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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 4 1248-1254
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Differential Sex Steroid Negative Feedback Regulation of Pulsatile Follicle-Stimulating Hormone Secretion in Healthy Older Men: Deconvolution Analysis and Steady- State Sex-Steroid Hormone Infusions in Frequently Sampled Healthy Older Individuals1

Johannes D. Veldhuis, Ali Iranmanesh, Eugeniusz Samojlik and Randall J. Urban

Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, National Science Foundation Center for Biological Timing (J.D.V.), Charlottesville, Virginia 22908; the Endocrine Section, Medicine Service, Salem Veterans Affairs Center (A.I.), Salem, Virginia 24153; the Endocrine and Metabolism Laboratory, Department of Medicine, New Jersey School of Medicine and Dentistry (E.S.), Princeton, New Jersey 07039; and the Department of Internal Medicine, University of Texas Medical Branch (R.J.U.), Galveston, Texas 77550

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Department of Medicine/Endocrinology & Metabolism, University of Virginia Health Sciences Center, NSF Center for Biological Timing, Box 202, Charlottesville, Virginia 22908.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The healthy aging male reproductive axis tends to exhibit a progressive decline in serum concentrations of biologically available testosterone with gradual concomitant reciprocal increases in both LH and FSH concentrations. However, relatively little is known about the sex steroid-mediated negative feedback regulation of physiologically pulsatile gonadotropin release in general, and episodic FSH release in particular, in older males. To examine the steroid hormone negative feedback control of pulsatile FSH secretion in healthy older men, we applied multiparameter deconvolution analysis to serum FSH (immunoradiometric assay) profiles obtained by sampling every 10 min over 24 h during steady state (4.5-day) infusions of estradiol (E2; 48 µg/day), 5{alpha}-dihydrotestosterone (DHT; 7.0 mg/day), or 5% dextrose in water in five healthy older men, aged 60–73 yr. We observed the following principal responses: 1) both E2 and DHT significantly suppressed mean and 24-h integrated serum FSH concentrations (P < 0.032); 2) the calculated daily secretion rate of FSH fell significantly in all five individuals during DHT infusion; 3) the apparent half-life of FSH decreased during E2 (but not DHT) infusion; 4) DHT infusion reduced the mass and frequency of FSH secretory bursts significantly; 5) neither E2 nor DHT treatment significantly attenuated the release of FSH stimulated by consecutive iv injections of GnRH (10 and 100 µg); and 6) integrated 24-h serum LH (immunoradiometric assay) concentrations decreased significantly during both DHT and E2 infusions, whereas mean LH release after the serial GnRH injections was not altered. Compared to younger men studied earlier in an identical fashion, older men had significantly reduced FSH intersecretory burst intervals, reflecting a higher FSH pulse frequency at baseline and during the steroid infusions and a significantly lower mass of FSH secreted per burst during E2 infusion.

We conclude that healthy older men maintain intact negative feedback responsiveness of the hypothalamo-pituitary gonadotroph unit to exogenously delivered sex steroid hormones, and that individual sex steroid hormones differentially regulate specific features of pulsatile FSH release and half-life in older men.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SEX STEROID hormones feed back negatively on the hypothalamo-pituitary-gonadotroph unit to regulate the pulsatile secretion of biologically active LH and FSH (1, 2, 3, 4, 5, 6, 7). FSH is not so well studied as LH, but a pulsatile mode of FSH release can be inferred by RIA, immunoradiometric assay (IRMA), immunofluorometric assay, and bioassay in children and young adults (1, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20).

Although FSH is required in man for quantitatively normal spermatogenesis (21), relatively little is known about FSH’s regulated secretion in the human. Continuous short term iv infusions of estrogen or androgen will suppress mean serum immunoreactive FSH concentrations (13, 22), as do depot injections of testosterone (3, 23, 24, 25, 26, 27, 28, 29, 30, 31). Conversely, nonsteroidal antagonists of estrogen or androgen tend to increase FSH release (1, 32).

