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C During Development in the Male Rhesus Monkey1
Departments of Medicine and Physiology and Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Stephen J. Winters, M.D., Department of Medicine, University of Pittsburgh Medical Center, Montefiore N-919, 200 Lothrop Street, Pittsburgh Pennsylvania 15213. E-mail: winters{at}msx.dept-med.pitt.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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C
were used to examine the circulating forms of inhibin in the neonatal
(age 2–6 weeks), juvenile (age 1–2 yr), and adult male rhesus
monkey. In all samples, isoforms of inhibin-B of 26–36K and 150K
were found. Both forms were significantly greater in the adult. The
-subunit assay detected major peaks at 45–60 and 29–31K, and a
minor peak of greater than 100K. As for inhibin-B, the major forms of
inhibin pro-C were highest in adulthood. Inhibin-B and pro-C were
measurable in peripheral plasma at age 1 week, increased with the
neonatal rise in plasma FSH, and then decreased but remained detectable
through age 1 yr. Values in adult males were higher than at any time
during the first year of life. Finally, mean values of plasma inhibin-B
and pro-C in five monkeys, based on multiple blood samples drawn
between age 1 week and 1 yr, were rank ordered and were found to be
highly positively correlated (r = 0.96), suggesting that inhibin
levels in the first year of life may be a marker of Sertoli cell
number, and may predict the spermatogenic capacity of the testis in
adulthood. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit and one of two ß-subunits
(ßA or ßB). The -ßB
heterodimer, inhibin-B, is the principal circulating form of inhibin in
the human male (1) and in the male monkey (2). Experiments in monkeys
(2, 3, 4) and observations in normal and hypogonadal men (1, 5) suggest
that inhibin-B is the major testicular regulator of FSH secretion (6).
Plasma also contains uncombined inhibin -subunit (7). A large number
of molecular weight forms of inhibin have been identified that are
thought to represent dimers of variably processed subunit precursors,
variation in the -subunit carbohydrate structure, and inhibin bound
to other proteins (8). We have shown previously that 31K inhibin is the
major form in the plasma of the adult male rhesus monkey (9), and that
infusion of recombinant human (rh) FSH increases both 50–60 and 31K
inhibin in the GnRH-driven juvenile monkey (10), but no other
information is available on the factors which regulate the isoforms of
inhibin in plasma.
The maturation of pituitary-testicular function from infancy to
adulthood is comparable in the human (11) and monkey (12). There is an
activation to adult levels of LH, FSH, and testosterone in the neonate,
followed by a stage of hypogonadotropic hypogonadism in the juvenile,
which lasts approximately 30 months in the rhesus monkey, and then
there is a pubertal reawakening in gonadotropin secretion, which leads
to dramatic testicular growth and adulthood. Early studies of inhibin
in plasma revealed higher levels of inhibin -subunit in male monkeys
aged 9–46 days than in monkeys aged 12–20 months (13), and a decline
in immunoreactive inhibin in young boys between ages 2 months and 2
years (14). Using the newer ELISA for inhibin-B, a cross-sectional
study found no significant difference in circulating inhibin-B levels
in male monkeys aged 5–40 days and 12–27 months, but increased levels
in adult males (2). Longitudinal (15) and cross-sectional (16) studies
in human males confirmed measurable plasma levels of inhibin-B in
prepubertal boys, and identified a temporary rise which begins between
ages 1–12 weeks and lasts for 1–2 yr.
