| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Other Original Articles |
Reproductive Endocrine Unit, Department of Medicine, and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Frances Hayes, M.B., M.R.C.P.I., Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. E-mail: hayes.frances{at}mgh.harvard.edu
Abstract
Regulation of FSH secretion in the male involves a complex balance between stimulation by GnRH from the hypothalamus, inhibitory feedback by sex steroids (T and E2) and inhibin B (Inh B) from the gonads, and autocrine/paracrine modulation by activin and follistatin within the pituitary. The aim of the present study was to delineate the feedback control of FSH in the human male with specific reference to the relative roles of sex steroids vs. Inh B. Two experimental human models were used: 1) normal (NL) men subjected to acute sex steroid withdrawal (-T, -E2, + Inh B), and 2) functional castrate males (-T, -E2, -Inh B).
Nine NL men (age range, 25–45 yr) and three castrate males (age range, 23–47 yr) were studied. The NL men underwent acute sex steroid suppression using high dose ketoconazole (1-g loading dose, followed by 400 mg, orally, four times daily for 150 h). Gonadotropin secretion was characterized by frequent blood sampling every 10 min for 12 h at baseline and on d 3 and 6 of sex steroid ablation. In the three castrate subjects, blood sampling was performed every 5 min for 24 h 8 wk after discontinuing androgen replacement therapy.
In the NL men, treatment with ketoconazole resulted in a decline to castrate levels in T (451 ± 20 to 38 ± 7 ng/dl; P < 0.0005) and E2 (39 ± 4 to 15 ± 2 pg/ml; P < 0.005) and a modest, but significant, decline in Inh B levels, which remained within the normal range (183 ± 19 to 136 ± 13 pg/ml; P < 0.005). This suppression of sex steroids was associated with a more marked increase in mean LH (9.5 ± 0.9 to 24.9 ± 2.0 IU/liter; P < 0.0001) than FSH levels (5.1 ± 0.7 to 10.0 ± 1.5 IU/liter; P < 0.005), with the latter not exceeding the normal adult male range. The castrate subjects had a mean T level of 66 ± 8 ng/dl, an E2 level of 20 ± 1 pg/ml, and undetectable Inh B levels. Despite a similar sex steroid milieu, the mean FSH levels observed in NL men after acute sex steroid ablation were approximately 6-fold lower than those seen in the castrate subjects (10.0 ± 1.5 vs. 59.5 ± 17.7 IU/liter; P < 0.0005). In contrast, mean LH levels in the NL men were less than 3-fold lower than those in castrate subjects (24.9 ± 2.0 vs. 66.8 ± 20.1 IU/liter; P < 0.005).
From this human model of acute sex steroid withdrawal, we conclude that Inh B is likely to be the major feedback regulator of FSH secretion in the human male.
IN THE UNITED States, 10–15% of couples are infertile, with a male factor implicated in up to 50% of cases (1). To date, the etiology of most cases of male infertility remains poorly understood, with inconsistent elevation of FSH levels. Indeed, the role of FSH in both the initiation and the maintenance of spermatogenesis is controversial and exhibits important species differences (2, 3, 4, 5, 6). In male mice rendered FSH deficient due to targeted disruption of the FSH ß-subunit (2) or FSH receptor gene (3), fertility is preserved despite reduced testes size and partial spermatogenic failure. In the human there is discordance between the phenotype of men with mutations in the FSH receptor gene who are oligospermic (4) and those with mutations of the FSH ß-subunit who are azoospermic (5, 6). This discrepancy in the degree of spermatogenic failure suggests that ligand deficiency may well have a more severe expression than that of the FSH receptor and raises question about the completeness of the receptor knockout models. Given these human data indicating that FSH is required for quantitatively normal spermatogenesis, delineating the feedback regulation of FSH is key to defining the pathophysiology of male infertility as well as determining the feasibility of hormonal approaches to male contraception.