Most clinical studies of FSH secretion in men have been carried out in young individuals. To investigate how sex steroid hormones regulate the dynamics of FSH secretion and/or removal in older men, we infused estradiol (E2) or the nonaromatizable androgen, 5{alpha}-dihydrotestosterone (DHT), iv over 4.5 days and evaluated feedback-directed changes in 24-h pulsatile FSH release via a two-site IRMA and deconvolution analysis. Results in healthy older individuals were compared with earlier data obtained in an identical fashion in young men (13).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patient characteristics

Five men, aged 60–73 yr, participated in this study after providing written informed consent, as approved by the human investigation committee. Each volunteer had normal biochemical tests of hepatic, renal, hematological, and metabolic function. In addition, there was no history of any acute or chronic medical illness, drug or medication use, recent weight loss, undue stress or physical exertion, or recent transmeridian travel in any of the participants. A detailed history and physical examination, including testis size and consistency were unremarkable, and no volunteer described any recent change or abnormality in sexual function. Volunteers also had normal age-specific fasting 0800 h serum concentrations of LH, FSH, T4, TSH, PRL, DHEA, total testosterone, and E2.

Clinical protocol

As described for younger adults (13) and concurrent with the earlier study, older men were studied in the General Clinical Research Center during three separate treatments assigned in randomized order. During each admission, blood sampling was carried out every 10 min for an interval of 28 h, which allowed for a 24-h baseline followed the next morning by two iv injections of GnRH (10 and 100 µg) given 2 h apart. Infusions consisted of 1 L 5% dextrose in water every 12 h containing either DHT (3.5 mg) or 17ß-estradiol (24 µg) for 4.5 days, as previously reported (13). Steady state blood levels of sex steroid hormones were evaluated in 24-h pooled sera.

Hormone assays

Blood samples were allowed to clot at room temperature, and sera were frozen at -20 C for later IRMA of FSH concentrations (Nichols Laboratory, San Juan Capistrano, CA) using a two-site assay standardized according to the Second International Reference Preparation of human menopausal gonadotropin (1, 33, 34, 35). Assay sensitivity was 0.2 IU/L and exhibited negligible (<0.1%) cross-reactivity with LH, hCG, TSH, or free {alpha}-subunit (1, 13, 33, 34, 35). The current mean within- and between-assay coefficients of variation ranged from 5.5–8.7%. All samples were assayed in duplicate, and each 28-h series was assayed within a single run. A dose-dependent (power) variance function was estimated for each set of 169 samples derived from any given sampling session (12, 36) for use as an inverse weighting function in deconvolution analysis (below). Serum concentrations of E2, estrone, DHT, sex hormone-binding globulin (SHBG), and total and free testosterone were measured by RIA (1, 8, 13, 35, 37, 38, 39).

Evaluating FSH secretion and half-life by deconvolution analysis

Each 28-h serum FSH concentration vs. time profile was submitted to deconvolution analysis to estimate the apparent half-life of endogenous FSH, the number of underlying secretory bursts, and their duration, amplitude, and mass via a multiparameter technique (40, 41, 42), here simplified to include purely pulsatile hormone secretion. After the complete series was analyzed for a common FSH half-life and burst half-duration (duration of the calculated secretory event at half-maximal amplitude in minutes), then the 24-h (endogenously driven) FSH pulse amplitude, mass, and frequency and the two 4-h (post-GnRH stimulation) pulses were evaluated separately for statistical purposes. We required 67% confidence interval tests on FSH secretory pulse amplitudes to exceed zero. As approximately 30–45 secretory parameters were estimated from 145 serum FSH concentrations in each time series, the number of statistical degrees of freedom exceeded 100 for the deconvolution fits.

Statistical analysis

To test the null hypothesis that a given steroid hormone infusion neither increased nor decreased any particular measure of FSH secretion or half-life consistently, the binomial distribution was applied. This analysis assumes that individual subjects show statistically independent responses to any given infusion, and the expected treatment responses are dichotomous. Inferences were confirmed by the Wilcoxon signed ranks (paired) test. Data from older and young men studied previously (13) were compared via the Wilcoxon rank sum (unpaired) test. Data are expressed as the mean ± SEM, and statistical significance was construed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
As shown in Fig. 1Go, both DHT and E2 infusions significantly suppressed mean 24-h serum FSH concentrations in all five subjects. There were commensurate decreases in integrated serum FSH concentrations (area under the 24-h serum FSH concentration vs. time curve).



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  		Figure 1. Mean 24-h serum FSH concentrations in five older men studied basally during 5% dextrose and water infusion alone (basal) or combined with the nonaromatizable androgen, DHT (7 mg daily) or E2 (48 µg daily) for 4.5 days. After 3.5 days of infusion, blood was sampled at 10-min intervals for 24 h to monitor pulsatile and mean serum FSH concentrations by IRMA (see Materials and Methods). Asterisks denote differences (P < 0.05) vs. basal in the same age group. For comparison, data from younger men studied earlier in an identical manner are also given (14).

