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Reproductive Endocrine Unit and National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Corrine K. Welt, Reproductive Endocrine Unit, BHX 511, Fruit Street, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: cwelt{at}partners.org.
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Abstract |
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-subunit) pulse frequency was assessed in normal women, and FSH levels were examined in GnRH-deficient women in whom hypothalamic output was fixed with GnRH administration. FSH was higher in the early follicular phase in the presence of estrogen receptor blockade (15.7 ± 3.1 vs. 13.2 ± 1.9 IU/liter; P < 0.05) but was not increased in the late follicular phase. In the luteal phase, FSH was elevated (10.1 ± 0.7 vs. 7.3 ± 0.6 IU/liter; P < 0.01). In normal women, free -subunit pulse frequency increased (7.3 ± 0.4 vs. 4.8 ± 0.4 pulses per 8 h; P < 0.003), but in GnRH-deficient women, there was no FSH increase (11.1 ± 1.6 vs. 12.5 ± 3.6 IU/liter) in the early follicular phase in the presence of estrogen blockade. In conclusion, estradiol exerts a greater role over inhibin in FSH-negative feedback regulation during the luteal phase and the luteal-follicular transition. In contrast, inhibin A and/or B plays a more critical role as the follicular phase progresses. In addition, these studies support a primary if not exclusive hypothalamic site of estrogen-negative feedback in the early follicular phase. |
Introduction |
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Although evidence for the role of estradiol in the negative feedback control of FSH secretion in women is well established (1, 2, 3, 4), the role of inhibin A and inhibin B relative to estradiol and relative to each other remains controversial. Regulation of the FSH rise across the luteal-follicular transition is controlled in part by release of negative feedback associated with declining levels of estradiol from the demise of the corpus luteum, but the similar decline of inhibin A suggests that it may also play a role. In the nonhuman primate, inhibin A infusions in the luteal phase suppressed FSH and prevented the peak in FSH at menses, providing direct evidence that inhibin A is an important feedback regulator (5). However, immunoneutralization of inhibin in the luteal phase of female macaques did not result in increased FSH (6, 7). In women, maintenance of a midluteal-phase estradiol level prevented the FSH rise at the luteal-follicular transition despite a decrease in inhibin A (8, 9), raising the question of whether inhibin A plays any role in FSH-negative feedback during the normal menstrual cycle. Thus, the importance of inhibin A in FSH-negative feedback control during the luteal-follicular transition remains controversial.
It has been even more difficult to dissect the relative importance of estradiol, inhibin A, and inhibin B in restraining FSH in the follicular phase and after the midcycle surge in women because all three hormones are secreted simultaneously. FSH begins to decline approximately 1 d before peak inhibin B levels are achieved in the follicular phase, suggesting that inhibin B may be the most proximate regulator of FSH in the follicular phase (9, 10, 11). The selective FSH increase that occurs in the early follicular phase during normal reproductive aging, associated with decreased inhibin B, provides indirect evidence for a role of inhibin B in the follicular phase (12, 13, 14, 15, 16). However, inhibin B has not been available to test directly. Daily inhibin A injections in the follicular phase in the nonhuman primate suppressed bioactive FSH levels (17), although a single inhibin A injection on d 3–4 of the follicular phase did not (6). The decrease in late follicular and luteal phase inhibin A levels in association with increased FSH and estradiol in women studied longitudinally during reproductive aging suggests a role for inhibin A in FSH restraint in the late follicular and early luteal phase (12); however, inhibin A has not been directly tested at these cycle stages. Thus, the relative roles of estradiol and the inhibins, and inhibin A vs. inhibin B in FSH restraint, remain poorly understood and may be dependent on the stage of the menstrual cycle.
To test the hypothesis that inhibin A and inhibin B contribute to FSH negative feedback, estradiol’s effect was blocked using tamoxifen and the change in FSH examined. Tamoxifen is a selective estrogen receptor modulator with estrogen agonist and antagonist properties that are species, tissue, dose, and gene specific (18, 19). In the brain, tamoxifen acts as an estrogen antagonist (19) on both positive and negative estrogen feedback (20, 21, 22) and progesterone receptor induction (23). As such, it is a valid model for examining estradiol blockade at the hypothalamus and pituitary. Furthermore, early studies demonstrated that basal and GnRH stimulated gonadotropin levels increase in premenopausal women treated with tamoxifen despite a concomitant increase in estradiol (24, 25), indicating that it acts as an antagonist in premenopausal, estrogen-sufficient women. In the current studies, estrogen blockade by tamoxifen permitted evaluation of the relative role of estradiol and the inhibins in FSH-negative feedback. In addition, estrogen blockade during an intact menstrual cycle permitted evaluation of the relative role of inhibin A vs. inhibin B at specific phases of the menstrual cycle in which secretion of the two inhibins differs.
