help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2262
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/7/4232    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Related Collections
Right arrow Male Endocrinology
Right arrow Neuroendocrinology and Pituitary
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4232-4237
Copyright © 2005 by The Endocrine Society

Combined Inhibition of Types I and II 5 {alpha}-Reductase Selectively Augments the Basal (Nonpulsatile) Mode of Testosterone Secretion in Young Men

Ali Iranmanesh and Johannes D. Veldhuis

Endocrine Service, Research and Development (A.I.), Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center (J.D.V.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Testosterone (Te) is metabolized in the hypothalamus and pituitary gland, where untransformed steroid and activated products participate in feedback regulation of GnRH and LH secretion. Genetic inactivation of 5 {alpha}-reductase type I remains undescribed clinically, whereas deficiency of the type II isoenzyme elevates both LH and Te concentrations.

Objective: The aim of this study was to test the combined feedback contribution of 5 {alpha}-reduced steroids.

Setting/Design/Intervention: In a university setting, nine young men received placebo and a dual (type I/type II) 5 {alpha}-reductase inhibitor, dutasteride.

Methods/Outcomes: LH and Te dynamics were assessed by: 1) 10-min blood sampling for 26 h; 2) GnRH stimulation (100 ng/kg iv); 3) discrete peak detection; 4) deconvolution analysis; 5) cosinor analyses of 24-h rhythmicity; and 6) pattern regularity

Results: Compared with placebo, dutasteride lowered 5 {alpha}-dihydro Te concentrations by 80% (P = 0.009), but did not alter any measure of LH dynamics. Conversely, dutasteride augmented: 1) total, bioavailable and free Te concentrations (0.002 < P < 0.032) without changing estradiol or SHBG concentrations; 2) nadir Te concentrations (P = 0.025); and 3) basal (P = 0.013) and thereby total (basal plus pulsatile) (P = 0.003) Te secretion.

Conclusion: Combined antagonism of types I and II 5 {alpha}-reductase preferentially drives nonpulsatile Te secretion in healthy men. The concomitant stability of LH outflow could indicate that intragonadal 5 {alpha}-reduced androgens repress basal Leydig-cell steroidogenesis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TESTOSTERONE (Te) IS the proximate substrate for the biosynthesis of the primary estrogen, estradiol, and the potent androgen, 5 {alpha}-dihydroTe (DHT). DHT is formed in the hypothalamus, pituitary gland, testis, and nonendocrine tissues via the widely distributed but distinct enzymes, 5 {alpha}-reductase types I and II (1, 2, 3). Genetic inactivation of the type II isozyme in mice and in rare patients with male pseudohermaphroditism type II enzyme inhibitors elevate both Te and LH concentrations, indicating feedback adaptations (1, 4, 5). On the other hand, transgenic mutation of the type I gene is lethal in murine progeny due to a parturitional defect (6). Genetic deficiency of the type I enzyme has not been described clinically. Because of such observational limitations, how the types I and II 5 {alpha}-reductase pathways jointly regulate gonadal-axis dynamics remains unknown (7).

The secretion of LH is subject to prominent negative feedback by Te, inferentially via combined actions of Te and its immediate metabolites, estradiol and DHT (8, 9, 10, 11). Given that both androgen and estrogen receptors mediate hypothalamopituitary inhibition (12, 13, 14, 15, 16, 17), we hypothesized that catalytic activity of 5 {alpha}-reductase may potentiate Te feedback signals acting via the androgen receptor (10, 18, 19). To examine this postulate, we evaluated LH and Te dynamics in young men administered placebo and a potent irreversible inhibitor with pseudobimolecular kinetics of inactivation of 5 {alpha}-reductase type II and high-affinity inactivation of the type I enzyme (20, 21). The rationale for antagonizing the activities of both enzymes is their significant but unequal topographic representation within the central nervous system-gonadotrope-testicular axis (22).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Clinical protocol

Nine healthy young men participated. The age range was 19–34 (median 23) yr, and the body mass index range was 21–26 (median 24) kg/m2. Each subject provided voluntary written informed consent approved by the Institutional Review Board. The study protocol was reviewed by the General Clinical Research Center (GCRC) and by the U.S. Food and Drug Administration. Entry criteria included an unremarkable medical history, physical examination, and biochemical measures of renal, hepatic, hematologic, and metabolic function and a normal prostate-specific antigen. All subjects had normal fasting concentrations of LH, FSH, prolactin, Te, estradiol, IGF-I, T4, and TSH (23, 24, 25). Exclusion criteria included acute or chronic systemic disease, alcohol or drug abuse, psychiatric illness, use of any prescription medications, unprotected intercourse for 6 wk after drug administration, and failure to provide written informed voluntary consent. Volunteers were reimbursed for the time spent in participation.