It has long been known that regulation of gonadotropin secretion in the human male involves a complex interplay between stimulation by GnRH secretion and inhibitory feedback by sex steroids comprising T and E2 from Leydig cells. However, in the last decade it has also been increasingly appreciated that for FSH, there is an additional level of complexity mediated by nonsteroidal factors. This nonsteroidal regulation of FSH comprises an endocrine negative feedback loop mediated by inhibin B (Inh B) secretion from Sertoli cells (7, 8, 9, 10, 11, 12, 13) in addition to autocrine/paracrine modulation within the pituitary mediated by activin and follistatin (14). Thus, an integrated approach to the study of FSH regulation requires utilization of models that permit isolation of the effects of sex steroids from those of nonsteroidal factors.
To date, most clinical investigation in the human has addressed only the sex steroid component of gonadal feedback (15, 16, 17, 18, 19, 20, 21, 22, 23, 24). However, the nonsteroidal component of gonadal feedback is particularly important given that most cases of male infertility represent a defect in the seminiferous tubule compartment of the testis in the absence of any obvious perturbation in Leydig cell function. It has only recently been possible to quantitate the biologically active nonsteroidal gonadal regulators of FSH reliably with the development of sensitive and specific assays for Inh B (25). To date, inhibin has not been available in sufficient purity or quantity for human administration; thus, for the present, studies on inhibin physiology in the human must remain inferential. In terms of the GnRH component to FSH regulation in the male, available data are limited to normal men with intact gonadal negative feedback. Although manipulation of GnRH pulse frequency has been shown to have little impact on serum FSH levels in the setting of a gonadally intact male (26, 27, 28), the effect of GnRH pulse frequency on FSH in the absence of gonadal feedback has not been determined.
Thus, in the present experiments we set out to elucidate the Inh B contribution to FSH regulation by comparing the FSH levels of normal men after acute sex steroid withdrawal with those in age-matched functional castrates who lack both sex steroids and Inh B. We hypothesized that suppression of sex steroid negative feedback to castrate levels would fail to recreate castrate levels of FSH in an Inh B-replete model, implying that Inh B is the major regulator of FSH secretion in the human male. We also hypothesized that Inh B would have no effect on GnRH pulse frequency, such that despite markedly different Inh B levels, similar pulse frequencies would be observed in the normal men after sex steroid withdrawal and in the functional castrates.
Subjects and Methods
Normal (NL) men
Ten NL men (age range, 25–45 yr) participated in the study. All NL study subjects met the following criteria: 1) normal pubertal development, sexual function, and general health; 2) normal physical examination including a testicular volume 20 ml or more; 3) normal serum levels of T, E2, LH, FSH, TSH, and PRL; and 4) normal semen analysis according to WHO criteria (29). Normal subjects represent the integrated model of both sex steroid and nonsteroidal components of gonadotropin negative feedback. Suppression of sex steroid synthesis in these subjects thus reveals the nonsteroidal input to FSH control.
Men with castrate T and Inh B levels
Three age-matched men (age range, 23–47 yr) with castrate levels of T and Inh B were also studied. Two patients were agonadal and thus true castrates; the first after a severe burn injury to the groin at the age of 10 yr, and the second after congenital unilateral torsion and contralateral reflex sympathetic orchiopathy. The third patient, who had Klinefelter syndrome, was not a true castrate, in that his testes were still present. However, we felt that it was appropriate to classify him as a functional castrate given a testes size of only 1 ml in association with a T level of 59 ng/dl (2.1 nmol/liter) and an undetectable Inh B level. All three patients had been off T replacement for at least 8 wk before participating in the study. Castrate men represent a model characterized by the complete absence of both gonadal sex steroids and nonsteroidal factors. Accordingly, they define the FSH levels that occur when the hypothalamic-pituitary axis is unrestrained by either component of gonadal feedback.
The study was approved by the human research committee at the Massachusetts General Hospital, and all subjects provided written informed consent.
