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Original Articles: Hormones and Reproductive Health |
Division of Endocrinology, Departments of Internal Medicine and Obstetrics and Gynecology, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: J. D. Veldhuis, M.D., Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health System, Charlottesville, Virginia 22908. E-mail: JDV{at}Virginia.Edu
Abstract
The present clinical study examines the neuroregulatory hypothesis that feedback restraint of LH and FSH secretion by testosterone requires in vivo aromatization. To test this postulate, we prospectively and randomly assigned 47 healthy young men to 1 of 5 parallel short-term (5-day) double-blind interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4 times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective and potent aromatase inhibitor, anastrazole (5 mg orally twice daily). Blood was sampled every 10 min for 27 h on the last day of intervention to quantitate 24-h mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH release. KTCZ administration lowered the serum total testosterone concentration markedly from (mean ± SEM) 423 ± 57 ng/dL (15 ± 2.0 nmo/L) during placebo ingestion to 58 ± 8.6 ng/dL (2.0 ± 0.3 nmol/L) (P < 10-3). Transdermal androgen addback along with KTCZ blockade increased testosterone levels to 607 ± 57 ng/dL (21 ± 2.0 nmol/L). KTCZ exposure alone drove a 3-fold increase in serum LH concentrations (P < 10-3) and a 2.5-fold rise in FSH secretion (P = 0.015), as assessed by high-specificity immunoradiometric assays. Concomitant transdermal testosterone (or estradiol) delivery repressed the elevated secretion of both LH and FSH to mid-normal baseline values. A 3-fold administration of anastrazole, KTCZ, and testosterone completely opposed exogenous testosterone’s suppression of 24-h LH and FSH secretion. Anastrazole coadministration likewise abolished testosterone-dependent inhibition of 3-h GnRH-stimulated LH and FSH release. In summary, assuming the specificity of anastrazole’s inhibition of aromatase activity, we conclude that circulating testosterone in healthy men curtails endogenously driven as well as exogenous GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.
ACCORDING TO AN integrative concept of the male reproductive axis, hypothalamic GnRH secretion drives pituitary gonadotropin release. LH feeds forward on testicular Leydig cells to stimulate the time-delayed output of sex-steroid hormones (1). Gonadal sex steroids in turn feed back to restrain activity of the GnRH-gonadotrope secretory unit (2, 3). Thus, pharmacological amounts of testosterone, dihydrotestosterone (DHT), and nonaromatizable anabolic steroids suppress LH release in healthy men and patients with primary gonadal failure (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Likewise, excessive estrogen delivery represses gonadotropin secretion in the human (4, 6, 8, 12, 14, 19, 20, 21, 22, 23). Conversely, selective nonsteroidal antagonists of the estrogen or androgen receptor moderately augment LH and FSH secretion (4, 8, 12, 21, 22, 23, 24, 25, 26).
Whereas the foregoing indirect evidence would suggest that endogenous
androgen and estrogen play important roles in the dynamic control of LH
and FSH production (27), some experimental observations
are flawed by the use of supraphysiological amounts of sex steroids
and/or are confounded by variable comorbidity associated with primary
gonadal failure (e.g. concurrent radiotherapy, chemotherapy,
systemic disease, or chromosomal abnormalities). In addition, the
precise mechanisms of action of testosterone remain uncertain, because
aromatizable androgens can exert distinct (and nonexclusive) regulatory
effects by way of: 1) the untransformed steroid, as inferred for native
testosterone in muscle and thymic epithelial cells (28);
2) reduction to 5 
-DHT, as emerges in the prostate gland (29, 30); and/or 3) A-ring aromatization to estrogenic products, as
evident in the GH axis (31, 32, 33, 34, 35). Thus, other studies have
monitored gonadotropin secretion in rare patients with inborn errors of
sex-steroid hormone action or production (27, 36, 37, 38, 39).
Such data, albeit important, are sparse and may be marred by unknown
longer-term effects on the gonadal axis of in utero and
perinatal loss of normal sex-hormone action.
