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Original Studies |
Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and the National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dr. C. K. Welt, Reproductive Endocrine Unit, Reproductive Endocrine Sciences Center and the National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: cwelt{at}partners.org
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Abstract |
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These findings demonstrate that inhibin B is secreted from developing preantral and small antral follicles, but is not directly stimulated by FSH. However, the combination of FSH and IGF-I enhanced inhibin B secretion. In contrast, inhibin A is not secreted from preantral follicles, but in small antral follicles FSH and cAMP stimulate inhibin A secretion. Further, FSH in combination with IGF-I results in a greater degree of stimulation of inhibin A than of inhibin B. These findings suggest that FSH and IGF-I differentially regulate inhibin A and inhibin B secretion. However, additional growth factors or increasing granulosa cell number may contribute to the preferential serum inhibin B increase across the luteal-follicular transition in the menstrual cycle.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit and one of two ß-subunits,
forming inhibin A (ßA) and inhibin B
(ßB). With the development of assays
specific for dimeric inhibin (1, 2, 3), distinct patterns of
circulating inhibin A and inhibin B secretion in the follicular phase
of the menstrual cycle have been described. Inhibin B increases from
the late luteal phase through the midfollicular phase in concert with
FSH (3, 4), whereas inhibin A rises in the late follicular
phase along with LH and peaks in the luteal phase (1, 2),
suggesting differing regulation of inhibin A and inhibin B by FSH and
LH. Inhibin subunit messenger ribonucleic acid (mRNA) expression in
granulosa cells is consistent with the patterns of inhibin B and
inhibin A secretion. Inhibin - and
ßB-subunits are the major mRNA species in small
antral follicles, whereas - and ßA-subunits
are expressed by dominant follicles (5). Taken together,
these observations suggest that differences in both gonadotropin
regulation and stage of follicle maturation may account for the
differences in the patterns of secretion of inhibin A and inhibin
B.
In vitro studies in the rat (6, 7, 8, 9), nonhuman
primate (10), and human (11) indicate that
FSH stimulates inhibin secretion in immature granulosa cells, whereas
both FSH and LH stimulate inhibin secretion in mature granulosa cells.
However, these studies used RIAs directed at the -subunit of inhibin
(12), and therefore did not distinguish between inhibin A
and inhibin B. Recent human studies that attempted to dissect the
specific regulation of dimeric inhibin A and inhibin B biosynthesis
employed luteinized granulosa cells from follicles stimulated with
exogenous gonadotropins and hCG for in vitro fertilization
(13, 14). These granulosa cells are well on the pathway to
luteinization and thus are not representative of granulosa cells from
follicles recruited in the normal follicular phase. One human study
examined dimeric inhibin regulation by FSH in vivo in
follicles not previously stimulated by exogenous gonadotropins. This
study suggested that FSH stimulates both inhibin A and inhibin B in the
early follicular phase (15); however, the size of the
follicles was not evaluated, nor was the presence of a dominant
follicle excluded. Thus, the regulation of dimeric inhibin biosynthesis
by gonadotropins in granulosa cells from normal developing follicles
has not been precisely delineated in the female.
There is also evidence that growth factors are involved in regulating
ovarian inhibin biosynthesis. Recent studies in immature rat granulosa
cells indicate a preferential stimulation of inhibin A by FSH, whereas
addition of insulin-like growth factor I (IGF-I), activin A, or
transforming growth factor-ß to FSH favored inhibin B secretion
(16). Studies of inhibin subunit mRNA expression in
luteinized human granulosa cells demonstrate that transforming growth
factor-ß and activin A induced inhibin
ßB-subunit expression, but not that of - or
ßA-subunit (17, 18). Therefore,
growth factors may be important in the differential regulation of
inhibin ßA- or
ßB-subunit biosynthesis alone or in the
presence of gonadotropins.
