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PubMed1995

An alternate pathway to androstenedione synthesis by human adrenals: evidence of a balance in 11 beta-hydroxylase and 17,20-lyase activities leading to androstenedione.

Until now, dehydroepiandrosterone and 17-hydroxyprogesterone were thought to be the main precursors for the synthesis of androstenedione by the human adrenal cortex. However, secretion of androstenedione and 11-deoxycortisol are increased when 11 beta-hydroxylase activity is impaired, e.g. by metyrapone test or by congenital adrenal hyperplasia resulting from 11 beta-hydroxylase deficiency. The present study with human adrenals shows that 11-deoxycortisol, the precursor of cortisol synthesis, is also a precursor of androstenedione in humans. Our data show that androstenedione synthesis is inversely related to the synthesis of cortisol and cortisone. This new pathway is thus triggered by a lower activity of 11 beta-hydroxylase that is responsible for the last step of cortisol. Indeed, when the activity of this enzyme is impaired, 11-deoxycortisol follows the pathway that leads to androstenedione synthesis in the adrenals. These data, together with the increase in ACTH secretion, may explain the increased androstenedione plasma levels observed in patients with congenital adrenal hyperplasia caused by 11 beta-hydroxylase deficiency and in patients given inhibitors of 11 beta-hydroxylase for therapeutic purposes.

Adenoma↗
PubMed1978

The relation between plasma androstenedione, plasma oestrone and androstenedione to oestrone conversion rates in post-menopausal women with and without fractures.

1. Plasma androstenedione, plasma oestrone and the conversion of plasma androstenedione into oestrone were measured in 19 post-menopausal women without fractures (six of them oophorectomized) and 18 with vertebral or femoral neck fractures (four of them oophorectomized). 2. In the series as a whole, the main determinant of the plasma oestrone level was the plasma androstenedione concentration. Only in the small oophorectomized group did the variation in conversion rate make a significant contribution to the variation in plasma oestrone. 3. The conversion rates were not different as between non-fracture and fracture cases but the mean plasma androstenedione and oestrone concentrations were lower (though not significantly) in the latter.

Adrenal Glands↗
PubMed1982

Androstenedione, dehydroepiandrosterone and testosterone in ovarian vein plasma and androstenedione in peripheral arterial plasma during the bovine oestrous cycle.

Catheters were placed in the carotid artery via a facial artery (n = 12) and in the ovarian vein (n = 12), and, in conjunction, electromagnetic flow meters were placed around the ovarian artery (n = 6) in cyclic beef cows. Androstenedione was quantitatively the highest and dehydroepiandrosterone the lowest of the ovarian androgens measured. Ovarian androgens were correlated positively with each other (P less than 0.05) but not with ovarian blood flow or day of the cycle. There was a trend for spikes of androgen release (ovarian vein concentration x ovarian blood flow) from the ovary to be greatest during the period of decreasing progesterone and CL regression. However, only with testosterone were spikes of release different (Days--13 to--9 less than Days -8 to -4; P less than 0.05; Day 0 = oestrus). The dynamic changes in ovarian androgens noted in this study were compatible with the concept of continuous follicular development and atresia throughout the oestrous cycle.

Androstenedione↗
PubMedDate not supplied

Trace contamination of over-the-counter androstenedione and positive urine test results for a nandrolone metabolite.