Subjects received placebo and dutasteride (5 mg orally once and then 1 mg daily for 10 d) single-blind in that order based upon the prolonged kinetics of this inhibitor (26). Study sessions were separated by 3 wk or more. Volunteers were admitted to the GCRC the evening of the ninth day of placebo/drug administration. Beginning at 0800 h the next morning (d 10), blood samples (1.5 ml) were withdrawn every 10 min for 26 h. A single pulse of GnRH (100 ng/kg) was injected iv after 24 h of baseline sampling. Meals were served at 0830, 1230, and 1700 h. Ambulation was permitted to the lavatory only. Cigarettes and caffeine-containing beverages were disallowed.

Hormone assays

LH and total Te concentrations were quantitated in duplicate in each 10-min sample as a batch (n = 314 per subject) using an automated random-access immunochemiluminescence-based assay (ACS:180, Chiron Corporation Diagnostic, Walpole, MA) (27). The LH reference preparation was the Second World Health Organization International Standard 80/552. Median within and between-assay coefficients of variation were 5.1 and 6.8%, respectively. Assay sensitivity was 0.05 IU/liter at 2.5 SD values above hypopituitary serum. Sensitivity and intra- and interassay precision of the chemiluminescent Te assay were 18 ng/dl, 5.2 and 6.5%, respectively. Bioavailable and dialyzably free Te concentrations were assayed exactly as reported (24). DHT and estradiol were quantitated by RIA, as described earlier (15, 28, 29). The sensitivity of the estradiol assay was 3 pg/ml, and intraassay reproducibility was 6.1%. SHBG concentrations were measured by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX).

Analytical methods

Absolute peak (maximum) and interpulse nadir (minimum) concentrations and the frequency (number per 24 h) of discrete LH and Te pulses were estimated by model-free Cluster analysis (30). Conservative (P < 0.05) pulse-detection parameters included two-by-one (LH) and two-by-two (Te) test cluster sizes and thresholds of t = 2.0 to identify significant upstrokes and down strokes, respectively, in the 24-h time series (31, 32). Basal and pulsatile secretion rates and slow-phase half-lives of LH and Te were estimated after GnRH injection by deconvolution analysis (33). The rapid-phase half-life of LH was fixed at the populational mean value of 18 min (allowing a 37% contribution of rapid to total decay amplitude) and that of Te at 4.9 min (assuming an 82% contribution) (34, 35).

Approximate entropy (ApEn)

ApEn (1, 20%) is a scale- and model-independent regularity statistic used to quantitate the orderliness of serial measurements (36). To normalize comparisons among subjects and between hormones, ApEn is first computed on the measured time series and then recalculated each of 1000 times that the series is shuffled randomly (rearranged by order without replacement or loss) (37). This procedure allows calculation of the mean ratio of observed to empirically random ApEn. A ratio of unity is mean random, whereas lower ApEn ratios denote more ordered (nonrandom) patterns. Mathematical models and feedback interventions establish that greater pattern orderliness (defined by a lower ApEn ratio) identifies enhanced feedback coupling within a coupled axis with high sensitivity and specificity (both > 90%) (38). Cross-ApEn provides an analogous statistic to quantitate the relative pattern regularity of (two) coupled time series (39). Lower cross-ApEn ratios denote greater pattern synchrony between the interlinked signals.

Statistical methods

Data are presented as the mean ± SEM. Between-subject contrasts were examined via a two-sample Student’s t test followed by Bonferroni adjustment. Derived data were first subjected to logarithmic transformation. Statistical significance was construed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1AGo illustrates paired LH and total Te concentration profiles of the median responder in the group. Data reflect sampling every 10 min for 24 h on the last day of administration of placebo and dutasteride. By visual inspection, exposure to dutasteride compared with placebo increased Te concentrations without affecting those of LH. The drug reduced 5 {alpha}-DHT concentrations from 407 ± 71 (median, 384) to 117 ± 34 (median, 76) pg/ml (P = 0.009) (80% median decrease). Estradiol concentrations did not change (viz., 12.5 ± 3.4 pg/ml placebo vs. 13.6 ± 2.7 pg/ml dutasteride). SHBG also remained similar (viz., 46 ± 3.9 nm/liter placebo vs. 47 ± 5.4 nm/liter dutasteride).



View larger version (32K):
[in this window]
[in a new window]
  		FIG. 1. A, Illustrative profiles of paired LH (top) and total Te (bottom) concentrations monitored by sampling blood every 10 min for 24 h in a young man administered placebo (Pl, left) and dutasteride (Du, right). Dutasteride was used as a combined inhibitor of types I and II 5 {alpha}-reductase enzymes. The profiles shown are from the median responder in the cohort. B, Total, bioavailable, and free Te concentrations in 24-h serum pools collected after placebo and dutasteride administration in nine young men. Data are the mean ± SEM. P values are parametric estimates.

