Influence of dexaminoglutethimide, an optical isomer of aminoglutethimide, on the disposition of estrone sulfate in postmenopausal breast cancer patients

Aminoglutethimide (AG) has been the most widely used aromatase inhibitor in breast cancer patients to date. Commercially, AG (Orimeten) is available as a racemate (DL-AG). Previous studies suggested the stereoisomers of AG (D-AG and L-AG) to differ considerably in their affinities and potencies to inhibit different cytochrome P-450-dependent enzymes, with D-AG being the potent aromatase inhibitor. DL-AG, apart from being an aromatase inhibitor, is known to enhance the metabolism of plasma estrone sulfate (E1S). In the present study we compared the effects of D-AG (500 mg daily) and DL-AG (1000 mg daily) on plasma estrogen levels and estrone (E1) and E1S clearance rates, determined after the injection of [14C]E1 and [3H]E1S, in a cross-over study involving 12 postmenopausal breast cancer patients. Treatment with DL-AG and D-AG suppressed plasma E1S to 18.6% and 15.0% of pretreatment levels, whereas E1 and estradiol E2 levels fell to 18.6% and 23.4% of their pretreatment levels during treatment with DL-AG and to 17.7% and 23.4% during treatment with D-AG, respectively. Thus, both treatment options suppressed all estrogens measured to a similar extent. The clearance rate of E1S increased from a mean pretreatment value of 5.9 to 14.0 and 10.0 L/h during treatment with DL-AG and D-AG, respectively (P < 0.05, comparing the two on-treatment situations), whereas the production rate of E1S decreased from a pretreatment value of 1.44 to 0.64 nmol/h with DL-AG and 0.36 nmol/h with D-AG (P < 0.05, comparing on-treatment values). These findings are consistent with the hypothesis that the D- as well as the L-form of AG may enhance the clearance rate of E1S. The finding of a higher estrogen production rate during treatment with DL-AG compared to D-AG probably reflects an increased plasma level of the estrogen precursor androstenedione (mean levels of androstenedione of 2.54 and 1.27 nmol/L during treatment with D-AG and DL-AG, respectively; P < 0.05).     

In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients

The effect of exemestane (6-methylenandrosta-1,4-diene-3,17-dione) 25 mg p.o. once daily on in vivo aromatization was studied in 10 postmenopausal women with advanced breast cancer. Aromatization was determined before treatment and after 6-8 weeks on therapy by administering a bolus injection of [3H]androstenedione (500 microCi) and [14C]estrone (5 microCi) followed by measurement of the isotope ratio of urinary estrogens after high-performance liquid chromatography purification. In addition, plasma endogenous estrogens were measured with highly sensitive radioimmunoassays after separation with high-performance liquid chromatography. Treatment with exemestane suppressed whole body aromatization from a mean pretreatment value of 2.059% to 0.042% (mean suppression of 97.9%). Plasma levels of estrone, estradiol, and estrone sulfate were found to be suppressed by 94.5%, 92.2%, and 93.2%, respectively. This is the first study revealing near total aromatase inhibition in vivo with the use of a steroidal aromatase inhibitor. The observation that exemestane is a highly potent aromatase inhibitor, together with the fact that the drug is administered p.o. and causes limited side effects, suggests that exemestane is a promising new drug for the treatment of hormone sensitive breast cancer.     

Th2 responses induce humorally mediated injury in experimental anti-glomerular basement membrane glomerulonephritis