CONTEXT: Several anabolic steroids are sold over-the-counter (OTC) in the United States, and their production is not regulated by the US Food and Drug Administration. Reports have suggested that use of these supplements can cause positive urine test results for metabolites of the prohibited steroid nandrolone. OBJECTIVES: To assess the content and purity of OTC androstenedione and to determine if androstenedione and 19-norandrostenedione administration causes positive urine test results for 19-norandrosterone, a nandrolone metabolite. DESIGN: Randomized controlled trial of androstenedione, open-label trial of 19-norandrostenedione, and mass spectrometry of androstenedione preparations, conducted between October 1998 and April 2000. SETTING: Outpatient facility of a university hospital. PARTICIPANTS: A total of 41 healthy men aged 20 to 44 years. INTERVENTION: Participants were randomly assigned to receive oral androstenedione, 100 mg/d (n = 13) or 300 mg/d (n = 11) for 7 days, or no androstenedione (n = 13); in addition, 4 patients received 10 microg of 19-norandrostenedione. MAIN OUTCOME MEASURES: Content of OTC androstenedione preparations; level of 19-norandrosterone in urine samples, determined by mass spectrometry, compared among the 3 randomized groups at day 1 and day 7, and among the participants who received 19-norandrostenedione from October 1998 to April 2000. RESULTS: All urine samples from participants treated with androstenedione contained 19-norandrosterone, while no samples from the no-androstenedione group did. Urinary concentrations were averaged for day 1 vs day 7 measurements; mean (SD) 19-norandrosterone concentrations in the 100-mg/d and 300-mg/d groups were 3.8 (2.5) ng/mL and 10.2 (6.9) ng/mL, respectively (P =. 006). The 19-norandrosterone content exceeded the cutoff for reporting positive cases (>2.0 ng/mL) in 20 of 24. The androstenedione preparation used was pure at a sensitivity of 0.1%, but at 0.001% 19-norandrostenedione was found. For the 4 participants to whom 10 microg of 19-norandrostenedione was administered, 19-norandrosterone was found in all urine samples. Of 7 brands of androstenedione analyzed at the 1% level, 1 contained no androstenedione, 1 contained 10 mg of testosterone, and 4 more contained 90% or less of the amount stated on the label. CONCLUSION: Our study suggests that trace contamination of androstenedione with 19-norandrostenedione is sufficient to cause urine test results positive for 19-norandrosterone, the standard marker for nandrolone use. Oral steroid doses as small as 10 microg are absorbed and excreted in urine. Some brands of androstenedione are grossly mislabeled. Careful analysis of androstenedione preparations is recommended in all studies of its biological effects. JAMA. 2000;284:2618-2621.

Adult↗
PubMed1992

Utilization of maternal and fetal androstenedione for placental estrogen production at mid and late baboon pregnancy.

The present study determined the placental and whole-body metabolism of androstenedione originating in the maternal and fetal compartments of the pregnant baboon at mid (day 100; n = 4) and late (day 165; n = 3) gestation (term = day 184) in untreated animals and at midgestation in animals (n = 3) treated with pellets (50 mg) of androstenedione inserted at 8-day intervals in the mother between days 70 and 100 of gestation. Baboons were anesthetized with ketamine-halothane-nitrous oxide, blood samples obtained from maternal, uterine, fetal and umbilical vessels during constant infusion of [3H] or [14C]androstenedione via the fetal or maternal circulation, respectively, and radiolabeled precursor/products in plasma purified by HPLC. The metabolic clearance rate (MCR; 1/day/kg body wt) of androstenedione in the mother was similar at mid (81 +/- 6) and late (69 +/- 12) gestation and was unaltered by treatment with androstenedione (92 +/- 17). Fetal MCR of androstenedione was 3-fold greater (P less than 0.05) than in the mother and was similar in the three treatment groups. In the maternal compartment, the conversion ratio of androstenedione to estradiol (range 26-37%) exceeded (P less than 0.05) that to testosterone (range 15-19%) which exceeded (P less than 0.05) that to estrone (range 7-14%), a pattern unaffected by stage of gestation or treatment with androstenedione in vivo. Similar results were observed in the fetal compartment although values for each conversion were always 3-4-fold lower (P less than 0.05) than in the maternal compartment. Regardless of stage of gestation or treatment with androstenedione, [14C]estradiol in the uterine vein (95 +/- 15 cpm/ml) exceeded (P less than 0.05) that in the umbilical vein (3 +/- 1) indicative of preferential secretion of estradiol to the maternal compartment. In contrast, the concentration of [14C]estrone in uterine (15 +/- 4) and umbilical (18 +/- 4) vessels were similar indicating that estrone was secreted equally into the mother and fetus. Similar observations were noted for respective values for [3H]estrogens derive from fetal [3H]androstenedione. Placental extraction of fetal androstenedione (range 86-93%) exceeded (P less than 0.05) that for androstenedione originating in the mother (range 44-54%) and neither were affected by stage of gestation or treatment with androstenedione in vivo. Less than 1% of fetal [3H]androstenedione reached the maternal circulation unaltered, presumably due to placental catabolism. Similarly, the concentration of maternally-derived [14C]androstenedione present in fetal plasma (less than 5%) was minimal.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstenedione↗
PubMed1991

Androgen metabolism by porcine granulosa cells during the process of luteinization in vitro: identification of 19-oic-androstenedione as a major metabolite and possible precursor for the formation of C18 neutral steroids.