 
Mean concentrations of LH, FSH, prolactin, estradiol, and total, bioavailable, and free Te were determined on 24-h pools of serum (n = 145 samples each). LH averaged 3.2 ± 0.18 (placebo) and 3.2 ± 0.20 (dutasteride) IU/liter [P = not significant (NS)]. FSH, prolactin, and estradiol did not differ by intervention (data not shown). In contrast, administration of dutasteride compared with placebo elevated each of total, bioavailable, and free Te concentrations; viz., by 17–28%, median increase 25% (0.002 < P < 0.032) (Fig. 1BGo).

Cluster analysis was used as a model-free tool to quantitate pulsatile hormone release. There were two major findings. Dutasteride compared with placebo did not change LH pulsatility, and dutasteride selectively augmented nadir Te concentrations (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Principal measures of model-free (cluster) pulse identification in 24-h LH and Te concentration profiles

 
To distinguish basal and pulsatile secretion of LH and Te, biexponential deconvolution analysis was applied to the GnRH-stimulated time series. Because the time of the GnRH-induced LH pulse is known a priori, this strategy allows valid simultaneous assessment of intercorrelated secretion and elimination parameters (35, 40). Statistical comparisons indicated that basal, pulsatile, and total LH secretion rates did not differ after dutasteride and placebo administration (Fig. 2AGo). In contrast, dutasteride compared with placebo elevated basal Te secretion (P = 0.013), secondarily increased total (basal plus pulsatile) Te secretion (P = 0.003), and minimally stimulated pulsatile Te secretion (P = 0.049) (Fig. 2BGo). Mean LH and Te concentration profiles after GnRH injection are given in Fig. 3Go for the cohort of nine men.



View larger version (26K):
[in this window]
[in a new window]
  		FIG. 2. Deconvolution-based estimates of basal (nonpulsatile), pulsatile (mass secreted in bursts), and total (basal plus pulsatile) LH (A) and Te (B) secretion after GnRH injection in young men administered placebo (Pl) and dutasteride (Du). P values reflect paired comparisons. NS, P > 0.05. Data are the mean ± SEM (n = 9 men).

 


View larger version (22K):
[in this window]
[in a new window]
  		FIG. 3. Mean LH and Te concentration time series (Con) based upon sampling every 10 min for 2 h after iv injection of a submaximally stimulatory dose of GnRH (100 ng/kg) in young men treated with placebo (left) and dutasteride (right) to inhibit both 5 {alpha}-reductase types I and II. Data are the mean ± SEM (n = 9).

 
Biexponential deconvolution analysis (see Subjects and Methods) allowed concomitant estimation of the slow-phase half-life of elimination of LH and Te (Fig. 4Go). Statistical comparisons indicated that dutasteride did not affect the kinetics of either LH or Te.



View larger version (19K):
[in this window]
[in a new window]
  		FIG. 4. Deconvolution estimates of the slow-phase half-lives of LH and Te elimination following GnRH injection after exposure to placebo (Pl) and dutasteride (Du). See data presentation in Fig. 2Go. P = NS, P > 0.05.

 
Cosinor analysis was applied to quantitate the 24-h rhythmic variation in LH and Te concentrations. Dutasteride compared with placebo administration did not influence the diurnal amplitude (50% of zenith-to-nadir difference), mesor (rhythmic mean), or acrophase (time of maximum) of LH concentrations. In contradistinction, the combined reductase inhibitor elevated the mesor of Te concentrations (P < 0.01) (Table 2Go). This analytical outcome is consistent with higher mean and interpulse nadir Te concentrations (41).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Nycthemeral rhythmicity of LH and Te concentrations

 
ApEn analysis provides a scale-free measure of the feedback-dependent regularity of hormone secretion patterns (38). As shown in Fig. 5Go, LH ApEn and Te ApEn were not affected by dutasteride administration. In addition, the relative pattern synchrony of LH-driven Te release and Te-inhibited LH secretion did not differ between interventions, as quantitated by cross-ApEn of the ordered pairs. These data strongly suggest that the effects of 5 {alpha}-reductase inhibition are local rather than general within the GnRH-LH-Te feedback-regulated axis (see Discussion). Secondarily, we observed higher ApEn of Te than LH series (indicating more irregularity of Te than LH secretion) and higher cross-ApEn of Te-LH (feedback) than LH-Te (feedforward) pairs (identifying less consistent feedback than feedforward coupling) (both P < 0.01 within intervention). Dutasteride exposure did not alter either of these physiological relationships.