The present study was conducted to examine the circulating forms of
inhibin-B and uncombined inhibin -subunit in the adult as well as
the neonatal and juvenile male rhesus monkey, and to understand further
the relationship between gonadotropin and inhibin secretion by
examining the ontogeny of these circulating hormones in greater
detail.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunoassays
Inhibin B and pro-C were measured using ELISA kits from
Serotec (Washington, D.C.) based on the methods described
by Groome and colleagues (1, 7). The pro-C ELISA detects uncombined
inhibin -subunit precursor and other forms of inhibin containing the
precursor prosequence (7). In both assays, increasing volumes of adult
male monkey plasma produced dose-response lines, which paralleled the
standard. The values for inhibin-B and pro-C in castrates were <40
pg/ml and <12 pg/ml, respectively. Column fractions, after
gel filtration, were assayed in single samples, and serum
samples were assayed in duplicate. The within assay coefficient of
variation for replicate samples was nearly always < 10%. The
between assay coefficients of variation were 14.8 and 17.0%,
respectively. Immunoreactive inhibin was measured with a double
antibody RIA using an antiserum to bovine 31K inhibin, bovine 31K
inhibin for iodination, and rh-inhibin-A as the reference standard, as
described previously (9).
Plasma FSH levels were measured using homologous RIA reagents: recombinant cynomolgus FSH (AFP6940A) for iodination and as the reference standard, and a polyclonal antiserum (AFP782594) raised in rabbits to recombinant cynomolgus FSH (17). The minimal detectable dose was approximately 5 pg/tube. The within assay coefficient of variation was <10% at various potencies.
Gel filtration chromatography
Plasma samples were fractionated on sequential columns of
Sephadex G-75 (1.6 x 70 cm; Amersham Pharmacia Biotech, Piscataway, NJ) and Sephadex G-100 (1.6 x
86 cm) or on Sephacryl S-300 HR (1.6 x 78 cm) at 4 C with 0.1
M ammonium bicarbonate buffer. Tracer quantities of
125I-rat FSH (33K) were cochromatographed with each sample
for internal calibration. 2-Macroglobulin from human plasma was
purchased from Sigma (St. Louis, MO). Fractions of the
column effluents were collected, counted to locate the radioactive FSH
peak, and lyophlized using a Speed-Vac concentrator (Savant
Instruments, Farmigdale, NY) for subsequent immunoassay.
Radioiodination of inhibin
rh-inhibin-A (2 µg; NHPP from Biotech Australia) was
radiodinated with NaI125 (1 mCi) using iodogen (4 µg;
Pierce Chemical Co., Rockford, IL) for 8 min at 4 C.
I125-rh-inhibin-A was separated from NaI125 on
a column of Sephadex G-10 (PD-10; Pharmacia & Upjohn) and
then used for size exclusion chromatography.
Data analysis
The peaks of inhibin immunoreactivity detected following gel
filtration chromatography were quantitated using a computer program for
area under a curve (18). Changes in hormone secretion during maturation
were analyzed using one-way ANOVA. Because of variation among animals,
the results were compiled for statistical analysis by setting the value
at 1 week equal to 100% for each animal, and expressing the individual
values as a percentage of that mean value. The transformed result was
analyzed by ANOVA. The results for two groups were compared by
Student’s t test, and multiple group differences were
analyzed by ANOVA and posthoc Tukey’s test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C in
adult, neonate aged 2–6 weeks, or juvenile male monkey plasma
fractionated on Sephadex G-75/G-100 are illustrated in Figs. 1
, 2, and 3, and the results for three to four
animals per group are compiled in Table 1. The inhibin-B assay identified two
peaks of immunoreactivity in all samples. Peak 1, which approached the
100K exclusion limit of this system, accounted for 30 ± 5.2% of
the immunoreactivity in neonates and 38 ± 8.2% of the
immunoreactivity in juveniles, but only 19 ± 2% of the
immunoreactivity in adults (P < 0.05 vs.
juveniles). Peak 2, the major peak in all samples, was broad with an
approximate Mr of 29–36K including a leading shoulder of
immunoreactivity. The absolute levels of both peaks 1 and 2 were
highest (P < 0.05) in adults, and were slightly higher
(P = 0.286 and P = 0.083, respectively)
in neonates than in juveniles.
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). Purified 2-macroglobulin, a
725K serum protein with protease-scavaging properties that bind
cytokines and growth factors, was found previously to bind inhibin
in vitro (19). However, Sephacryl S-300 readily separated
2-macroglobulin from inhibin-B peak 1 in adult, juvenile and
neonatal monkey plasma (Fig. 4).