The present studies were conducted to define the pathway(s) by which androstenedione is metabolized in porcine granulosa cells (pGC) and determine whether metabolism of this steroid is affected by in vitro luteinization. pGC isolated from large preovulatory follicles were cultured for up to 2 days in the presence of 5 microM unlabeled or [4-14C]-labeled androstenedione. Metabolism of androstenedione was assessed by HPLC, using in-line liquid scintillation detection. Metabolite identification was confirmed by gas chromatography-mass spectrometry of HPLC fractions isolated from medium conditioned by granulosa cells (pGCCM) cultured for 48 h in the presence of unlabeled androstenedione. The metabolites identified were 19-oic-androstenedione (3,17-dioxo-4-androsten-19-oic acid), 19-hydroxytestosterone, 19-hydroxyandrostenedione, 19-nor-testosterone, an estrenolone of as yet unproven stereoisomerism, 5(10)-estrene-3 beta, 17 beta-diol, 17 beta-estradiol, testosterone, and 19-nor-androstenedione. Results indicate that 19-nor-androstenedione is artifactually derived from 19-oic-androstenedione as a result of degradation in storage and during isolation. After metabolite identification, studies of the time course of androstenedione metabolism by pGC during in vitro luteinization were conducted. 17 beta-Estradiol and 19-oic-androstenedione were the predominant metabolites, and accumulation of these steroids was virtually identical. Production of these metabolites was maximal during the first 12 h of culture. The accumulation of 5(10)-estrene-3 beta,17 beta-diol and 19-nor-testosterone was maximal at 48 h of culture, with 5(10)-estrene-3 beta,17 beta-diol consistently accumulating in greater concentrations than 19-nor-testosterone. Aromatase activity of pGC was negligible from 36-48 h of culture, as demonstrated by minimal accumulation of 17 beta-estradiol during this period of culture. The accumulation of 19-oic-androstenedione, 5(10)-estrene-3 beta,17 beta-diol, and 19-nor-testosterone was also negligible during this latter time period, suggesting that their formation is associated with aromatase. From these results, pGC from preovulatory follicles undergoing luteinization in vitro lose the ability to convert androstenedione to estrogens. The formation of 19-oic-androstenedione, shown here for the first time, parallels the formation of 17 beta-estradiol, and this acidic steroid is proposed to be a product of aromatase. As reported in previous studies, pGC do produce C18 neutral steroids from exogenous androstenedione. The production of these steroids requires an active aromatase to produce their immediate precursor, which is here hypothesized to be 19-oic-androstenedione. However, their maximal production does not commence until aromatase activity has declined, and it is hypothesized that their production depends on modifications in steroid metabolism associated with luteinization.

Androgens↗
PubMed1999

Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men: a randomized controlled trial.

CONTEXT: Androstenedione, a precursor to testosterone, is marketed to increase blood testosterone concentrations as a natural alternative to anabolic steroid use. However, whether androstenedione actually increases blood testosterone levels or produces anabolic androgenic effects is not known. OBJECTIVES: To determine if short- and long-term oral androstenedione supplementation in men increases serum testosterone levels and skeletal muscle fiber size and strength and to examine its effect on blood lipids and markers of liver function. DESIGN AND SETTING: Eight-week randomized controlled trial conducted between February and June 1998. PARTICIPANTS: Thirty healthy, normotestosterogenic men (aged 19-29 years) not taking any nutritional supplements or androgenic-anabolic steroids or engaged in resistance training. INTERVENTIONS: Twenty subjects performed 8 weeks of whole-body resistance training. During weeks 1, 2, 4, 5, 7, and 8, the men were randomized to either androstenedione, 300 mg/d (n = 10), or placebo (n = 10). The effect of a single 100-mg androstenedione dose on serum testosterone and estrogen concentrations was determined in 10 men. MAIN OUTCOME MEASURES: Changes in serum testosterone and estrogen concentrations, muscle strength, muscle fiber cross-sectional area, body composition, blood lipids, and liver transaminase activities based on assessments before and after short- and long-term androstenedione administration. RESULTS: Serum free and total testosterone concentrations were not affected by short- or long-term androstenedione administration. Serum estradiol concentration (mean [SEM]) was higher (P<.05) in the androstenedione group after 2 (310 [20] pmol/L), 5 (300 [30] pmol/L), and 8 (280 [20] pmol/L) weeks compared with presupplementation values (220 [20] pmol/L). The serum estrone concentration was significantly higher (P<.05) after 2 (153 [12] pmol/L) and 5 (142 [15] pmol/L) weeks of androstenedione supplementation compared with baseline (106 [11] pmol/L). Knee extension strength increased significantly (P<.05) and similarly in the placebo (770 [55] N vs 1095 [52] N) and androstenedione (717 [46] N vs 1024 [57] N) groups. The increase of the mean cross-sectional area of type 2 muscle fibers was also similar in androstenedione (4703 [471] vs 5307 [604] mm2; P<.05) and placebo (5271 [485] vs 5728 [451] mm2; P<.05) groups. The significant (P<.05) increases in lean body mass and decreases in fat mass were also not different in the androstenedione and placebo groups. In the androstenedione group, the serum high-density lipoprotein cholesterol concentration was reduced after 2 weeks (1.09 [0.08] mmol/L [42 (3) mg/dL] vs 0.96 [0.08] mmol/L [37 (3) mg/dL]; P<.05) and remained low after 5 and 8 weeks of training and supplementation. CONCLUSIONS: Androstenedione supplementation does not increase serum testosterone concentrations or enhance skeletal muscle adaptations to resistance training in normotestosterogenic young men and may result in adverse health consequences.