View larger version (25K):
[in this window]
[in a new window]
  		FIG. 5. ApEn calculations (left), which define signal regularity (orderliness) under modulation by negative feedback. Lower ApEn ratios for LH than Te in both interventions denote greater reproducibility (less randomness) of LH than Te subpatterns (as indicated by superscripts and P < 0.01). The cross-ApEn statistic quantitates synchrony between LH and Te (feedforward) or Te and LH (feedback) patterns. Lower cross-ApEn ratios for coupling between LH/Te than Te/LH in both interventions (P < 0.01, right) signify greater synchrony of feedforward than feedback signaling. Dutasteride administration did not affect ApEn values or the foregoing physiological relationships.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Virtually nothing is known about the regulation of basal (nonpulsatile) Te secretion in the human or experimental animal. Thus, a singular outcome of the present study is that putative inhibition of both types I and II 5 {alpha}-reductase enzyme activity in young men preferentially stimulates basal, and thereby total, Te secretion, as assessed by deconvolution analysis. This adaptation in Te production occurred without measurable changes in the 24-h concentration, pulsatility, nyctohemeral rhythmicity, pattern regularity, half-life, or amount of GnRH-stimulated LH secretion.

At present, we are unaware of any other well-defined nonpathological mechanisms that selectively drive the basal (time-invariant) mode of Te production. However, recent clinical studies of the dynamics of Te secretion indicate that aging increases basal Te secretion and decreases pulsatile Te secretion (25, 35). Fractional basal (of total) hormone secretion is also disproportionately elevated in patients with autonomous adenomas producing GH, ACTH, prolactin, or PTH (42, 43, 44, 45). A plausible inference, therefore, is that basal hormone secretion is sparingly regulated physiologically and may be constitutive in pathological states.

Direct sampling of the human spermatic vein has disclosed an admixture of pulsatile and nonpulsatile Te secretion (46, 47). More recently, basal Te secretion was estimated analytically as 40–60% of total Te production based on spermatic vein Te measurements made every 20 min for 17 h in the awake human and peripheral venous Te measurements performed every 5–15 min for 6–12 h in the unanesthetized ram and stallion (40). The current computation of fractional basal Te secretion falls within the foregoing range and was unaffected by dutasteride administration. In addition, the calculated half-life of Te disappearance (Fig. 4Go) agrees with earlier experimental determinations and analytical predictions (35, 48). The reason that estradiol concentrations did not increase concurrently is not known but in principle could reflect an increase in metabolic clearance and/or distribution volume of estrogen. A speculative explanation is that inhibition of types I vs. II reductase exerts an opposing effect on estradiol synthesis, resulting in no net change.

An LH pulse stimulates an increase in Te concentrations after a time delay of about 40 min, followed by a decline to baseline 45–60 min later (40, 47, 49, 50). Conversely, administration of a GnRH receptor antagonist suppresses the amplitude of LH and Te pulses without evidently altering basal LH or Te output (51). Thus, basal, unlike pulsatile, Te production does not appear to depend so acutely on LH pulses. In this regard, numerous testicular paracrine and autocrine factors, including sex steroids, neurotransmitters, and peptides, can modulate Leydig cell steroidogenesis under in vitro conditions (52). For example, Te, estradiol, and cytokines inhibit and growth factors enhance LH-stimulated androgen biosynthesis (53, 54, 55). Estradiol and SHBG concentrations did not change. Thus, a straightforward postulate based on the accompanying outcome is that intratesticular DHT concentrations, which presumptively decline during combined 5 {alpha}-reductase inhibition, otherwise repress Te synthesis via direct or indirect pathways. By way of precedence, administration of DHT in vivo inhibits exogenous gonadotropin-stimulated ovarian steroidogenesis in the Rhesus monkey (56).

An intragonadal effect of 5 {alpha}-reductase blockade is favored further by the stability of ApEn values for LH and Te (39). This is because ApEn confers >90% sensitivity and >90% specificity in detecting within-axis changes in feedback and/or feedforward signaling (38, 57). In corollary, the cross-ApEn statistic quantitates adaptations in coupling between two functionally interlinked signals (39). Statistical comparisons of LH ApEn, Te ApEn, LH-Te cross-ApEn (feedforward), and Te-LH cross-ApEn (feedback) after placebo vs. dutasteride administration revealed no significant interventional effect.