In an effort to address some of the above interpretative issues, the present clinical investigation uses a novel experimental paradigm of short-term (5-day) reversible pharmacological blockade of adrenal and Leydig-cell steroidogenesis to achieve a profoundly hypoandrogenemic milieu in healthy young men (40, 41). In this context, we selectively add back transdermal testosterone alone or in combination with a potent and specific aromatase inhibitor. Estradiol alone was used as a positive control. Thereby, we appraise the role of in vivo androgen aromatization in the testosterone’s feedback control of LH and FSH secretion in normal individuals.
Materials and Methods
Steroidogenic inhibitors
Ketoconazole (KTCZ) is an antifungal drug that inhibits cytochrome P-450-containing steroidogenic enzymes (42, 43, 44, 45). This agent has been evaluated in the treatment of prostatic carcinoma and tumoral hyperandrogenism (46, 47, 48), as a test of testosterone abuse (49) and as a stimulus of gonadotropin secretion (45, 50). Anastrazole is a potent, selective, and orally active fourth-generation aromatase inhibitor that can suppress estradiol production nearly maximally in postmenopausal women (51, 52). In one study in young men, both a 0.5-mg and a 1.0-mg daily dose of anastrazole reduced serum estradiol concentrations by 50% (53).
Subjects
Fifty young men (ages 18–35 yr) volunteered for the study, which was approved by the Human Investigation Committee. Medical history, physical examination, and screening measurements of hepatic, renal, metabolic, endocrine, and hematological function were all normal.
Experimental protocol
Five interventions were imposed in a randomized, prospective, parallel (noncrossover), placebo-controlled, single-blind design. The first 3 volunteers received oral KCTZ and cortisone acetate (25 mg) twice daily, but experienced addisonian-like symptoms of nausea, myalgias, and fatigue. Hence, the remaining 38 volunteers were given 0.75 mg dexamethasone orally twice daily as concurrent glucocorticoid replacement without adverse events (54).
Subjects returned daily for outpatient medication review and were admitted to the Clinical Unit on the evening of the fourth day. The next morning (day 5) at 0800 h, blood was sampled at 10-min intervals for 27 h. At 0800 h on day 6 (after 24 h of baseline sampling), GnRH (100 ng/kg iv bolus) was injected once.
Placebo (control)
Nine volunteers received dexamethasone (above), oral placebo, and a placebo skin patch each evening for 5 days.
KTCZ
Nine subjects received dexamethasone (above), a placebo skin patch, and high-dose KTCZ (400 mg orally four times daily) for 5 days, including during the 27 h of blood sampling. KTCZ was given with a nondairy snack.
Testosterone or estradiol addback
Ten men received oral dexamethasone and KTCZ (above), along with 3 testosterone skin patches daily (Androderm, 2.5 mg each; SmithKline Beecham, Philadelphia, PA) for 5 days. Nine other men received the foregoing, except an estradiol 0.05 mg transdermal patch daily.
Aromatase inhibitor
Ten volunteers received dexamethasone, KTCZ, and transdermal testosterone addback (above) plus oral anastrazole (loading dose of 30 mg on the first day, and then 5 mg twice daily) for 5 days.
Analytical methods
Aliquots of 20 µL sera were pooled across the 145 samples collected over the basal 24 h, and across the 18 samples withdrawn after GnRH infusion (3-h interval). Sera were analyzed for concentrations of LH and FSH (all 24-h and 3-h pools), or TSH, PRL, progesterone, T4, T3, resin T3 uptake, and total testosterone (all 24-h samples) by automated chemiluminescence assay (55, 56). Gonadotropin standards were the WHO Second International Reference Preparations 80/552 (LH) and 94/632 (FSH). Within-assay coefficients of variation (CV) were less than 6.5%, and between-assay CV less than 10%. Free testosterone, estrone, androstenedione, DHEA-S, cortisol, GH, insulin-like growth factor I, and leptin concentrations were assayed in 24-h serum pools by immunoradiometric assay or RIA (40). Estradiol was assayed by double-antibody RIA with a sensitivity of 2 pg/mL, using an antiserum that cross-reacts less than 7% with estrone (Third-Generation Estradiol kit; Diagostics Systems Laboratories, Inc., Webster, TX). The latter intraassay and interassay CV averaged 6.3 and 8.7% (55).