Administration, Oral↗
PubMed1976

Cytochrome P-450 and the aromatization of 16alpha-hydroxytestosterone and androstenedione by human placental microsomes.

When measured in vitro using human placental microsomal preparations, the aromatization of 16alpha-hydroxytestosterone to estriol and androstenedione to estrone and estradiol proceeds at almost identical initial rates. Important differences between 16alpha-hydroxytestosterone and adrostenedione aromatization are evident, however. While substantial findings have implicated cytochrome P-450 in placental aromatization, the aromatizaiton of androstenedione is insensitive to CO although it is competitively inhibited by metyrapone. 16alpha-Hydroxytestosterone aromatization, in contrast, is inhibited 50-60% by CO and is strongly inhibited by metyrapone. 16alpha-hydroxytestosterone aromatization is strongly inhibited in a competitive manner by androstenedione, while 16alpha-hydroxytestosterone has essentially no effect on androstenedione aromatization, althogh at very high 16alpha-hydroxytestosterone concentrations (65 muM) and subsaturating androstenedione concentrations, 16alpha-hydroxytestosterone appears to noncomptitively inhibit androstenedione aromatization. The apparent Km for the aromatization of androstenedione is 95 nM and for 16alpha-hydroxytestosterone, 7 muM. Both androstenedione and 16alpha-hydroxytestosterone cause type I spectral perturbations associated with binding to cytochrome P-450 when added to placental microsomes; however, the deltaA390-420 is twice as great in response to saturating amounts of androstenedione than in response to 16alpha-hydroxytestosterone. If androstenedione is added to 16alpha-hydroxytestosterone, the same spectral change as that caused by androstenedione alone is expressed. The apparent spectral dissociation constant for androstenedione is 93 nM while for 16alpha-hydroxytestosterone it is 11muM; both essentially the same as the comparable apparent Kms for aromatization. The evidence suggests the presence of two aromatase P-450's in human placenta.

Androstenedione↗
PubMed1980

Enhanced conversion of androstenedione to estrogens in obese males.

In normal and obese young males [90--120% and > 160% of ideal body weight (IBW); IBW = 100%], plasma concentrations of testosterone, androstenedione, estrone, and estradiol were measured. Metabolic clearance and production rates of androstenedione and the conversion ratios of androstenedione to testosterone, estrone, and estradiol were determined using the constant infusion technique. In the obese subjects, IBW was inversely correlated (P < 0.001) with plasma concentrations of androstenedione (r = 0.81) and testosterone (r = 0.87), while the levels of estrone (r = 0.92) and estradiol (r = 0.95) increased with IBW (P < 0.001). Thus, when normal and obese subjects were compared as groups, plasma androstenedione decreased form 1.24 +/- 0.13 to 0.93 +/- 0.15 ng/ml (mean +/- SD) and plasma testosterone decreased from 5.89 +/- 0.82 to 3.29 +/- 0.92 ng/ml (P < 0.001), while estrone increased from 28.2 +/- 3.4 to 60.0 +/- 9.4 pg/ml, and estradiol increased from 21.7 +/- 3.5 to 43.9 +/- 5.3 pg/ml. The testosterone to androstenedione and the estradiol to estrone ratios were not different in obesity, but changes in IBW were positively correlated (P < 0.001) with differences in the estrone to androstenedione (r = 0.93) and estradiol to testosterone ratios (r = 0.93), indicating that fat tissue may aromatize androgens, whereas reduction of 17-oxo-steroid appears to be of minor importance. As the MCR of androstenedione increased with IBW (from 2156 to 2636 liters/day P < 0.05) while plasma levels decreased, the apparent production rate of androstenedione was not influenced by the degree of obesity. The conversion of androstenedione to estrone (r = 0.89) and of androstenedione to estradiol (r = 0.82) was enhanced in obese subjects (P < 0.001). We suggest that enhanced aromatization of androstenedione due to an increased adipose tissue mass may account for the high plasma estrogen levels observed in obese men.

