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Department of Pediatrics, Obstetrics, and Reproductive Medicine (A.T., L.B., F.R., F.P.), University of Siena, 53100 Siena, Italy; and Department of Internal Medicine (S.M., A.B., P.C., M.L.B., V.B., A.F.), Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, 06126 Perugia, Italy
Address all correspondence and requests for reprints to: Alberto Falorni, M.D., Ph.D., Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, Via E.Dal Pozzo, 06126 Perugia, Italy. E-mail: falorni{at}dimisem.med.unipg.it.
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Abstract |
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Design: We have determined the serum concentrations of total inhibin and inhibin B by sensitive ELISAs in 22 women with autoimmune POI (aPOI), 71 women with non-autoimmune idiopathic POI (iPOI), 77 postmenopausal women, and 90 healthy, fertile women (HW). Diagnosis of aPOI was made according to the presence of steroid cell autoantibodies and/or 17
-hydroxylase autoantibodies and/or cytochrome P450 side-chain cleavage autoantibodies. All aPOI patients were also positive for adrenal autoantibodies.
Results: Total inhibin levels were significantly higher in women with aPOI (median, 281 pg/ml) than in women with iPOI (median, 74 pg/ml) or HW (median, 133.5 pg/ml) (P < 0.001). Levels of inhibin B were also significantly higher in women with aPOI (median, 109 pg/ml) than in women with iPOI (median, 18 pg/ml) (P < 0.001) or HW (median, 39 pg/ml) (P < 0.05). Serum concentrations of total inhibin and inhibin B were significantly higher in women with POI than in postmenopausal women (P < 0.001), irrespective of the presence/absence of autoantibodies. At receiver-operating characteristic analysis, cutoff values of 133 pg/ml for total inhibin and 60.5 pg/ml for inhibin B ensured 86.4% sensitivity and 81–84.5% specificity for aPOI vs. iPOI.
Conclusions: We conclude that a variable degree of ovarian function is preserved in women with POI and that aPOI is characterized by increased inhibin production resulting from a selective theca cell destruction, with initial preservation of granulosa cells.
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Introduction |
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-hydroxylase (17OH), and cytochrome P450 side-chain cleavage (P450scc) (6, 7, 8, 9, 10, 11, 12). StCA, 17OH autoantibody (17OHAb), and P450sccAb are rarely detected in patients negative for adrenal autoantibodies, whereas they are present in over 90% of POI cases associated with clinical or preclinical autoimmune Addison’s disease (6, 8, 9). Although autoimmune POI appears strongly associated with adrenal insufficiency, a diagnosis of autoimmune POI, better defined as autoimmune oophoritis (5), requires the demonstration of circulating StCA, as not all forms of adrenal insufficiency are autoimmune. In addition, the possibility of the occurrence of non autoimmune POI in patients with autoimmune Addison’s disease cannot be ruled out. Clinical adrenal insufficiency may be a late sequela for some women with POI and only the detection of StCA may reveal the autoimmune origin of the ovarian dysfunction and enable the identification of subjects with preclinical adrenal insufficiency.
Granulosa cells of human ovary produce and release two forms of inhibins, inhibin A and inhibin B. They are glycoproteins; inhibin A consists of an -subunit disulfide linked to a βA subunit (+βA) and inhibin B consists of an -subunit and βB subunit (+βB) (13). The -subunit is unique to all inhibin molecules and is synthesized as a 53-kDa, 366-amino-acid (aa) (depending on species) precursor containing an 18-aa signal sequence, a 43-aa pro-region (also called pro-), and a 305-aa mature form. The mature form is divided into a 171-aa N-terminal segment (N) and a 133- to 134-aa C-terminal segment (C).
Typically, POI, similarly to natural menopause, is characterized by elevated FSH levels and reduced production of estrogens, inhibin A, and inhibin B due to a decreased number of follicles and follicle development (14, 15). More specifically, a decrease in inhibin B production appears to be the first sign of an incipient ovarian insufficiency (16). However, high levels of inhibin A and inhibin B have recently been demonstrated in three women with autoimmune POI and multifollicular development (17), thus leading to the formulation of the hypothesis of a selective theca cell destruction in autoimmune oophoritis, with initial preservation of granulosa cells and lack of substrates for the production of 17β-estradiol (17).