Statistical analysis
ANOVA was applied after logarithmic transformation of the data, followed by Duncan’s multiple-range test to compare means post hoc. P less than 0.05 was construed as significant. Data are expressed as the mean ± SEM (n = 9 or 10 subjects per group). Box-and-whisker plots are used to present the median, interquartile, and interdecile values and absolute range.
Results
The pooled (24-h) serum total testosterone concentration averaged
423 ± 57 ng/dL (15 ± 2.0 nmol/L) in the placebo group. KTCZ
lowered this value to 58 ± 8.6 ng/dL (2.0 ± 0.30 nmol/L)
(P < 10-3 by ANOVA
vs. placebo). Testosterone replacement elevated the serum
total testosterone concentration to 607 ± 57 ng/dL (21 ±
2.0 nmol/L), which level was unaffected by further addition of
anastrazole, viz., 630 ± 50 ng/dL (22 ± 1.7
nmol/L) (P = NS vs. testosterone alone).
Free testosterone (P < 10-3)
and androstenedione (P = 0.006) concentrations
generally paralleled the foregoing pattern (Table 1
).
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). KTCZ alone did not lower estradiol. Combined anastrazole and
testosterone reduced estradiol significantly compared with testosterone
alone. Estrone rose during KTCZ exposure, except in the presence of
anastrazole (Table 1).
The mean (24-h pooled) serum LH concentration increased 3-fold during
KTCZ administration (P < 10-3
compared with placebo) (Fig. 1A).
Testosterone or estradiol addback repressed LH to control levels. In
contrast, combining anastrazole with KTCZ and testosterone completely
antagonized testosterone’s suppression of LH secretion
[P = not significant (NS) vs. KTCZ
alone].
|
).
Transdermal testosterone or estradiol addback normalized FSH excess
(P = NS vs. placebo). Anastrazole
cotreatment blocked testosterone’s suppression of FSH entirely.
Mean (3-h pooled) serum LH and FSH concentrations measured following a
single iv bolus injection of GnRH (100 ng/kg) are summarized in Fig. 2. GnRH-stimulated LH responses to the
foregoing interventions mirrored those observed for spontaneous (24-h)
LH secretion (P < 10-3).
GnRH-stimulated FSH secretion rose above that in the control group only
during 3-fold simultaneous exposure to KTCZ, testosterone, and
anastrazole (P = 0.003), possibly reflecting its
greater inhibition (relative to LH) by available estradiol and estrone
(Table 1).
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Discussion
The present clinical investigation documents the ability of high-dose oral KTCZ administration to achieve and maintain profound (approximately 90%) depletion of systemic testosterone availability for 5 days in healthy young men, and thereby drive consistent secondary (2- to 3-fold) hypergonadotropism. Transdermal testosterone addback in this experimental setting effectually repressed elevated LH and FSH secretion to mid-normal baseline values, thereby affirming specificity of the intervention. Such findings extend earlier analyses showing the ability of 48 h of this dosing schedule of KTCZ to induce testosterone-reversible elevations in daily pulsatile LH secretion in young men (40, 41). Moreover, we here show that coadministration of anastrazole, a so-called fourth-generation aromatase inhibitor, completely reverses exogenous testosterone’s suppression of both endogenous GnRH-driven (daily integrated) and exogenous (acute 3-h) GnRH-stimulated LH and FSH secretion. Thus, assuming the pharmacological specificity of the foregoing aromatase inhibitor, these experimental observations point to a key physiological role of aromatization in mediating testosterone’s feedback restraint of the hypothalamo-pituitary (GnRH/LH-FSH) secretory unit in normal young men.
Administration of KTCZ and dexamethasone replacement reduced the total serum testosterone concentration to a mean (24-h pooled) value of 58 ± 8.6 ng/dL (2.0 ± 0.3 nmol/L). The combined regimen achieved commensurate reductions in 24-h serum-free testosterone, androstenedione, and DHEA-S (and cortisol) concentrations. The resultant marked hypoandrogenemia allows one to add back either near-physiological (present data) or subphysiological amounts of testosterone, and thus explore concentration-targeted actions of androgen. Whereas glucocorticoid administration is required concurrently to avert adrenal insufficiency (see Materials and Methods), we earlier documented that twice the present dose of dexamethasone given for 2 weeks does not alter 24-h pulsatile or bolus GnRH-stimulated LH secretion (54).
