/18 (33%) and 12/18 (66%) of T-II subjects having PSA and testosterone levels, respectively, above the T-I range. In contrast, serum SHBG levels decreased markedly from stages I to II (P < 0.001). At the calculated best cut-off point for SHBG of 50 nmol/l, 16/18 T-II subjects had values below the T-I range (sensitivity = 89%). Because of this decrement of SHBG and the increasing testosterone secretion in early puberty, the Free Androgen Index (FAI = Testosterone/SHBG) could even better differentiate the onset of puberty with all except one of the T-II subjects having FAI levels above the T-I range (sensitivity = 94.4%). The decrease of SHBG in T-II subjects coincided with an increase in total body weight (P = 0.001) and body mass index (BMI, P = 0.0003). Despite the continuing pubertal rise in testosterone, SHBG levels showed a rebound increment from T-II-T-III subjects (P = 0.02) with a concomitant decrease in BMI (P = 0.0014). Prostate specific antigen closely reflects serum free androgen activity during puberty. However, it was unable to differentiate the earliest pubertal development. In comparison, SHBG levels and Free Androgen Index are more sensitive markers for the onset of puberty in boys. The inverse association between SHBG levels and BMI in pubertal stages Tanner stages, I to III suggests that body fatness, via its effect on insulin sensitivity, may play an important role in the regulation of SHBG production during early pubertal development.

Sex hormone binding globulin and free levonorgestrel index in the first week after insertion of Norplant® implants

Levonorgestrel has an inhibitory effect on sex hormone binding globulin (SHBG). This decrease in SHBG leads to an increase in the free levonorgestrel index (FLI), which has a stronger biological effect. The interaction between serum levels of levonorgestrel and SHBG in long-term users of Norplant® implants has been described. This study was designed to understand the same interaction immediately after the insertion of the implants, in a group of 16 women, sampled at 0 and 6 h and at 1, 3, and 7 days after Norplant implant insertion. Peak serum levonorgestrel levels were achieved at 24 h after insertion, remaining stable on day 3 and decreasing by >10% by day 7. SHBG did not change during the first 24 h, but decreased by 19% and 60% on days 3 and 7, respectively. FLI more than doubled from day 1 to day 7 after insertion. The large decrease in SHBG and doubling of FLI is not followed by a similar reduction in levonorgestrel, which is hard to explain without an increase in the release rate of the steroid from the capsule.

Effects of danazol and progesterone on sex hormone-binding globulin mRNA expression in human endometrial cancer cell line Ishikawa

To ascertain one of the biological effects of danazol and progesterone on the uterine endometrial cancer cell line, Ishikawa, we investigated the effects of these steroids on sex hormone-binding globulin (SHBG) mRNA expression by competitive reverse transcription-polymerase chain reaction-Southern blot analysis (RT-PCR-SBA). Estradiol-17β (E2) in any concentration given did not exert any significant effect on the expression of SHBG mRNA. Danazol and progesterone significantly ( P < 0.05) suppressed the expression of SHBG mRNA dose-dependently starting at a concentration of 10 −6 and 10 −8 M, respectively. Progesterone, in a low concentration (10 −10 M) with E2 (10 −8 M), significantly ( P < 0.05) increased the expression of SHBG mRNA, but danazol did not. In contrast, danazol and progesterone in high concentrations (10 −6 to 10 −5 M) with E2 (10 −8 M) significantly ( P < 0.05) suppressed its expression. The time course study showed the time-dependent decrease of SHBG mRNA level by danazol and progesterone (10 −6 M) with or without E2 (10 −8 M), except for a temporal increase by progesterone. These findings suggest that danazol and progesterone in a superphysiological milieu down-regulate the intracellular SHBG-related steroidal actions, and that progesterone in a physiological milieu with estrogen up-regulates it in a hormone-dependent cell line. A decrease of intracellular SHBG caused by high-dose danazol or progesterone might partly contribute to the abolition of the intracellular estrogen-dominant milieu, and be related to the inhibition of estrogen-dependent growth of some endometrial cancer cells.

