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Original Studies |
School of Nursing (N.E.R.)., Department of Pediatrics (V.P.), and Reproductive Sciences Program (N.E.R., T.L.W., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and the Institute of Reproduction and Development, Monash University (D.J.P., D.M.d.K.), Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Vasantha Padmanabhan, Ph.D., Reproductive Sciences Program, University of Michigan, 300 North Ingalls Building, Ann Arbor, Michigan 48109-0404. E-mail: vasantha{at}umich.edu
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Abstract |
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8.0 mIU/mL; younger, <8
mIU/mL). Circulating FSH regulatory peptide concentrations were
determined from samples pooled from blood drawn every 10 min for 8
daytime h using specific 2-site assays. In the older group, cycle
length was shorter (29.1 ± 0.5 vs. 26.1 ±
0.5, young vs. older; P < 0.001),
mean LH levels during the follicular phase were higher (LH, 5.6 ±
0.8 vs. 8.8 ± 1.1 mIU/mL, young vs.
older; P < 0.001). Mean FSH levels for the older
and younger groups averaged 10.8 ± 0.8 and 6.2 ± 0.3
mIU/mL, respectively. Estradiol levels were higher, but not
statistically different, than those in the younger group (99 ± 13
vs. 169 ± 25 pmol/L, young vs.
older; P = 0.06). In both age groups, inhibin B
levels were higher in the FOLL vs. ML phase, inhibin A
levels were higher in the ML vs. FOLL phase, but total
activin A and total and free follistatin did not differ across cycle
days. FOLL phase inhibin A levels were higher in the older group
(16.3 ± 2.4 vs. 26.4 ± 3.4 pg/mL, young
vs. older; P = 0.024), but levels of
inhibin B were lower (323 ± 80 vs. 163 ± 24
pg/mL, young vs. older; P = 0.03).
Overall, the estimated total inhibin activity (inhibin A plus inhibin
B) was lower in older cycling than in younger women (339 ± 82 and
189 ± 24 pg/mL, young vs. older). Total and free
follistatin levels were not different among the 2 groups of women. In
contrast, total activin A levels were higher in the older cycling group
(0.51 ± 0.05 and 0.68 ± 0.05 ng/mL, young
vs. older; P = 0.02). No differences
in age groups were observed during the ML phase for any of the
variables measured. These data suggest that a net increase in
stimulatory input resulting from a decrease in inhibin B and an
increase in activin A may contribute in part to the monotropic FSH
increase in aging women. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Before determining whether the monotropic rise in FSH is the
consequence of declining inhibin tone, it is essential to address the
structural and functional overlap that exists among members of this
family of proteins and their binding proteins. The inhibin 
,
ßA, and ßB subunits are encoded by distinct
genes and dimerize to give rise to inhibin A (ßA),
inhibin B (ßB), activin A
(ßAßA), activin AB
(ßAßB), and activin B
(ßBßB) (5). In terms of FSH secretion,
inhibins and activins are functional opposites; inhibins suppress FSH,
and activins stimulate FSH production (5, 6, 7). Follistatins, monomeric
proteins distinct from both inhibins and activins, have functional
overlap with inhibins in suppressing FSH release (8). They act as
binding proteins for both activins and inhibins (9, 10, 11). Although
binding of follistatin to activin completely overrides activin action
(12, 13), binding of follistatin to inhibin (14) does not negate
inhibin action (15, 16) (Padmanabhan, V., unpublished observations).
2-Macroglobulin, another binding protein of inhibins and
activins (17, 18), does not negate the actions of activin and inhibin
(6).