Unexpectedly, administration of KTCZ alone did not lower serum estradiol concentrations significantly. Indeed, KTCZ combined with transdermal testosterone tended to stimulate a rise in serum estradiol concentrations, which was partially opposed by coadministration of anastrazole. Another recent analysis using a recombinant estrogen receptor-based bioassay revealed that anastrazole alone reduced serum estradiol concentrations by 50% in healthy young men at a 20-fold lower dose (53). KTCZ administration especially in the presence of testosterone increased the serum concentration of estrone, thus indicating that this drug may alter estrogen metabolism and/or induce aromatase activity (44, 45, 50). Anastrazole significantly opposed the latter elevation in estrone levels. Thus, the present paradigm offers an experimental strategy for achieving preferential androgen depletion with a rise only in weaker estrogens.
In vivo aromatization of testosterone also seems to modulate LH release in the male dog, as inferred by increased gonadotropin secretion during administration of a less specific aromatase inhibitor, aminoglutethimide (57). The present investigation in humans used anastrazole, as a potent and highly specific aromatase antagonist with no known intrinsic estrogenic, progestational, or androgenic activity (52). In contrast, two earlier clinical studies used a less specific microbial progestin-derived aromatase inhibitor, testolactone (58), and came to opposite conclusions (10, 59). In the first report, testolactone administration failed to block the marked inhibition of LH release achieved by constant iv infusion of testosterone (10). In the second analysis, the same schedule of testolactone pretreatment ameliorated suppression of LH secretion by a reportedly identical infusion of testosterone (59). The basis for these disparate outcomes is not evident. However, the present investigations document unequivocal relief by anastrazole of (exogenous) testosterone’s negative feedback regulation of both endogenous (24-h) and exogenous (3-h) GnRH-driven LH and FSH secretion.
The thesis that endogenous aromatase activity mediates the negative feedback actions of testosterone on LH and FSH secretion in normal men is consistent with other independent clinical observations; e.g. the emergence of moderate hypergonadotropism (2- to 3-fold elevations in serum LH and FSH concentrations) during antiestrogen administration in young men and in rare patients harboring loss-of-function mutations of the estrogen receptor or aromatase enzyme (8, 12, 21, 22, 23, 25, 60, 61). Normal LH and/or FSH secretory responses to bolus supraphysiological GnRH injections were described in the only two such male patients given GnRH. In contrast, the present analysis disclosed accentuated GnRH-stimulated LH (albeit not FSH) secretion during short-term aromatase blockade in a larger group of testosterone-replete healthy men stimulated with a submaximally effective dose of GnRH (27, 62, 63, 64).
Antiandrogen administration in young men also elicits measurable
hypergonadotropism, which is reminiscent of that observed in patients
with inactivating mutations of the androgen receptor or the 5-
reductase enzyme (1, 4, 20, 24, 26, 27, 65, 66, 67, 68). However,
neither LH nor FSH secretion achieves castrate (10- to 30-fold)
elevations in such gonadally intact individuals. Here, the elevation in
LH and FSH concentrations in men treated with KTCZ (in whom
testosterone levels decreased, estradiol values were unchanged, and
estrone concentrations actually rose) also supports a role for
androgens in the regulation of gonadotropin secretion in males.
Accordingly, we infer that androgen and estradiol serve nonexclusive
and joint negative feedback roles in regulating secretory output of the
GnRH-gonadotropin unit in healthy men.
If bipartite mechanisms mediate the feedback actions of aromatizable
androgen on LH and FSH secretion in the adult human male, then
available clinical data would suggest that the relevant mechanisms of
testosterone feedback would likely include: 1) inhibition of
hypothalamic GnRH secretion by in situ central nervous
system (CNS) (but not peripheral) estrogen formation (below); 2)
suppression of gonadotropin secretion at the pituitary level by
systemic estrogen and aromatized androgen; and 3) repression of
hypothalamic GnRH secretion by pure androgen (1, 4, 7, 9, 11, 12, 14, 19, 21, 22, 23, 24, 26, 27, 59, 62, 63, 64, 69, 70, 71, 72) (Fig. 3). The foregoing multilevel feedback
construct predicts that anastrazole should antagonize testosterone’s
ability to: 1) repress endogenous GnRH secretion by blocking CNS
aromatization of androgen (first mechanism listed above); and 2)
inhibit endogenous and exogenous GnRH-stimulated LH secretion at the
pituitary level (second mechanism listed above) by attenuating systemic
(and putatively pituitary aromatase-dependent) estrogen biosynthesis.