There may also be differences in dimeric inhibin regulation in granulosa cells of follicles from normal and polycystic ovaries (PCO). PCO are characterized by a peripheral array of follicles arrested at the small antral stage. The granulosa cells from these follicles demonstrate altered sex steroid regulation compared with normal follicles, including an enhanced estradiol response to FSH with or without IGF-I or insulin (19, 20, 21), premature estradiol stimulation by LH (22) and a decreased progesterone response to FSH (23). Dimeric inhibin regulation has not been compared in PCO and normal granulosa cells; however, recent data indicating that inhibin A and inhibin B levels are decreased in the follicular fluid of size-matched polycystic ovarian syndrome (PCOS) follicles compared with normal follicles (24) suggest that dimeric inhibin regulation by FSH, LH, or growth factors may also be altered in PCO.
To examine the differential regulation of inhibin A and inhibin B from developing follicles, we studied intact preantral follicles and isolated granulosa cells from small antral follicles of normal and polycystic ovaries. We hypothesized that inhibin B is preferentially secreted from preantral and small antral follicles and that gonadotropins and local growth factors differentially regulate inhibin A and inhibin B. Our results suggest that inhibin A and inhibin B are regulated by different mechanisms, perhaps accounting for the differential pattern of inhibin A and inhibin B secretion in the follicular phase of the menstrual cycle.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ovaries were obtained from six women, aged 34–37 yr (mean
± SD, 35.3 ± 1.0 yr), after oophorectomy for a
nonovarian cause (Table 1
). All ovaries
were examined by pathology and were grossly and microscopically normal.
Subjects were taking no hormonal medication known to interfere with
follicle development. Ovarian tissue was cut into 5-mm pieces, then
digested in 5 mL serum-free medium 199 containing 2472 U/mL collagenase
type I (Worthington Biochemical Corp., Lakewood, NJ) and
180 U/mL deoxyribonuclease I (no. DN-25, Sigma, St. Louis,
MO) overnight at 4 C, followed by 1–2 h at 37 C (25). The
digested ovary was diluted approximately 1:10, and preantral follicles
were isolated using a 10-µL pipette. Follicles were washed in
serum-free medium 199, then cultured in 200 µL DMEM/Ham’s F-12 (1:1)
containing 1 mg/mL BSA, 100 µg/mL transferrin, 20 nmol/L insulin, 20
nmol/L selenium, 1 µmol/L vitamin E, and antibiotic/antimycotic
solution (1:100; no. 15240–062, Life Technologies, Inc.,
Grand Island, NY). Preantral follicles cultured in the absence of serum
secreted no detectable inhibin A or inhibin B; therefore, 10% FCS was
subsequently added to all cultures. Large preantral follicles with
multiple granulosa cell layers and small preantral follicles with one
to three granulosa cell layers were pooled and cultured separately.
Medium was removed after 48 h and assayed for inhibin A and
inhibin B.
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Ovarian tissue was obtained from 21 women, aged 24–45 yr
(mean ± SD, 36.4 ± 6.4 yr), after oophorectomy
for a nonovarian cause (Table 2). Twelve
subjects had regular menstrual cycles, as documented by the medical
record, and normal ovaries on pathological examination. Nine subjects
had irregular menstrual cycles and ovaries with three of four of the
following criteria: 1) more than eight follicles 10 mm or less in one
cross-section, 2) enlarged total ovarian volume (>9 mL), 3) increased
volume or density of stroma, or 4) thickened tunica albuginea
(19). There were no other abnormalities on pathological
examination. These ovaries were called polycystic ovaries based on
their morphology (19) and the subject’s history of
irregular menstrual cycles.