 
Deconvolution analysis was used to evaluate the mechanisms by which DHT and E2 reduce mean 24-h serum FSH concentrations in older men. Only DHT infusions significantly suppressed FSH secretory burst frequency, which occurred in all five individuals studied (P < 0.05). The mean ± SEM values for FSH secretory pulse frequency were 19 ± 1 (median, 43) pulses/day at baseline vs. 14 ± 1.7 (median, 11) during DHT infusion (P < 0.05), and 18 ± 2 (median, 2) during E2 delivery. There were corresponding (reciprocal) changes in FSH intersecretory burst intervals (Fig. 2AGo). Older men had consistently (P < 0.05) shorter FSH intersecretory burst intervals during all three infusions compared to those in young men (13).



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  		Figure 2. Upper left, Impact of pure androgen (DHT) or E2 infusions for 4.5 days on deconvolution estimates of FSH intersecretory burst interval (time in minutes separating consecutive release episodes) in older men (hatched bars). DHT reduced the estimated number of FSH secretory episodes in each of the five men studied with concomitant increases in interpulse intervals, whereas E2 did not exert this consistent effect. For comparison, data from younger men (open bars) studied earlier in an identical manner are also given (14). Data are the mean ± SEM. Asterisks denote significant differences vs. baseline corresponding to that age group. Upper right, Androgen (DHT) but not estrogen (E2) infusion over 4.5 days suppressed the FSH secretory burst mass (amount of FSH secreted per burst, international units per L distribution volume). Lower left, Calculated mean daily FSH production rates (international units per L/24 h) in older men infused with 5% dextrose and water alone (basal), the unimpeded androgen (DHT), or E2. Lower right, Calculated FSH half-time of disappearance (minutes) in older men infused with 5% dextrose and water (basal), androgen (DHT), or E2 over 4.5 days.

 
Figure 2BGo demonstrates that DHT infusion significantly suppressed FSH secretory burst mass, which is the calculated amount of FSH (international units) secreted per pulse/L distribution volume. In contrast, E2 did not modify estimated FSH secretory burst mass, although the latter value in older men was significantly lower than that in young men (13). Neither DHT nor E2 affected the calculated secretory burst half-duration, which averaged 8.0 ± 3 (median, 6) min at baseline, 7.5 ± 3 (median, 5.9) min during DHT infusion, and 7.7 ± 2.2 (median, 6.4) min during E2 infusion (P = NS). In contrast, the maximal FSH secretory rate attained within a burst, namely its amplitude, decreased from 0.21 ± 0.06 (median, 0.17) IU/L·min at baseline to 0.16 ± 0.05 (median, 0.11) during DHT infusion and 0.14 ± 0.02 (median, 0.16) IU/L·min during E2 infusion (P < 0.05).

The calculated 24-h endogenous FSH production rate in a model of purely pulsatile hormone secretion is the product of the mass of hormone secreted per burst and the pulse frequency. The mean daily secretion rate of FSH fell significantly during DTH infusion (see Fig. 2CGo).

The estimated half-lives of endogenous FSH averaged 200 ± 30 (median, 200) min basally, 230 ± 12 (median, 240) min during DHT infusion, and 170 ± 11 (median, 170) min during E2 infusion (P < 0.05 for basal vs. E2; Fig. 2DGo).

Figure 3Go illustrates deconvolution-fitted serum FSH concentration profiles over 24 h in one elderly volunteer for each treatment condition. Calculated FSH secretory bursts are depicted also.



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  		Figure 3. Illustrative profiles of serum FSH concentrations (IRMA) observed by sampling blood at 10-min intervals in an individual older man infused with 5% dextrose and water alone (control), E2 (48 µg/day), or DHT (7 mg daily) for 4.5 days. Vertical error bars are within-sample dose-dependent SDs of the assay. The curves through the observed data are predicted by deconvolution analysis assuming a purely pulsatile model of hormone secretion. The right column depicts the calculated FSH secretory events as a function of time. Deconvolution data are summarized in Figs. 1Go and 2Go (and Results) for the group of five subjects as a whole compared to those in young controls.