To test the hypothesis that the pathophysiology of autoimmune oophoritis is distinct from that of other forms of ovarian insufficiency, we tested serum samples from a large population of women with POI, previously classified as autoimmune or non-autoimmune, according to the presence of StCA, for the concentration of inhibin B and total inhibin by a new ELISA that detects the free inhibin -subunit.
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Subjects and Methods |
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The study design included four groups of women (Table 1
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Group 2 comprised 22 women with autoimmune POI. In this group, a diagnosis of autoimmune POI was formulated because these women were younger than 40 yr at diagnosis, were all positive for both adrenal and StCA, had increased levels of gonadotropins (both higher than 25 mIU/ml), and have had a menarche between 10 and 13 yr and secondary amenorrhea for 6–40 months (median 13 months) at the time of blood sampling. StCA (range of end-point dilution titer, 1/7–1/128) were present in 20 of the 22 women with autoimmune POI. Of the 22 women with autoimmune POI, all were positive for adrenocortical autoantibodies (ACA) and 21OHAb; 14 (64%) were positive for StCA, 17OHAb, and P450sccAb simultaneously; two (9%) were positive for StCA and 17OHAb; three (13.5%) were positive for StCA and P450sccAb; one (4.5%) was positive only for StCA, one (4.5%) only for 17OHAb, and one (4.5%) only for P450sccAb. A total of 17 women with autoimmune POI had clinical autoimmune Addison’s disease and were treated with substitutive doses of cortisone acetate and fluorohydrocortisone. Of the five women with autoimmune POI with no clinical signs of adrenal insufficiency, all were positive for 21OHAb and ACA and had normal basal cortisol and ACTH levels, but two had an impaired cortisol response to the ACTH stimulation test. All women with autoimmune POI had a normal chromosomal karyotype (46,XX), and none had autoimmune polyendocrine syndrome type I. Thirteen of 22 (59%) women with autoimmune POI had APS II and were also affected by other autoimmune diseases, including thyroid autoimmune diseases, type 1 diabetes mellitus, vitiligo, chronic atrophic gastritis, or rheumatoid arthritis.
Group 3 comprised 77 postmenopausal women who had experienced a natural menopause. The time between last menstruation and blood sampling for the present study was 5–13 yr. All women had serum 17β-estradiol concentrations of less than 20 pg/ml and FSH and LH concentrations of more than 40 mIU/ml.
Group 4 comprised 90 healthy, fertile women. All healthy control women had regular ovulatory menstrual cycles, normal body mass index, and no documented fertility or endocrine disturbances. In these women LH, FSH, and 17β-estradiol concentrations were measured in the early follicular phase (d 3–5), and gonadotropin concentrations were less than 10 mIU/ml in all studied healthy women.
The study was approved by the local Ethics Committees at University of Perugia and University of Siena, and all patients gave their informed consent to be enrolled in the study.
Inhibin ELISA
Total inhibin and inhibin B concentrations were measured according to the description by the manufacturer (Diagnostic Systems Laboratories/Oxford Bio Innovation, Oxford, UK). The new total inhibin assay detects both dimeric and free -subunits and is more sensitive and rapid than previous methods, such as C immunofluorometric assay (18). It uses two monoclonal antibodies: one detection antibody (PO#23), raised to aa 79–98 of the inhibin C subunit, and one capture antibody (R1) to aa 1–32 of the inhibin C subunit. The characteristics of these antibodies, including the chromatographic profile of the molecular forms of inhibin detected, have been described elsewhere (19, 20). Inhibin B sensitivity was 10 pg/ml, and within- and between-assay variations were 6.9 and 14.3%, respectively. Total inhibin sensitivity was 2.5 pg/ml, and within- and between-assay variations were 7.9 and 8.6%, respectively.
LH, FSH, and 17β-estradiol assays
Serum LH and FSH levels were evaluated by immunoassays provided by Cis Bio International (Gif-sur-Yvette, France). These immunometric assays used monoclonal antibodies raised against LH and FSH. Results are expressed as milli-IU per milliliter in terms of the First International Reference Preparation 68/40 (LH) and the Second International Reference Preparation 78/549 (FSH). FSH and LH concentrations were measured in duplicate using the commercially available immunoassays.
