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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 3040-3046
Copyright © 1997 by The Endocrine Society

Original Studies

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 Regulation1

C. Foresta, P. Bordon, M. Rossato, R. Mioni and J. D. Veldhuis

Instuto di Semeiotica Medica, Universita Degli Studi Di Padova (C.F., P.B., M.R., R.M.), Patologia Medica III, Via Nazareth 2, 35128 Padua, Italy; and Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: J.D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail:JDV{at}Virginia.Edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We have investigated possible (negative) feedback and (positive) feed-forward activity within the human male gonadotropic axis by measuring serum concentrations of LH, FSH, and testosterone in blood sampled frequently and for a prolonged interval (every 20 min for 19 h) simultaneously from the peripheral circulation and the left spermatic vein. Cross-correlation analysis with time lag was used to evaluate relationships among serial serum LH, FSH, and/or testosterone concentrations over time (i.e. consistency or dissociation of trends in concentrations). Separately, Cluster analysis was applied to identify discrete LH, FSH, and testosterone pulses, which were cataloged for possible peak coincidence. The hypergeometric probability distribution was then used to test the null hypothesis that LH, FSH, and testosterone pulses are randomly associated. Cross-correlation analysis revealed: 1) peripheral blood LH and testosterone concentrations correlate positively at lags of 40–120 min with LH increases preceding testosterone increases, viz., feed-forward (P < 0.001); 2) LH and FSH concentrations in peripheral blood are positively correlated in simultaneous blood samples, as well as when FSH lags LH by 20 min (P < 0.01); 3) unexpectedly, LH and FSH concentrations in peripheral blood are inversely related at a lag of 80–100 min (P = 0.002 and 0.004, respectively) where LH lags FSH; 4) LH and testosterone concentrations in the spermatic vein show strongly positive correlations at lags of 80, 100, and 120 min (P = 0.002, 0.004, and 0.021, respectively); 5) spermatic vein testosterone concentrations correlate negatively with peripheral blood LH concentrations 20 or 40 min later (P = 0.012 and 0.05, respectively), which indicates autonegative feedback; and 6) in contrast, testosterone levels in the spermatic vein correlate negatively with FSH values in the periphery 100 and 120 min later (P < 0.01), indicating more delayed negative feedback of testosterone on serum FSH concentrations. Discrete pulse coincidence analysis disclosed: 1) a total of 30 testosterone pulses in the spermatic vein and 25 testosterone pulses in peripheral blood, with 28 LH and 29 FSH pulses in the periphery; 2) individual LH and FSH peak concordance was significantly nonrandom for FSH pulse maxima lagging LH pulse maxima by 20 min (P < 0.05 vs. randomness), with 6 observed coincidences vs. 2.9 ± 1.5 (SD) expected; 3) peripheral LH pulses and spermatic vein testosterone pulses were strongly nonrandomly coupled at an 80-min lag, with 8 events observed vs. 3.0 ± 1.5 events expected (P = 0.004); and 4) LH peaks in peripheral blood followed testosterone peaks in the spermatic vein by 40 min in a nonrandom manner, specifically, n = 11 observed vs. 3.0 ± 1.5 expected (P < 0.001), indicating possible LH escape from testosterone’s negative feedback.

In summary, physiological regulation of the human male LH, FSH, and testosterone axis comprises multidirectional interactions, consisting of both (positive) feed-forward and (negative) feedback coupling. Based on a concept of network integration, we propose that age and other pathophysiological factors might modulate and/or disrupt these dynamic within-axis multihormonal linkages.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EARLIER STUDIES of the male hypothalamic (GnRH)-pituitary (gonadotropin)-testis (testosterone) axis have indicated that serum LH and FSH concentrations in peripheral blood are statistically cross-correlated over time (1, 2). Separate coincidence analyses indicate that LH and FSH peaks occur concordantly more often than expected on the basis of chance associations alone (3, 4, 5). Other measurements of LH action in vitro and LH and testosterone concentrations in vivo have suggested positive (feed-forward) relationships between serum LH concentrations and testosterone concentrations (2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). Moreover, in a report from a single laboratory, short-term catherization of the human spermatic vein in men with varicoceles revealed that peripheral LH pulses are often coincident visually with testosterone pulses identified via gonadal sampling (20). An issue not addressed in such earlier studies is whether the concordance of individual LH and testosterone pulses exceeds simple chance associations. In addition, to our knowledge, no studies have evaluated possible in vivo negative feedback within the human gonadotropic axis (autonegative feedback), e.g. between testosterone and LH or between testosterone and FSH.

