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Prince Henry’s Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, 3168, Australia
Address all correspondence and requests for reprints to: Professor Henry G. Burger, Prince Henry’s Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, 3168, Australia.
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Introduction |
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 Top Introduction References |
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The cloning of human inhibin showed that there were two major species,
inhibins A and B, dimers which shared a common 
-subunit,
disulphide-linked to one of two different ß subunits,
ßA or ßB. Both of these inhibins were shown
to be detectable by the RIA, as were peptides related to the inhibin
-subunit.
While the application of the RIA to studies of inhibin physiology in the female has generated data consistent with a physiological role for inhibin in women (10), problems arose with data generated in men. Initial studies as reviewed (11) were promising. Immunoreactive inhibin levels were elevated at the time of hypothalamo-pituitary-testicular axis activation in young boys and rose during normal human puberty, being correlated with rising levels of the gonadotropins and testosterone. Levels fell with increasing age in men, were suppressed by exogenous testosterone administration, and responded to the administration of both FSH and human CG, suggesting the possibility of dual gonadotropic control, a somewhat unexpected finding.
In contrast, in states of disordered spermatogenesis, leading to human male infertility, no correlation could be found between FSH and immunoreactive inhibin, with levels in severe spermatogenic failure, e.g. Klinefelter’s syndrome, often being normal or even raised (12).
Elaboration of the inhibin hypotheses had postulated that it was a
factor produced by the seminiferous epithelium (specifically the
Sertoli cell), involved in the regulation of FSH, whereas Leydig cell
testosterone was the primary feedback factor for LH. Testosterone was
known to be capable of FSH suppression. The failure to find a
correlation between FSH and inhibin in disorders of the seminiferous
epithelium was puzzling. When it became clear that inhibin -subunit
related peptides were present in the circulation (13) and that cultured
rat testicular Leydig cells could secrete immunoreactive inhibin and
could be stimulated by LH (14), an explanation for the paradoxical
findings in Klinefelter’s syndrome and other forms of male infertility
could be postulated. It was possible that bioactive inhibin normally
secreted by the Sertoli cell was absent but that the Leydig cells, and
where evident, Sertoli cells remaining in the testis of severely
infertile men, were capable of producing immunoreactive inhibin species
without biological activity, hence leading to elevated FSH levels.
The recent and clearly very important development of assays specific
for the dimeric inhibins, A (15) and B (16), has shed some light on the
situation, particularly the recent demonstration that inhibin B, which
is inducible by exogenous FSH (17), is the only inhibin detectable in
adult men and that its levels are very low in men with Klinefelter’s
syndrome and other forms of severe male infertility. A recent and
rapidly growing body of evidence is consistent with inhibin B being the
relevant physiological inhibin involved in FSH negative feedback in the
male. In this issue (18), evidence is reported that inhibin B is
present in the circulation of the juvenile Rhesus monkey whose
pituitary-testicular axis has been driven by intermittent iv GnRH
infusion, though it is not clear from the data presented that FSH
specifically stimulated levels of inhibin B in this situation. While
persuasive evidence is accumulating that inhibin B may represent a
physiologically relevant species, no clear cut explanation has been
found for the quantitatively much larger amounts of -subunit related
immunoreactivity present in male serum and apparently responsive to FSH
stimulation as shown both in the human male and in the present report
in juvenile Rhesus monkeys. What is the function of subunit-related
peptides? Do they necessarily arise from the testis? Some evidence
suggests that they may not (19).
Further complexities have been identified by the recognition that
inhibin in serum is present in a variety of molecular weight forms due,
in the main, to cleavage at specific sites on both subunits. Thus,
inhibin is found in human serum as the mature 30K (ß) dimer with
extensions of either or both subunits resulting in additional mol wt
species of 50–70K and 90–110K (20). It would also appear that inhibin
A and B are processed differentially in serum, with the -subunit
precursor of inhibin B more readily cleaved than that of inhibin A
(21). Recent studies by Mason (22) have showed that the in
vitro biological activity of noncleavable high molecular weight
forms of inhibin produced by recombinant expression was markedly
reduced, suggesting that processing of inhibins may be critical for
biological activity. It would thus appear that inhibin biological
activity is dependent on the degree of subunit processing either in the
circulation or at the pituitary.
