Androgen-Receptor Blockade Enhances Pulsatile Luteinizing Hormone Production in Late Pubertal Males: Evidence for a Hypothalamic Site of Physiologic Androgen Feedback Action

Kerrigan, James R.; Veldhuis, Johannes D.; Rogol, Alan D.

doi:10.1203/00006450-199401000-00021

Cited by 29 publications

(8 citation statements)

References 19 publications

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“…Variation to this extent was not observed in any other treatment group and may stem from the relatively low affinity of flutamide for the androgen receptor (Edelson, 1984;Simard, Luthy, Guay, Belanger, and Labrie, 1986), making it difficult to maintain a complete occupation of androgen receptors with flutamide. This is particularly problematic because blockade of the receptor with flutamide is also likely to remove negative feedback control of gonadotropin secretion (Veldhuis, Urban, and Dufau, 1992;Kerrigan, Veldhuis, and Rogol, 1994), increasing fetal T secretion. Under such conditions, any momentary reduction in the flutamide androgen receptor blockade would allow the larger pool of fetal T to interact with androgen receptors.…”

Section: Discussionmentioning

confidence: 99%

Timing of Prenatal Androgen Exposure: Anatomical and Endocrine Effects on Juvenile Male and Female Rhesus Monkeys

Herman¹,

Jones²,

Mann³

et al. 2001

Hormones and Behavior

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Prenatal androgen shapes genital differentiation. In humans, genital anatomy determines sex of rearing and subsequent behavioral development. Rhesus monkey genital anatomy and neuroendocrine function are sexually differentiated, and behavioral development occurs in a complex social environment. We investigated prenatal hormonal influences on sexual differentiation by suppressing or increasing androgens in male and female rhesus monkeys. Pregnant multiparous female rhesus monkeys received 35-40 days of testosterone enanthate (TE) treatment, androgen antagonist (flutamide, FL) treatment, or vehicle starting on gestation day (GD) 35 or 40 (early) or GD 110 or 115 (late). Exogenous androgen increased neonatal LH secretion in females when given early and altered female genital differentiation when administered either early or late. TE treatment, early or late in gestation, had no measurable effects on male genital differentiation or neuroendocrine function. Early FL treatment, however, radically altered male genital differentiation, producing in two cases males with a urethral opening separate from the glans. In females, early FL treatment produced detectable alterations in genitalia consistent with a reduced exposure to prenatal androgen, suggesting that female rhesus monkeys are naturally exposed prenatally to meaningful levels of T. Late FL treatment reduced male penis size and increased neonatal T secretion, but had no effect in females. This is the first study to block endogenous prenatal testosterone in rhesus monkeys, thereby altering sexual differentiation. These findings illustrate the complexity of prenatal influences on anatomical and neuroendocrine development. The relationship between the anatomical changes reported here and sex differences in behavior is currently under investigation.

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Section: Discussionmentioning

confidence: 99%

Timing of Prenatal Androgen Exposure: Anatomical and Endocrine Effects on Juvenile Male and Female Rhesus Monkeys

Herman¹,

Jones²,

Mann³

et al. 2001

Hormones and Behavior

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“…Androgens have been shown to regulate LH secretion negatively in late-pubertal boys [26], as well as in adult males [27]. Our observations suggest that androgens have a minor role compared with oestrogens in regulating LH as well as FSH secretion in early- and mid-pubertal boys.…”

Section: Discussionmentioning

confidence: 46%

Novel Treatment of Delayed Male Puberty with Aromatase Inhibitors

Dunkel

Wickman²

2002

Horm Res Paediatr

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Background: As the evidence for the role of oestrogens in epiphyseal closure appears unequivocal, we hypothesized that boys with constitutional delay of puberty would attain greater adult height if oestrogen action was suppressed. Methods: We conducted a randomized, double-blind, placebo-controlled study in which we treated boys with constitutional delay of puberty with testosterone plus placebo or testosterone plus a potent fourth-generation aromatase inhibitor, letrozole. Findings: Letrozole effectively inhibited oestrogen synthesis. The 17β-oestradiol concentrations increased in the untreated group and in the testosterone/placebo-treated group, but in the testosterone/letrozole-treated group no such increase was observed until letrozole treatment was discontinued. Testosterone concentrations were threefold higher in the testosterone/letrozole-treated group than in the other groups. Within 18 months, bone age had advanced by 1.1 ± 0.3 years in the untreated group and by 1.7 ± 0.3 years in the testosterone/placebo-treated group, but only by 0.9 ± 0.2 years in the testosterone/letrozole-treated group (p = 0.02 between treatment groups). Predicted adult height did not change significantly in the untreated group and in the testosterone/placebo-treated group, whereas in the testosterone/letrozole-treated group the increase was 5.1 ± 1.2 cm (p = 0.004). Conclusions: Our findings suggest that, if oestrogen action is inhibited in growing adolescents, adult height will increase. This observation provides a rationale for studies aimed at delaying bone maturation in several growth disorders.