17β-Estradiol was determined by RIA, and the early follicular phase range of the assay was 20–110 pg/ml.
Adrenal and StCA assays
ACA were evaluated by indirect immunofluorescence against bovine adrenal gland using serial 2-fold dilutions of subject serum. StCA were detected by indirect immunofluorescence against cryostatic sections of monkey ovary and testis (Bios GmbH, Grafelfing, Germany). The results of indirect immunofluorescence assays are expressed as the lowest 2-fold serial dilution of subject serum with a positive result. 21OHAb, 17OHAb, and P450sccAb were measured using radiobinding assays to recombinant human 21OH, 17OH, and P450scc radiolabeled with 35S as previously described (21, 22).
The full-length cDNAs for human 17OH (23) and for human P450scc (24) were donated by Dr. Walter L. Miller, Department of Pediatrics and Metabolic Research Unit, University of California, San Francisco, California.
Autoantibody levels were expressed as relative indices (mean cpm unknown – mean cpm of two negative control samples)/(mean cpm positive control sample – mean cpm of two negative control samples), with the upper limit of normal defined as the mean + 3 SD of 130 healthy control samples.
Statistical analysis
Differences between groups were tested by Kruskal-Wallis ANOVA followed by Dunn’s test for multiple comparisons or by the nonparametric Mann-Whitney U test. The correlation between inhibin B and difference in total inhibin – inhibin B (
tot-inhB) was tested by Spearman rank correlation. Sensitivity and specificity for autoimmune POI (vs. idiopathic POI) of inhibin B, total inhibin, and tot-inhB levels were tested by using receiver-operating characteristic (ROC) curves with cutoffs corresponding to the best combination of high sensitivity and high specificity. Differences in area under ROC curves were tested with modified Z-test (25). In all analyses, a P value < 0.05 was considered significant.
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Results |
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FSH concentration was significantly lower among the 22 women with autoimmune POI (range, 26–64 mIU/ml; median, 32 mIU/ml) than among the 71 women with idiopathic POI (range, 55–166 mIU/ml; median, 99 mIU/ml) (P < 0.001). On the contrary, the LH concentration was similarly distributed among the 22 women with autoimmune POI (range, 43–138 mIU/ml; median, 68 mIU/ml) and the 71 women with idiopathic POI (range, 47–142 mIU/ml; median, 70 mIU/ml).
17β-Estradiol concentration did not differ significantly between autoimmune POI (median: 12 pg/ml, range 5–55 pg/ml) and idiopathic POI (median: 10 pg/ml, range 5–61 pg/ml).
Inhibins concentration in autoimmune POI and idiopathic POI
Total inhibin levels were significantly higher in women with autoimmune POI (range, 110–500 pg/ml; median, 281 pg/ml) than in women with idiopathic POI (range, 10–439 pg/ml; median, 74 pg/ml) (P < 0.001) (Fig. 1A). Similarly, inhibin B levels were also significantly higher in autoimmune POI (range, 28–340 pg/ml; median, 109 pg/ml) than in idiopathic POI (range, 10–220 pg/ml; median, 18 pg/ml) (P < 0.001) (Fig. 1B). Serum concentrations of total inhibin and inhibin B were significantly higher in women with autoimmune POI than in both postmenopausal women (total inhibin range, 2.5–25 pg/ml; median, 6 pg/ml; inhibin B range, 10–22 pg/ml; median, 10 pg/ml) (P < 0.001) and healthy control women (total inhibin range, 22–297 pg/ml pg/ml; median, 133.5 pg/ml, P < 0.001; inhibin B median, 39 pg/ml; range, 2.5–141 pg/ml, P < 0.05). In addition, both total inhibin and inhibin B concentrations were significantly higher among women with idiopathic POI than among postmenopausal women (P < 0.001). Finally, total inhibin concentration among healthy control women was significantly higher than in both women with idiopathic POI (P < 0.01) and postmenopausal women (P < 0.001).
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tot-inhB was calculated, the serum concentration of non-B inhibin chains were significantly higher among autoimmune POI than among idiopathic POI (P < 0.001) and postmenopausal women (P < 0.001) (Fig. 1C
). No statistically significant differences in tot-inhB were observed between autoimmune POI patients and healthy control women or between idiopathic POI patients and healthy control women (Fig. 1C).