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After examination by pathology, a section of ovarian tissue ranging from a thickness of 3 mm to one quarter of the whole ovary was obtained and transported from pathology in sterile, ice-cold culture medium (medium 199 supplemented with 100 IU/mL penicillin, 100 µg/mL streptomycin, and 2 mmol/L L-glutamine). All grossly normal, nonhemorrhagic follicles 2 mm or larger were dissected from the ovary using a dissecting scissors. The number and size of all follicles recovered from the tissue section were recorded. Follicular fluid was aspirated from individual follicles, the follicle was opened, and the granulosa cells were washed from the inner surface with medium. The remaining granulosa cells were gently scraped from the follicle surface with a scalpel blade. Granulosa cell clumps were picked up individually with a pipette, washed once in culture medium, centrifuged at 735 x g for 5 min, and resuspended in culture medium. Viability was assessed using trypan blue exclusion and was more than 50% in all samples. Granulosa cells from all follicles 10 mm or smaller from a single ovary were pooled and plated at a density of 1–5 x 104 cells/well in serum-free medium 199 supplemented with 100 IU/mL penicillin, 100 µg/mL streptomycin, and 2 mmol/L L-glutamine. Granulosa cells were treated with FSH or hCG (30 ng/mL; National Hormone and Pituitary Distribution Program, NICHHD, NIH), androstenedione (1 x 10-7 mol/L; no. A-9630, Sigma), dibutyryl cAMP (1 mmol/L; no. D-0627, Sigma), activin (30 ng/mL; National Hormone and Pituitary Distribution Program, NICHHD, NIH), bovine insulin (5 µg/mL; no. I-5500, Sigma), or IGF-I (100 ng/mL; no. I-3769, Sigma). Two or three wells received identical treatments ,and experiments were repeated in two to nine individual ovaries.
Assays
Estradiol was assayed using a two-site monoclonal nonisotopic system (Abbott Laboratories, Abbott Park, IL). Inhibin A and inhibin B were assayed by enzyme-linked immunosorbent assay (Serotec, Oxford, UK), as previously described (2, 26). Inhibin A results are reported as international units per mL of the WHO International Standard (WHO IS) 91/624 (0.15 IU WHO IS = 1 pg inhibin A against Serotec calibrators). The intraassay coefficient of variation for the dimeric inhibin A assay was 3.9% at the ED20 dose, and the interassay coefficient of variation was 6.8% at the ED30 dose (2). The intraassay coefficient of variation for the dimeric inhibin B assay was 4–6%, and the interassay coefficient of variation was 15–18% for serum spiked with 121, 250, and 723 pg/mL inhibin B (26). All samples for a given individual were run in the same assay for both inhibin A and inhibin B.
Data analysis
Estradiol, inhibin A, and inhibin B levels were log transformed for analysis. Hormonal values were compared in the absence and presence of androstenedione and were compared in normal and polycystic ovaries using Student’s t test. Estradiol, inhibin A, and inhibin B concentrations after FSH and hCG treatment in the absence and presence of activin, insulin, and IGF-I were compared with levels in wells receiving no treatment using paired t test. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The patient’s age, diagnosis, the number of preantral follicles
cultured per well, and preantral follicle size for each patient are
indicated in Table 1
. Inhibin B secretion was detectable from preantral
follicle cultures, whereas inhibin A was not detectable (Table 1).
Medium alone had no detectable inhibin A or B. In contrast, both
inhibin B and inhibin A were detectable in all granulosa cell cultures
from small antral follicles (Table 3).
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Normal compared with PCO. Menstrual cyclicity, age, number of
follicles recovered from the available tissue section, total ovarian
volume, and diagnostic indication for surgery in each patient are
indicated in Table 2. The number of follicles recovered and ovarian
volume were greater for PCO compared with normal ovaries, whereas age
was not different.
Estradiol, inhibin A, and inhibin B levels in cultured granulosa cells
from normal and PCO ovaries are presented in Table 3. There was no
difference between PCO and normal ovaries in the no treatment, FSH, or
hCG wells in the absence and presence of androstenedione; therefore,
results from normal and PCO follicles were combined for further
analysis.