Because both clinical and physiological considerations would suggest that negative as well as positive associations between LH and FSH release likely exist (1, 2, 8, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33), we designed the present experiments in healthy young men to investigate: 1) the relative temporal patterns of LH, FSH, and testosterone release in peripheral vs. spermatic vein blood, using the latter gonadal sampling site to enhance the testosterone signal; 2) the relationships among the serum concentrations of these hormones over time, using cross-correlation analysis to delineate the tendency of blood levels to vary together or in opposite directions; 3) the extent, if any, of statistically nonrandom coincidence among individual peaks of LH, FSH, and testosterone, after marking discrete pulse events, e.g. by Cluster analysis; and 4) possible negative feedback among one or both gonadotropic hormones and the Leydig-cell product, testosterone.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human subjects

The experimental protocol was approved by the Hospital Ethical Committee, and informed consent was obtained from each patient. Five men age 18–29 yr were studied in whom a left-sided varicocele was diagnosed by physical examination. The sampling study (below) was performed during catheterization for contrast imaging of the varicocele via a femoral vein approach.

Each volunteer had normal basal serum FSH, LH, testosterone, estradiol, and PRL concentrations. All subjects were in good health without endocrine, liver, kidney, or heart disease. None was taking drugs. Before the study, at least three ejaculates were obtained from each patient for sperm analysis. All patients showed moderate oligoasthenozoospermia (sperm density between 10–20 million/mL and sperm motility between 20–50%).

Blood sampling

Blood was sampled every 20 min for 19 h, beginning at 0800–1100 h in the periphery as well as simultaneously in the left internal spermatic vein (above). We obtained a total of 285 paired peripheral/spermatic vein samples in all five study sessions combined.

Assays

Serum concentrations of LH, FSH, and testosterone were determined by RIA. LH and FSH were assayed by 125I-labeled LH and FSH using a monoclonal antibody (Biodata, Rome, Italy). Inter- and intraassay variation coefficients for LH were 2.8% and 3.7%, respectively, and for FSH 2.3% and 3.8%, respectively. Testosterone was assayed by RIA using 3H-labeled testosterone (Radim, Rome, Italy). Intra- and inter-assay coefficients of variation were 7.8% and 7.0%, respectively. Testosterone concentrations in serum from the internal spermatic vein were determined after dilutions of 1:20–1:500 with PBS. Each patient’s spermatic and peripheral samples were assayed together.

Cross-correlation analysis

Cross-correlation analysis was used to measure the strength of the tendency of paired serum hormone concentrations to vary in the same or the opposite direction over time (2). Thus, cross-correlation generates multiple linear correlation coefficients (Pearson’s r value) based on paired hormone concentrations in the same blood sample (0 lag), or in blood samples collected at different lag times of interest (e.g. 20 min apart, 40 min apart, etc.). Individual r values were determined in each of the five men based on all the measured serum LH, FSH, and testosterone concentrations in each individual series (usually 57 samples/subject). The r values were converted to z scores by the relationship, z = r/SD, where SD = 1/(n-k)1/2, n is the number of blood samples, and k is the number of lag units (in this case, a lag unit equals 20 min). The z score distributions at each lag within the group of five men were then evaluated against the null hypothesis of a random and normal distribution about 0 with unit standard deviation; i.e. the null hypothesis states that correlation coefficients are randomly distributed between -1 and +1 with no evidence of systematic correlation between the hormone pairs of interest. This statistical comparison was carried out using the Kolmogorov-Smirnov statistic (34).