Investigation of oestrogen receptors, sex steroids and soluble adhesion molecules in the progression of malignant melanoma

The question of whether melanoma tumours have classical oestrogen receptors (ERs) is unresolved, but epidemiological data clearly show a survival benefit for female patients with metastatic melanoma. The aims of this study were to examine to what extent the presence of ER in melanoma tumours might relate to disease progression and whether disease progression relates to patients' sex steroid status. Additionally, levels of two soluble adhesion molecules [circulating intercellular adhesion molecule-1 (sICAM-1) and circulating vascular cell adhesion molecule-1 (sVCAM-1)] were examined as independent, possibly prognostic indicators of disease progression. ER immunocytochemical assay identified only two lesions (out of 69 investigated) which had any evidence of the receptors, and staining in these lesions was very modest. No significant changes in oestrone or androstenedione levels were noted for male or female patients with disease progression. As expected, oestradiol levels reflected the menopausal status of the female patients but, for all post-menopausal female patients and male patients, there was no significant relationship to tumour stage. However, a significant decrease in sex hormone-binding globulin occurred with disease progression in male but not female patients, and sex differences in the levels of soluble adhesion molecules were also seen in advanced metastatic disease.

Biochemical selection of prepubertal patients with androgen insensitivity syndrome by sex hormone-binding globulin response to the human chorionic gonadotropin test.

Before puberty, the diagnosis of androgen insensitivity syndrome (AIS) can be difficult. We studied whether the decrease of sex hormone-binding globulin (SHBG) during the human chorionic gonadotropin (hCG) test may represent a biochemical test to select prepubertal patients with AIS. We examined prepubertal patients with AIS (n = 9, age 0.9-8.2 y), male pseudohermaphroditism not due to AIS (other-MPH) (n = 8, age 0.6-10.7 y), and control boys (n = 12, age 0.8-12.5 y). Testosterone and SHBG levels (mean +/- SD) were measured before (d 0) and after (d 5) a hCG test (1500 IU X 3 d). Testosterone levels (nmol/L) increased in all groups [AIS: from 1.5 +/- 1.2 to 22.1 +/- 11.8 (p < 0.001); other-MPH: from 0.6 +/- 0.6 to 9.2 +/- 7.4 (p < 0.02); controls: from 1.8 +/- 1.4 to 22.8 +/- 14.4 (p < 0.001)]. SHBG concentrations (nmol/L) did not change in AIS [from 66.2 +/- 15.1 to 67.5 +/- 18.6 (p = NS), delta-variation 1.7 +/- 12.7%], whereas they were significantly decreased in other-MPH [from 59.9 +/- 14.2 to 46.5 +/- 18.6 (p < 0.005), delta-variation -23.7 +/- 19.6%] and controls [from 63.0 +/- 16.9 to 33.7 +/- 14.6 (p < 0.003), delta-variation -46.9 +/- 15.2%]. Our data suggest that the SHBG changes during the hCG test can be used to assess in vivo the biologic response to androgens in prepubertal patients with ambiguous genitalia, selecting those patients in whom it is worth performing second level investigations to confirm the AIS diagnosis.

Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group.

In the genetic male, mutations of the androgen receptor (AR) gene cause phenotypes ranging from female to subfertile male. Binding assays on genital skin fibroblasts and DNA analysis alone provide incomplete information about receptor function. We used the sex hormone-binding globulin (SHBG) response to stanozolol as a measure of AR function and correlated the results with phenotypes which were classified according to the degree of defective masculinization. Of the 34 patients investigated, 9 had complete, and 14 had partial androgen insensitivity syndrome (AIS) with predominantly female, ambiguous, or predominantly male phenotype. Eleven subjects served as controls. Mutations were characterized using polymerase chain reaction-single strand conformation polymorphism analysis and direct DNA sequencing. DNA analysis revealed two major deletions, two minor defects leading to premature stop codons in exon 1, and 19 point mutations in the DNA- and hormone-binding domains of the AR gene. After stanozolol, SHBG remained unchanged in patients with complete AIS (102.0 +/- 3.8 [SE]%; range 92.4%-129% of the initial value). The SHBG decrease was diminished in partial AIS with predominantly female (83.8% +/- 1.7%; range 81.3%-87.0%), ambiguous (80.4% +/- 4.4%, range 68.4%-89.1%), and predominantly male (mean 65.9% +/- 4.9%, range 48.6%-80.8%) phenotypes, and normal in controls (51.4% +/- 2.1%, range 35.6%-62.1%). Differences between controls and each AIS group were statistically significant (P < 0.05 - < 0.0001). A close correlation was found between the degree of undermasculinization (AIS phenotype) and the SHBG response. The SHBG test provides functional information about the severity of the receptor defect in vivo and hence adds to the structural information provided by DNA analysis. It detects receptor defects due to mutations within the entire gene, including the DNA-binding domain, and is a rapid, simple, and cost effective procedure. It may provide useful information for the diagnosis and management of affected children.