To presume that a singular deficiency in inhibin activity could account for age-related elevations in FSH fails to consider the extensive structural and functional overlap that exists among the other component FSH regulatory proteins known to mediate FSH regulation. On the contrary, the monotropic rise in FSH is more likely to be dictated by the sum effect of inhibitory inputs stemming from inhibins, follistatins, as well as estradiol (E2), and the stimulatory inputs from GnRH and activin. As such, it is essential to determine the relative contributions of all of these regulators in assessing whether the collective input in older cycling women is one of inhibition or stimulation. To test the hypothesis that changes in the overall tone of ovarian feedback may contribute to the age-related rise in FSH, we compared the concentrations of E2, dimeric inhibin A, inhibin B, activin A, total follistatin, and free follistatin in young and older cycling women during the follicular and midluteal phases of the menstrual cycle.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Before initiation of the study, approval of the study protocol was obtained from the University of Michigan Hospitals institutional review board for use of human subjects. All volunteers provided informed consent. Subjects were a subset of normal volunteers, aged 20–50 yr, previously assessed for LH pulsatility and hourly FSH determinations on menstrual cycle day 6 (FOLL study) and on day 7 after the LH surge (ML study) (19). All subjects had regular cycles every 25–35 days, body mass index (BMI) of 20–25, normal endocrine screen, no current medical or psychiatric illness, no current use of oral contraceptives, no pregnancy or breastfeeding in the past 6 months, no current history of dieting or excessive exercise, and evidence of presumptive ovulation as determined by a midluteal serum progesterone (P4) value above 9.5 nmol/L in a prestudy cycle. For the current study, samples (women) were selected based on availability of complete FOLL and ML phase sets of frozen aliquots of plasma remaining from the prior study (19). To enhance the probability of detecting subtle differences in circulating FSH regulatory peptide concentrations that may be associated with the age-related rise in FSH, subjects were further selected based on the mean follicular phase FSH value in their study cycle. All older subjects had a FSH value greater than 8.0 IU/L, and all younger controls had a FSH value less than 8.0 IU/L. The cut-off value of 8.0 IU/L used in distinguishing these two groups is 2 SD below the mean follicular phase FSH concentration of women over age 40 yr from our original study (19). Using a different FSH assay but a similar threshold value, Klein et al. (4) demonstrated age-related changes in inhibin B. By this criterion, 7 women, aged 19–38 yr, and 10 women, aged 40–50 yr, were selected for the study.
Protocol and procedures
All participants had undergone intensive blood sampling every 10 min for 8 daytime h of a FOLL and a ML study in the out-patient division of the General Clinical Research Center of the University of Michigan Hospitals (19). The plasma was frozen and stored at -80 C before being analyzed for FSH, LH, E2, P4, and the FSH regulatory peptides. Plasma LH and FSH were determined by previously validated RIAs (20, 21) and were reported for the larger group (19). Plasma FSH concentrations are expressed in terms of the Second International Reference Preparation of human menopausal gonadotropin after conversion from WHO 78/549, which was used as the assay standard. The limit of detection of the FSH assay was 1.4 IU/L, and the interassay coefficient of variation was 8%. Plasma E2 (assay sensitivity, 5 pg/mL or 18 pmol/L) and P4 (assay sensitivity, 0.2 ng/mL or 0.64 nmol/L) were measured using RIA kits [Diagnostic Products Corp. (Los Angeles, CA) and Radioassay Systems Laboratories (Carson, CA), respectively] and were previously reported for the larger group (19). Mean LH, FSH, E2, and P4 concentrations for the subgroup of subjects used in this study are discussed in Results for comparison.
FSH regulatory peptides
Integrated measures of plasma gonadal peptide concentrations
were determined from samples pooled (equal aliquots from all 48 samples
in the series) from blood drawn every 10 min for 8 daytime h
(0900–1700 h). New two-site, highly specific assays for these FSH
regulators were used that have been shown not to cross-react with one
another (<0.5%). For each of the FSH regulatory proteins, all samples
were measured in a single assay. Circulating levels of inhibin A were
measured using a two-site chemiluminescent assay (22). The sensitivity
of the inhibin A assay is 10 pg/mL, and the intraassay coefficient of
variation is 8%. Circulating inhibin B levels were measured using a
two-site enzyme-linked immunosorbent assay that also uses two
monoclonal antibodies, one directed to the -subunit and the other to
the ßB-subunit of inhibin (23). The assay sensitivity and
intraassay coefficient of variation of the inhibin B assay were 22
pg/mL and 6%, respectively. Both inhibin A and inhibin B detect total
dimer (free and bound) and do not cross-react with
2-macroglobulin, follistatin, or activin. Circulating
levels of activin A were measured using a two-site enzyme-linked
immunosorbent assay (24). Activin A also detects both bound and free
forms of activin A. The assay sensitivity and intraassay coefficient of
variation of the activin A assay were 200 pg/mL and 5%, respectively.