Cluster and discrete peak coincidence

Separate coincidence analysis was used to determine whether the number of observed coincidences between distinct pulse events determined by cluster analysis in paired hormone series exceeded chance associations (5, 35, 36). If two hormone series each contain some number of pulses, there is a finite probability of observing a certain number of purely random peak coincidences depending on the frequency of pulsatile events in the two series (3, 36). The expected rate of purely chance peak concordance can be estimated from the hypergeometric probability distribution (5). Accordingly, we first carried out Cluster analysis using a 2 x 2 point moving test cluster for significant increases and decreases in the FSH and testosterone time series, as judged by a pooled t statistic of 2.0 and 2.0 for the upstroke and downstroke, respectively (37). Similar cluster analysis was carried out to detect LH pulses, using a 2-point moving test nadir against a 1-point test peak (and t statistics of 2.0). The identified pulse locations (samples containing peak maxima) for LH, FSH, and testosterone in any given individual were used to evaluate coincidences between relevant paired pulse trains; specifically, LH and testosterone, FSH and testosterone, and LH and FSH. Coincident peak maxima were enumerated either in the same blood sample (0 lag), or in blood samples separated by various time lags of interest, e.g. testosterone peaks occurring 20, 40, 60, etc. min after the LH peak maxima (denoted as 20, 40, or 60 min testosterone lags, respectively) (38). Group P values for nonrandom peak concordance were computed as the probability of observing at least the identified total number of coincidence peaks solely on the basis of chance (i.e. right-hand tail of the probability distribution for expected random coincidences) given concatenated paired hormone pulse trains.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1Go shows a typical profile of serum FSH, LH, and testosterone concentrations in the peripheral and internal spermatic veins of one man sampled every 20 min for 19 h. Note that LH concentration pulses are followed by large increases in testosterone levels after a time lag.



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  		Figure 1. Illustrative profiles of serum FSH, LH, and testosterone concentrations obtained by sampling blood every 20 min for 19 h from antecubital and left spermatic veins in one young man.

 
Cross-correlation analysis revealed strongly positive correlations between LH measured in peripheral blood, and testosterone measured in the spermatic vein (Fig. 2Go), such that increases in peripheral serum LH concentrations preceded rises in spermatic vein serum testosterone levels by 60, 80, 100, and 120 min. The corresponding (group) P values against random associations at these four time lags were 0.028, 0.009, 0.002, and 0.002, respectively. In contrast, serum LH concentrations compared with preceding testosterone concentrations showed significant negative feedback, viz., a testosterone increase preceded a fall in LH concentrations by 20 and 40 min (P < 0.01 and 0.05, respectively). Thus, both positive and negative feedback between LH and testosterone was demonstrable.



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  		Figure 2. Standard-deviate (or z) scores reflecting strength and direction of cross-correlations between peripheral serum LH concentrations (LHp) and spermatic vein testosterone concentrations (Ts) in a group of five men. Volunteers were sampled at 20-min intervals simultaneously via a peripheral vein and left internal spermatic vein (see Materials and Methods). Data are median z scores at indicated lags (time in min separating correlated samples). Purely random associations predict a median z score of 0 with unit SD (dashed lines). P values were calculated for entire group of z scores in five men. Asterisks denote significant group P values.

 
Figure 3Go shows cross-correlations between serum LH and testosterone concentrations when both were measured in spermatic vein blood. As in the periphery (above), LH and testosterone were positively cross-correlated when testosterone lagged LH by 80, 100, and 120 min (P = 0.021, 0.004, and 0.002, respectively). Spermatic vein sampling also corroborated negative feedback, whereby a testosterone concentration increase preceded a LH concentration decrease by 20, 40, or 60 min (P < 0.05 to P = 0.01 vs. chance).



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  		Figure 3. Cross-correlation coefficient z score values relating spermatic vein LH (LHs) and spermatic vein testosterone concentrations (Ts) in a group of five men. Data are presented as in Fig. 2Go.

 
Comparisons of serum LH and testosterone concentrations both measured in peripheral blood showed significant (P < 0.05 to < 0.001) and extended positive cross-correlations between LH and testosterone, when the latter lagged by 0–120 min. These extended lag times (compare above, 80–120 min in spermatic vein blood) reflect the expected autocorrelation within an LH (or testosterone) profile, given the relatively long half-life of each of these two hormones in peripheral blood.

Cross-correlation relationships between serum LH and FSH concentrations are shown in Fig. 4Go. LH changes in the periphery were mirrored by similar FSH changes 0–60 min later (negative lag). Unexpectedly, FSH increases were associated with delayed LH decreases (and vice versa) 80 and 100 min later; i.e. there is a lagged negative correlation between (peripheral) serum FSH and LH concentrations (P < 0.01).



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  		Figure 4. Cross-correlation z score values relating peripheral serum LH (LHp) and FSH (FSHp) concentrations in a group of five men (see legend of Fig. 2Go).

 
In Fig. 5Go, serum FSH concentrations in the periphery are correlated negatively with testosterone concentrations in the spermatic vein; the latter increased 100 and 120 min before FSH concentrations decreased in the periphery (P < 0.01). In contrast to LH and testosterone (above), no positive (feed-forward) correlation was found between serum FSH levels in the periphery and testosterone concentrations in the spermatic vein.