While results from the present paper highlight some of these structural
complexities, it does appear that there are differences between the
human and monkey. In the human, -subunit immunoassays including the
Monash RIA are able to readily detect high molecular weight forms of
inhibin (20, 21), whereas in the monkey, even though high molecular
weight forms are measurable as seen in Figs. 1 and 2 of Majumdar
et al. (18), they are seemingly poorly detected, at least in
stored serum (Fig. 4). It will clearly be important to resolve the
basis for these apparent differences particularly if there are
questions of assay specificity.
Over a number of years, Plant and colleagues have undertaken a series of studies using elegant physiological models to explore the regulation by testicular factors of FSH secretion in monkeys. Earlier studies examined the effects of inhibin immunoneutralization (23) and recombinant inhibin administration on FSH secretion (6), as well as the contribution of testosterone to suppressing FSH. In this issue (18), these authors have continued these studies by exploring the stimulatory effects of of FSH and LH (human CG) on inhibin production. FSH showing a clear stimulatory effect on inhibin levels in contrast to the absence of effects of CG despite supraphysiological circulating testosterone levels. These studies have established the overall importance of inhibin, and the limited importance of testosterone in regulating FSH in the monkey and extend studies undertaken in other species.
The present discussion has focused only on the characteristics of the long loop feedback system between the pituitary and the testis. The local intrapituitary production of the inhibin-related peptides (11) no doubt complicates any of the interpretations proposed. It is also interesting to comment on the complexity of the pituitary-testicular feedback system. Not only is it clear that a variety of inhibin species is present in the circulation, at least some of which appear very likely to be of testicular origin, it is also clear that both FSH and LH exist in multiple isoforms of various biological and immunological activity. It is difficult to postulate reasons for the apparent complexity of the reproductive axis control system, in contrast with what appear to be relatively much simpler systems in the control of thyroid and adrenocortical function.
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Footnotes |
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Received February 3, 1997.
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References |
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TopIntroductionReferences |
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subunit in human serum:
implications for radioimmunoassay. J Clin Endocrinol Metab 70:1208–1212[Abstract]
-subunit expression in rat Leydig cell cultures. Mol
Cell Endocrinol 66:119–122
-inhibin precursor proteins circulate in human
male serum. J Clin Endocrinol Metab 80:3043–3049This article has been cited by other articles:
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  V. Sundblad, V. A. Chiauzzi, L. Andreone, S. Campo, E. H. Charreau, and L. Dain Controversial role of inhibin {alpha}-subunit gene in the aetiology of premature ovarian failure Hum. Reprod., May 1, 2006; 21(5): 1154 - 1160. [Abstract] [Full Text] [PDF]
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E.V. Velasquez, R.V. Trigo, S. Creus, S. Campo, and H.B. Croxatto Pituitary-ovarian axis during lactational amenorrhoea. I. Longitudinal assessment of follicular growth, gonadotrophins, sex steroids and inhibin levels before and after recovery of menstrual cyclicity Hum. Reprod., April 1, 2006; 21(4): 909 - 915. [Abstract] [Full Text] [PDF]
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 L L Burger, D J Haisenleder, A C Dalkin, and J C Marshall Regulation of gonadotropin subunit gene transcription J. Mol. Endocrinol., December 1, 2004; 33(3): 559 - 584. [Abstract] [Full Text] [PDF]
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 L. O'Donnell, K. M. Robertson, M. E. Jones, and E. R. Simpson Estrogen and Spermatogenesis Endocr. Rev., June 1, 2001; 22(3): 289 - 318. [Abstract] [Full Text] [PDF]
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 S. J. Winters and T. M. Plant Partial Characterization of Circulating Inhibin-B and Pro-{alpha}C During Development in the Male Rhesus Monkey Endocrinology, December 1, 1999; 140(12): 5497 - 5504. [Abstract] [Full Text]
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 J. M. Martin-Villa, J. Longás, and A. Arnáiz-Villena Cyclic Expression of HLA Class I and II Molecules on the Surface of Purified Human Spermatozoa and Their Control by Serum Inhibin B Levels Biol Reprod, December 1, 1999; 61(6): 1381 - 1386. [Abstract] [Full Text]
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