Circulating levels of free follistatin were measured using a second
generation two-site chemiluminescent assay that uses two monoclonal
antibodies generated against nonoverlapping epitopes of human
follistatin (25). The free follistatin assay used human recombinant
follistatin 288 as the standard and does not recognize inhibin,
activin, or activin-bound follistatin (recognizes only the activin-free
moiety). The assay sensitivity and intraassay coefficient of variation
for free follistatin were 0.8 ng/mL and less than 4%, respectively.
Total follistatin levels were measured using a heterologous RIA (26)
that employs dissociating reagents (20% Tween-20, 10% sodium
deoxycholate, and 0.4% SDS) to remove the interference of bound
activin. The rabbit polyclonal antiserum used in this assay was raised
against 35-kDa bovine follistatin (27). In the assay,
recombinant human follistatin 288 is used as both tracer and standard.
The cross-reactivity is 100% for recombinant human follistatin 288 and
33% for recombinant human follistatin 315. The sensitivity was 1.6
ng/mL, and the intraassay coefficient of variation was 12.3%.
Statistical analysis
Data are presented as the mean ± SE. Hormone values are expressed as international units per L for LH and FSH, nanomoles per L for P4 (1 ng = 3.18 nmol), and picomoles per L for E2 (1 pg = 3.6 pmol). The distribution of hormone values was assessed for normality. In some cases, a log transformation was needed due to skewed distribution. Differences in mean hormone characteristics across the two cycle phases in both groups were determined by two-tailed nonparametric tests for paired (Wilcoxon signed rank test) and nonpaired (Mann-Whitney test) observations. P < 0.05 was selected to indicate a significant difference.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Table 1
presents the clinical
characteristics of the two age groups. The older cycling group (mean
age, 43.7 ± 0.9 yr) had shorter cycles (P <
0.001) and higher BMI (P = 0.03) compared to the group
under 40 yr of age (mean age, 27.9 ± 2.6 yr). As expected, mean
FSH concentrations in the follicular phase were higher in the older
cycling group (6.2 ± 0.3 vs. 10.8 ± 0.8 IU/L in
the young and older groups, respectively; P < 0.001).
Mean LH concentrations were also higher in the older group (5.6 ±
0.8 vs. 8.8 ± 1.1 IU/L in the young and older groups,
respectively; P = 0.04; Fig. 1). No group differences in gonadotropin
concentrations were observed during the ML study day. Although a trend
for higher mean E2 in the older group was observed on the
FOLL study day (99 ± 13 vs. 169 ± 25 pmol/L, young
vs. older group, respectively; P = 0.06), no
group differences were detected in plasma E2 or
P4 on either study day (Fig. 1). The expected effects of
cycle phase on gonadotropin and steroid profiles were seen in both
study groups, as was the case in the larger group (19).
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Circulating inhibin A in both groups of women showed the expected
changes and were higher in the luteal than the follicular phase (Fig. 2). Comparison of circulating inhibin A
levels between young and older cycling women showed that inhibin A
levels during the follicular study day were higher in the older than in
the younger group (16.3 ± 2.0 vs. 26.4 ± 3.0,
young vs. older; P = 0.024). Changes in
inhibin B levels were the opposite of what was seen with inhibin A. In
both age groups, inhibin B levels were higher on the FOLL than on the
ML study day [young FOLL vs. young ML, 323 ± 80
vs. 164 ± 53 (P = 0.014); older FOLL
vs. older ML, 163 ± 24 vs. 92 ± 34
(P = 0.02)]. However, follicular levels of inhibin B
were lower in the older cycling group (323 ± 80 vs.