Subtle changes in serum thyrotrophin (TSH) and sex-hormone-binding globulin (SHBG) levels during long-term follow-up after radioactive iodine in multinodular non-toxic goitre.

We investigated possible changes in the pituitary-thyroid axis after radioactive iodine (RAI) treatment of multinodular non-toxic goitre. Consecutive patients with multinodular non-toxic goitre, who remained euthyroid after radioactive iodine (RAI) treatment. Twenty-three women with multinodular non-toxic goitre were followed after treatment with RAI. Free T4 index (FT4I), FT3I, free T4, SHBG (immunoradiometric assay), and a third-generation TSH assay (chemiluminetric assay) TSH were measured. Three weeks after RAI treatment TSH had decreased and SHBG increased (P < 0.05). Only 2/18 patients actually had suppressed TSH values, while 12/18 had values in between euthyroid and toxic levels. Trend analysis from 1.5 to 24 months after RAI treatment demonstrated a progressive increase in TSH (P < 0.01) and gradual decrease in SHBG (P < 0.02). No changes in FT4I, FT3I, or free T4 were found. A third-generation TSH assay gave detailed information about changes in thyroid status when TSH was below normal values. FT4I, FT3I, and free T4 seem to be less sensitive parameters than TSH and SHBG for recording subtle changes in thyroid status after RAI treatment of nodular non-toxic goitre. We demonstrated that changes in the pituitary-thyroid axis continue for a long time after RAI treatment of multinodular non-toxic goitre. These patients should be followed up in order to detect possible late hypothyroidism.

Endocrine effects in female weight lifters who self-administer testosterone and anabolic steroids

It appears that the self-administration of testosterone and anabolic steroids is increasingly practiced by women in sports where strength and endurance are important. We recently evaluated endocrine parameters in nine female weight lifters using steroids and seven not using these agents. Of the nine anabolic steroid users, seven took multiple anabolic steroids simultaneously. Thirty-fold elevations of serum testosterone were noted in the women injecting testosterone. In three of these women serum testosterone levels exceeded the upper limits for normal male testosterone concentrations. A significant compensatory decrease in sex hormone-binding globulin and a decrease in thyroid-binding proteins were noted in the women steroid users. Also, a 39% decrease in high-density lipoprotein cholesterol was noted in the steroid-using weight lifters. Most of the subjects in this study used anabolic steroids continuously, which raises concern about premature atherosclerosis and other disease processes developing in these women.

Direct effect of plasma sex hormone binding globulin (SHBG) on the metabolic clearance rate of 17β-estradiol in the primate

Sex hormone binding globulin (SHBG) has been shown to be a major determinant of testosterone clearance in the primate. It has also been suggested that SHBG would also be a determinant of estradiol clearance (MCR-E 2). However, published studies have suggested that the MCR-E 2 do not always vary with changes in the level of SHBG. Therefore, the present study was undertaken to address this issue. The baseline MCR-E 2 was determined in adult male pigtail macaques ( Macaca nemestrina). Following the baseline determination of MCR-E 2 the animals were infused with either purified human (h)SHBG or antibody against hSHBG, which also has a high degree of cross-reactivity with primate SHBG. Following the infusions of either hSHBG or anti-SHBG, MCR-E 2 was again determined. In addition, luteinizing hormone (LH) was measured using a mouse Leydig cell bioassay. Following the infusion of hSHBG, a marked increase in serum SHBG was noted and the MCR-E 2 decreased. Associated with the increase in SHBG, the SHBG bound T levels decreased and LH increased. Following the infusion of antibody, serum SHBG decreased, and the MCR-E 2 also decreased. With the decrease in SHBG following the antibody infusion, non-SHBG bound T increased and serum LH fell. This study demonstrates that an increase in the serum SHBG levels is associated with a decrease in MCR-E 2, however, an acute decrease in serum SHBG also decreases the MCR-E 2. This later result demonstrates that factors in addition to serum SHBG binding may be important in determining the MCR-E 2.