By way of qualifications, first, the current cohort size confers greater than 0.90 statistical power at P < 0.05 for detecting a 30% or greater change in paired mean LH concentrations, which are well-determined by 10-min sampling over 24 h (11). A nominal 30% effect size is reasonable, in that this degree of contrast typifies responses to modulation of other sex steroid-dependent feedback pathways (see introductory section). Second, the double-monoclonal immunoradiometric LH assay used here correlates strongly (r = +0.973, P < 0.001) with in vitro Leydig cell bioassay, suggesting valid quantitation of LH drive (58). The consistency of estimated LH kinetics in the presence of dutasteride and placebo would further argue against any major change in bioactivity. This is because more biopotent LH molecules manifest an alkaline isoelectric profile due to reduced sialic acid content and exhibit more rapid disappearance from the circulation (59, 60). Third, given the prolonged residence time of dutasteride, the drug was always given on the second study session. Although an order effect cannot be excluded absolutely, it would have occurred only for Te (and not LH or estradiol) measurements. Test-retest analyses in young men studied three times without intervention establish high intraindividual reproducibility of estimates 24-h LH secretion (61). And, fourth, dutasteride reduced DHT concentrations by 80%, indicating some residual enzymic activity.

In conclusion, administration of a potent, irreversible combined inhibitor of 5 {alpha}-reductase types I and II elevates 24-h mean total, bioavailable, and free Te concentrations without altering SHBG or estradiol concentrations in healthy young men. The proximate mechanism entails stimulation of basal (nonpulsatile) Te secretion. This adaptation accounts for augmentation of interpulse nadir, daily mean, and the mesor of 24-h rhythmic Te concentrations. Amplified basal Te secretion is selective, in that dutasteride does not alter the amplitude of the 24-h Te rhythm, the slow-phase half-life of Te, Te secretory regularity, and any of multiple measures of LH dynamics. A frugal hypothesis to account for these data is that intratesticular 5 {alpha}-reduced androgens repress basal Te biosynthesis by Leydig cells.


   Acknowledgments
 
We thank Kris Nunez for preparing the manuscript, Brenda Grisso for performing the immunoassays, the GCRC nursing staff for conducting the research protocols, Dr. Stacey Anderson for seeing patients on a fee-for-service basis, and Glaxo-Wellcome Laboratories (Middlesex, UK) for donating dutasteride under a Food and Drug Administration-approved Investigator New Drug assignment by the authors.


   Footnotes
 
This work was supported in part by National Center for Research Resources (Rockville, MD) Grants MO1 RR00847 and RR00585 to the GCRCs of the University of Virginia and Mayo Clinic and by Grant RO1 AG023133 from the National Institutes of Health (Bethesda, MD).

First Published Online April 5, 2005

Abbreviations: ApEn, Approximate entropy; DHT, 5 {alpha}-dihydroTe; GCRC, General Clinical Research Center; NS, not significant; Te, testosterone.

Received November 18, 2004.