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  		Figure 5. Cross-correlation z score values peripheral FSH (FSHp) and spermatic vein testosterone (Ts) concentrations in a group of five men, presented as described in Fig. 2Go.

 
We next evaluated whether pulses occur coincidentally more often than expected on the basis of chance alone, as defined by discrete peak coincidence analysis (3, 5, 35). This analysis showed that the individual LH and testosterone pulses were strongly nonrandomly associated (Fig. 6Go), e.g. individual testosterone (spermatic vein) and LH (peripheral) pulses were significantly concordant after an 80-min testosterone lag. Thus, an LH peak maximum tended to precede a testosterone peak maximum by 80 min [P = 0.004, for eight peaks observed vs. 3 ± 1.5 (SD) expected]. Conversely, testosterone pulses in the spermatic vein significantly preceded LH pulses in the periphery by 40 min; viz., 11 such concordant events were observed over an expected random value of 3 ± 1.5 (P = 0.001). This suggests that LH pulses may escape inhibition by a testosterone peak after an interval of 40 min.



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  		Figure 6. Observed vs. randomly expected numbers of coincident serum LH and testosterone peaks in five men. Testosterone pulses were detected in spermatic vein and LH pulses in peripheral blood by Cluster analysis (see Materials and Methods). Expected numbers of purely randomly coincident peaks (mean ± SD) are shown by horizontal lines, assuming merely chance concordance given individual pulse numbers encountered (and sampling frequency employed) in this study. Observed coincidence rate is depicted by individual symbols represented at various time lags (time in minutes separating peak maxima in two hormone pulse profiles). Statistical significance is shown based on hypergeometric probability distribution as confirmed by Monte Carlo simulations (3, 5, 36).

 
Individual testosterone and FSH pulse coincidences are shown in Fig. 7Go. Unlike LH, FSH pulses never significantly preceded testosterone pulses at any interval studied (i.e. lowest absolute P value against randomness was 0.084 for five concordant pulses at a 40 min testosterone lag). In contrast, testosterone pulses preceded FSH pulses significantly at an 80-min lag; seven observed coincidences vs. 3.1 ± 1.6 expected (P = 0.021). This would suggest that testosterone pulses may suppress FSH peaks for up to 80 min.



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  		Figure 7. Serum FSH and testosterone discrete peak coincidence in five men. Data are presented as described in legend of Fig. 6Go.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study combines several new experimental strategies (e.g. simultaneous peripheral and spermatic vein blood sampling, Cluster analysis to identify discrete and potentially coincident hormone peaks, and cross-correlation analysis to assess parallel vs. divergent trends in serum hormone concentrations over time) to investigate the physiology of LH, FSH, and testosterone corelease and feedback in the human male. Extended and repetitive blood sampling every 20 min over 19 h allowed us to delineate for the first time both feed-forward (positive) and feedback (negative) relationships among the three reproductive hormones. First, we confirmed earlier studies showing that LH and FSH and LH and testosterone concentrations in peripheral blood are positively cross-correlated (2, 19). Second, in this independent population of men, we corroborated that discrete pulses of LH and FSH occur coincidentally (at a 20-min FSH lag) more often than expected on the basis of chance associations alone (3, 5). Third, we showed that individual LH pulses in peripheral blood precede testosterone pulses in the spermatic vein by 80 min significantly nonrandomly (P = 0.004). Fourth, by measuring LH and testosterone concentrations in the same spermatic vein samples, we identified strongly positive correlations when testosterone levels lagged LH levels by 80–120 min (P < 0.02 for each lag). This represents an expected physiological (positive) feed-forward relationship, reflecting pituitary LH drive of gonadal Leydig cell testosterone secretion (9, 10, 14, 16, 18, 39, 40). And, fifth, we established a significant cross-correlation between LH concentrations in the spermatic vein and periphery, as well as between testosterone levels at these two locations (P = 0.001, with a lag encompassing ± 20 min), as expected, thus validating these measures. Accordingly, the current studies document concurrent LH and FSH release and define feed-forward LH and testosterone coupling in the human male, both at the level of hormone concentrations and in relation to discrete pulse events.