Adult↗
PubMed1993

The concomitant release of androstenedione with cortisol and luteinizing hormone pulsatile releases distinguishes adrenal from ovarian hyperandrogenism.

Androstenedione secretory characteristics and its possible temporal correlation with luteinizing hormone (LH) and/or cortisol, intended as the markers of, respectively, ovarian stimulation and adrenal secretion, were evaluated in 24 patients affected by clinical hyperandrogenism. A pulsatility test was carried out for 8 h, with sampling every 10 min, and LH, cortisol and androstenedione profiles were determined by radioimmunoassay. Time series were analyzed with the computer program DETECT and with a program for specific concordance estimation. A distinct episodic release of LH, cortisol and androstenedione was observed in all patients (6.9 +/- 0.8, 5.2 +/- 0.6 and 5.5 +/- 1 peaks/8 h, respectively). When specific concordance was tested between LH and androstenedione, and between cortisol and androstenedione, two distinct groups of patients could be identified. Group A (n = 13) showed a significant specific concordance (SC) index only for LH and androstenedione while group B (n = 11) showed a significant SC also for cortisol and androstenedione, thus demonstrating a consistent adrenal participation in the androstenedione secretion in these patients. In addition, specific differences were observed on androstenedione secretory profiles of group B which showed a significant (p < 0.05) decrease of androstenedione plasma concentrations emulating cortisol behavior. No such observation was noted in group A, whose androstenedione plasma levels did not show any reduction. In conclusion, our data support the use of circulating androstenedione, LH and cortisol plasma levels and copulsatile assessment to distinguish the presence of two populations of hyperandrogenic patients: one whose hyperandrostenedionemia is mainly due to ovarian secretion (group A) and one which showed a hyperactivation of the adrenal gland (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1967

Splanchnic extraction and interconversion of testosterone and androstenedione in man.

A constant infusion of (3)H-testosterone and (14)C-androstenedione was administered to four human subjects, two males and two females, until the concentrations of radioactive testosterone and androstenedione in systemic plasma became constant. At that time the concentrations of radioactive testosterone and androstenedione in hepatic vein plasma were determined. Splanchnic extraction of testosterone and androstenedione and the contribution of the splanchnic system to the blood interconversion of testosterone and androstenedione were calculated. Androstenedione is extracted by the splanchnic system more efficiently than testosterone since 82.3% of androstenedione and 44% of testosterone were removed from the plasma after one passage. The fraction of testosterone entering the splanchnic system that is transferred to blood androstenedione was 0.011 and the maximum possible transfer due to recirculation was 0.026. This was 28% of the total blood transfer from testosterone to androstenedione. The fraction of androstenedione entering the splanchnic system that is transferred to blood testosterone after one passage was 0.005, whereas the maximum possible transfer in this system was 0.006. This represented only 16% of the total transfer from androstenedione to testosterone. Therefore, a large fraction of the interconversion of testosterone and androstenedione in vivo occurs outside the splanchnic system.

Adolescent↗
PubMed2004

Effects of androstenedione on in utero development in rats.