Accepted March 28, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Wilson JD, Griffin JE, Russell DW 1993 Steroid 5 {alpha}-reductase 2 deficiency. Endocr Rev 14:577–593[Abstract]
  2. Poletti A, Coscarella A, Negri-Cesi P, Colciago A, Celotti F, Martini L 1998 5 {alpha}-reductase isozymes in the central nervous system. Steroids 63:246–251[CrossRef][Medline]
  3. Berman DM, Tian H, Russell DW 1995 Expression and regulation of steroid 5 {alpha}-reductase in the urogenital tract of the fetal rat. Mol Endocrinol 9:1561–1570[Abstract]
  4. Imperato-McGinley J, Zhu YS 2002 Androgens and male physiology the syndrome of 5{alpha}-reductase-2 deficiency. Mol Cell Endocrinol 198:51–59[CrossRef][Medline]
  5. Andersson S, Berman DM, Jenkins EP, Russell DW 1991 Deletion of steroid 5 {alpha}-reductase 2 gene in male pseudohermaphroditism. Nature 354:159–161[CrossRef][Medline]
  6. Mahendroo MS, Cala KM, Hess DL, Russell DW 2001 Unexpected virilization in male mice lacking steroid 5 {alpha}-reductase enzymes. Endocrinology 142:4652–4662[Abstract/Free Full Text]
  7. Veldhuis JD, Iranmanesh A, Keenan DM 2004 An ensemble perspective of aging-related hypoandrogenemia in men. In: Winters SJ, ed. Male hypogonadism: basic, clinical, and theoretical principles. Totowa, NJ: Humana Press; 261–284
  8. Scott CJ, Kuehl De, Ferreira SA, Jackson GL 1997 Hypothalamic sites of action for testosterone, dihydrotestosterone, and estrogen in the regulation of luteinizing hormone secretion in male sheep. Endocrinology 138:3686–3694[Abstract/Free Full Text]
  9. Schaison G, Renoir M, Lagoguey M, Mowszowicz I 1980 On the role of dihydrotestosterone in regulating luteinizing hormone secretion in man. J Clin Endocrinol Metab 51:1133–1137[Abstract]
  10. Shakil T, Hoque AN, Husain M, Belsham DD 2002 Differential regulation of gonadotropin-releasing hormone secretion and gene expression by androgen: membrane versus nuclear receptor activation. Mol Endocrinol 16:2592–2602[Abstract/Free Full Text]
  11. Urban RJ, Evans WS, Rogol AD, Kaiser DL, Johnson ML, Veldhuis JD 1988 Contemporary aspects of discrete peak detection algorithms: I. The paradigm of the luteinizing hormone pulse signal in men. Endocr Rev 9:3–37[Medline]
  12. Noe G, Suvisaari J, Martin C, Moo-Young AJ, Sundaram K, Saleh SI, Quintero E, Croxatto HB, Lahteenmaki P 1999 Gonadotrophin and testosterone suppression by 7{alpha}-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men. Hum Reprod 14:2200–2206[Abstract/Free Full Text]
  13. Kuhn JM, Rieu M, Laudat MH, Forest MG, Pugeat M, Bricaire H, Luton JP 1984 Effects of 10 days administration of percutaneous dihydrotestosterone on the pituitary-testicular axis in normal men. J Clin Endocrinol Metab 58:231–235[Abstract]
  14. Winters SJ, Janick JJ, Loriaux LD, Sherins RJ 1979 Studies on the role of sex steroids in the feedback control of gonadotropin concentrations in men: II. Use of the estrogen antagonist, clomiphene citrate. J Clin Endocrinol Metab 48:222–227[Medline]
  15. Veldhuis JD, Rogol AD, Samojlik E, Ertel N 1984 Role of endogenous opiates in the expression of negative feedback actions of estrogen and androgen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest 74:47–55
  16. Veldhuis JD, Dufau ML 1987 Estradiol modulates the pulsatile secretion of biologically active luteinizing hormone in man. J Clin Invest 80:631–638
  17. Urban RJ, Davis MR, Rogol AD, Johnson ML, Veldhuis JD 1988 Acute androgen receptor blockade increases luteinizing-hormone secretory activity in men. J Clin Endocrinol Metab 67:1149–1155[Abstract]
  18. Belsham DD, Evangelou A, Roy D, Duc VL, Brown TJ 1998 Regulation of gonadotropin-releasing hormone (GnRH) gene expression by 5 {alpha}-dihydrotestosterone in GnRH-secreting GT1–7 hypothalamic neurons. Endocrinology 139:1108–1114[Abstract/Free Full Text]
  19. Hileman SM, Lubbers LS, Kuehl De, Schaeffer DJ, Rhodes L, Jackson GL 1994 Effect of inhibiting 5 {alpha}-reductase activity on the ability of testosterone to inhibit luteinizing hormone release in male sheep. Biol Reprod 50:1244–1250[Abstract]
  20. Bramson HN, Hermann D, Batchelor KW, Lee FW, James MK, Frye SV 1997 Unique preclinical characteristics of GG745, a potent dual inhibitor of 5 {alpha}-reductase. J Pharmacol Exp Ther 282:1496–1502[Abstract/Free Full Text]
  21. Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S 2004 Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5 {alpha}-reductase inhibitor. J Clin Endocrinol Metab 89:2179–2184[Abstract/Free Full Text]
  22. Normington K, Russell DW 1992 Tissue distribution and kinetic characteristics of rat steroid 5 {alpha}-reductase isozymes. Evidence for distinct physiological functions. J Biol Chem 267:19548–19554[Abstract/Free Full Text]