Other new observations in the present study are that individual LH peaks in the peripheral blood tend to arise approximately 40 min following testosterone pulses in the spermatic vein (P < 0.001 vs. chance association). This timing suggests escape or recovery of the GnRH-LH neurosecretory unit following delivery of an (inhibitory) testosterone pulse into the peripheral blood. Corresponding measurements in spermatic vein blood disclosed a 60-min delay between an increase in testosterone concentrations and a decrease in LH concentrations (P = 0.028). Thus, the current data define significant bidirectional interactions between LH and testosterone pulse signals, namely both feed-forward and feedback interplay within the male GnRH-LH-testosterone axis. An analogous negative-feedback relationship was recognized between serum testosterone concentrations in the spermatic vein and serum FSH concentrations in the periphery but with a more extended delay, specifically 100 and 120 min (P < 0.01). This longer delay may reflect the 3- to 4-fold longer half-life of FSH, e.g. as determined by FSH infusions in the human male (41), as well as possibly a more delayed inhibition of FSH release by testosterone (31, 42). Our experiments do not distinguish between these two possibilities.

Unexpectedly, serum LH and FSH concentrations were negatively correlated at an 80- and 100-min LH lag (time separating the correlated serum FSH and LH concentrations). Specifically, when FSH concentrations decreased, LH concentrations tended to increase after a lag of 80 and 100 min (P = 0.002 and 0.004, respectively). Conversely, when FSH concentrations increased, LH levels tended to fall 80 and 100 min later. The exact mechanisms underlying this possible negative intergonadotropic hormone linkage are not evident from the present analysis and experiments but warrant confirmation and further evaluation.

The above results indicate that the human male reproductive axis is dynamically interactive and maintains both feedback and feed-forward relationships between LH and testosterone release and between FSH and testosterone release. Available data do not address the possible roles of inhibin B, estradiol, or other testicular products (43) in modifying or endowing some of the foregoing negative-feedback relationships. Indeed, an earlier study using short-term spermatic vein sampling identified pulsatile (co-)release of estradiol and inhibin {alpha} subunit in men (44). Although not yet readily practicable, even more frequent blood sampling may be required to determine the exact time constants of delay within the male reproductive feedback and feed-forward signaling system. Further studies will also be required over a broader span of ages, to assess whether aging disrupts the LH, FSH, and/or testosterone interactions inferred in this study in young men. This possibility is suggested by recent overnight 2.5-min peripheral blood sampling in young vs. older men, which revealed significant loss of synchrony (reduced conditional regularity between LH and testosterone release in older individuals) (45). Lastly, although varicoceles are not known to markedly alter the LH-FSH-testosterone axis, spermatic vein data are not available to our knowledge to define episodic gonadotropin and sex-steroid corelease in the absence of this anomaly.

The foregoing gonadal catheterization data suggest the analytical possibility that one might deconvolve peripheral serum testosterone concentrations, and then correlate calculated testosterone secretion rates with measured serum LH concentrations, as suggested earlier on theoretical grounds (35). This strategy might not be so incisive as directly sampling the spermatic vein, but would likely enhance identification of the testosterone pulse signal with less experimental invasiveness. Calculated overnight testosterone secretory profiles in (young vs. older) men sampled every 2.5 min also indicate that testosterone secretion is pulsatile admixed with basal secretion (46), and that pulsatile but not basal testosterone secretion is blunted with aging. Via a converse analytical strategy, negative-feedback was also identified between peripheral serum testosterone concentrations and calculated LH secretion rates in normal young and older men (47), with older men showing greater time delays in negative-feedback.

In conclusion, using cross-correlation analysis and discrete (Cluster) peak detection as complementary analytical strategies, and simultaneous spermatic and peripheral vein blood sampling in young men, we could identify both feedback and feed-forward relationships between: 1) LH and FSH; 2) LH and testosterone; and 3) FSH and testosterone release. Disclosure of both feedback and feed-forward signaling interactions among LH, FSH, and testosterone raises the consideration that additional pathophysiologies may arise by way of disruption of these relationships in aging and/or various reproductive disorders.


   Acknowledgments
 
We thank Patsy Craig for her skillful preparation of the manuscript and Paula P. Azimi for the artwork.


   Footnotes
 
1 This work was supported in part by an NIH Research Career Development Award 1-KO4-HD-00634 (to J.D.V.), the Baxter Healthcare Corporation (Round Lake, IL), the NIH-supported Clinfo Data Reduction Systems, the University of Virginia Pratt Foundation and Academic Enhancement Program, the National Science Foundation Center for Biological Timing (Grant DIR89–20162), and the NIH P-30 Center for Reproduction Research (HD-28934) from National Institute of Child Health and Human Development. Back

Received March 24, 1997.

Accepted May 21, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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