Stimulation by gonadotropins and cAMP. FSH increased inhibin
A, but not inhibin B, secretion independently of the presence of
androstenedione (Fig. 1). These findings
were replicated by treatment with cAMP. In addition, FSH increased
estradiol production. There was no increase in inhibin A, inhibin B, or
estradiol biosynthesis after hCG stimulation (Fig. 1).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies demonstrate that differences in the inhibin subunit
promoters may partially account for the unique regulation of the two
inhibins. In the rat, both the inhibin - and
ßA-subunit promoters contain a cAMP response
element (CRE) or variant CRE that mediates cAMP regulation by
gonadotropins (27, 28, 29). In contrast, the
ßB-subunit promoter does not contain a CRE
(27, 30) and does not respond to cAMP when transfected
into a granulosa cell line (30). Consistent with these
findings, both FSH and cAMP stimulated dimeric inhibin A, but not
inhibin B, secretion in the current study. Nevertheless, studies in rat
granulosa cells reveal that FSH stimulates both inhibins, with inhibin
A secretion 2-fold greater than that of inhibin B (16). An
in vitro human study examining dimeric inhibin regulation by
FSH in granulosa cells from follicles previously exposed to high doses
of exogenous gonadotropin and hCG for in vitro fertilization
demonstrated a 57% increase in inhibin A and a 50% increase in
inhibin B, although inhibin B stimulation was not maintained at higher
FSH doses or longer incubation times (13). Species
differences or the differentiated state of luteinized granulosa cells
(31) may account for the minimal FSH-mediated inhibin B
secretion in these previous studies. Addition of insulin in the medium
of the luteinized granulosa cells (13) may also have
mediated FSH stimulation of inhibin B in the luteinized granulosa cells
via IGF-I receptors. Taken together, although FSH, probably acting via
the cAMP pathway, stimulates inhibin A secretion, inhibin B secretion
requires additional growth factors.
IGF-I appears to be critical for FSH-mediated inhibin B secretion. In
rat granulosa cells, FSH-mediated stimulation of inhibin -subunit
expression required IGF-I (32) and addition of IGF-I to
FSH favored inhibin B secretion (16). In the human, IGF-I
is expressed in thecal cells, and IGF-I receptors are present on
granulosa cells of small antral follicles (33),
demonstrating that the necessary components are in place for IGF-I to
enhance inhibin B secretion at this stage of follicle development.
Nonetheless, the mechanism through which IGF-I mediates FSH-stimulated
inhibin B secretion is unclear. In the ovary, IGF-I appears to act by
amplifying gonadotropin-mediated signaling both proximal and distal to
cAMP production (34). As cAMP did not stimulate inhibin B
directly, these findings suggest that IGF-I facilitates FSH-stimulated
inhibin B secretion through pathways acting distal to cAMP production.
It is also possible that IGF-I improves overall granulosa cell
biosynthesis and proliferation, resulting in increased inhibin B
secretion on the basis of increased cell number or enhanced protein
production.
The current data suggest a remarkable paradox between FSH-mediated dimeric inhibin stimulation in vitro and in vivo. In vivo, the rise in FSH across the luteal-follicular transition results in a 6-fold rise in inhibin B, whereas inhibin A does not increase significantly (4). Similarly, administration of exogenous FSH to women in the early follicular phase results in a greater increase in inhibin B than inhibin A (15), and administration in women with ovarian suppression results in a doubling of inhibin B within 24 h, whereas inhibin A does not increase until 72 h (35). In contrast, the current in vitro data paradoxically demonstrate that FSH- plus IGF-I-mediated inhibin B secretion is minimal (65%) compared with that of inhibin A (340%). Nonetheless, the current data also show that inhibin B is secreted by granulosa cells from preantral and small antral follicles without treatment. Therefore, although FSH and IGF-I stimulation in vivo may increase inhibin B secretion directly from each granulosa cell, FSH may also increase inhibin B by increasing the number of granulosa cells and follicles, thus contributing to the overall output of inhibin B in serum.