163 ± 24 pg/mL, young vs. older; P =
0.03) than in the younger group. Overall, total inhibin levels (inhibin
A plus inhibin B; a highly derived number) during the follicular phase
were lower (339 ± 82 vs. 189 ± 24 ng/mL) in
older cycling women than in the younger group. In contrast, circulating
levels of total activin A, although not differing between cycle phases,
were higher in the older cycling group (0.51 ± 0.05
vs. 0.68 ± 0.05 ng/mL, young vs. older;
P = 0.02). Circulating levels of free follistatin
levels were near the detection limit and did not differ between cycle
days and age groups. Total follistatin levels were not statistically
different between follicular and luteal study days (P =
0.81 for FOLL vs. ML young; P = 0.63 for
FOLL vs. ML old) or between age groups (P =
0.51 for young vs. old FOLL and P = 0.64 for
young vs. old ML). The directionality of changes in the
various FSH regulators in the older group compared to the younger group
of women is summarized in Fig. 3.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To understand the sum input of the various gonadal proteins in the control of FSH, it is important to consider the enormous functional overlap that exists among them. Several studies have documented the positive feedback effects of activin on FSH (5). In contrast, inhibin is a potent suppressor of FSH (5). Although there is information to suggest the existence of an inhibin-specific receptor (28), inhibins can also bind the activin receptor (29, 30, 31). In this capacity, inhibins have the ability to antagonize activin action. Furthermore, follistatin, a binding protein of activin, suppresses FSH by binding and negating activin’s action (11, 12, 13). In contrast, follistatin, although capable of binding inhibin (14), does not overcome inhibin’s ability to suppress FSH (15, 16) (Padmanabhan, V., unpublished observations). To add to this complexity, these regulators are also shown to exist in multiple forms. For instance, there are two known forms of inhibins, inhibin A and inhibin B, both of which have been shown to suppress FSH (5).
Viewed in this context, the sum total of both inhibin A and inhibin B input should provide an index of the total peripheral inhibin contribution. Both inhibin A and inhibin B have similar mol wt and have been shown to be equipotent in suppressing FSH from rat pituitary cells in culture (32, 33). In contrast, sheep pituitary cells are relatively insensitive to inhibin B (33). Studies testing the efficacies of the two inhibins in suppressing FSH from human pituitary cells are not available. Nonetheless, comparison of inhibin A and inhibin B levels in the young and older cycling groups show that, on the surface, there appears to be a decline in overall inhibin tone during the follicular phase in older cycling women that stems mainly from the declining inhibin B (circulating inhibin B levels are severalfold higher than circulating inhibin A levels). However, the total inhibin estimate must be interpreted with caution. It should be noted that this is a highly derived number. Until we can demonstrate that the two immunoassays are predicting the protein mass of inhibin A and B correctly and can prove that the relative biological potencies of these two isomers in suppressing human FSH are similar, these estimates may not be precise.
Circulating levels of follistatin, as measured in the total and free assays, are not different between the younger and older cycling groups, suggesting minimal contribution from follistatin in setting the overall inhibitory tone. Circulating E2 levels, a major negative feedback regulator of FSH, were also not different despite the age-related increase in BMI, suggesting minimal change in negative input from this steroid as well. Taking into consideration the FSH-suppressive effects of inhibin A, inhibin B, follistatin, and E2 (34), the peripheral inhibitory input in older cycling women may be mainly dictated by declining inhibin B levels. Integrated E2 and FSH regulatory peptide measures from daily samples spanning the follicular phase may provide a better estimate of the overall peripheral inhibitory input to FSH.
In terms of the stimulatory inputs, our studies show that circulating levels of total activin A are elevated in older cycling women compared to those in young women. In the absence of any change in follistatin levels, one can speculate that an increase in total activin A means an increase in stimulatory input. Overall, the net peripheral contribution appears to be one of stimulation, as dictated by the declining inhibin B and increasing activin A levels. Although tantalizing, this conclusion must be tempered with caution because the picture is less than complete. First the information on activin is not complete, as the circulating levels of other stimulatory regulators, such as activin B and activin AB, are unknown. A recently validated activin AB assay (35) reports that activin AB levels are below the sensitivity of the assay (190 pg/mL) during all phases of the menstrual cycle. Until more sensitive assays are available, one cannot rule out the contribution of activin AB. Total activin B assays are not yet available. However, very little free activin B has been reported to circulate in cycling women (36). Second, the constituent isomers of follistatin contributing to the total follistatin estimate and their relative affinities to bind various forms of activin are also not known. Third, sensitive assays to detect changes in circulating levels of the free (biologically active) form of activin are not available. Fourth, it is unclear whether follistatin-bound activin can be released at the cell surface level by yet to be identified mechanisms. It will also be important for future studies to clarify whether the low levels at which these FSH regulators circulate in the peripheral blood are of sufficient magnitude to play an endocrine role. Such a hypothesis must also be reconciled with evidence that these regulators are produced in the pituitary and appear to act in an autocrine/paracrine manner (6, 7, 37, 38, 39).