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“…Despite differences in experimental design, duration of androgen withdrawal, analytical methods, and the choice of volunteers/ patient populations, an earlier study also reported a hypoandrogenemia-stimulated increase in LH pulse frequency, albeit in primary hypogonadal men withdrawn for a longer interval from im testosterone ester replacement therapy (41). Likewise, increased LH pulse frequency occurs in men treated with an androgen receptor antagonist to impede testosterone's negative feedback actions (1,42,43). Conversely, slowing of LH pulse frequency results from infusions of pharmacological amounts of 5␣-reduced androgen (6).…”

Section: Discussionmentioning

confidence: 99%

Disparate Serum Free Testosterone Concentrations and Degrees of Hypothalamo-Pituitary-Luteinizing Hormone Suppression Are Achieved by ContinuousVersusPulsatile Intravenous Androgen Replacement in Men: A Clinical Experimental Model of Ketoconazole-Induced Reversible Hypoandrogenemia with Controlled Testosterone Add-Back¹

Zwart

Iranmanesh

Veldhuis

1997

The Journal of Clinical Endocrinology & Metabolism

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To investigate the neuroendocrine mechanisms underlying the negative feedback actions of testosterone on both the pulsatile mode of LH release and the entropy or disorderliness of the LH release process, we blocked testicular androgen biosynthesis using oral high dose ketoconazole treatment with concomitant low dose glucocorticoid replacement for 48 h in six healthy young men. Volunteers were then infused iv with saline or a total of 8.0 mg testosterone base over the second 24 h via either a continuous or a pulsatile (90-min boluses) delivery pattern. Discrete peak detection (Cluster analysis) was applied to obtain a model-independent estimate of the frequency of serum LH concentration peaks, maximal and incremental LH peak amplitudes, peak area, and interpeak nadir serum LH concentrations. Approximate entropy was used to quantify the relative orderliness/disorderliness of the LH release process over 24 h. Ketoconazole treatment markedly lowered 24-h mean serum total and free testosterone concentrations (by 17-and 9-fold respectively), and significantly increased LH pulse frequency, maximal LH peak height, and interpeak nadir serum LH concentrations. Continuous iv testosterone add-back increased 24-h pooled serum free testosterone concentrations 3-fold more and concomitantly reduced mean (24-h) serum LH concentrations by at least 2-fold more than pulsatile delivery of the same total daily amount of androgen. Both modes of testosterone infusion suppressed pulsatile LH release, but the effects were distinguishable; namely, treatment with continuous vs. intermittent androgen add-back, respectively, decreased LH pulse frequency and incremental LH pulse amplitude. Ketoconazole treatment alone also significantly increased approximate entropy values, indicating greater disorderliness of LH release during androgen removal. Approximate entropy/orderliness was restored to baseline by continuous, but not pulsatile, iv testosterone replacement.In conclusion, the present novel testosterone add-back clinical experimental paradigm indicates that 1) remarkably different 24-h mean serum free testosterone concentrations can result from continuous vs. pulsatile testosterone delivery into the bloodstream; 2) androgen negative feedback can exert frequency-as well as amplitudedependent suppression of pulsatile LH release; and 3) testosterone is required to maintain an orderly 24-h LH release process in young men. (J Clin Endocrinol Metab 82: 2062-2069, 1997 G ONADAL HORMONES participate in regulating the pulsatile output of the hypothalamo-pituitary-gonadotroph unit in men and women. In particular, both steroidal and nonsteroidal feedback effectors are produced by various gonadal compartments. Feedback from the testis is important, because rodents and men with bilateral orchidectomy and/or primary testicular failure exhibit increased serum LH (and FSH) concentrations, defined as a castration response (1-5). Conversely, the administration of synthetic androgens or testosterone will suppress blood gonadotropin concentrations (6...

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Androgen-Receptor Blockade Enhances Pulsatile Luteinizing Hormone Production in Late Pubertal Males: Evidence for a Hypothalamic Site of Physiologic Androgen Feedback Action

Cited by 29 publications

References 19 publications

Timing of Prenatal Androgen Exposure: Anatomical and Endocrine Effects on Juvenile Male and Female Rhesus Monkeys

Timing of Prenatal Androgen Exposure: Anatomical and Endocrine Effects on Juvenile Male and Female Rhesus Monkeys

Novel Treatment of Delayed Male Puberty with Aromatase Inhibitors

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