Androgen levels in women using NORPLANT® implants

Plasma concentrations of sex hormone binding globulin (SHBG), testosterone, free testosterone, androstenedione (A4) and levonorgestrel were studied in 17 women before and during use of two levonorgestrel covered rods resulting in identical plasma concentrations of levonorgestrel as Norplant® implants. There was a highly significant decrease in SHBG during treatment. Total testosterone and A4 also decreased significantly. Free testosterone remained unchanged. Diurnal variations were found to occur for A4, total and free testosterone, but not for SHBG or levonorgestrel. Moreover, plasma concentrations of testosterone, free testosterone, levonorgestrel and SHBG were measured in a second group of 88 women participating in a clinical study on Norplant® implants, who at the one year follow-up visit either denied or claimed to have developed increased facial acne during treatment. There was no difference regarding SHBG, total testosterone, free testosterone or levonorgestrel between the groups of women with and without facial acne. However, the women in the group noticing increased acne during treatment, reported significantly more often to have had acne before treatment compared to the women who did not notice increased acne during treatment. It is concluded that treatment with Norplant® implants does not result in increasing plasma levels of androgens.

Pituitary function and DHEA-S in male acne and DHEA-S, prolactin and cortisol before and after oral contraceptive treatment in female acne

Pituitary function (TRH-LHRH stimulation test) was investigated in male acne patients and serum levels of dehydroepiandrosterone sulphate (DHEA-S), sex hormone binding globulin (SHBG) and other biochemical parameters were investigated in male acne patients and in female acne patients before and after treatment with an oral contraceptive. The TRH-LHRH stimulation test was performed with 15 male patients suffering from severe cystic acne and 7 healthy volunteers. Basal and stimulated prolactin, LH and FSH levels were statistically similar in the patients and control groups. However, the stimulated LH levels of the patients were 60% higher than those in controls. SHBG levels were significantly) higher in the patient group compared to those in the control group. Thirty-three female acne patients were randomly divided into two groups and treated for six months with an oral contraceptive containing 0.030 mg ethinylestradiol (EE) plus 0.150 mg levonorgestrel or 0.150 mg levonorgestrel. After six months´ treatment a 30% decrease in DHEA-S levels were observed in the desogestrel/EE group and a 15% decrease in the levonorgestrel/EE group; the difference was not statistically significant. At the same time serum total cortisol increased by 75-100% and free testosterone fell by 30-40% in both groups, whereas SHBG elevated 250% in the desogestrel/EE group and 30% in the levonorgestrel/EE group. Acne improved significantly in both groups, desogestrel/EE showing greater improvement. A decrease in SHBG and increase in DHEA-S levels appear to be the most common hormonal changes in acne. Oral contraceptive treatment induces an increase in SHBG and decrease in DHEA-S and also improves acne.

Decrease of circulating level of SHBG in postmenopausal obese women as a risk factor in breast cancer: Reversible effect of weight loss

Levels of circulating estrone (E 1), estradiol (E 2), androst-4-ene-3,17-dione (Adione), 3,5,3′-triiodothyronine (T 3), thyroxine (T 4), and sex hormone-binding globulin (SHBG) were measured in 10 obese postmenopausal patients with breast cancer and in 10 obese postmenopausal control subjects matched for age, body size, and menopausal status. T 3, T 4, and SHBG were also measured in 10 lean postmenopausal control subjects. In cancer patients after mastectomy, the cytosolic estrogen receptors (E 2R) in tumor specimens were determined. No significant differences between the two groups of obese postmenopausal women were found for levels of all determinations carried out in serum. Comparing obese subjects (with or without breast cancer) with lean controls, circulating levels of T 3 were found approximately 50% higher in the obese group. Conversely, SHBG was found around 50% of the value observed in lean controls. The changes presumably produced by obesity on serum SHBG levels appear to be reversible, tending toward normality with weight reduction. In cancer patients SHBG correlated negatively with cytosolic E 2R concentrations ( P < 0.01). In conclusion, it is considered that obesity implies a double risk for breast cancer in susceptible postmenopausal women, by inducing a decrease of SHBG and a concomitant increase of the supply of “free” E 2 to target tissues, in absence of cyclic endogenous progesterone.