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C/ßB). Inhibin-B peak 1 could
represent an incompletely processed dimer (e.g. pro-
ßB/ ßB linked to pro
N-C/ßB), or inhibin-B bound to plasma protein. To
begin to distinguish between these possibilities, radioiodinated
inhibin-A was preincubated with plasma from intact or orchidectomized
monkeys before gel filtration chromatography. No consistent shift in
the peak of radiolabled inhibin-A was found suggesting that 150K
inhibin-B does not represent inhibin-B bound to a plasma
inhibin-binding protein.
Three peaks of inhibin pro-C immunoreactivity were identified
using the Sephadex G-75/G-100 system in serum from monkeys at all
stages of development (Table 1
). Peak 1, a minor peak in all samples,
was found in the exclusion range of this system. Peak 2, a broad peak
with a Mr of 45–60K, was increased in neonates and adults
compared with juveniles (P < 0.05). Peak 3 (29–31K)
was likewise lowest in juveniles, but was higher in adults than in
neonates (P < 0.05). The relative amounts (%
activity) of peaks 2 and 3 were comparable at all stages of
development.
Developmental changes in circulating inhibin
The plasma concentration of inhibin B in individual monkeys from
age 1 week to 1 yr is shown in Fig. 5, and the mean values are summarized in Table 2. Plasma inhibin-B levels at age 1 week
were 280 ± 56 pg/ml (M ± SEM), and
ranged from 154–446 pg/ml. Inhibin-B levels changed significantly from
age 1 week to 1 yr (F = 48.3; P < 0.01).
Inhibin-B increased 2-fold from age 1 week to peak values at age 6–24
weeks, gradually returned to values similar to those of newborn males
by age 30 weeks, and then remained about 1/3 the value for adult males
through age 1 year. Mean plasma inhibin-B levels at all time points
measured during the neonatal and juvenile period were less
(P < 0.05) than those of adult male monkeys that were
922 ± 94 pg/ml (range 477-1315 pg/ml; n = 11).
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C activity was likewise readily detectable in the plasma
of all neonatal males age 1 week at a level of 924 ± 228 pg/ml
(range 772–1276 pg/ml), and changed significantly during the first
year of life (F = 8.37; P < 0.01). As shown in
Fig. 5 and summarized in Table 2, plasma inhibin pro-C activity
increased in the first months of life, but the maximum level at age 6
weeks was only 44% higher than the level at age 1 week. The percentage
rise in pro-C between ages 1 and 6 weeks was significantly less
(P < 0.05) than the percentage rise in plasma
inhibin-B levels. After reaching a peak at age 6 weeks, pro-C levels
declined by about 50% to reach stable levels between ages 32 and 52
weeks, which were 22% of the value for adults. Inhibin pro-C levels
in male monkeys at all time points between ages 1 week and 1 yr were
less (P < 0.01) than those of adult males which were
2830 ± 169 pg/ml. Perhaps because of interassay variation, these
values for adults are higher than reported previously (17).
Plasma levels of immunoreactivactive inhibin were 1207 ± 118
pg/ml at age 1 week and rose 49% to peak levels at age 7 weeks (Table 2). Thereafter, immunoreactive active inhibin concentrations fell to
values that were approximately 60% of the value at age 1 week, where
they remained from age 40 to 52 weeks.
Plasma FSH levels, also depicted in Fig. 5, were 357 ± 80 pg/ml
at age 1 week, and rose rapidly to a peak value of 807 ± 89 pg/ml
at age 5 weeks. Thereafter, plasm FSH declined, and by age 30 weeks
most values were undetectable (< 25 pg/ml). Plasma FSH levels in adult
males (160 ± 63 pg/ml) were not significantly different from
values at age 1 week, but were less (P < 0.05) than
those of monkeys age 3–5 weeks.