Study protocol
Exp 1: neuroendocrine characterization of NL men before and after acute sex steroid suppression. Subjects were admitted to the General Clinical Research Center of Massachusetts General Hospital at 1700 h and had an iv cannula inserted in a forearm vein. Commencing at 1800 h, blood sampling was performed every 10 min for 12 h, after which subjects were discharged home. On completion of the baseline frequent sampling study, an interval of at least 14 d was allowed to elapse before commencing sex steroid suppression due to blood volume considerations. Acute sex steroid withdrawal was induced in 10 NL men using high dose ketoconazole, an antifungal imidazole that blocks steroidogenesis predominantly by inhibiting C17–20 lyase (30, 31). The ketoconazole regimen employed comprised a loading dose of 1 g at midnight, followed by a maintenance dose of 400 mg, four times daily, as previously described (24). Because this dose of ketoconazole may impair cortisol biosynthesis, glucocorticoid replacement was provided in the form of dexamethasone (0.5 mg twice daily). We (19) and others (32) have demonstrated previously that this dose of dexamethasone does not suppress gonadotropin secretion in men. In view of the potential hepatotoxicity of ketoconazole (31), liver function tests were monitored daily. Participants were withdrawn from the study if hepatic transaminases increased to greater than 3 times the upper limit of normal. The same 12-h frequent blood-sampling paradigm performed at baseline was repeated during h 66–78 (d 3) and 138–150 (d 6) of sex steroid ablation to define the extent and time course of changes in gonadotropin secretion during acute sex steroid ablation.
Exp 2: neuroendocrine characterization of men with castrate T and Inh B levels In the three patients with castrate levels of T and Inh B, a more intensive sampling paradigm (every 5 min for 24 h) was employed given the importance of sampling interval and duration on analysis of pulsatile hormone secretion (33, 34) and the absence of blood volume considerations, as frequent sampling was performed on just one occasion.
In both Exp 1 and Exp 2, all samples were assayed for LH and free
-subunit (FAS), whereas FSH was measured in hourly samples. T and E2
levels were determined at baseline and at 6-h intervals during the
study. Inh B was measured in a pool comprising equal aliquots of each
sample obtained during the study. Mean LH and FSH levels were
calculated for each frequent blood-sampling study. Pulsatile LH and FAS
secretion were analyzed using a modification of the Santen and Bardin
method (35) as previously validated by our group
(36).
Hormone assays
Serum LH and FSH concentrations were determined by microparticle
enzyme immunoassay using the automated Abbott AxSYM system (Abbot Laboratories, Inc., Chicago, IL). The Second International
Reference Preparation was used as the reference standard. The assay
sensitivity for both LH and FSH was 1.6 mIU/ml. The intraassay
coefficients of variation (CVs) for LH and FSH were less than 7% and
less than 6%, respectively, with interassay CVs for both hormones of
less than 7.4%. The reference range for gonadotropins in this assay
was based on the 95% confidence limits of 36 NL men, aged 18–45 yr,
and was 4.9–14.9 IU/liter for LH and 1.3–10.1 IU/liter for FSH. Serum
FAS concentrations were determined by a monoclonal antibody RIA using
highly purified -subunit of hCG as the assay calibrator
(37). Serum T concentrations were measured using the
Coat-A-Count RIA kit (Diagnostic Products, Los Angeles,
CA), which has intra- and interassay CVs of less than 10% and a
detection limit of 4 ng/dl. E2 was measured by the Abbott AxSYM system,
which has an analytical sensitivity of 10 pg/ml, an intraassay CV of
less than 6.4%, and an interassay CV of less than 10.6%. Inh B was
measured using a commercially available, double antibody ELISA
(Serotec, Oxford, UK) as previously described
(25). In our use, the clinical detection limit of this
assay is 50 pg/ml, with a CV of 4–6% within plate and 15–18%
between plates.
Statistical methods
In the NL men, mean hormone levels at baseline were compared with those during d 3 and 6 of sex steroid suppression using ANOVA for repeated measures followed by post-hoc Newman-Keuls testing for individual differences. The gonadotropin responses (mean LH and FSH levels, mean pulse frequency, and amplitude of both LH and FAS) of the NL men on d 6 of ketoconazole administration were compared with those in the castrate subjects using an unpaired t test. To correct for the different sampling paradigms employed, only data from samples drawn every 10 min for 12 h were included when comparing gonadotropin secretion in the functional castrates with that in the NL men after sex steroid ablation. P < 0.05 was taken to be statistically significant.