Clinical and endocrinological effects of exemestane (6-methylenandrosta-1,4-diene-3,17-dione; PNU 155971) were evaluated in an open Phase I study. Thirteen postmenopausal women suffering from advanced breast cancer received exemestane in escalating doses over a 12-week period. Starting on 5 mg once daily (o.d.), exemestane was subsequently escalated at 2-week intervals to 10, 25, 50, 100, and 200 mg o.d. Each patient subsequently continued treatment on the highest tolerated dose until time of progression. One patient terminated treatment after 6 days due to diarrhea that was probably not related to drug therapy, although a relationship could not be excluded. Apart from this, no serious side effects were seen during the dose escalation period. Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E2) and estrone (E1) to a mean of 14.6 and 5.8% of pretreatment levels, respectively, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) to 8.9% of pretreatment levels. No fall in adrenal steroid levels was recorded. Exemestane (5 mg o.d.) suppressed urinary E2 and E1 to a mean of 11.9 and 12.2% of pretreatment levels, respectively. Administering exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E1, whereas urinary E2 fell to 6-7% of pretreatment levels. Median time to progression was 63 weeks. We conclude that exemestane is a well-tolerated aromatase inhibitor that effectively suppresses plasma and urinary estrogens in postmenopausal patients with breast cancer.     

Estrogen metabolism and excretion in Oriental and Caucasian women

BACKGROUND: Caucasian and Oriental women have different incidence rates of breast cancer. Among the underlying risk factors for the development of breast cancer in the women of these two groups may be their different diets and patterns of estrogen metabolism and excretion. The absolute levels and relative ratios of 16 alpha-hydroxylated estrogens and 2-hydroxylated estrogens (catechol estrogens) in the body may have a role in the etiology of breast cancer, but studies so far have provided only conflicting results. PURPOSE: Our goal was to study estrogen metabolism, in particular, the extent of 2-hydroxylation and 16 alpha-hydroxylation of estrogens in two groups of women, one Caucasian and one Oriental, with inherently different breast cancer risks. METHODS: Dietary records were analyzed over 3-day periods in the mid-follicular phase, twice, at 6-month intervals for 13 premenopausal Oriental women, recent immigrant arrivals in Hawaii with presumed low risk of breast cancer, and for 12 premenopausal Finnish women with presumed higher risk. The urinary estrogen profile was measured by gas chromatography-mass spectrometry and plasma and fecal estrogens were assayed by chromatographic radioimmunoassays. RESULTS: Mean fat intake per 1000 kcal was 73% higher (P < .001) in the Finnish women, but the mean fiber intake and fecal weights were similar to those of the Oriental women. Compared with Oriental women, Finnish women had 46% higher plasma estradiol (P < .01) and 124% higher plasma estrone sulfate (P < .01); however, after adjustment for differences in age and body mass index, only the difference in estrone sulfate remained statistically significant (P < .05). Mean plasma levels of estrone and estradiol correlated with height after adjustment for body mass index (P < .05). Mean plasma levels of estrone and sex hormone-binding globulin were similar. The Finns had higher mean urinary estrone (193%), estradiol (166%), various catechol estrogens (130%-439%), and total estrogen excretion (123%) (all P < .001), but similar 16 alpha-hydroxylated estrogen excretion. As calculated, 16 alpha-hydroxylation of estrone was significantly increased (P < .01) in the Oriental women, but 2-hydroxylation, 4-hydroxylation, and 16 beta-hydroxylation of estrone were similar in both groups. The ratio of catechol estrogen to 16 alpha-hydroxylated estrogen was four to five times higher (P < .001) in the Finnish women. The Oriental women had two to three times higher fecal excretion of estrogens than the Finnish women (P < .01). CONCLUSIONS: Our results indicate that high catechol estrogen formation may be a greater risk factor for breast cancer than high 16 alpha-hydroxylation of estrogens. However, the main risk factor for the Finnish women, as opposed to the Oriental women, may be their higher estrogen levels that result from a higher fat diet, higher estrogen production related to their greater height, and lower fecal estrogen excretion.     

Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients

This report concerns the evaluation of various estrogens, estrone (El), estradiol (E2), and estrone sulfate (E1S), as well as E1S-sulfatase and aromatase activities in pre- and postmenopausal women with breast cancer. The levels (in picomoles per g; mean +/- SEM) of the various estrogens in the breast tissue from premenopausal patients (n = 11) are: El, 1.4 +/- 0.5; E2, 1.2 +/- 0.6; and E1S, 1.2 +/- 0.3. In postmenopausal patients (n = 23), the values are, respectively, 1.0 +/- 0.4, 1.4 +/- 0.7, and 3.3 +/- 1.9. These concentrations of estrogens in the tumors of postmenopausal patients are significantly higher than those found in plasma. The activity of E1S-sulfatase in both pre- and postmenopausal patients was 50-200 times higher than that of aromatase. E1S-sulfatase and aromatase activities are significantly higher in post-menopausal than in cycling patients. It is concluded that despite the low levels of circulating estrogens in postmenopausal patients, the tissue concentrations of these steroids are several-fold higher than those in plasma, suggesting tumor accumulation of these estrogens. The physiopathology and clinical significance of these high levels of the various estrogens (E1, E2, and E1S) as well as sulfatase and aromatase activities in postmenopausal patients with breast cancer is yet to be explored.     

Inhibition of breast cancer tissue aromatase activity and estrogen concentrations by the third-generation aromatase inhibitor vorozole

In about one-third of advanced breast cancers, estrogen deprivation causes tumor regression. Estrogen concentrations in tumor tissue seem to depend largely on local production. The aromatase enzyme complex is thought to be the key enzyme in this respect. In the present study, the effect of the new third-generation nonsteroidal aromatase inhibitor vorozole (Rivizor) on tumor tissue aromatase activity and estrogen concentrations was evaluated. During 7 days preceding mastectomy, 11 postmenopausal breast cancer patients were treated with 2.5 mg of vorozole once daily. Eight patients could be evaluated. Intratumoral aromatase activity and estrone and estradiol levels were measured and compared to the values of nine untreated postmenopausal breast cancer patients. In treated patients, median tissue aromatase activity was 89% lower than that in controls (P < 0.001). Similarly, median tissue estrone and estradiol concentrations were 64 and 80% lower, respectively, in treated patients (P = 0.001 and P < 0.05, respectively). These results support the hypothesis that depleting the tumor of estrogens, thus impairing estrogenic stimulation, is an important mechanism in the antitumor activity of aromatase inhibitors.     

Chronotropic competence in endurance trained heart transplant recipients: heart rate is not a limiting factor for exercise capacity

Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.     

Migration and international health policies

Parity, age at first birth, age at menarche, and a family history of breast cancer have each been associated consistently with breast cancer risk. Whether this increase in risk is mediated, at least in part, through changes in endogenous hormone levels is unclear. We conducted a cross-sectional study of the relationships between these factors and plasma hormone levels in 216 healthy postmenopausal women in the Nurses' Health Study (United States). The hormones evaluated were estradiol, percent and total free estradiol, percent and total bioavailable estradiol, estrone, estrone sulfate, and prolactin. After controlling for age, body mass index (weight/height2), and alcohol use, we observed inverse associations between estrone sulfate and parity (r = -0.15, P = 0.03) and between percent bioavailable estradiol and age at first birth (r = -0.17, P = 0.02). Although women with a family history of breast cancer tended to have higher estrogen levels compared with women without such history, the differences were not statistically significant. Age at menarche was not related significantly to any of the hormones. These data provide some additional evidence that the inverse relationship observed between parity and breast cancer risk may be mediated, at least in part, through decreased estrogen levels. Our data do not support a substantial influence of either family history of breast cancer or age at menarche on postmenopausal estrogen or prolactin levels.     

Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women

BACKGROUND: A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study. METHODS: Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection. RESULTS: From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. CONCLUSION: Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.     