According to this perspective, any purely androgenic effect of
testosterone remaining in the face of anastrazole blockade and
near-physiological testosterone addback (third mechanism listed above)
was insufficient in the present setting to suppress mean daily LH
production. This inference does not exclude possible inhibition of
pulsatile LH secretion, which was not studied here. Indeed, LH pulse
frequency can be increased by antiandrogens and decreased by
pharmacological amounts of nonaromatizable androgens in healthy young
men (1, 6, 27, 73).
|
), whereas both
peripheral and CNS-derived estrogen are effectively inhibitory in the
hypogonadal female. The foregoing reasoning would forecast that: 1) LH
pulse frequency will increase in response to anastrazole treatment in
young men (and women), as inferred in one preliminary analysis
(77); and 2) an exogenous testosterone clamp combined with
anastrazole should still elicit moderate hypergonadotropism, as
reported here. The latter inference would follow, inasmuch as the
systemic availability of physiological amounts of testosterone in this
context would not suppress hypothalamic GnRH secretion via estrogen
(due to concurrent blockade of CNS aromatase activity by anastrazole)
and also would not oppose endogenous or exogenous GnRH’s stimulation
of gonadotropin secretion (due to anastrazole’s inhibition of estrogen
biosynthesis).
Less is known about the negative feedback control of FSH secretion by
sex-steroid hormones in men (1, 27, 73, 78, 79).
Pharmacological amounts of estradiol and DHT can suppress (80, 81), whereas antiestrogens and to a lesser degree antiandrogens
stimulate FSH secretion in the eugonadal male (8, 82). The
present clinical analysis unmasks a clear role for in vivo
aromatization in mediating testosterone’s feedback restraint of FSH
secretion in healthy men. In contrast, male mice selected for
transgenic deletion of the estrogen-receptor gene maintain
apparently normal serum FSH concentrations (83). If such
observations are relevant to the human, then we forecast that the
estrogen-receptor ß isotype may be pertinent to testosterone’s
(postaromatization) negative feedback control of FSH secretion in
men.
In summary, a novel short-term (5-day) paradigm of high-dose oral KTCZ administration depletes systemic testosterone markedly (by 10- to 12-fold) and elicits 2.5- to 3.0-fold elevations in daily LH and FSH secretion in healthy young men. Transdermal testosterone replacement restores normal mean daily LH and FSH release via neuroendocrine mechanisms that are expressly dependent on endogenous aromatase activity. Thus, this clinical investigative model may find further utility in examining the acute dose- and time-dependencies of testosterone’s target-tissue effects in the normal male.
Acknowledgments
We thank Drs. Richard J. Santen (University of Virginia, Charlottesville, VA) and Paul Plourde (Zeneca Pharmaceuticals Group, Wilmington, DE) for helpful discussions and the donation of anastrazole tablets for study use; Patsy Craig for skillful preparation of the manuscript; Paula P. Azimi for data analysis, management, and graphics; Ginger Bauler for performance of the assays; and Sandra Jackson and the nursing staff at the University of Virginia General Clinical Research Center for conducting the research protocols.
Footnotes
1 This work was supported in part by NIH Grant MO1 RR00847 to the
General Clinical Research Center of the University of Virginia Health
System, the National Science Foundation Center for Biological Timing
(DIR 89-20162), the NIH U-54 Specialized Cooperative Centers Program in
Reproductive Research (HD-28934), and NIH Grant RO1 AG14799. 
2 Present address: Jones Institute for Reproductive Medicine,
Department of Obstetrics and Gynecology, Eastern Virginia Medical
School, Norfolk, Virginia 23507.
Received March 29, 2000.
Revised August 21, 2000.
Revised November 13, 2000.
Accepted January 26, 2001.
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