Inhibin B and tot-inhB serum concentrations correlated significantly and positively with each other in idiopathic POI (r = 0.377; 95% confidence interval = 0.131–0.578; P = 0.004) but not in autoimmune POI (r = 0.114; 95% confidence interval = –0.323–0.511; P = 0.613) (Fig. 2).
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tot-inhB for autoimmune POI vs. idiopathic POI by ROC analysis (Fig. 3). The cutoff that combined both high sensitivity and high specificity was 133 pg/ml for total inhibin (Fig. 3A), 60.5 pg/ml for inhibin B (Fig. 3B), and 115 pg/ml for tot-inhB (Fig. 3C). For total inhibin, a cutoff value of 133 pg/ml ensured 86.4% sensitivity and 81% specificity for autoimmune POI. For inhibin B, a cutoff value of 60.5 pg/ml ensured 86.4% sensitivity and 84.5% specificity. Finally, for tot-inhB, a cutoff value of 115 pg/ml ensured a 77.3% sensitivity and a 91.4% specificity.
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tot-inhB (P = 0.004), whereas no statistically significant differences were observed for area under inhibin B vs. area under total inhibin or vs. area under tot-inhB. The analysis of the diagnostic sensitivity and specificity showed that all autoimmune POI samples had total inhibin concentrations higher than 100 pg/ml, and 50% of samples had values higher than 300 pg/ml. On the contrary, two thirds of samples from women with idiopathic (non-autoimmune) POI had total inhibin values lower than 100 pg/ml, with only three of 71 samples (3%) having values higher than 300 pg/ml. Similarly, 91% of samples from women with autoimmune POI had inhibin B concentration higher than 50 pg/ml, compared with only 19% of samples from women with idiopathic POI.
Among women with POI, inhibin levels did not vary significantly in relation to autoantibody titer, number of different autoantibodies, age of the patient, months of amenorrhea, or number of associated autoimmune diseases.
Similarly, no clinical or hormonal characteristics differentiated the women with idiopathic POI and high inhibin levels from the remaining patients with idiopathic POI. More specifically, the three women with idiopathic POI and total inhibin values higher than 300 pg/ml had no family history of POI or of POI-related conditions and had no associated autoimmune diseases.
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Discussion |
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-subunits, enabled also the demonstration that the non-inhibin B components of total inhibin (namely inhibin A and free -chain) are also increased in autoimmune oophoritis compared with other forms of ovarian insufficiency. Little is known of the molecular mechanisms underlying autoimmune oophoritis. In humans, autoimmune oophoritis is made evident by the appearance of StCA, as detected by indirect immunofluorescence on cryostatic sections of ovary, adrenal, testis, and placenta (6, 7, 8, 9, 10, 11, 12). Although all the tissue components are present in the ovarian cryostatic sections used for the autoantibody assay, the immunofluorescence pattern of StCA is restricted to the theca cells of the growing follicle with no staining of primary follicles or granulosa cells in secondary and tertiary follicles. Although autoantibodies to a long series of potential autoantigens, such as LH receptor (26), FSH receptor (27), zona pellucida (28), 82- to 86-kDa antigens and 52- to 63-kDa antigens (29) have been proposed as markers of ovarian autoimmunity in some studies, the association of these autoantibodies with POI has not been confirmed in others (30, 31), nor are reliable immunoradiometric assays currently available for these markers. Only the detection of autoantibodies against steroidogenic enzymes can ensure, at present, an accurate identification of women with autoimmune oophoritis. Thus, using steroidogenic enzyme autoantibodies, autoimmune oophoritis accounts for approximately 4–5% of all POI cases (6, 7).