Thrombosis of mechanical heart valve prosthesis. Predisposing factors and results of surgical treatment

There is both epidemiologic and experimental support for the hypothesis that a high-fiber diet can reduce breast cancer risk; this may be due, at least in part, to a reduction in circulating estrogens. This study examined the effects of three levels of wheat bran supplementation (5, 10, and 20 g/d for 2 mo) on the major serum estrogens during both the luteal and follicular phases of the menstrual cycle. The 10- and 20-g supplements, which increased the total dietary fiber intakes to approximately 20 and 32 g/d, respectively, resulted in significant decreases in the luteal serum estrone (P < 0.05 and < 0.02, respectively). The serum estradiol was significantly reduced in the 10-g wheat bran group after 2 mo (P < 0.05); the 20-g supplemented group showed a significant decrease in estradiol at 1 mo (P < 0.02), but not at 2 mo. No changes occurred in the estrone sulfate concentrations. During the follicular phase, the 10-g wheat bran group exhibited a significant reduction in the serum estrone (P < 0.02). Only the serum estrone sulfate showed any reduction with the 20-g supplement, and this just failed to achieve significance (P = 0.07). Serum sex hormone-binding globulin levels were unaffected by wheat bran. When of long duration, these effects may be sufficient to favorably influence breast cancer risk in Western women.     

Polysaccharide vaccines. II. Meningococcal vaccines

A variety of indirect evidence suggests that mammary tumors can synthesize free estrogens in situ via the sulfatase enzyme. The present study utilized an isotopic kinetic technique to provide direct confirmation of local tumor synthesis. Animals bearing nitrosomethylurea (NMU)-induced rat mammary tumors were infused with 14C-estrone as well as 3H-estrone sulfate and plasma:tissue gradients for each steroid measured. Liver, serving as a control tissue, uniformly synthesized free estrone from estrone sulfate with local synthesis in this organ providing an average of 78 +/- 1.0% of the estrone in this tissue. In rat mammary tumors, five out of seven synthesized estrone locally with individual values ranging from 19 to 50% synthesized in tissue. These data indicate that liver uniformly converts estrone sulfate to free estrone, whereas the majority, but not all, breast tumors synthesize estrogen locally via this pathway.     

Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study

Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.     

Aromatase inhibitors--new possibilities in treatment of breast carcinoma

Aromatase inhibition is now an acknowledged second line treatment modality for advanced breast cancer in postmenopausal women. Aminoglutethimide is an inhibitor of adrenal steroid biosynthesis and blocks the conversion of cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens, which are a source of estrogens in both premenopausal and postmenopausal women. Aminoglutethimide has produced antitumor response rates of 35% in unselected patients, most of whom have undergone prior therapy with either chemotherapy or hormonal manipulation. As is true of other hormonal responses, high response rates of up to 70% are observed in patients who are ER and/or PR positive. The reason why these drugs are currently used after tamoxifen is mainly due to the side effects of aminoglutethimide, which impairs the mineralocorticoid and glucocorticoid synthesis. New, less toxic compounds appear, which block the conversion of androstenedione to estrone and efficiently suppress plasma estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase inhibitors are now being compared to tamoxifen as first-line endocrine treatment in relapsing patients. If these trials confirm a similar or better response rate to new aromatase inhibitors compared to tamoxifen, the time will come to study them as the first line adjuvant treatment in non-metastatic disease.     

In vivo studies on the metabolism of estrogens by muscle and adipose tissue of normal males