Results
Exp 1: neuroendocrine characterization of NL men before and after acute sex steroid suppression
One individual was withdrawn from the study on d 2 of ketoconazole
administration because of a greater than 3-fold increase in hepatic
transaminases, which returned to normal within 2 wk of discontinuation
of the drug. The data reported are therefore for the nine subjects who
completed 6 d of ketoconazole administration. Ketoconazole induced
a fall to castrate levels of T [451 ± 20 to 38 ± 7 ng/dl
(16 ± 1 to 1.4 ± 0.2 nmol/liter); P <
0.0005] and E2 [39 ± 4 to 15 ± 2 pg/ml (143 ± 15 to
55 ± 7 pmol/liter); P < 0.005] and a modest
decrease in Inh B levels, which remained within the normal range
(183 ± 19 to 136 ± 13 pg/ml; P < 0.005;
Fig. 1
). Suppression of sex steroids was
associated with a more marked increase in mean LH (9.5 ± 0.9 to
24.9 ± 2.0 IU/liter; P < 0.0001) than FSH levels
(5.1 ± 0.7 to 10.0 ± 1.5 IU/liter; P <
0.005; Fig. 1), with the latter remaining in the normal adult male
range. Comparison of mean gonadotropin levels on d 3 vs. d 6
of ketoconazole administration reveled no significant differences
(26.2 ± 2.2 vs. 24.9 ± 2.0 IU/liter for LH and
8.6 ± 1.2 vs. 10.0 ± 1.5 IU/liter for FSH,
respectively); therefore, only the d 6 data are presented in the
figures. GnRH pulse frequency increased, as evidenced by a decrease in
interpulse interval [IPI; 167 ± 28 vs. 90 ± 17
min for LH (P < 0.05) and 169 ± 25
vs. 55 ± 4 min for FAS (P < 0.005)].
There was no change in LH pulse amplitude (6.2 ± 1.3
vs. 4.9 ± 0.6 IU/liter; P = NS),
whereas FAS pulse amplitude increased from 86.2 ± 11.3 to
196.4 ± 30.9 IU/liter (P < 0.005).
|
The castrate subjects had a mean T level of 66 ± 8 ng/dl
(2 ± 0.4 nmol/liter), an E2 level of 20 ± 1 pg/ml (73
± 4 pmol/liter), undetectable Inh B levels (<50 pg/ml), an LH level
of 67.2 ± 20.1 IU/liter, and a FSH level of 59.5 ± 17.7
IU/liter. Despite having a similar sex steroid milieu, the mean FSH
levels observed in NL men after sex steroid ablation were approximately
6-fold lower than those seen in the castrate subjects (10.0 ± 1.5
vs. 59.5 ± 17.7 IU/liter; P < 0.0005;
Fig. 2). In contrast, mean LH levels in
the NL men were less than 3-fold lower than those in castrate subjects
(24.9 ± 2.0 vs. 66.8 ± 20.1 IU/liter;
P < 0.005; Fig. 2). The mean GnRH pulse frequency
tended to be faster if FAS rather than LH were used as the surrogate
marker of GnRH secretion (IPI of 34.6 ± 2.3 vs.
47.5 ± 6. 0 min, respectively; P = 0.07). When
the data were analyzed comparably (i.e. employing a 10-min
sampling interval for 12 h), there was no difference between the
GnRH pulse frequency in the NL men on d 6 of sex steroid suppression
and that in the castrate subjects whether either LH (IPI of 77 ±
2 vs. 90 ± 17 min) or FAS (52 ± 4 vs.
55 ± 4 min) was used as the marker of GnRH.
|
Using an in vivo human model of short-term gonadal steroid withdrawal, this study demonstrates that selective ablation of sex steroids results in only a modest increase in FSH levels, which remain within the normal adult male range, implying that a nonsteroidal factor, presumably Inh B, is likely to be the major regulator of FSH secretion in the human male.