The high accuracy of steroidogenic enzyme autoantibodies for autoimmune POI has been demonstrated in histological studies of ovarian biopsy that have shown the presence of oophoritis in virtually all autoantibody-positive patients and the absence of signs of lymphocytic infiltration in autoantibody-negative patients (6, 7, 32, 33, 34, 35, 36). Thus, the diagnostic accuracy of adrenal autoantibodies and StCA for autoimmune oophoritis approaches 100 and 80%, respectively (7). Interestingly, StCA, 17OHAb, and P450sccAb are detectable almost exclusively in patients with POI who are positive for 21OHAb, the major immune marker of autoimmune Addison’s disease (7, 12). Hence, adrenal autoantibodies have a diagnostic sensitivity for autoimmune POI higher than StCA, 17OHAb, and P450sccAb, and histological signs of autoimmune oophoritis are not present in those cases of ovarian insufficiency associated with other autoimmune diseases in the absence of adrenal autoantibodies (7, 12).
Recently, it has been shown that immunization of mice with a peptide of inhibin -chain induces an initial increase in fertility, which is mediated by high serum levels of inhibin- neutralizing antibodies that prevents inhibin-mediated down-regulation of activin-induced FSH release (37). In a second, delayed phase, the activation of CD4+ T cells results in a lymphocytic infiltration of the ovary that occurs in parallel with a progressive decrease in fertility and ovarian function (37). The association of lymphocytic infiltration of the ovary, increased levels of FSH, and increased levels of inhibin in this mouse model resembles the human POI observed in women positive for steroidogenic enzyme autoantibodies, even though it is not yet known whether inhibin autoantibodies are produced in human autoimmune oophoritis.
Several publications have demonstrated that the inhibin- gene is a candidate of POI pathogenesis (38, 39). Hence, a solid rationale motivated our decision to estimate the serum concentration of inhibin B and total inhibin in women with ovarian insufficiency of different origin.
Typically, inhibin concentrations are reduced in women with ovarian insufficiency, in agreement with the reduced production of estradiol (14, 15, 16). However, in a preliminary study of three women with POI positive for StCA, increased inhibin levels were detected, along with a reduced production of 4-androstenedione, estrone, and estradiol (17). These results, along with a significantly lower increase of FSH levels than LH levels, were interpreted to indicate a selective theca cell destruction with lack of substrates for the production of estradiol by otherwise viable and functioning granulosa cells that react to the increased levels of gonadotropins with an increase in production of inhibin A and inhibin B (17). The increased production of inhibin would ultimately be responsible for a partial negative feedback on FSH production. This hypothesis is indirectly supported by the already mentioned selective targeting of StCA toward theca cells and the selective infiltration of the theca layer in the growing follicles of ovaries from women with autoimmune oophoritis (6, 7).
Our present study confirms and expands the results of that preliminary observation (17), thus confirming that high inhibin concentrations discriminate autoimmune oophoritis from other forms of ovarian insufficiency. The high inhibin levels observed in the sera from women with autoimmune POI in our study demonstrate unequivocally that viable granulosa cells are present in these patients for several years after the initial diagnosis (up to 40 months in our study population).
We determined also serum total inhibin levels by a new ELISA able to detect all inhibin forms containing the /β dimers and pro and C regions of the -subunit as well as the free -subunit. The established inhibin A and inhibin B ELISA detect the /β dimers but are unable to detect the free -subunit and pro/C region. The total inhibin assay showed for the first time high serum concentrations of total inhibin (median, 281 pg/ml) in women who screened positive for adrenal and StCA compared with women with idiopathic POI or with natural menopause. When compared with healthy fertile women, inhibin B and total inhibin levels were significantly reduced in women with idiopathic POI and in postmenopausal women, which is in agreement with previous publications (14, 15, 16). However, inhibin levels in women with non-autoimmune POI were significantly higher than in postmenopausal women, thus confirming that POI should not be considered an early form of menopause, and a variable degree of ovarian activity can be detected in many patients, as also shown by other studies (3, 4).