  23. Veldhuis JD, Urban RJ, Lizarralde G, Johnson ML, Iranmanesh A 1992 Attenuation of luteinizing hormone secretory burst amplitude is a proximate basis for the hypoandrogenism of healthy aging in men. J Clin Endocrinol Metab 75:52–58
  24. Mulligan T, Iranmanesh A, Kerzner R, Demers LW, Veldhuis JD 1999 Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig-cell) defects in the healthy aging male gonadotropic axis. Eur J Endocrinol 141:257–266[Abstract]
  25. Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD 1995 Amplified nocturnal luteinizing hormone (LH) secretory burst frequency with selective attenuation of pulsatile (but not basal) testosterone secretion in healthy aged men: possible Leydig cell desensitization to endogenous LH signaling: a clinical research center study. J Clin Endocrinol Metab 80:3025–3031[Abstract/Free Full Text]
  26. Olsson GP, Hermann D, Hammarlund-Udenaes M, Karlsson MO 1999 Validation of a population pharmacokinetic/pharmacodynamic model for 5 {alpha}-reductase inhibitors. Eur J Pharm Sci 8:291–299[Medline]
  27. Veldhuis JD, Iranmanesh A, Mulligan T, Pincus SM 1999 Disruption of the young-adult synchrony between luteinizing hormone release and oscillations in follicle-stimulating hormone, prolactin, and nocturnal penile tumescence (NPT) in healthy older men. J Clin Endocrinol Metab 84:3498–3505[Abstract/Free Full Text]
  28. Schnorr JA, Bray MJ, Veldhuis JD 2001 Aromatization mediates testosterone’s short-term feedback restraint of 24-hour endogenously driven and acute exogenous GnRH-stimulated LH and FSH secretion in young men. J Clin Endocrinol Metab 86:2600–2606[Abstract/Free Full Text]
  29. Veldhuis JD, Iranmanesh A, Demers LM, Mulligan T 1999 Joint basal and pulsatile hypersecretory mechanisms drive the monotropic follicle-stimulating hormone (FSH) elevation in healthy older men: concurrent preservation of the orderliness of the FSH release process. J Clin Endocrinol Metab 84:3506–3514[Abstract/Free Full Text]
  30. Veldhuis JD, Johnson ML 1986 Cluster analysis: a simple, versatile and robust algorithm for endocrine pulse detection. Am J Physiol 250:E486–E493
  31. Urban RJ, Johnson ML, Veldhuis JD 1989 Biophysical modeling of the sensitivity and positive accuracy of detecting episodic endocrine signals. Am J Physiol 257:E88–E94
  32. Urban RJ, Johnson ML, Veldhuis JD 1989 In vivo biological validation and biophysical modeling of the sensitivity and positive accuracy of endocrine peak detection: I. The LH pulse signal. Endocrinology 124:2541–2547[Abstract]
  33. Veldhuis JD, Carlson ML, Johnson ML 1987 The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc Natl Acad Sci USA 84:7686–7690[Abstract/Free Full Text]
  34. Veldhuis JD, Fraioli F, Rogol AD, Dufau ML 1986 Metabolic clearance of biologically active luteinizing hormone in man. J Clin Invest 77:1122–1128
  35. Keenan DM, Veldhuis JD 2004 Divergent gonadotropin-gonadal dose-responsive coupling in healthy young and aging men. Am J Physiol 286:R381–R389
  36. Pincus SM 2000 Irregularity and asynchrony in biologic network signals. Methods Enzymol 321:149–182[Medline]
  37. Veldhuis JD, Johnson ML, Veldhuis OL, Straume M, Pincus S 2001 Impact of pulsatility on the ensemble orderliness (approximate entropy) of neurohormone secretion. Am J Physiol 281:R1975–R1985
  38. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe CA, Barkan A, Johnson ML, Pincus SM 2001 Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol 280:R721–R729
  39. Pincus SM, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD 1996 Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc Natl Acad Sci USA 93:14100–14105[Abstract/Free Full Text]
  40. Keenan DM, Alexander SL, Irvine CHG, Clarke IJ, Canny BJ, Scott CJ, Tilbrook AJ, Turner AI, Veldhuis JD 2004 Reconstruction of in vivo time-evolving neuroendocrine dose-response properties unveils admixed deterministic and stochastic elements in interglandular signaling. Proc Natl Acad Sci USA 101:6740–6745[Abstract/Free Full Text]
  41. Veldhuis JD, Evans WS, Johnson ML 1995 Complicating effects of highly correlated model variables on nonlinear least-squares estimates of unique parameter values and their statistical confidence intervals: estimating basal secretion and neurohormone half-life by deconvolution analysis. Methods Neurosci 28:130–138
  42. van den Berg G, Frolich M, Veldhuis JD, Roelfsema F 1994 Growth hormone secretion in recently operated acromegalic patients. J Clin Endocrinol Metab 79:1706–1715[Abstract]