Most of the literature on FSH regulation in the human has focused on the sex steroid component of gonadal feedback. Previous studies from our group focused on determining the relative importance of T vs. E2 to FSH regulation using in vivo human models of selective sex steroid withdrawal (selective E2 suppression achieved by aromatase inhibition, on the one hand, vs. suppression of both T and E2 with ketoconazole, on the other) (24). These studies demonstrated that in terms of sex steroid feedback, E2 is the major regulator of FSH in the male (24). In eugonadal men, the suppressive effects of pharmacological doses of sex steroids on FSH secretion have been established unequivocally (15, 16, 17, 18, 19, 20, 21, 22). However, in subjects with primary gonadal failure, sex steroid administration alone fails to reduce FSH levels to the normal range (18, 38, 39), pointing to a major role for a nonsteroidal factor in FSH regulation. Therefore, the focus of the present studies was to determine the relative importance of sex steroids vs. Inh B to FSH regulation in the human.
The concept of dual endocrine activity of the testis was first proposed more than 65 yr ago with the demonstration that administration of an aqueous testicular extract to gonadectomized male rats could suppress the formation of castration cells in the anterior pituitary, suggesting a physiological role for a nonsteroidal gonadal secretory product (40). Over the last several decades, efforts to explore inhibin physiology in the human have been hampered by numerous methodological difficulties, including the lack of inhibin for human administration (13). For this reason studies on inhibin physiology in the human have, of necessity, been indirect and inferential. There is now an abundance of literature attesting to the importance of Inh B as an important endocrine feedback regulator of FSH secretion in the human male (8, 9, 10, 11, 41, 42). However, the relative importance of Inh B vs. sex steroids to FSH control in the human has not been established.
In the present study short-term, reversible sex steroid withdrawal with ketoconazole was employed to isolate the sex steroid and nonsteroidal components of FSH feedback. Clearly, the duration of castration is an important limitation of this study, in that the impact of acute sex steroid ablation is being compared with that of longer term castration. Although there are few data on the time course of the gonadotropin rise after gonadectomy in the human male, studies in the monkey suggest that gonadotropins reach stable castrate levels approximately 20 d after orchidectomy (43). Although our sequential frequent sampling studies demonstrated that gonadotropin levels had actually reached a plateau during the 1-wk period of ketoconazole administration, it is possible that a further secondary rise in gonadotropins would have been observed had the duration of castration been extended. However, in a study of nine men with prostate cancer treated with a similar ketoconazole regimen for 12 months, no significant change was observed in FSH levels, whereas LH levels continued to rise until approximately 60 d (44). Although neither LH nor FSH reached castrate levels in the short window of sex steroid ablation employed in this study, a differential gonadotropin response was already clearly apparent, such that LH had increased to approximately 40% of castrate levels, whereas FSH remained at only approximately 15% of castrate levels. The fact that removal of sex steroid negative feedback caused LH levels to increase well above the normal adult male range compared with a modest rise in FSH that did not exceed normal levels thus points to an important role of Inh B in FSH regulation. The modest increase in FSH is all the more significant given the 25% decrease in Inh B levels observed in this study, which is also likely to have contributed to the FSH rise given the known correlation between Inh B and FSH in normal men (8, 45, 46).
The impact of inhibin administration (47, 48, 49, 50) and immunoneutralization (51, 52, 53) on FSH levels has been examined in a variety of animal models. However, one must be cautious about extrapolating data from nonprimates to the human given the species differences that have been observed in FSH regulation. Thus, although administration of inhibin antiserum results in an increase in FSH levels in the adult male rhesus monkey (52), no effect on FSH is observed in the adult male rat (53). Support for the hypothesis that Inh B is likely to be the most important regulator of FSH secretion in the human male is provided by a series of elegant studies in the monkey demonstrating that only the institution of combined treatment with T and gonadal peptides derived from charcoal-extracted porcine follicular fluid prevents the postcastration rise in FSH (48). Selective withdrawal of follicular fluid treatment then results in a dramatic rise in serum FSH levels, which returns to normal once therapy with gonadal peptides is restored. Subsequent studies performed after inhibin had been purified and isolated confirmed that the biologically active gonadal peptide present in the follicular fluid was indeed inhibin (49). Although in retrospect these studies employed pharmacological doses of inhibin A (12), and it is now known that it is Inh B that is the physiologically relevant form of inhibin in the male (8, 12, 54), there are no data to suggest that the potencies of Inh A and B differ.