Interesting comparisons can be drawn with the male. Both granulosa cells and Sertoli cells are derived from sex cord cells, and there is evidence in the male that the number of Sertoli cells makes an important contribution to circulating inhibin B levels. In the adult male, the Sertoli cell is the primary site of inhibin B biosynthesis (36), and Sertoli cell number is fixed (37). Unilateral testicular removal in the adult nonhuman primate results in a 50% decrease in the inhibin B level, which is not restored by the compensatory increase in FSH (38). Similarly, experimental manipulation of Sertoli cell number in the neonatal rat was directly related to serum inhibin B levels (39). Taken together, these findings are consistent with the hypothesis that the sum of basal inhibin B secretion by granulosa or Sertoli cells makes a significant contribution to serum inhibin B levels.
Based on the selective increase in inhibin B secretion across the luteal-follicular transition of the menstrual cycle, it has previously been suggested that inhibin B is a product of the cohort of developing follicles recruited in the late luteal phase of the menstrual cycle (3, 4), whereas inhibin A is a product of the dominant follicle (3). The current data confirm that inhibin B is indeed secreted from granulosa cells of preantral and small antral follicles. Nonetheless, small antral follicles also synthesize inhibin A subunits (5), their follicular fluid contains inhibin A (24, 40), and we have now demonstrated that their granulosa cells secrete inhibin A and increase secretion in direct response to FSH. Therefore, although serum inhibin A levels parallel development of the dominant follicle, smaller follicles probably contribute to the serum inhibin A level throughout the follicular phase of the menstrual cycle.
Unlike IGF-I, addition of activin A or insulin alone and in the
presence of FSH did not affect inhibin A or inhibin B secretion. These
findings contrast with studies in immature rat granulosa cells in which
activin A preferentially stimulated inhibin B over inhibin A
(16), possibly representing a species difference. Activin
A treatment in luteinized human granulosa cells induced
ßB-subunit mRNA expression, but not that of
- or ßA-subunit (17), and thus
activin B, which cannot be measured at present, would be the expected
secretory product. The effect of insulin on dimeric inhibin secretion
has not previously been tested. In the current study the insulin dose
used was 50-fold in excess of the IGF-I concentrations required to
elicit inhibin B stimulation and would not have been sufficient to
cross-react with IGF-I receptors significantly (41).
Therefore, IGF-I appears to be the most important growth factor tested
influencing the regulation of dimeric inhibin secretion.
Regulation of inhibin A and inhibin B by gonadotropins was not
different in polycystic and normal ovaries. Serum inhibin B and inhibin
A levels were demonstrated to be higher (42, 43), similar,
or lower (44) in PCOS patients compared with those in
normal subjects. The variability in these studies probably reflects
differences in subject number, body mass index, recent hormone
exposure, and possibly ovarian follicular development. Further, serum
data measure the aggregate output of all follicles in the ovary. Recent
studies examining dimeric inhibin production from granulosa cells or
follicular fluid of individual follicles demonstrate decreased inhibin
-subunit mRNA expression in granulosa cells (45, 46)
and decreased inhibin A and inhibin B protein in the follicular fluid
of size-matched PCOS compared with normal follicles (24).
Thus, studies of individual follicles suggest that inhibin production
may be decreased in PCOS follicles compared with that in normal
follicles. The estradiol, inhibin A, and inhibin B responses to FSH
were similar in PCO and normal follicles in the current study. Taken
together, these findings suggest that a molecular defect in
FSH-mediated inhibin biosynthesis is not responsible for the decreased
inhibin -subunit mRNA expression and lower follicular fluid inhibin
A and inhibin B levels in individual PCOS follicles.