As a measure of Sertoli cell secretory activity, a mean value for
inhibin-B and for inhibin pro-C was calculated for each monkey from
the 19 plasma samples collected between ages 1 week and 1 yr. This mean
value ranged from 232 to 622 pg/ml for inhibin-B, and from 675 to 1110
pg/ml for inhibin pro-C among the five animals. As shown in Fig. 6, there was a strong positive
correlation relating the 12-month mean inhibin-B and pro-C levels
(r = 0.96; P < 0.01) among the monkeys. The
correlation between plasma inhibin-B and pro-C among the adult males
was less strong (r = 0.45).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit ELISA, which detects forms of uncombined -subunit
containing the pro sequence, identified prominent peaks in the 31K and
56–60K range, and a minor peak of > 100K. Using the Monash
inhibin RIA to examine inhibin in male monkey plasma, we previously
identified a major peak at 31–36K with minor peaks of 50–60K and near
to the void volume of 90–100K in adult male monkey plasma (9), and
found that 56–60K and 31–36K inhibins are increased by FSH (10). That
assay identified both inhibin-B and pro-C. Robertson et
al. (8) used immunoaffinity chromatography to purify inhibin from
adult human male plasma and found two peaks of inhibin-B of 36K and
66K, and peaks of pro-C immunoreactivity which were 29K, 36K, and
55K. Gel filtration analysis of human spermatic vein plasma in this
laboratory (unpublished) confirms those results. Thus the molecular
forms of inhibin-B and pro-C in human and monkey plasma do not
appear to be entirely identical.
Two peaks of inhibin-B were found in monkey plasma at all stages of
development. The maturational pattern of both isoforms was similar, and
paralleled that of total inhibin-B in plasma. The predominant form in
the adult monkey, as in the adult human male (8), was 30–36K, and
presumably represents the mature C/ßB dimer. Previous results with
the Monash inhibin RIA produced comparable results (10) at which time
we ascribed the leading edge of this diffuse peak to variable
glycosylation of the inhibin -subunit (20). The 150K inhibin-B does
not appear to represent inhibin bound to plasma proteins, but rather
could represent an inhibin precursor consisting of pro
ßB/ßB sequences (58K) linked to the Pro
/N/C subunit (46–49K), and accounts for 19–38% of the
inhibin-B immunoreactivity in male monkey plasma. In our calculations
of the relative distribution of inhibin isoforms during development, we
have assumed that all forms of inhibin-B are detected equivalently by
the ELISAs, but this assumption may be incorrect.
The heterogeneity of circulating inhibin-B adds yet another element of complexity to efforts to understand the FSH-inhibin feedback system because the bioactivity of the large mol wt form of inhibin-B is unknown. This heterogeneity may contribute to the variation in plasma inhibin-B levels for a given plasma level of FSH observed in epidemiological studies in men (21).
Three peaks of pro-C immunoreactivity were observed in the male
monkey at >100K, 55–60K, 29–31K. The developmental patterns of peaks
2 and 3 paralleled the total serum inhibin pro-C concentration,
whereas peak 1 was a minor peak, and only in the juvenile did it
account for more than 10% of the total pro-C immunoreactivity. The
nature of this high mol wt minor peak remains unknown. Peak 2 is likely
to represent 50–55K Pro-NC, whereas peak 3 could be 26–29K
Pro-C. As with dimeric inhibin-B, both forms are likely to be
variably glycosylated given the broad nature of the peaks. Because the
two-site assay used detects a pro-C sequence, the presence of mature
17–20K inhibin -subunit could not be evaluated.
Both inhibin-B and FSH were readily measurable in male monkey plasma at age 1 week. FSH increased to peak levels at age 5 weeks followed by inhibin-B at age 6–24 weeks. Thereafter, FSH levels declined followed by a slow decline in plasma inhibin-B, a pattern similar to that recently observed in newborn boys (15, 16). The present longitudinal analysis extends the cross-sectional study of inhibin-B in male monkeys published previously (2). In that study, plasma levels of inhibin-B in neonatal and juvenile monkeys were not statistically different. The age of the younger animals, however, was only age 1–7 weeks, and therefore the peak in inhibin-B levels identified in the present study at 6–24 weeks would not have been detected. Between-animal variation may explain the failure of another study (22) to detect differences in plasma inhibin-B levels among male rhesus monkeys aged 8, 24, and 52 weeks in which plasma samples represented pools from groups of monkeys.