It is interesting that ablation of sex steroids caused an approximately 25% reduction in Inh B levels despite a 2-fold increase in FSH levels as we have previously reported (24). These data are in keeping with the hypothesis that the negative feedback effect of Inh B on FSH secretion is more robust than the positive stimulating effect of FSH on Inh B secretion (55). The mechanism for the decline in Inh B after biochemical castration is unclear. Potential explanations are that lack of T or E2 either directly affects Sertoli cell production of Inh B or, alternatively, interferes with spermatogenesis and thus the paracrine regulation of inhibin by germ cells (56, 57, 58). It is possible, therefore, that transient disruption of spermatogenesis at the spermatid stage resulting from castrate levels of T during the period of ketoconazole administration led to the decrease in Inh B levels observed in this study. It also possible that ketoconazole may have had a direct suppressive effect on Inh B secretion independent of its effect to lower T levels. However, given the rapid fall in T after administration of the loading dose of ketoconazole, it is impossible to distinguish between these two effects.
Concerning the GnRH pulse frequency estimations in these studies, two important conclusions can be made. First, when a comparable sampling paradigm is used, a similar GnRH pulse frequency is observed in normal men after sex steroid withdrawal and in functional castrates, indicating that GnRH pulse frequency is regulated by sex steroids rather than by Inh B. Second, using FAS as a marker of GnRH pulse frequency, pulses of GnRH occur approximately every 35 min in castrate men, indicating that the true castrate frequency is significantly faster than what we and others proposed based on analysis of LH pulsatility (18, 59). In future experiments it will be interesting to examine the impact on FSH secretion of increasing GnRH pulse frequency to castrate levels using the model of GnRH-deficient men in whom sex steroid secretion has been blocked with ketoconazole.
Using the acute model of ketoconazole-induced gonadal steroid withdrawal, we demonstrated that suppression of sex steroids in normal men results in increases in LH, but not FSH, to levels above the normal range. From these experiments we infer that a nonsteroidal gonadal factor, most likely Inh B, is a major regulator of FSH in the human male. Confirmation of this hypothesis awaits the availability of inhibin for human administration.
Acknowledgments
We gratefully acknowledge the nurses of the General Clinical Research Center for their excellent clinical care, and the technicians of the Reproductive Endocrine Sciences Center RIA Core for their superb technical contributions to this study.
Footnotes
This work was supported in part by Grants R01-HD-15788-15, DK-07028-24, P30-HD-28138, and M01-RR-01066. Presented in part at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, 2000.
Abbreviations: CV, Coefficient of variation; FAS, free
-subunit; Inh B, inhibin B; IPI, interpulse interval; NL,
normal.
Received February 2, 2001.
Accepted August 15, 2001.