3H and 14C-Labeled estrone, estradiol, and estrone sulfate were infused at constant rates into brachial arm veins of normal men. In any one experiment, subjects generally received two estrogens, one 3H-labeled and one 14C-labeled. During the infusions, blood samples were obtained from the brachial artery, a deep vein draining primarily muscle and a superficial vein draining primarily adipose tissue of the arm contralateral to the infusion. In 11 men the mean +/- SE value for the metabolism of estrone by muscle, rho1,0A,M(rho1,0A,M = fraction of estrone in arterial blood which is metabolized by muscle) is 0.17 +/- 0.02 which is not (P greater than 0.1) significantly different from the mean +/- SE value for the metabolism of estrone by adipose tissue, rho1,0A,AT, 0.22 +/- 0.02. Both tissues convert estrone to estradiol, rho1,2A,M(rho1,2A,M = fraction of estrone in arterial blood which is measured as estradiol in venous blood draining muscle) is 0.026 +/- 0.005 and rho1,2A,AT is 0.022 +/- 0.005. Both tissues metabolized estradiol, rho2,0A,M = 0.09 +/- 0.01 and rho2,0A,AT = 0.12 +/- 0.03, and for each tissue the metabolism of estradiol was significantly less than that of estrone (P less than 0.01). Estradiol was converted to estrone by both tissues; rho2,1A,M = 0.007 +/- 0.003 and rho 2,1A,AT = 0.017 +/- 0.003. For estrone sulfate, tissue metabolism could be demonstrated in only 2 of 5 infusions; the values being 0.04 and 0.03, and 0.04 and 0.03 in muscle and adipose tissue, respectively. In only 1 of 3 infusions was evidence obtained for the conversion, by muscle, of estrone sulfate to estrone, rhoS,1A,M = 0.003 and only in one of the 5 subjects was adipose tissue active in this conversion. In no instance were we able to show conversion of estrone sulfate to estradiol by either tissue. In only 1 of 3 infusions could we measure demonstrable conversion of estrone to estrone sulfate by adipose tissue, rho1,SA,AT = 0.02, and we could not demonstrate conversion of estrone to estrone sulfate by muscle or of estradiol to estrone sulfate by either tissue. Both muscle and adipose tissue metabolize and interconvert the free estrogens, estrone and estradiol. The total metabolism by both tissues accounts for 5-10% of the overall metabolic clearance rate of each steroid. The formation of estrone sulfate from estrone and estradiol and the hydrolysis of estrone sulfate occurs to only a minor extent in these tissues.     

The effect of clotrimazole on the pathogen of toxoplasmosis, Toxoplasma gondii

A previous study showed activity of megestrol acetate in advanced breast cancer; as a result the study was expanded. Of 101 patients treated with this compound, 26 (26%) met our criteria of improvement. The drug was well tolerated and produced no toxicity and, as opposed to androgens and estrogens, no endocrine effects were observed. Prior hormonal or cytotoxic compounds, including alkylating agents, did not appear to reduce the subsequent responsiveness to this potent progestational compound. We now include it, often as the initial hormonal trial in postmenopausal patients, in our sequential treatment of disseminated breast cancer because of its favorable therapeutic ratio.     

Role of 17 beta-hydroxysteroid dehydrogenase type 1 in endocrine and intracrine estradiol biosynthesis

Enzymes with 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity catalyse reactions between the low-active female sex steroid, estrone, and the more potent estradiol, for example. 17 beta-HSD activity is essential for glandular (endocrine) sex hormone biosynthesis, but it is also present in several extra-gonadal tissues. Hence, 17 beta-HSD enzymes also take part in local (intracrine) estradiol production in the target tissues of estrogen action. Four distinct 17 beta-HSD isozymes have been characterized so far, and the data strongly suggests that different 17 beta-HSD isozymes have distinct roles in endocrine and intracrine metabolism of sex steroids. Current data suggest that 17 beta-HSD type 1 is the principal isoenzyme involved in glandular estradiol production both in humans and rodents. During ovarian follicular development and luteinization, rat 17 beta-HSD type 1 is regulated by gonadotropins, and the effects of gonadotropins are modulated by steroid hormones and paracrine growth factors. Human 17 beta-HSD type 1 favors the reduction reaction, thereby converting estrone to estradiol both in vitro and in cultured cells. Hence, the enzymatic properties of the enzyme are also in line with its suggested role in estradiol biosynthesis. Interestingly, 17 beta-HSD type 1 is also expressed in certain target tissues of estrogen action such as normal and malignant human breast and endometrium. Hence, 17 beta-HSD type 1 could be one of the factors leading to a relatively high tissue/plasma ratio of estradiol in breast cancer tissues of postmenopausal women. We conclude that 17 beta-HSD type 1 has a central role in regulating the circulating estradiol concentration as well as its local production in estrogen target cells.     