Effect of gestrinone in endometriosis tissue and endometrium.

The effects of gestrinone (R 2323) on endometrial and endometriosis tissue concentrations of cytosol estrogen and progestin receptors and the activity of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) were investigated in 11 patients operated on because of suspected external endometriosis. Serum concentrations of luteinizing hormone, follicle-stimulating hormone, estradiol (E2), progesterone, testosterone (T), and sex-hormone-binding globulin (SHBG) were also investigated. After one control cycle, the patients received 2.5 mg of oral gestrinone twice weekly from the fifth day of the first treatment cycle until the eighth day of the second treatment cycle, the day of operation being day 10. Treatment with gestrinone decreased serum concentrations of T during the second treatment cycle and effected a major decrease in SHBG during both treatment cycles, resulting in highly increased free T and free E2 indices. The effects of gestrinone on the endometrium, a decrease in estrogen and progestin receptors, and induction of 17 beta-HSD are characteristic progestin actions. These parameters remained unchanged in endometriosis tissue. Our data indicate that gestrinone has effects that are typical of androgens and progestins in patients with endometriosis.

Changes in the SHBG concentration during danazol treatment.

Serum levels of sex hormone binding globulin (SHBG) were measured by radioelectro-immunoassay before and during administration of danazol in daily doses varying between 200 and 800 mg for a period of 1-6 months. The patients consisted of different groups of regularly menstruating women (n = 76) and of postmenopausal women (n = 12). A rapid proportional decrease in SHBG was seen at all dose levels in both pre- and postmenopausal women, starting within the first 24 hours and reaching statistical significance by 48 hours. The fractional rate of fall appeared to be determined by the metabolic half-life of the protein itself. Plotting log concentrations of SHBG versus time and using the slope of the linear regression for calculations, the half-life of SHBG appeared to be 15 +/- 5.7 (SD) days. After approximately one month of treatment, the SHBG concentrations began to approach a new steady state at a level of approximately 20-30% of the original concentration, depending on the dose of danazol. The proportional suppression of SHBG was significantly greater following 600 or 800 mg of danazol daily than following 200 or 400 mg. However, with all doses the SHBG levels after one month of treatment were well below the levels normally found in healthy males. The mean proportional reduction following a certain dose was almost identical in premenopausal and postmenopausal women. The findings of the present investigation suggest that danazol exerts a direct inhibitory effect on the hepatic synthesis of SHBG, which is dependent of the dose of danazol, independent of estrogen concentration, but possibly accentuated by endogenous androgens.

Administration of dehydroepiandrosterone enanthate to oophorectomized women - effects on sex hormones and lipid metabolism

Eight bilaterally oophorectomized women were given a depot injection of 200 mg DHEA-enanthate to study the effect on endocrine and lipid metabolism. A decrease in sex-hormone binding globulin (SHBG) and an increase in androstenedione was found 14 and 30 days after the injection. No changes could be detected in LH, FSH, oestrone, oestradiol or oestriol. Testosterone showed a tendency towards an increase. As compared to pre-treatment values, plasma lipids were unaltered after 30 days. A decrease in high density lipoproteins (HDL), cholesterol and in very low density lipoproteins (VLDL), free cholesterol, total cholesterol and phospholipids were seen in the lipid composition of the lipoproteins on day 30. These findings are in agreement with previous data reported after the administration of drugs with androgen-like effects. The relative fatty acid composition of plasma lecithin revealed only minor changes while the fatty acid composition of cholesterol esters indicated a decreased portion of essential fatty acids. These results suggest, in agreement with previous studies, an impaired endogenous cholesterol formation in the liver. The results from the analysis of the fatty acid composition of lecithin and cholesterol esters might indicate a decreased percentage of exogenous (dietary) cholesterol ester in plasma.