References
subunit is superior to luteinizing hormone as a
marker of gonadotropin-releasing hormone despite desensitization at
fast pulse frequencies. J Clin Endocrinol Metab 84:1028–1036-subunit mRNA levels by specific germ cell types. Mol Cell
Endocrinol 72:13–22[CrossRef][Medline]
- and ß-B subunits during
the cycle of the rat seminiferous epithelium. Endocrinology 124:987–991This article has been cited by other articles:
 |
|
 |
|
  R. M. Suehiro, E. F. Borba, E. Bonfa, T. S. Okay, M. Cocuzza, P. M. F. Soares, and C. A. A. Silva Testicular Sertoli cell function in male systemic lupus erythematosus Rheumatology, November 1, 2008; 47(11): 1692 - 1697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Pitteloud, A. A. Dwyer, S. DeCruz, H. Lee, P. A. Boepple, W. F. Crowley Jr., and F. J. Hayes The Relative Role of Gonadal Sex Steroids and Gonadotropin-Releasing Hormone Pulse Frequency in the Regulation of Follicle-Stimulating Hormone Secretion in Men J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2686 - 2692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Page, J. K. Amory, and W. J. Bremner Advances in Male Contraception Endocr. Rev., June 1, 2008; 29(4): 465 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Boepple, F. J. Hayes, A. A. Dwyer, T. Raivio, H. Lee, W. F. Crowley Jr, and N. Pitteloud Relative Roles of Inhibin B and Sex Steroids in the Negative Feedback Regulation of Follicle-Stimulating Hormone in Men across the Full Spectrum of Seminiferous Epithelium Function J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1809 - 1814. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Pitteloud, A. A. Dwyer, S. DeCruz, H. Lee, P. A. Boepple, W. F. Crowley Jr., and F. J. Hayes Inhibition of Luteinizing Hormone Secretion by Testosterone in Men Requires Aromatization for Its Pituitary But Not Its Hypothalamic Effects: Evidence from the Tandem Study of Normal and Gonadotropin-Releasing Hormone-Deficient Men J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 784 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mhaouty-Kodja, A. Lozach, R. Habert, M. Tanneux, C. Guigon, S. Brailly-Tabard, J.-P. Maltier, and C. Legrand-Maltier Fertility and spermatogenesis are altered in {alpha}1b-adrenergic receptor knockout male mice J. Endocrinol., November 1, 2007; 195(2): 281 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Dhooge, N. Van Larebeke, F. Comhaire, and J.-M. Kaufman Regional Variations in Semen Quality of Community-Dwelling Young Men From Flanders Are Not Paralleled by Hormonal Indices of Testicular Function J Androl, May 1, 2007; 28(3): 435 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Matthiesson and R. I. McLachlan Male hormonal contraception: concept proven, product in sight? Hum. Reprod. Update, July 1, 2006; 12(4): 463 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sutcliffe, H. A. Spoudeas, D. Nair, P. Bouloux, T. Oliver, P. Sambrook, W. Bannister, C. B. Lambalk, and T. Spector Comparison of serum FSH and Inhibin B levels between adult male dizygotic and monozygotic twins Hum. Reprod., February 1, 2006; 21(2): 447 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Foresta, A. Bettella, D. Spolaore, M. Merico, M. Rossato, and A. Ferlin Suppression of the high endogenous levels of plasma FSH in infertile men are associated with improved Sertoli cell function as reflected by elevated levels of plasma inhibin B Hum. Reprod., June 1, 2004; 19(6): 1431 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hestiantoro and D. F. Swaab Changes in Estrogen Receptor-{alpha} and -{beta} in the Infundibular Nucleus of the Human Hypothalamus Are Related to the Occurrence of Alzheimer's Disease Neuropathology J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1912 - 1925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.M. Robertson, T. Stephenson, and R.I. McLachlan Characterization of plasma inhibin forms in fertile and infertile men Hum. Reprod., May 1, 2003; 18(5): 1047 - 1054. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Matthiesson, D. M. Robertson, H. G. Burger, and R. I. McLachlan Response of serum inhibin B and pro-{alpha}C levels to gonadotrophic stimulation in normal men before and after steroidal contraceptive treatment Hum. Reprod., April 1, 2003; 18(4): 734 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tiitinen and M. Valimaki Primary Infertility in 45-Year-Old Man with Untreated 21-Hydroxylase Deficiency: Successful Outcome with Glucocorticoid Therapy J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2442 - 2445. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
, Mean ± SEM data
for the group; 
, individual data. Asterisks represent
a significant change from mean baseline values: *,
P < 0.05; **, P < 0.0005. The
shaded area represents the 95% confidence limits for 36
normal men, aged 18–45 yr. To convert the values for T to nanomoles
per liter, multiply by 0.03467. To convert the values for E2 to
picomoles per liter, multiply by 3.671.
) with those in functional castrates (