The elevation in inhibin secretion in monkeys between age 6–24 weeks may be due to the antecedent peak in plasma gonadotropins. In previous studies, inhibin-B levels in 2-month-old monkeys were reduced by more than 50% following administration of a GnRH-antagonist beginning at birth (22), and FSH treatment increased plasma immunoreactive inhibin in GnRH-driven juvenile male monkeys (10). Moreover, plasma inhibin-B levels are low in gonadotropin-deficient men and are increased by pulsatile GnRH treatment (23), and inhibin-B levels were reduced in nomal men when gonadotropin secretion was suppressed by testosterone administration (5). Preliminary data indicate that FSH but not LH increased inhibin-B production by testicular cells obtained at necropsy from boys aged 1 to 9 months (24). On the other hand, a very large dose of rh-FSH was used to increase inhibin-B levels in normal men (5), and the 2-fold increase in plasma FSH that followed unilateral orchidectomy in adult male rhesus monkeys produced only a 24% rise in plasma inhibin-B concentrations (25; Ramasmamy, S., G. R. Marshall, A. S. McNeilly, T. M. Plant, unpublished data). Taken together, these data suggest that inhibin production by the neonatal primate testis may be more responsive to gonadotropin stimulation than in adults, in much the same way that adenylyl cylase activity is stimulated by FSH in the testes of immature but not mature rats (26).
Inhibin-B was present in plasma throughout the juvenile period even when FSH was undetectable, however, indicating that inhibin-B secretion at this phase of primate development is relatively gonadotropin independent. In rats, the level of testicular inhibin-ßB messenger RNA is unaffected by hypophysectomy or by FSH treatment (27). Thus, other factors may stimulate inhibin gene expression and secretion. In this regard, monkey Sertoli cell cultures produce bioactive inhibin in the absence of FSH stimulation (28). Allenby et al. (29) presented evidence that a germ cell factor stimulates inhibin production in the rat, and germ cell depletion in men following cancer chemotherapy is associated with a rapid and pronounced decline in circulating inhibin-B levels (30). Because undifferentiated spermatogonia appears to be the only germ cell type in the juvenile monkey testis (31), inhibin production could be influenced by these spermatogonia. Inhibin-B is also detectable in plasma from normal prepubertal boys (15, 16), and in men with congenital GnRH deficiency in proportion to the size of their testes (23). Because sensitive immunochemiluminometric assays reveal that FSH is low but detectable in plasma from prepubertal boys (32), and 34K immunoreactive FSH is present in the plasma of men with marked GnRH deficiency (33), whether inhibin-B production also requires FSH stimulation remains uncertain.
The elevation in inhibin secretion between weeks 6–24 may also be partly explained by an increase in Sertoli cell number. Although detailed studies of Sertoli cell proliferation during the neonatal period in primates have not been conducted, Sertoli cell number was 4- to 6-fold higher in the testes of juvenile than of neonatal monkeys (31, 34), and 6-fold higher in previously healthy prepubertal boys dying a sudden death than in stillborn boys of 28–40 weeks gestation (35). Moreover, FSH increases Sertoli cell number in neonatal rats (36). If more Sertoli cells, rather than FSH activation of inhibin subunit gene expression, explains the neonatal increase in circulating inhibin-B levels, the partial decline during the first year of life could be due to an increase in body weight (37) and surface area, rather than to a decrease in inhibin production, between ages 24–52 weeks.
The secretion of the inhibin -subunit precursors measured by the
pro-C assay appears to be also partly up-regulated by gonadotropins.