In summary, our findings suggest that the monotropic rise in follicular phase FSH in aging women may result from a net increase in stimulatory tone consequent to the combined effects of a decrease in inhibin tone and an increase in activin A. Although this view may have to be modified as changes in other FSH regulators become available and the local contributions of these regulators at the pituitary level become known, our data challenge the view that early aging effects on the reproductive axis are limited exclusively to declining peripheral inhibin input.
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Acknowledgments |
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Footnotes |
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Received February 20, 1998.
Revised June 3, 1998.
Accepted June 15, 1998.
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References |
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2-Macroglobulin is a binding protein of inhibin and
activin. Endocrinology 132:2038–2050.
-subunit knockout mice. J Biol Chem. 273:398–403., ßA, and ßB subunits in
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N. A. Klein, D. E. Battaglia, T. K. Woodruff, V. Padmanabhan, L. C. Giudice, W. J. Bremner, and M. R. Soules Ovarian Follicular Concentrations of Activin, Follistatin, Inhibin, Insulin-Like Growth Factor I (IGF-I), IGF-II, IGF-Binding Protein-2 (IGFBP-2), IGFBP-3, and Vascular Endothelial Growth Factor in Spontaneous Menstrual Cycles of Normal Women of Advanced Reproductive Age J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4520 - 4525. [Abstract] [Full Text]
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A. N. Shelling, K. A. Burton, A. L. Chand, C. C. van Ee, J. T. France, C. M. Farquhar, S. R. Milsom, D. R. Love, K. Gersak, K. Aittomaki, et al. Inhibin: a candidate gene for premature ovarian failure Hum. Reprod., December 1, 2000; 15(12): 2644 - 2649. [Abstract] [Full Text] [PDF]
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M. Creus, J. Penarrubia, F. Fabregues, E. Vidal, F. Carmona, R. Casamitjana, J. A. Vanrell, and J. Balasch Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome Hum. Reprod., November 1, 2000; 15(11): 2341 - 2346. [Abstract] [Full Text] [PDF]
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C. H. de Koning, C. Popp-Snijders, J. Schoemaker, and C. B. Lambalk Elevated FSH concentrations in imminent ovarian failure are associated with higher FSH and LH pulse amplitude and response to GnRH Hum. Reprod., July 1, 2000; 15(7): 1452 - 1456. [Abstract] [Full Text] [PDF]
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C. M. Foster, D. J. Phillips, T. Wyman, L. W. Evans, N. P. Groome, and V. Padmanabhan Changes in serum inhibin, activin and follistatin concentrations during puberty in girls Hum. Reprod., May 1, 2000; 15(5): 1052 - 1057. [Abstract] [Full Text] [PDF]
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M. W. Elting, T. J.M. Korsen, L. T.M. Rekers-Mombarg, and J. Schoemaker Women with polycystic ovary syndrome gain regular menstrual cycles when ageing Hum. Reprod., January 1, 2000; 15(1): 24 - 28. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, A. Iranmanesh, L. M. Demers, and T. Mulligan Joint Basal and Pulsatile Hypersecretory Mechanisms Drive the Monotropic Follicle-Stimulating Hormone (FSH) Elevation in Healthy Older Men: Concurrent Preservation of the Orderliness of the FSH Release Process: A General Clinical Research Center Study J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3506 - 3514. [Abstract] [Full Text] [PDF]
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C. K. Welt, D. J. McNicholl, A. E. Taylor, and J. E. Hall Female Reproductive Aging Is Marked by Decreased Secretion of Dimeric Inhibin J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 105 - 111. [Abstract] [Full Text]
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