 
Deconvolution analysis of FSH pulses stimulated by iv injections of 10 and 100 µg GnRH indicated that the mass of FSH secreted was no different for the two doses. Hence, we compared the mean mass of FSH released, which was 4.5 ± 1.0 IU/L at baseline, 6.2 ± 2.0 IU/L during DHT infusion, and 3.0 ± 0.45 IU/L during E2 treatment (P = NS). The corresponding mean (4-h) serum FSH concentrations after GnRH injections were 8.3 ± 2.0, 5.4 ± 2.1, and 4.0 ± 2.1 IU/L, respectively (P = NS). Typical profiles of deconvolution-fitted serum FSH concentration responses to 10 and 100 µg GnRH are illustrated in Fig. 4Go.



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  		Figure 4. Illustrative serum FSH concentrations in response to two consecutive bolus iv injections of GnRH 2 h apart in one healthy older male infused for 4–5 days with vehicle alone (control), E2, or the potent androgen, DHT (see Materials and Methods). The fitted curves (predicted) through the 4 h of 10-min sampled serum FSH measurements (IRMA) are shown in the left column, and the calculated FSH secretory rates over time are shown in the right column.

 
Pooled serum samples from the 145 samples at baseline and separately from the 25 samples after GnRH injections indicated that mean 24-h serum LH concentrations fell from a baseline of 6.1 ± 2.1 to 2.8 ± 0.82 IU/L during DHT infusion and to 4.8 ± 2.2 IU/L during E2 infusion (P < 0.05 for each treatment effect). Mean 4-h serum LH concentrations after GnRH injections were 17 ± 5.1 IU/L (baseline), 18 ± 6.4 IU/L (DHT), and 16 ± 7.7 IU/L (E2; P = NS).

Mean serum sex steroid hormone and SHBG concentrations in older men are shown in Table 1Go. Significant changes were observed as expected during the 4.5-day infusions.


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  		Table 1. Impact of 4.5-day estradiol or DHT infusion on serum sex steroid hormone concentrations in older men

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although serum FSH concentrations tend to rise progressively with advancing age in healthy men (1, 13, 32, 34, 44, 45, 46, 47), to our knowledge the present study is the first to demonstrate negative feedback actions of (exogenous) androgen and estrogen on pulsatile FSH release and/or the estimated FSH half-life in healthy older men. All five older individuals exhibited sex steroid-induced suppression of 24-h mean serum FSH concentrations by 35–50%, as estimated in a two-site IRMA capable of measuring intact FSH in plasma, which correlates well with our earlier independent in vitro bioassay of FSH by aromatase induction in cultured rat Sertoli or granulosa cells (13, 33).

By deconvolution analysis, we could estimate the relative contributions of pulsatile FSH secretion and FSH half-life to the overall (24-h) serum FSH concentrations. This analysis indicated that in older men pure androgen (DHT) infusion at the daily secretion rate of testosterone suppressed the calculated daily FSH secretion rate by 35–50%. In contrast, E2 diminished the apparent FSH half-life by approximately 50%. Accordingly, androgen and estrogen infusions achieved equivalent suppression of mean serum FSH concentrations in older men, but via distinct mechanisms. Our inference of an increase in FSH clearance (shorter FSH half-life) in response to E2 is consistent with the tendency of basic FSH isoforms to predominate in an estrogen-rich milieu and to exhibit shorter half-lives (2, 48, 49, 50). Conversely, the ability of DHT to decrease FSH secretion rates is consistent with its suppressive effect on LH production rates in older men here and in young individuals studied previously (22, 37, 51).

The nonaromatizable androgen, DHT, reduced total daily FSH secretion via a bipartite mechanism; namely, it significantly decreased (~25–30%) FSH secretory pulse frequency and FSH secretory burst mass. In a simple model of purely pulsatile FSH secretion, the mass of hormone secreted per burst and the number of secretory episodes per day jointly determine the overall secretion rate (40, 52). Thus, the combined inhibitory effects of DHT on FSH secretory burst frequency and mass fully account for the observed 50% fall in mean (24-h) serum FSH concentrations.

In contrast to the ability of E2 to suppress FSH concentrations in older men, this schedule of estrogen infusion did not achieve significant inhibition in the younger population studied previously (13). On the other hand, the present observations in older individuals, that E2 shortens the FSH half-life and that DHT reduces the mass of FSH secreted per burst, are consistent with similar findings in younger men (13). Of note, the DHT-induced decrease in the calculated FSH secretory burst frequency in older subjects recognized here was not observed earlier in six younger individuals, although there was a tendency toward increased interpulse interval length (i.e. decreased FSH pulse frequency) (13). In brief, the inhibitory actions of DHT and E2 in older men are similar to but not identical with those defined in their younger counterparts. Our experiments using a single dose of DTH did not directly test an earlier suggestion that older men may be more susceptible to the negative feedback actions of androgen (7). In addition, whether our inferences in a small healthy cohort of older men apply more generally to older men selected from larger populations without or with concomitant diseases, such as primary gonadal failure, and/or concurrent medication use cannot be determined from our experiments.