In the present study, the level of pro-C activity in the plasma of
neonatal male monkeys rose with the increase in plasma FSH, and then
declined slowly during the first year of life. In normal men, plasma
levels of inhibin pro-C, like inhibin-B, were increased by FSH, and
were suppressed by testosterone (5). Moreover in the rat,
hypophysectomy decreases, and FSH treatment stimulates, testicular
inhibin- subunit gene expression (27). However, inhibin pro-C
levels were reported to be similar in GnRH-deficient and normal men
(5), and like inhibin-B, pro-C in the plasma of juvenile monkeys was
consistently detectable at a level 50-fold higher than in castrates.
Thus other factors may regulate inhibin pro-C secretion as well.
There is a strong positive correlation between Sertoli cell number and
plasma inhibin-B in the normal adult male rhesus monkey (25). The
striking variation in mean inhibin-B levels among monkeys during the
first year of life in the present study, together with the strong
positive correlation between circulating levels of inhibin-B and
pro-C, may indicate that differences in Sertoli cell number among
adult monkeys (and perhaps among men) are partially established before
puberty. Each Sertoli cell supports a finite number of germ cells, and,
therefore, Sertoli cell number before puberty may predict the
spermatogenic capacity of the adult testis. With further followup, it
will be possible to determine whether the rank order of inhibin
production among monkeys during the first year of life persists into
adulthood, and whether there is a comparable ranking in sperm output
and fertility.
Finally, there is an interesting reciprocal relation between inhibin-B and FSH in the plasma of adult male monkeys and men. Mean circulating inhibin-B levels in adult rhesus monkeys are 1.5-fold higher than the peak level for neonates, whereas FSH levels are lower in adults than throughout the period of neonatal activation. In adult men, by contrast, FSH levels are higher in adults (29, 30), and inhibin-B levels were either similar to (16) or lower than (15) the values for boys age 3–6 months. Moreover, circulating inhibin B levels in adult male monkeys (this study, 2, 17, 22) exceed the values for normal adult men (1, 21, 38) by 3- to 4-fold. Although the explanation for this quantitative difference between the nonhuman and human primate is uncertain, one possibility is a difference in Sertoli cell number in relation to body size. Estimates of Sertoli cell number in the adult rhesus monkey (31), and in men (35) are similar, although the ratio of testicular weight to body weight in the monkey is 0.50% compared with 0.06% in men (39). Thus, a higher Sertoli cell number relative to body size in adult monkeys than in men could explain the higher circulating level of inhibin-B in the monkey, and in turn, the lower plasma FSH.
In summary, both inhibin-B and pro-C immunoreactivity in male monkey
plasma are mixtures of various molecular weight forms, and between
19–38% of plasma inhibin-B appears to represent a macromolecular form
of secreted inhibin. Both inhibin-B and pro-C are present in
neonatal plasma, increase with the neonatal activation of gonadotropin
secretion, and thereafter decrease slowly but remain readily detectable
in juvenile monkeys in which plasma FSH is low or absent. The major
isoforms of inhibin-B and pro-C decrease from the neonatal to the
juvenile period, but remain detectable, and increase with adulthood.
Finally, the rank order in plasma inhibin-B and pro- C levels is
maintained among monkeys during the first year of life, and plasma
levels of inhibin-B and pro C are highly positively correlated.
Together, these data suggest that inhibin-B in the first year of life
may be a marker of the spermatogenic potential of the adult testis.
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Acknowledgments |
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Footnotes |
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Received June 30, 1999.
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References |
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C-containing forms in human serum by a new ultrasensitive
two-site enzyme-linked immunosorbent assay. J Clin Endocrinol
Metab 80:2926–2932 concentrations in infant, prepubertal, and
adult male rhesus monkeys (Macaca mulatta) and in juvenile
males during premature initiation of puberty with pulsatile
gonadotropin-releasing hormone treatment. Endocrinology 125:250–256This article has been cited by other articles:
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globulin (mw 150K); B,
BSA; C, 125I-rFSH. Note the different scale for inhibin-B
in each panel.