The use of follicles from surgical ovarian specimens allows examination of follicles in the absence of previous gonadotropin exposure. Care was taken to ensure that the pathology of the ovaries used was normal; however, it is possible that the subjects’ underlying disease affected baseline inhibin production or response. Nevertheless, the baseline inhibin secretion and hormone responsiveness were consistent between subjects with different diagnoses, suggesting that the source of ovarian tissue did not confound the results.
The current study demonstrates distinct regulation of inhibin B and inhibin A secretion from granulosa cells of developing follicles. Inhibin B is secreted from developing preantral and small antral follicles, but is not directly stimulated by FSH. However, the combination of FSH and IGF-I did enhance inhibin B secretion. In contrast, inhibin A is not secreted from preantral follicles, but in small antral follicles FSH and cAMP stimulate inhibin A. Further, FSH in combination with IGF-I results in a greater degree of stimulation of inhibin A than of inhibin B. These findings suggest that FSH and IGF-I differentially regulate inhibin A and inhibin B secretion. However, additional growth factors or increasing granulosa cell number may contribute to the preferential serum inhibin B increase across the luteal-follicular transition in the menstrual cycle.
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Acknowledgments |
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Footnotes |
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Received May 8, 2000.
Revised August 22, 2000.
Revised September 22, 2000.
Accepted September 26, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit in human serum.
Implications for radioimmunoassay. J Clin Endocrinol Metab. 70:1208–1212.[Abstract]
- and ßA-subunit messenger ribonucleic acid
levels by chorionic gonadotropin and recombinant follicle-stimulating
hormone in cultured human granulosa-luteal cells. J Clin
Endocrinol Metab. 79:1670–1677.[Abstract]
- and ß-B-subunit genes
suggests two different regulatory mechanisms. Mol Endocrinol. 89:1914–1925.
inhibin gene by cyclic adenosine
3',5'-monophosphate after transfection into rat granulosa cells. Mol
Endocrinol. 5:521–534.[Abstract]
-subunit expression by follicle-stimulating hormone. Biol Reprod. 58:219–225.This article has been cited by other articles:
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 Y. Makanji, C. A. Harrison, P. G. Stanton, R. Krishna, and D. M. Robertson Inhibin A and B in Vitro Bioactivities Are Modified by Their Degree of Glycosylation and Their Affinities to Betaglycan Endocrinology, May 1, 2007; 148(5): 2309 - 2316. [Abstract] [Full Text] [PDF]
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 C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]
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R. Jaatinen, J. Bondestam, T. Raivio, K. Hilden, L. Dunkel, N. Groome, and O. Ritvos Activation of the Bone Morphogenetic Protein Signaling Pathway Induces Inhibin {beta}B-Subunit mRNA and Secreted Inhibin B Levels in Cultured Human Granulosa-Luteal Cells J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1254 - 1261. [Abstract] [Full Text] [PDF]
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T. Fujiwara, Y. Sidis, C. Welt, G. Lambert-Messerlian, J. Fox, A. Taylor, and A. Schneyer Dynamics of Inhibin Subunit and Follistatin mRNA during Development of Normal and Polycystic Ovary Syndrome Follicles J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4206 - 4215. [Abstract] [Full Text] [PDF]
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) and presence (
) of androstenedione
(10-7 mol/L). Numbers in
parentheses represent the number of experiments, which
was equal to the number of individual ovaries used. The lower inhibin
A, inhibin B, and estradiol levels in the No Tx/hCG group in the
absence of androstenedione represent variability in the ovaries
used for analysis. **, P < 0.05 compared with no
treatment.
); FSH (30 ng/mL; 
); and activin (30 ng/mL)
plus androstenedione (10-7 mmol/L), insulin (5
µg/mL), or IGF-I (100 ng/mL) in the presence of FSH (30 ng/mL; 
).
Numbers in parentheses represent the number of
experiments, which was equal to the number of individual ovaries used.
Differences in baseline levels in no treatment wells for inhibin A and
inhibin B represent variability in the ovaries used for analysis. **,
P < 0.05 compared with no treatment.