Effects of treatment with megestrol acetate, aminoglutethimide, or formestane on insulin-like growth factor (IGF) I and II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status in patients with advanced breast cancer

The effects of treatment with the aromatase inhibitors aminoglutethimide (AG) and formestane or the synthetic progestin megestrol acetate (MA) on plasma levels of insulin-like growth factor I (IGF-1), IGF-II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status were investigated in 39 patients suffering from advanced breast cancer. Treatment with AG and MA elevated plasma levels of IGF-I by mean values of 27% (n = 15; P < 0.025) and 81% (n = 7; P < 0.025), respectively, whereas treatment with formestane had no effect (n = 13). Treatment with AG increased plasma levels of IGFBP-2, as evaluated by Western blotting (P < 0.01). MA caused a significant reduction in IGFBP-3 protease activity (mean reduction, 69%; P < 0.05). These alterations in plasma IGF-I and IGFBP-3 protease activity were reversed 4 weeks after terminating MA therapy (n = 8; P < 0.025). Taken together, 13 of 15 patients had reduced IGFBP-3 protease activity during treatment with MA compared to the control situation (P < 0.0025). Total levels of IGFBP-3 as measured by RIA were moderately elevated by treatment with MA (mean increase, 19%; P < 0.05), and Western immunoblotting revealed an increase in the amount of intact IGFBP-3 and reduced amounts of IGFBP-3 in the modified form. None of the treatment modalities had any influence on plasma levels of IGF-II. The increase in the plasma IGF-I concentration seen during treatment with MA may be secondary to an increased level of intact IGFBP-3. This could reflect an alteration in IGF availability that contributes to the antitumor effect of MA.     

An increase in fetal plasma cortisol but not dehydroepiandrosterone sulfate is followed by the onset of preterm labor in patients with preterm premature rupture of the membranes

OBJECTIVE: The role of steroid hormones in the control of human parturition has been a subject of debate. Activation of the fetal hypothalamic-pituitary-adrenal axis leading to an increase in plasma cortisol is followed by the onset of parturition in sheep. In contrast, androgens, specifically, dehydroepiandrosterone sulfate, have been implicated in the control of parturition in nonhuman primates. The purpose of this study was to determine the relationship between human fetal plasma cortisol and dehydroepiandrosterone sulfate and the onset of preterm labor in patients with preterm premature rupture of the membranes. STUDY DESIGN: Fetal blood sampling was performed in 51 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for aerobic and anaerobic bacteria and mycoplasmas. Corticosteroids had not been administered before fetal blood sampling. Cortisol and dehydroepiandrosterone sulfate were measured with sensitive and specific immunoassays. Analysis was conducted with nonparametric statistics and survival analysis. RESULTS: (1) Patients who went into spontaneous labor and delivered within 7 days of cordocentesis had a significantly higher median level of fetal plasma cortisol but not of dehydroepiandrosterone sulfate than those delivered after 7 days (for fetal plasma cortisol: median 8.35 [4.7 to 12.4] micrograms/dL vs median 4.75 [3.0 to 10.4] micrograms/dL, P <.0001; for fetal plasma dehydroepiandrosterone sulfate: median 154.4 [8.6 to 333.8] micrograms/dL vs median 194.6 [96.7 to 402.5] micrograms/dL, P =.09). (2) The cordocentesis-to-delivery interval was significantly shorter in patients with a fetal plasma cortisol value of >/=7 micrograms/dL (derived by receiver-operating characteristic curve analysis) than in those with fetal cortisol <7 micrograms/dL (median 49 [4 to 1849] hours vs median 325 [11 to 2590] hours, P <.001). (3) Fetal plasma cortisol, but not maternal cortisol, was an independent predictor of the duration of pregnancy after we adjusted for gestational age and the results of amniotic fluid culture (hazards ratio 2.9, P <.05). (4) There was a significant correlation between fetal plasma cortisol and fetal plasma interleukin-6 (r = 0.3, P <.05). (5) A strong relationship was found between the fetal plasma cortisol/dehydroepiandrosterone sulfate ratio and the interval to delivery (P <.005). CONCLUSION: An elevation in fetal plasma cortisol but not dehydroepiandrosterone sulfate was followed by the onset of spontaneous preterm labor in patients with preterm premature rupture of the membranes.     