This study was conducted to characterize the effect of androstenedione on estrous cyclicity, mating behavior and fetal development. Thirty-day old rats received corn oil alone or androstenedione (in corn oil) at one of four concentrations (0, 1.0, 5.0, 10.0 or 30.0 mg/kg body weight) by gavage for two weeks prior to mating, during the mating period and throughout gestation. Dose related increases in serum androstenedione, estradiol and estrone were observed in all androstenedione treated animals at gestation day 20. A statistically significant increase in serum testosterone concentration was observed in the 30 mg/kg dose group. Feed and fluid consumption were not affected by androstenedione treatment during the pre-mating or gestational periods, however a statistically significant decrease in the number of females with regular estrous cycles was observed in the 10.0 and 30.0 mg/kg dose groups. Exposure to androstenedione did not affect mean body weight gain during pre-mating or gestation. Slight not statistically significant reductions in the number of implants, number of viable fetuses and number of viable male fetuses were observed in the 30.0 mg/kg androstenedione group. Reductions were not observed in the number of corpora lutea. Fetal growth in terms of fetal weight, crown-rump length, anogenital distance and the number of external abnormalities was not affected by androstenedione exposure. At the doses given, androstenedione had no specific effect on the development of individual bones, including sternebrae. Dose related effects of androstenedione were not observed on the development of soft tissues. A statistically significant increase in moderately enlarged ureter at the kidney was observed in both the 1.0 and 5.0 mg/kg dose groups. Organ weights (expressed per gram of body weight or per gram of brain weight) were not affected by androstenedione treatment.

Administration, Oral↗
PubMed2001

Disruption of the joint synchrony of luteinizing hormone, testosterone, and androstenedione secretion in adolescents with polycystic ovarian syndrome.

The present study explores the postulate that the polycystic ovarian syndrome (PCOS) is marked by failure of physiological feedforward and feedback signaling between pituitary LH and ovarian androgens. To this end, we appraised the 3-fold simultaneous overnight release of LH (assayed by high precision immunofluorometry), testosterone (RIA), and androstenedione (RIA) in 12 an- or oligoovulatory adolescents with PCOS (mean +/- SEM age, 16.4 +/- 0.47 yr) and 10 eumenorrheic girls (age, 16.5 +/- 0.45 yr). Gynecological (postmenarchal) ages (years) were also comparable at 4.8 +/- 0.39 (PCOS) and 4.0 +/- 3.6 (control; P = NS). Body mass index and fasting serum insulin and estradiol concentrations were indistinguishable in the two study cohorts. Mean overnight serum concentrations of LH (assayed by both immunofluorometry and Leydig cell bioassay), testosterone, androstenedione, and 17alpha-hydroxyprogesterone were each elevated significantly in patients with PCOS (all P </= 0.027). The bivariate cross-approximate entropy (cross-ApEn) statistic was used as a sensitive barometer of altered within-axis feedback. This scale-invariant metric is designed to quantitate the joint synchrony of putatively linked (neurohormone) time series in a lag-independent pattern-sensitive manner. Here, we applied cross-ApEn to the coupled release of LH and testosterone, LH and androstenedione, and testosterone and androstenedione. Statistical comparisons of the two adolescent study cohorts unveiled consistently elevated cross-ApEn in patients with PCOS, denoting disruption of the pairwise synchrony of LH and testosterone (P = 0.0055), LH and androstenedione (P = 0.0076), and testosterone and androstenedione (P = 0.014) secretion. As an analytically distinct technique to monitor coordinate hormone release, we also applied cross-correlation analysis with variable lag. This appraisal revealed that adolescents with PCOS further exhibit 1) loss of rapid feedforward coupling between LH and testosterone output, 2) erosion of the time-lagged positive linkages between LH and androstenedione secretion, and 3) attenuation of the coordinate relationship between testosterone and androstenedione release. In summary, based on complementary, but independent, statistical tools, the present two-variable analyses unmask vivid deterioration of the joint synchrony of LH-testosterone, LH-androstenedione, and testosterone-androstenedione secretion in adolescents with PCOS. The multiplicity of the bihormonal coupling defects points to impaired feedforward and feedback signaling interfaces among the hypothalamus, pituitary gland, and ovary. Disruption of interandrogen synchrony also identifies pathophysiological dissociation of testosterone and androstenedione cosecretion. Whether presumptive failure of integrative hypothalamo-pituitary-gonadal control emerges prepubertally in girls at risk for PCOS or persists in adults with PCOS is not known.

Adolescent↗
PubMed2000

Oral androstenedione administration and serum testosterone concentrations in young men.