These studies demonstrated a distinct FSH increase in the early follicular and luteal phases after estrogen blockade, suggesting an important role for estradiol at these cycle phases. The site at which estradiol exerts its negative feedback on FSH (i.e. hypothalamus vs. pituitary) was further examined in normal cycling women and compared with GnRH-deficient women in whom hypothalamic output was fixed.
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Subjects and Methods |
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All subjects (n = 7) had normal prolactin and TSH levels, were on no medication, had normal body weight with body mass index 18–27 kg/m2, had no history of excessive exercise, and had no evidence of androgen excess on physical examination. All subjects had a history of regular 25- to 35-d menstrual cycles with evidence of ovulation in the preceding cycle as indicated by a serum progesterone level of more than 6 ng/ml.
Blood samples were drawn daily across two menstrual cycles and for up to 6 d in a third cycle. The first cycle was a control cycle. Subjects were treated with tamoxifen, 20 mg daily, to block estrogen feedback beginning in cycle 2 and continuing through the completion of the study in cycle 3. LH, FSH, estradiol, progesterone, inhibin A, and inhibin B were measured in all samples.
Subjects also underwent transvaginal ultrasounds (ATL HDI 1500, 5 MHz convex array transducer; ATL Ultrasound, Bothell, WA) in the midfollicular and late follicular phases to assess follicular development and the number of dominant follicles. The number and maximum diameter of all follicles greater than 10 mm were recorded.
To examine hypothalamic function, subjects were admitted for 8 h of every 10-min blood sampling in the early follicular phase (d 4–7) of the control cycle and in the early follicular phase of cycle 3 during tamoxifen treatment. LH and free -subunit (FAS) levels were measured in all samples.
GnRH-deficient women
Subjects with GnRH deficiency (n = 5), two with Kallmann’s syndrome and three with idiopathic hypogonadotropic hypogonadism, were studied. All subjects had undergone 12 h of every 10-min blood sampling for LH, and no pulses were documented after analysis using a modified Santen and Barden method (26). Other pituitary axes were intact and magnetic resonance imaging scans were normal. Subjects were otherwise healthy and on no medication. Oral contraceptives and estrogen replacement were stopped 3 months before the study.
GnRH-deficient women were treated with pulsatile GnRH, 75 or 100 ng/kg per bolus during the follicular phase for two cycles, and blood samples were drawn daily. The same dose of GnRH was administered in both cycles to a given subject. One cycle was a control cycle and the other was a treatment cycle in which 20 mg tamoxifen was administered daily. The control and tamoxifen cycles were performed in random order and separated by 1 month to 5 yr. GnRH was administered every 90 min until the development of a dominant follicle (
11 mm) during both studies, at which time the frequency was increased to every 60 min until 2 d after ovulation to simulate the normal menstrual cycle frequency. Ultrasounds were performed in the mid and late follicular phase, as for ovulatory subjects.
The study was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital. Informed consent was obtained from each subject before participation.
Assays
Serum LH, FSH, estradiol, and progesterone were measured using a two-site monoclonal nonisotopic system according to the manufacturer’s directions (Abbott Laboratories, Abbott Park, IL) as previously described (27). All samples for LH, FSH, estradiol, and progesterone were analyzed in duplicate, and all samples from an individual were analyzed in the same assay. LH and FSH levels are expressed in international units per liter, as equivalents of the Second International Reference Preparation 71/223 of human menopausal gonadotropins. The inter- and intra-assay coefficients of variation were similar to those previously described (28). Serum FAS concentrations were measured in a monoclonal antibody RIA using highly purified -subunit of human chorionic gonadotropin as the assay calibrator as previously described (26, 29). Assay sensitivities, inter- and intra-assay coefficients of variation, and cross-reactivities were similar to those previously described (26).
Inhibin A was measured in duplicate by ELISA (Serotec, Oxford, UK) as previously described (30). The assay uses a lyophilized human follicular fluid calibrator standardized as equivalents of the World Health Organization recombinant human inhibin A preparation 91/624, and values are reported as international units per milliliter. The limit of detection of the assay was 0.6 IU/ml. The intra-assay 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. All samples for a given individual were run in the same assay.
Inhibin B was measured in single samples by ELISA (Serotec) as previously described (12). The limit of detection of the inhibin B assay (mean ± 2 SD of multiple zero standard measurements) was 15.6 pg/ml. The intra-assay coefficient of variation was 4–6%, and the interassay coefficient of variation was 15–18% for serum spiked with 121, 250, and 723 pg/ml inhibin B. All samples with levels in excess of 500 pg/ml were appropriately diluted. All samples for a given individual were run in the same assay.
Data analysis and statistics
In normal ovulatory women, data were centered to ovulation for comparison of hormonal dynamics across the follicular and luteal phases of the menstrual cycle using three of four of the following criteria: 1) day of LH peak, 2) day of the midcycle FSH peak, 3) day of or following the midcycle estradiol peak, and 4) day the progesterone doubled from baseline or reached 0.6 ng/ml (31). Mean values for each hormone were calculated across the follicular phase from menses to the day before ovulation and the luteal phase from the day after ovulation to the day before menses. In addition, the follicular phase in normal and GnRH-deficient women was standardized to 14 d, with the day of ovulation as d 14. Mean early (d -13 to -9), mid (d -8 to -5), and late (d -4 to -1) follicular phase hormone levels were calculated as previously described (12). In two of the GnRH-deficient women, the initial dose of GnRH did not result in development of a dominant follicle in either the control or tamoxifen cycles (75 ng/kg per bolus in one idiopathic hypogonadotropic hypogonadism subject and 100 ng/kg per bolus in one Kallmann’s syndrome subject). In these two subjects, hormone levels from the first 5 d of treatment only were used for comparison of the early follicular phase in the two cycles. Values were log normalized if the data were not normally distributed and were compared between control and tamoxifen treatment cycles using a two-tailed, paired t test.
Pulsatile secretion of LH and FAS was determined using a modified version of the Santen and Bardin algorithm, which has been validated in an in vivo model (26). A pulse was identified in the frequent sampling series when the peak minus the nadir exceeded 3 times the assay coefficient of variation determined for the individual study and 1 IU/liter for LH or 30 pg/ml for FAS. In addition, each pulse was required to have a second point that met at least one of these two criteria.
Results are expressed as mean ± SEM unless otherwise indicated. A P value of less than 0.05 was considered significant.
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Results |
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In the presence of estrogen receptor blockade with tamoxifen, FSH was higher in the early follicular phase (15.7 ± 3.1 vs. 13.2 ± 1.9 IU/liter; P < 0.05; Figs. 1
and 2). The higher levels of FSH resulted in an increase in inhibin B (198.3 ± 27.8 vs. 129.0 ± 6.2 pg/ml; P < 0.05) and inhibin A (7.5 ± 1.0 vs. 3.2 ± 0.4 IU/ml; P < 0.01) in the late follicular phase (Figs. 1 and 2) in association with an increased number of dominant follicles (1.7 ± 0.2 vs. 1.0; P < 0.05). Although estradiol was also higher in the late follicular phase [498.7 ± 54.7 vs. 219.4 ± 18.3 pg/ml (1831 ± 201 vs. 805 ± 67 pmol/liter); P < 0.01], its effects on FSH secretion were blocked by tamoxifen. The heights of the LH (167 ± 31 vs. 105 ± 10 IU/liter; P < 0.05) and FSH surges (27.1 ± 4.5 vs. 18.8 ± 1.6 IU/liter; P = NS) were increased after tamoxifen administration. There was no difference in follicular phase length between tamoxifen-treated and control cycles (13.6 ± 0.5 vs. 14.1 ± 1.3 d).
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) despite an increase in inhibin A (10.4 ± 1.3 vs. 5.6 ± 1.2 IU/ml; P < 0.01). However, peak FSH levels were considerably less than levels previously reported in postmenopausal women (171.6 ± 16.9 IU/liter) (32). Progesterone was higher in the luteal phase [19.7 ± 3.0 vs. 8.9 ± 1.1 ng/ml (62.6 ± 9.5 vs. 28.3 ± 3.5 nmol/liter); P < 0.01] consistent with the formation of two corpora lutea. Estradiol [425.0 ± 144.0 vs. 145.1 ± 6.7 pg/ml (1560 ± 529 vs. 533 ± 25 pmol/liter); P < 0.01] was also elevated in the luteal phase (Fig. 1), but its effects on FSH were blocked by tamoxifen. There was no difference in luteal phase length between tamoxifen-treated and control cycles (15.6 ± 0.9 vs. 13.9 ± 0.6 d). Site of estradiol feedback in normal ovulatory women
GnRH pulse frequency was assessed by frequent sampling of LH and FAS in the early follicular phase. LH pulse frequency (5.5 ± 0.5 vs. 5.5 ± 0.8 pulses per 8 h), interpulse interval (93.1 ± 15.4 vs. 83.2 ± 11.4 min), and pulse amplitude (5.1 ± 1.3 vs. 2.9 ± 0.5 IU/liter; Fig. 3) were not significantly different in tamoxifen, compared with control cycles. However, FAS pulse frequency was higher after tamoxifen administration (7.3 ± 0.4 vs. 4.8 ± 0.4 pulses per 8 h), with a shorter interpulse interval (59.2 ± 4.5 vs. 94.6 ± 19.6 min; Fig. 3).
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In GnRH-deficient women, in contrast to ovulatory subjects, FSH failed to increase in the early follicular phase after estrogen blockade (11.1 ± 1.6 vs. 12.5 ± 3.6 IU/liter; Fig. 4). There was also no difference in inhibin B (110.6 ± 26.1 vs. 159.2 ± 14.9 pg/ml), inhibin A (4.2 ± 1.2 vs. 4.1 ± 1.7 IU/ml), or number of dominant follicles (1.3 ± 0.3 vs. 3.0 ± 2.0) in the late follicular phase (Fig. 4). Estradiol was also similar in the late follicular phase in control and tamoxifen-treated cycles in which estradiol was blocked [564.4 ± 172.9 vs. 400.4 ± 158.2 pg/ml (2072 ± 635 vs. 1470 ± 581 pmol/liter)]. There was no difference in the follicular phase length in tamoxifen treated and control cycles (14.7 ± 0.9 vs. 14.3 ± 1.3 d). Estradiol levels were not different between normal and GnRH-deficient women in the early follicular phase during tamoxifen treatment [56.8 ± 6.2 vs. 46.7 ± 10.9 pg/ml (209 ± 23 vs. 171 ± 40 pmol/liter)], ruling out the possibility that estradiol blockade was different in the two groups.
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Discussion |
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Although the current data provide support for a role of both estradiol and the inhibins in FSH control, it is possible that tamoxifen did not completely block estradiol action, resulting in an overestimate of the role of the inhibins. The tamoxifen dose used increased FSH levels in premenopausal women in the setting of increased estradiol levels in this and previous studies (24, 25), demonstrating the efficacy of the 20-mg dose in blockade of estrogen-negative feedback. However, tamoxifen administration failed to block estrogen-positive feedback at the midcycle LH surge in these studies (24). Although estrogen-positive and -negative feedback have a different time and dose dependence (33) and may involve different estrogen receptor coregulators, it is possible that estrogen-negative feedback blockade was also incomplete. Regardless of whether estrogen was completely blocked, the relative role of estradiol in FSH control can be determined by comparing FSH levels during cycle phases in which serum estradiol levels are equivalent because tamoxifen should block estradiol to a similar degree. FSH is not increased in the late follicular phase, whereas it is increased in the luteal phase despite similar estradiol levels, suggesting that estradiol plays a more important role in FSH suppression in the luteal phase than in the late follicular phase. It is therefore possible that the effect of estradiol on FSH is more clearly demonstrated when the GnRH pulse generator is slowed by progesterone (4, 34, 35, 36). A greater suppression of FSH is also seen in postmenopausal women receiving progesterone and estradiol as opposed to estradiol alone (2, 3, 4, 37). Thus, it appears that estradiol-negative feedback on FSH is dependent on cycle phase, with estradiol exerting a particularly important negative feedback effect in the luteal phase and in the luteal-follicular transition.
The relative contribution of inhibin A and inhibin B can also be evaluated by comparing relative changes in FSH at distinct cycle stages in which one inhibin is predominant. FSH increases with tamoxifen-induced estradiol blockade in the early follicular phase when inhibin B is predominant and in the luteal phase when inhibin A is predominant. Thus, neither inhibin alone is sufficient to control FSH secretion, but both are able to prevent the increase in FSH to postmenopausal levels, a rise that begins 48–72 h and plateaus 3 wk after oophorectomy (38, 39). In the late follicular phase, estrogen blockade was not associated with an increase in FSH, implying that the combined effects of inhibin A and/or inhibin B contribute to the majority of FSH-negative feedback, and consequently estradiol’s negative feedback effects are less important. Inhibin B is higher in the late follicular phase when FSH did not increase than in the early follicular phase when it did, but inhibin A is similar in the late follicular phase and luteal phase despite changes in FSH levels. Taken together, these relationships suggest that inhibin B may be the more important inhibin in FSH control in the late follicular phase, a conclusion supported by studies in nonhuman primates. Macaques treated with the antiestrogen Faslodex during the FSH decline in the midfollicular phase had an initial FSH increase with estrogen blockade, but FSH levels subsequently returned to normal values when inhibin B increased (40). Inhibin A levels did not change.
Tamoxifen’s half-life is 14 d, suggesting that a steady state is not reached for several weeks after administration begins. Nevertheless, in the current study, FSH increased in the early follicular phase, during the first 5 d of tamoxifen administration, and estradiol levels begin to increase in less than 1 wk after the onset of tamoxifen administration. Thus, the time frame of tamoxifen’s onset of action appears to be adequate for analysis of the effect of estradiol blockade. Although previous studies did not demonstrate this early FSH increase, the number of subjects studied was smaller (24, 25).
Selective estrogen blockade also permitted evaluation of the site of estrogen negative feedback on FSH in the early follicular phase when there were no concomitant changes in the inhibins. Although there was no change in LH pulse frequency after estrogen blockade during the early follicular phase, FAS clearly increased, indicating a hypothalamic site of estradiol action. FAS is a more discerning marker of GnRH pulse frequency than LH based on its short half-life (26, 32, 41). This is particularly true in postmenopausal women (32, 42) and likely is due to the effect of estrogen deprivation on the isoforms of LH (43), a situation that may be comparable with tamoxifen administration in the current study. Absence of the early follicular phase FSH increase after estrogen blockade in GnRH-deficient women in whom hypothalamic output is fixed confirms the findings in ovulatory women and further suggests that estradiol exerts its negative feedback effect only at the hypothalamus in the early follicular phase. Estradiol levels are equivalent in ovulatory women and GnRH-deficient women receiving pulsatile GnRH in the early follicular phase in this study and therefore should be equally blocked by tamoxifen in the two subject populations, allowing for this direct comparison.
Our finding of a hypothalamic site of estrogen-negative feedback in the current study is consistent with previous studies in a variety of animal models (33, 44). The unique finding in the current studies is that in the early follicular phase, estrogen negative feedback is specific to the hypothalamus and does not involve the pituitary. When estradiol was administered coincident with a fixed regimen of pulsatile GnRH in the nonhuman primate, gonadotropin secretion was suppressed, suggesting a pituitary site of action (45). Similarly, estradiol administration coincident with initiation of pulsatile GnRH treatment in GnRH-deficient women prevented the typical selective FSH increase (46). The estradiol levels achieved in GnRH-deficient women in this study were equivalent to those in the normal mid to late follicular phase (46), however. Furthermore, estrone was not measured and would likely have been supraphysiologic in these subjects treated with oral estradiol, as shown previously (47, 48). Taken together with data from the current study, these findings suggest that estradiol may exert a primarily hypothalamic effect at low, early follicular phase levels, but pituitary negative feedback may also occur at higher estradiol levels.
In summary, the current study demonstrates that both estradiol and the inhibins contribute to the negative feedback regulation of FSH during the follicular phase, with inhibin B playing a more critical role in FSH control as the follicular phase progresses. In contrast, estradiol exerts a greater role than inhibin in FSH-negative feedback regulation during the luteal phase and luteal-follicular transition. Finally, at low estradiol levels typical of the early follicular phase, estradiol exerts its negative feedback effect at the hypothalamus. Thus, both estradiol and the inhibins are important for FSH control in the normal menstrual cycle.
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Acknowledgments |
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Footnotes |
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Abbreviation: FAS, Free -subunit.
Received September 27, 2002.
Accepted November 22, 2002.
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References |
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subunit during the mid-luteal phase in the stump-tailed macaque. J Endocrinol 133:341–347 subunit is superior to luteinizing hormone as a marker of gonadotropin-releasing hormone despite desensitization at fast pulse frequencies. J Clin Endocrinol Metab 84:1028–1036This article has been cited by other articles:
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) and tamoxifen-treated cycles (•) in ovulatory women, expressed as a percentage of the control mean. To calculate the percentage of control mean in individual subjects, daily hormone data from control and tamoxifen cycles were divided by the mean hormone level across the control cycle for each subject and multiplied by 100. ***, P < 0.05.
) and tamoxifen-treated cycles (
) in the early (EFP), mid (MFP), and late (LFP) follicular phase of the menstrual cycle in ovulatory women. To convert estradiol concentrations to picomoles per liter, multiply by 3.671. *, P < 0.05.