The effects of a low-fat dietary intervention and tamoxifen adjuvant therapy on the serum estrogen and sex hormone-binding globulin concentrations of postmenopausal breast cancer patients

The purpose of the study was to determine the effect of a low-fat dietary intervention, with or without concomitant tamoxifen adjuvant therapy, on serum estrogen and sex hormone-binding globulin (SHBG) levels in postmenopausal patients with resected breast cancer. Ninety-three patients were randomized to either reduce their fat intake to 15-20% of total calories, or to a dietary control group. Serum estradiol, estrone, estrone sulfate, and SHBG concentrations were assayed at baseline, and at 6, 12, and 18 months thereafter. In 19% of patients, the preintervention serum estradiol levels were below the sensitivity of the assay (5 pg/ml). Tamoxifen had no significant effect on serum estrogen levels, but produced an elevation in SHBG. Patients with reliably quantifiable preintervention estradiol concentrations (> or = 10 pg/ml) showed a significant reduction in serum estradiol after 6 months on the low-fat diet (average, 20%; p < 0.005); this was sustained over the 18 month study period. Serum SHBG levels were increased by tamoxifen therapy, but were reduced significantly (p = 0.01) after 12 months on the low-fat diet in patients not receiving tamoxifen. No changes in serum estrone or estrone sulfate resulted from the dietary intervention. While the low-fat diet produced significant weight loss, patients treated with tamoxifen without dietary intervention showed a gain in body weight. These weight changes produced disruptions in the normal positive correlation between body weight and serum estrone sulfate, and the negative correlation with SHBG concentration.     

Massive extranglandular aromatization of plasma androstenedione resulting in feminization of a prepubertal boy

This report describes the mechanism of origin and the quantity of estrogen produced in a prepubertal boy who developed severe feminization at 8 yr of age as the result of a heretofore undescribed metabolic abnormality. The clinical findings were gynecomastia and accelerated linear growth and bone maturation. At the time feminization developed, there were no signs of growth or development of the otherwise normal prepubertal male external genitalia or any increase of muscle mass that normally accompanies male puberty. The hyperestrogenism was found to be the consequence of massive extraglandular conversion of plasma androstenedione to estrone. During a 6-mo period of study, the plasma production rate of androstenedione ranged from 1.2 to 1.6 mg/day. More than 55% of plasma androstenedione was metabolized by aromatization to estrone which, in turn, was extensively sulfurylated in the tissue sites of aromatization before its entry into the blood. Thus, estrone sulfate was the final product in the aromatizing sites, and the plasma production rate of estrone sulfate derived from plasma androstenedione was 782 mug/24 h. The extent of extraglandular conversion of plasma androstenedione to estrone measured in this boy was 50 times that observed in two normal prepubertal boys. Moreover, 94% of the extraglandular aromatization occurred in extrahepatic sites. The metabolic clearance rate of plasma androstenedione, 2,380 liters/day per m(2), was markedly increased in this boy. Approximately 1,500 liters of plasma androstenedione clearance was accounted for by extrahepatic, extraglandular aromatization. The fractional conversion of testosterone to estradiol, 0.16, was 50 times greater in this boy than that observed in normal young adult men. The total extent of aromatization of plasma prehormones was even greater in this boy inasmuch as evidence was obtained that aromatization of 16-hydroxysteroids, e.g. 16alpha-hydroxy androstenedione and 16alpha-hydroxy dehydroisoandrosterone (sulfate), resulted in estriol formation independent of estrone formation. Thus, extensive extrahepatic, extraglandular aromatization resulted in advanced feminization in this prepubertal boy by a previously undescribed metabolic abnormality.