Comparison of measures of pulsatile FSH secretion in older men with values in young men studied earlier in an identical manner (13) showed that FSH intersecretory burst intervals were consistently shorter in older men, indicating an increased FSH pulse frequency basally as well as after sex steroid hormone infusion. Recently, using 2.5-min sampling overnight in a separate group of older and young men (53), we identified a significantly higher LH (IRMA) pulse frequency (albeit with lower mean amplitude) in the older cohort. In addition, the older men studied here exhibited a significantly lower FSH secretory burst mass during E2 infusion compared to their younger counterparts (13). As serum E2 concentrations during the infusions were comparable in the two age groups [~60–65 pg/mL (220–240 pmol/L)], and SHBG levels actually rise with age, it is possible that older men are somewhat more sensitive to feedback inhibition by this amount of exogenous estrogen. Our data do not include free E2 levels or address this possibility directly. In contrast, young and older men manifested similar FSH responses to antiestrogen treatment to (partially) antagonize endogenous E2 action (1).

Although our studies do not exclude age-related differences in the GnRH dose-FSH secretory response curve in vivo, we found preserved exogenous GnRH actions during short term infusions of sex steroids (administered at doses that suppress serum FSH concentrations by 35–50%). However, we have not yet examined the dispersion of biochemical FSH isoforms in various sex steroid milieus in young and older men, as observed recently within the changing estrogen milieu of the normal menstrual cycle (2). Lastly, as in young men studied previously, older men showed no difference in the mass of FSH released after iv injection of 10 vs. 100 µg GnRH. This agrees with our more recent detailed GnRH dose-FSH secretory response studies in approximately 20 healthy young and older men showing near-maximal FSH (and LH and {alpha}-subunit) release at a 10-µg dose of GnRH (34).

Endogenous FSH half-lives calculated earlier in young (221 ± 36 min) and older men (220 ± 30 min) (1, 13, 34) agree well with values estimated here (200 ± 30 min) as well as those determined directly by IRMA and bioassay of injected FSH decay curves in hypopituitary men, namely 287 ± 13 min (33). Thus, we infer that the deconvolution-estimated half-life of FSH is comparable in young and older men and is modified by E2, but not DHT, infusions over 4.5 days.

Although apparent basal or non-GnRH-dependent FSH release can be observed in vitro (14, 54, 55) and perhaps in some species in vivo (56), nonpulsatile secretion of FSH is more difficult to evaluate in humans in view of its long plasma half-life (above) (12, 33, 57, 58, 59, 60, 61). GnRH antagonists suppress serum FSH concentrations with a delayed time course and to a lesser final degree than LH (62, 63, 64, 65), consistent with differences in LH/FSH kinetics as well as unequal dependencies on GnRH (38, 66, 67) and on non-GnRH effectors (4, 68, 69, 70, 71, 72). In addition to biological issues, technical considerations make it difficult to simultaneously estimate basal and pulsatile release of a hormone with a prolonged half-life (42, 73, 74), although maximal rates of basal secretion can be estimated for hormones with shorter half-lives, for example testosterone, {alpha}-subunit, insulin, GH, and PTH (34, 43, 53, 75, 76). Thus, here we accepted the provisional assumption of a predominantly pulsatile mode of FSH secretion to allow comparisons with earlier studies in young men (1, 13, 34, 40). A simplifying assumption of negligible basal (interpulse) FSH secretion would predispose to an overestimated half-life and/or pulse mass in the event that substantial basal hormone release was present (42, 74).


   Footnotes
 
1 This work was supported in part by NIH Grant RR-00847 to the General Clinical Research Center of the University of Virginia; Clinical Associate Physician Award 3-MO1-RR-00847–1493 (to R.J.U.); Biomedical Research Support Grant 5-SO7–55-05431–26 (to R.J.U.); Research Career Development Award 1-K04-HD-00634 (to J.D.V.); Diabetes and Research Training Center Grant P60-AM-22125–05; NIH-supported Clinfo Data Reduction Systems; the NSF Science Center for Biological Timing (to J.D.V.); and P-30 Reproduction Research Center Grant P30-HD-28934–03 from the NICHHD. Back

Received October 24, 1996.

Revised December 18, 1996.

Accepted December 26, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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