CONTEXT: Androstenedione, a steroid hormone and the major precursor to testosterone, is available without prescription and is purported to increase strength and athletic performance. The hormonal effects of androstenedione, however, are unknown. OBJECTIVE: To determine if oral administration of androstenedione increases serum testosterone levels in healthy men. DESIGN: Open-label randomized controlled trial conducted between October 1998 and April 1999. SETTING: General clinical research center of a tertiary-care, university-affiliated hospital. PARTICIPANTS: Forty-two healthy men aged 20 to 40 years. INTERVENTION: Subjects were randomized to receive oral androstenedione (either 100 mg/d [n = 15] or 300 mg/d [n = 14]) or no androstenedione (n = 13) for 7 days. MAIN OUTCOME MEASURES: Changes in serum testosterone, androstenedione, estrone, and estradiol levels, measured by frequent blood sampling, compared among the 3 treatment groups. RESULTS: Mean (SE) changes in the area under the curve (AUC) for serum testosterone concentrations were -2% (7%), -4% (4%), and 34% (14%) in the groups receiving 0, 100, and 300 mg/d of androstenedione, respectively. When compared with the control group, the change in testosterone AUC was significant for the 300-mg/d group (P<.001) but not for the 100-mg/d group (P = .48). Baseline testosterone levels, drawn 24 hours after androstenedione administration, did not change. Mean (SE) changes in the AUC for serum estradiol concentrations were 4% (6%), 42% (12%), and 128% (24%) in the groups receiving 0, 100, and 300 mg/d of androstenedione, respectively. When compared with the control group, the change in the estradiol AUC was significant for both the 300-mg/d (P<.001) and 100-mg/d (P = .002) groups. There was marked variability in individual responses for all measured sex steroids. CONCLUSIONS: Our data suggest that oral androstenedione, when given in dosages of 300 mg/d, increases serum testosterone and estradiol concentrations in some healthy men.

Administration, Oral↗
PubMed1989

Regulation of androstenedione production by adenosine 3',5'-monophosphate and phorbol myristate acetate in ovarian thecal cells of the domestic hen.

Although factors that regulate cAMP and steroid production in granulosa cells of hen preovulatory follicles have been well studied, much less is known of the mechanisms that control steroidogenesis in the adjacent thecal layer. These studies were conducted to examine the involvement and interaction of cAMP and protein kinase-C in modulating androstenedione output from isolated ovarian thecal cells collected from the second largest preovulatory follicle. Treatment of thecal cells with ovine LH (0.01-100 ng/tube) caused a dose-dependent increase in androstenedione secretion. Although coincubation of cells with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1 mM) potentiated the effects of LH on steroid production, cAMP levels increased only in response to the higher doses of LH (10-100 ng/tube). Small but significant increases in cAMP accumulation and androstenedione production were observed in response to vasoactive intestinal peptide (0.1 and 1.0 microM), but not to 100 ng/tube chicken FSH, in the presence of 0.1 mM 3-isobutyl-1-methylxanthine. Treatment of thecal cells with cholera toxin (0.001-100 ng/tube) or forskolin (0.001-10 microM) resulted in a dose-dependent increase in cellular cAMP levels and androstenedione secretion. Thecal cell androstenedione production was also stimulated by the cAMP analog 8-bromo-cAMP (0.1-1.0 mM). Incubation of thecal cells with phorbol 12-myristate 13-acetate (PMA; 0.32-162 nM) or 1-oleoyl-2-acetylglycerol (OAG; 2.5-126 microM) increased basal steroidogenesis (progesterone and androstenedione production) in the absence of a rise in cAMP levels. By contrast, the stimulatory effects of 1 ng/tube LH on androstenedione, but not progesterone, production were attenuated by the presence of PMA (3.2-162 nM) or OAG (25-126 microM). Only a high concentration of OAG (126 microM) suppressed cAMP accumulation stimulated by LH (50 ng/tube). Phorbol ester treatment (32-162 nM PMA) also inhibited androstenedione production in thecal cells stimulated by the presence of 8-bromo-cAMP (1 mM), indicating a post-cAMP effect of protein kinase-C activity on steroidogenesis. In contrast to the effects of PMA, phorbol 13-monoacetate (162 nM), a nontumor-promoting analog of PMA which does not activate protein kinase-C, did not alter basal steroidogenesis, nor did it affect androstenedione secretion stimulated by LH or 8-bromo-cAMP. Data from the present studies indicate that the adenylyl cyclase-cAMP pathway can mediate the induction of thecal cell steroidogenesis by extracellular signals (i.e. LH and vasoactive intestinal peptide), whereas activated protein kinase-C can both stimulate and inhibit androstenedione production, depending upon the hormonal environment.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-3-isobutylxanthine↗