  43. van den Berg G, Frolich M, Veldhuis JD, Roelfsema F 1996 Combined amplification of the pulsatile and basal modes of adrenocorticotropin and cortisol secretion in patients with Cushing’s disease: evidence for down-regulation of the adrenal glands. J Clin Endocrinol Metab 80:3750–3756
  44. Veldman RG, Frolich M, Pincus SM, Veldhuis JD, Roelfsema F 2001 Basal, pulsatile, entropic and twenty-four-hours rhythmic features of secondary hyperprolactinemia due to functional pituitary stalk disconnection fully mimic tumoral (primary) hyperprolactinemia. J Clin Endocrinol Metab 86:1562–1567[Abstract/Free Full Text]
  45. Schmitt CP, Locken S, Mehls O, Veldhuis JD, Lehnert T, Ritz E, Schaefer F 2003 PTH pulsatility but not calcium sensitivity is restored after total parathyroidectomy with heterotopic autotransplantation. J Am Soc Nephrol 14:407–414[Abstract/Free Full Text]
  46. Winters SJ, Troen P 1986 Testosterone and estradiol are co-secreted episodically by the human testis. J Clin Invest 78:870–873
  47. Foresta C, Bordon P, Rossato M, Mioni R, Veldhuis JD 1997 Specific linkages among luteinizing hormone, follicle stimulating hormone, and testosterone release in the peripheral blood and human spermatic vein: evidence for both positive (feed-forward) and negative (feedback) within-axis regulation. J Clin Endocrinol Metab 82:3040–3046[Abstract/Free Full Text]
  48. Horton R, Shinsako J, Forsham PH 1965 Testosterone production and metabolic clearance rates with volumes of distribution in normal adult men and women. Acta Endocrinol (Copenh) 48:446–458[Medline]
  49. Veldhuis JD, Johnson ML, Keenan D, Iranmanesh A 2003 The ensemble male hypothalamo-pituitary-gonadal axis. In: Timiras PS, ed. Physiological basis of aging and geriatrics. 3rd ed. Boca Raton, FL: CRC Press; 213–231
  50. Mulligan T, Iranmanesh A, Johnson ML, Straume M, Veldhuis JD 1997 Aging alters feedforward and feedback linkages between LH and testosterone in healthy men. Am J Physiol 273:R1407–R1413
  51. Pavlou SN, Veldhuis JD, Lindner J, Souza KH, Urban RJ, Rivier JE, Vale WW, Stallard DJ 1990 Persistence of concordant LH, testosterone and {alpha} subunit pulses following LHRH antagonist administration in normal men. J Clin Endocrinol Metab 70:1472–1478[Abstract]
  52. Veldhuis JD 1999 Male hypothalamic-pituitary-gonadal axis. In: Yen SSC, Jaffe RB, Barbieri RL, eds. Reproductive endocrinology. 4th ed. Philadelphia: W.B. Saunders Co.; 622–631
  53. Darney KJ, Jr., Zirkin BR, Ewing LL 1996 Testosterone autoregulation of its biosynthesis in the rat testis: inhibition of 17 {alpha}-hydroxylase activity. J Androl 17:137–142[Abstract/Free Full Text]
  54. Calkins JH, Sigel MM, Nankin HR, Lin T 1988 Interleukin-1 inhibits Leydig cell steroidogenesis in primary culture. Endocrinology 123:1605–1610[Abstract]
  55. Lin T, Wang D, Hu J, Stocco DM 1998 Upregulation of human chorionic gonadotrophin-induced steroidogenic acute regulatory protein by insulin-like growth factor-I in rat Leydig cells. Endocrine 8:73–78[CrossRef][Medline]
  56. Zeleznik AJ, Little-Ihrig L, Ramasawamy S 2004 Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-stimulated ovarian steroidogenesis. J Clin Endocrinol Metab 89:860–866[Abstract/Free Full Text]
  57. Pincus SM, Hartman ML, Roelfsema F, Thorner MO, Veldhuis JD 1999 Hormone pulsatility discrimination via coarse and short time sampling. Am J Physiol 277:E948–E957
  58. Veldhuis JD, Wilkowski MJ, Urban RJ, Lizarralde G, Iranmanesh A, Bolton WK 1993 Evidence for attenuation of hypothalamic GnRH impulse strength with preservation of gonadotropin-releasing hormone (GnRH) pulse frequency in men with chronic renal failure. J Clin Endocrinol Metab 76:648–654[Abstract]
  59. Dufau ML, Veldhuis JD 1987 Pathophysiological relationships between the biological and immunological activities of luteinizing hormone. In: Burger HG, ed. Bailliere’s clinical endocrinology and metabolism. Philadelphia: W. B. Saunders; 153–176
  60. Ropelato MG, Garcia-Rudaz C, Castro-Fernandez C, Ulloa-Aguirre A, Escobar ME, Barontini M, Veldhuis JD 1999 A preponderance of basic luteinizing hormone (LH) isoforms accompanies inappropriate hypersecretion of both basal and pulsatile LH in adolescents with polycystic ovarian syndrome. J Clin Endocrinol Metab 84:4629–4636[Abstract/Free Full Text]
  61. Partsch C-J, Abrahams S, Herholz N, Peter M, Veldhuis JD, Sippell WG 1994 Variability of pulsatile LH secretion in young male volunteers. Eur J Endocrinol 131:263–272[Abstract]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/7/4232    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Iranmanesh, A.
Right arrow Articles by Veldhuis, J. D.
Related Collections
Right arrow Male Endocrinology
Right arrow Neuroendocrinology and Pituitary

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals