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Relationship of Estradiol and Inhibin to the Follicle-Stimulating Hormone Variability in Hypergonadotropic Hypogonadism or Premature Ovarian Failure

Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Corrine K. Welt, Reproductive Endocrine, BHX 511, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: cwelt{at}partners.org.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Recent studies have demonstrated the presence of ovarian follicular development in up to 78% of women with premature ovarian failure (POF). The purpose of this study was to examine the control of FSH by estradiol and inhibin secretion from these follicles. Weekly blood samples were collected in conjunction with assessment of ovarian follicle development by ultrasound for at least 12 wk in 49 subjects with POF. Results were compared with those of 44 normal cycling women. Ovulatory cycles occurred in 24 subjects (49%) with POF. These ovulatory cycles were characterized by higher FSH and lower inhibin B and inhibin A levels, whereas estradiol levels were higher compared with those in normal women. Follicles developed in the absence of ovulation in 18 women (37%) with POF, whereas the ovaries were inactive in seven women (14%). FSH levels were lower in POF women with ovulatory or anovulatory follicle development compared with levels in women with inactive ovaries. These findings demonstrate that ovulatory cycles in women with POF are characterized by a persistent elevation in FSH compared with levels in normal cycling women. The association of increased FSH with lower levels of inhibin B and inhibin A, but higher estradiol levels provides additional evidence for an important physiological role of the inhibins in the negative feedback control of FSH. These data also demonstrate the variability in FSH levels as a function of underlying follicular development in women with POF.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
AMENORRHEA AND ELEVATED gonadotropin levels in women under the age of 40 yr characterize premature menopause or ovarian failure (POF), which is better termed hypergonadotropic hypogonadism. Follicle development and vaginal bleeding can occur sporadically for several years after a diagnosis of premature ovarian failure is made (1, 2), and pregnancy has been documented in a number of reports (3, 4, 5, 6). We have previously shown that in women with hypergonadotropic amenorrhea, ovarian follicles developed in 78%, and ovulation occurred in 46% during a 12-wk randomized, cross-over trial of estradiol replacement therapy, whereas estradiol therapy had no effect on follicular development or ovulation rate (6).

The waxing and waning nature of follicle development can cause difficulty in diagnosing hypergonadotropic hypogonadism or POF, because FSH levels may be elevated on one occasion, but in the normal range on another (6, 7). However, the extent to which FSH levels are altered during follicular development and ovulatory cycles in women with a diagnosis of ovarian failure has not been extensively documented. The observed variability in FSH levels may be due to feedback by estradiol and/or inhibin A and inhibin B secretion from developing follicles. There is evidence that estradiol, inhibin A, and inhibin B play a role in the dynamic negative feedback control of FSH secretion across the normal menstrual cycle (8), and that inhibin B and inhibin A are the most important negative feedback regulators of FSH during normal reproductive aging (9, 10, 11, 12). However, other studies suggest that inhibin may not be critical for FSH control (13).

The goals of this study were to examine FSH levels in women with hypergonadotropic hypogonadism in the absence of follicle development, during follicle development, and during ovulatory cycles and to determine the relative importance of estradiol, inhibin A, and inhibin B to FSH negative feedback. These data not only provide important clinical information for the diagnosis of hypergonadotropic hypogonadism or POF, but also address the physiological roles of estradiol and the inhibins in the negative feedback control of FSH during the menstrual cycle.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Fifty-six hypergonadotropic subjects were studied. A subset of these subjects (n = 37) participated in a previous study examining follicle development in a randomized, cross-over trial of estradiol, in which it was determined that estradiol treatment did not influence follicle development in POF (6). All subjects were less than 40 yr old, had at least 2 months of amenorrhea, and had at least two FSH measurements above 40 IU/liter Second International Reference Preparation of human menopausal gonadotropin, which represents the upper 95% confidence limit of the midcycle FSH peak in 118 normal menstrual cycles (6). The etiology of POF in these subjects is outlined in Table 1. All women had at least one intact ovary, normal thyroid function tests, and good general health and were taking no medications, with the exception of thyroid hormone replacement. The Partners human research committee approved the study, and all subjects gave written informed consent.

Protocol

After a baseline ultrasound, subjects were randomized to receive micronized estradiol (2 mg daily) or no treatment for 6 wk. After 6 wk, the subjects were switched to the alternate treatment for an additional 6 wk. Each subject had weekly blood samples and pelvic ultrasounds performed. Ultrasounds were performed transvaginally or transabdominally by a single investigator (J.M.A.) using a Sonolayer L, SAL-778 machine (Toshiba Corp., Tokyo, Japan). Subjects who were interested in pregnancy were monitored weekly after the 12-wk interval (n = 44) for an additional 1–95 wk. Two of these subjects had ovulatory cycles that occurred after the initial 12 wk of monitoring, at wk 30 and 57. These subjects were designated ovulatory, and the hormonal data from their ovulatory cycles were included in the comparison with normal cycling women.

Assays

LH, FSH, estradiol, and progesterone were analyzed by RIA (14, 15). All samples for LH, FSH, estradiol, and progesterone were analyzed in duplicate, and all samples from an individual were analyzed in the same assay. For LH, the interassay coefficients of variation (CVs) were 6.0% and 11.4% for quality control sera containing 10.3 and 24.6 IU/liter LH, respectively. For FSH, the interassay CVs were 8.4% and 11.8% for quality control sera containing 7.7 and 21.9 IU/liter, respectively. FSH and LH samples with levels above the highest standard were diluted to obtain values on the standard curve. For estradiol, the interassay CVs were 6–13%, and for progesterone, the interassay CVs were 9–12% for quality control sera at low, medium, and high concentrations within the range of the assays. Gonadotropin levels are expressed as international units per liter, as equivalents of the Second International Reference Preparation 71/223 of human menopausal gonadotropins. To conserve serum, the estradiol assay was performed with lower preextraction serum volumes, yielding a sensitivity of 40 pg/ml (147 pmol/liter). For purposes of analysis, 40 pg/ml (147 pmol/liter) was used for estradiol levels below the sensitivity of the assay.

Inhibin A was measured in duplicate by ELISA (Serotec, Oxford, UK), as previously described (16). The assay uses a lyophilized human follicular fluid calibrator standardized as equivalents of the WHO 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 interassay CVs for the dimeric inhibin A assay were 11.7% and 10.3% for quality control sera containing 5.01 and 10.01 IU/ml, respectively. All samples for a given individual were run in the same assay.

Inhibin B was measured as single samples by ELISA (Serotec), as previously described (17). The limit of detection of the inhibin B assay (mean ± 2 SD of multiple zero standard measurements) was 15.6 pg/ml. The intraassay CV for the dimeric inhibin B assay was 4–6%, and the interassay CV was 15–18% for quality control sera containing 121, 250, and 723 pg/ml, respectively. 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.

Analysis

Of the 56 subjects who participated in the study, seven were not included in the analysis (four subjects dropped out of the study, and three subjects had <12 wk of data); thus, the total number of subjects with data analyzed was 49. To compare the roles of endogenous estradiol, inhibin A, and inhibin B in FSH regulation between women with POF and normal cycling women, hormone levels were only examined off estradiol treatment.

Follicle development was determined after reviewing sequential ultrasound films and identifying cystic structures that had not been present previously based on location, as previously described (6). All follicles 5 mm in maximal diameter or larger were documented. Ovulation was determined by the presence of a new cystic structure on ultrasound of 10 mm or larger, an increase in the follicle size during the study, and a serum progesterone level greater than 4 ng/ml (12.72 nmol/liter) in association with follicle collapse on ultrasound. For ovulatory cycles, cycle day was estimated by follicle size and the timing of the progesterone rise. Follicles 11 mm or larger were considered dominant follicles (18).

Three nonoverlapping groups of hypergonadotropic subjects were identified based on ultrasound and hormonal measures: 1) at least one ovulatory follicle; 2) dominant (11 mm) follicles, but failure to ovulate; and 3) inactive ovaries with no dominant follicle development. In ovulatory hypergonadotropic subjects (group 1), mean FSH, LH, estradiol, progesterone, inhibin A, and inhibin B levels were compared in the follicular and luteal phases of that cycle to levels in normal cycling subjects using two-tailed, unpaired t tests. FSH, LH, estradiol, inhibin A, and inhibin B levels were also compared among the three hypergonadotropic groups using ANOVA on ranks or one-way ANOVA, as appropriate. Hormone measurements were performed in subjects with anovulatory follicles on the day they developed the largest follicle and in the ovulatory subjects on the day that was closest to the day of ovulation. Therefore, anovulatory and ovulatory follicles were all 14 mm or larger at the time of hormonal measurement. Hormone levels in hypergonadotropic women in whom no follicles grew were compared at one visit between wk 1 and 4 when the subjects were receiving no treatment.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
As previously described, three patient subgroups could be identified based on the pattern of follicular development (6). Nine subjects (18%) failed to develop dominant follicles; seven subjects (14%) demonstrated a totally inactive pattern, characterized by small cystic structures of 2 mm and no follicle development, and two subjects (4%) had follicle growth, but only to 8 mm. In 16 subjects (33%) there was evidence of dominant follicle growth (11 mm), but no ovulation, and 24 women (49%) demonstrated follicle growth with ovulation. These rates of follicle development are similar to those reported previously (6).

FSH levels were related to follicle development in the three groups of hypergonadotropic subjects. FSH levels were lower in subjects with ovulatory and anovulatory follicle development compared with those in women with no follicle development (26.4 ± 7.7, 62.2 ± 19.6 and 182.8 ± 16.3 IU/liter, respectively; P < 0.001; Fig. 1). FSH levels were suppressed below 40 IU/liter in seven of nine hypergonadotropic women with ovulatory cycles and in five of 11 women with anovulatory follicle development, although FSH levels remained higher, on the average, than those in normal cycling women (Fig. 1).

View larger version (34K): [in this window] [in a new window]   FIG. 1. FSH, estradiol (E2), inhibin B (Inh B), and inhibin A (Inh A) levels (vertical bars) in hypergonadotropic women with no dominant follicles (no foll; n = 8), anovulatory follicles (anov foll; n = 11), and ovulatory follicles (ov foll; n = 9). The dotted line indicates the mean hormone level in the late follicular phase in normal cycling women. Data marked by the same letter are different at P < 0.05. To convert estradiol to Systeme International units, multiply by 3.671.

View this table: [in this window] [in a new window]   TABLE 2. Hormone levels in subjects with anovulatory follicles (14 mm)

View larger version (28K): [in this window] [in a new window]   FIG. 2. Inhibin B (Inh B), FSH, estradiol (E2), inhibin A (Inh A), LH, and progesterone (P4) levels in ovulatory hypergonadotropic women (n = 24) at each cycle stage (; mean ± SEM) and in normal subjects (shaded area; mean ± 1 SD). Significant differences across the follicular and luteal phases in women with hypergonadotropic hypogonadism compared with normal women are indicated (**, P < 0.05). Conversion factors to Systeme International units: estradiol, 3.671; progesterone, 3.18.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The importance of inhibin A and inhibin B in FSH control in primates remains controversial. In the nonhuman primate, inhibin A infusions in the luteal phase suppressed FSH and prevented the peak in FSH at menses (19), and daily inhibin A injections in the follicular phase suppressed bioactive FSH levels (20), providing direct evidence that inhibin A is an important feedback regulator. However, a single inhibin A injection in the follicular phase (21) and immunoneutralization of inhibin in the luteal phase of female macaques did not increase FSH levels (21, 22). Inhibin has not been available for administration to humans; therefore, evidence for a feedback role in humans has been necessarily indirect. Selective estrogen blockade provides evidence that the inhibins restrain FSH across the menstrual cycle and may be more important than estradiol in suppressing FSH in the late follicular phase (8). However, when estradiol is held constant during the luteal-follicular transition, the fall in inhibin A is not sufficient to permit the normal rise in FSH (13, 23), bringing the role of inhibin A in the acute control of follicular phase FSH into question. In contrast, data from the current study demonstrate that decreased inhibin A and inhibin B levels are associated with increased FSH levels not only in the follicular phase, but across the entire cycle, despite increased levels of estradiol. These findings support and expand the results of previous studies demonstrating that inhibin B (9, 10, 11, 12) and inhibin A (9, 24) are the most important regulators of FSH during normal reproductive aging and in the perimenopause. Thus, the evidence continues to support a role for inhibin A and inhibin B in the overall regulation of FSH, although there is less evidence to support a role for inhibin in acute regulation of FSH at specific phases of the cycle.

The variability in FSH as a function of underlying follicular development in women with hypergonadotropic hypogonadism may have important clinical implications. FSH levels were highest and within the expected elevated range when there was no follicle development evident on ultrasound in women with hypergonadotropic hypogonadism. Suppression of FSH occurred during ovulatory and anovulatory cycles when follicles reached 14 mm or larger, and in individual subjects FSH levels were suppressed into the premenopausal range (<40 IU/liter), as described previously (7). Importantly, FSH levels were lower in subjects with anovulatory follicle development regardless of whether the follicles secreted estradiol and/or inhibin B. These findings indicate that an FSH level determined during follicular development to diagnose or confirm the diagnosis of POF could result in a false negative test. Thus, underlying follicular development must be taken into consideration when diagnosing or confirming a diagnosis of hypergonadotropic hypogonadism or POF.

Our previous study demonstrated that women with POF and amenorrhea for less than 3 months are more likely to ovulate than women with a longer period of amenorrhea (6), and we have now shown that these ovulatory cycles are associated with lower FSH levels, although they remain elevated compared with FSH levels in regularly cycling women. Nevertheless, these promising findings do not translate into a better prognosis for pregnancy. When the cycle to cycle variability in FSH levels was examined as a prognostic indicator of outcome during assisted reproduction in cycling women, an elevated FSH level during any cycle predicted a poor outcome (25). This latter point is supported by the results of our previous study. Despite documented ovulation and carefully monitored cycles in highly motivated subjects, there were only five pregnancies in 37 hypergonadotropic women, and the pregnancy rate was independent of the duration of amenorrhea (6). Although ovulation is more likely to occur in women with POF and a shorter duration of amenorrhea, and FSH levels are lower during these ovulatory cycles than in anovulatory women with POF, the pregnancy rate is poor regardless of the duration of amenorrhea (6). Documented exceptions occur in the setting of chemotherapy or radiation-induced ovarian dysfunction, which can be reversible (26). Thus, POF is probably a continuum, starting with infertility and elevated FSH levels during ovulatory cycles and progressing to complete amenorrhea. Therefore, a broad, standardized, clinical definition for POF is needed, and the terminology should be changed to hypergonadotropic hypogonadism or ovarian insufficiency, which emphasizes the fertility defects that are paramount in this disorder while deemphasizing the amenorrhea, which can be quite variable.

Although we cannot rule out the possibility of differences in the patterns of hormonal secretion associated with follicle development within a subject over time, the data presented here point to the possibility of identifying subsets of women with hypergonadotropic hypogonadism. Of particular interest are those who have follicular development with secretion of estradiol only or secretion of inhibin A and inhibin B only. The absence of estradiol suggests aromatase defects (27) or LH receptor abnormalities (28); however, these congenital defects are associated with primary amenorrhea and are not acquired defects as in the hypergonadotropic woman studied here with low estradiol and increased inhibin B production. It is also possible that decreased estradiol is related to decreased precursor production. The selective absence of inhibin B is consistent with luteinization of the follicle, because inhibin ßB mRNA subunit expression and inhibin B secretion are absent in the corpus luteum (29). Previous studies provide evidence for premature luteinization of follicles in women with hypergonadotropic hypogonadism (1). It is possible that the isolated secretion of inhibin or estradiol is unique to hypergonadotropic hypogonadism. Although inhibin A and inhibin B were undetectable in approximately 40% of perimenopausal women starting 2 yr before the final menses, these results included women who had been amenorrheic for up to 3 months, and the estradiol levels in these particular subjects were not specified (30). Additional studies are needed to determine whether the mechanisms of POF are different from the decline in ovarian follicle number, which is mainly responsible for hormonal changes in the perimenopause (9, 24, 30, 31).

The data in the current study demonstrate that FSH levels at any one time in women with POF or hypergonadotropic hypogonadism are dependent on underlying follicular activity and the resultant estradiol and inhibin secretion. Although FSH levels remain, on the average, increased in hypergonadotropic compared with normal cycling women, it may be necessary to document follicle activity by ultrasound or hormone levels before interpreting FSH levels as normal when the clinical suspicion of POF is high or when confirming a previously elevated value. These careful assessments are critical to accurately confirm such a devastating diagnosis and provide the patient with accurate clinical information.

	Acknowledgments

 
We gratefully thank Patrick Sluss, Ph.D., and the members of the core laboratory for their assay expertise. We also thank the subjects in this protocol for their patience and persistence.

	Footnotes

 
This work was supported by National Institutes of Health Grants U54-HD-29164 and M01-RR-01066.

Current address for C.K.W.: Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340.

First Published Online November 23, 2004

Abbreviations: CV, Coefficient of variation; POF, premature ovarian failure.

Received July 8, 2004.

Accepted November 14, 2004.

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