ROC curve analysis demonstrated the high diagnostic sensitivity and specificity of the inhibin B and total inhibin assay for autoimmune POI. Although the inhibin assays have a high diagnostic accuracy for autoimmune POI that could pave the way to their potential clinical application in the management of women with POI, the gold standard for the diagnosis of autoimmune oophoritis remains the detection of StCA. At present, there is no evidence that women with high inhibin levels and negative for StCA have an autoimmune oophoritis. Accordingly, the inhibin assays should not be considered an alternative to the autoantibody assays for the identification of the autoimmune cases of ovarian insufficiency. Nevertheless, the results of the ROC curve analysis demonstrate that the increase in inhibin release by granulosa cells of women with autoimmune POI is a consistent and conserved phenomenon in the population of women with autoimmune oophoritis. This finding is of high relevance because it allows us to conclude that the pathophysiology of autoimmune oophoritis is distinct from that of other forms of ovarian insufficiency. The selective destruction of theca cells, with initial preservation of the function of the granulosa cells, and the absence of signs of infiltration in primordial and primary follicles at histology (6, 7, 32, 33, 34, 35, 36), provide a sound rationale for future clinical therapeutic trials aimed at preventing the extension of the ovarian damage with the ultimate goal of preserving ovarian function in women with autoimmune oophoritis.
The significant correlation between inhibin B and tot-inhB in idiopathic, non-autoimmune POI suggests that the production of both inhibin B and non-inhibin B -chains is similarly impaired, according to the degree of ovarian dysfunction. Conversely, no significant correlation was found in women with autoimmune POI between serum inhibin B and tot-inhB, which demonstrates that total inhibin concentration cannot be directly predicted from inhibin B concentration and that both assays are required to fully characterize inhibin production in autoimmune oophoritis. Furthermore, the lack of significant correlation in autoimmune POI reveals a differential regulation and/or secretion of inhibin B and non-inhibin B -chains in the ovary with autoimmune oophoritis. It is noteworthy that preantral follicles secrete selectively inhibin B (40), and preantral primordial and primary follicles are preserved from the autoimmune infiltration and destruction (5, 6, 7, 32, 33, 36, 41). Granulosa cells appear to be protected in developing follicles until they are luteinized by LH and produce steroids (5, 6, 7, 32, 33, 41). Our data on higher inhibin and lower FSH levels in autoimmune oophoritis compared with other forms of ovarian insufficiency support this conclusion and demonstrate the importance of detecting the total production of inhibin -chains by using the total inhibin assay. Whether the increased production of inhibin -chains results in part also from a switch of the -inhibin synthesis and processing from granulosa to theca-interstitial cells in the arrested follicles of women with autoimmune oophoritis is at present unclear. Interestingly, a switch of the -inhibin synthesis and processing from granulosa to theca-interstitial cells has been demonstrated in the arrested follicles of polycystic ovaries (42, 43). Additional studies are required to clarify the importance of inhibin -chain production in women with POI, especially in the presence of autoimmune oophoritis.
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Acknowledgments |
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OH cDNA and human P450scc cDNA. |
Footnotes |
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First Published Online January 22, 2008
Abbreviations: aa, Amino acids; ACA, adrenocortical autoantibodies; C, 133- to 134-aa C-terminal segment; N, 171-aa N-terminal segment; 17OH, 17-hydroxylase; 17OHAb, 17OH autoantibody; 21OH, 21β-hydroxylase; P450scc, cytochrome P450 side-chain cleavage; POI, primary ovarian insufficiency; ROC, receiver-operating characteristic; StCA, steroid-cell autoantibodies; tot-inhB, difference in total inhibin – inhibin B.
Received July 26, 2007.
Accepted January 14, 2008.
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-subunit ELISA with broad specificity. Mol Cell Endocrinol 180:79–86[CrossRef][Medline]-hydroxylase in Addison’s disease and autoimmune polyendocrine syndrome type III. Eur J Endocrinol 142:187–194[Abstract]-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNA indicates the same gene is expressed in both tissues. Proc Natl Acad Sci USA 84:407–411 gene in a cohort of Italian women affected by ovarian failure. Hum Reprod 17:1741–1745This article has been cited by other articles:
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  N. Soto, G. Iniguez, P. Lopez, G. Larenas, V. Mujica, R. A. Rey, and E. Codner Anti-Mullerian hormone and inhibin B levels as markers of premature ovarian aging and transition to menopause in type 1 diabetes mellitus Hum. Reprod., November 1, 2009; 24(11): 2838 - 2844. [Abstract] [Full Text] [PDF]
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 A. La Marca, S. Marzotti, A. Brozzetti, G. Stabile, A. C. Artenisio, V. Bini, R. Giordano, A. De Bellis, A. Volpe, A. Falorni, et al. Primary Ovarian Insufficiency due to Steroidogenic Cell Autoimmunity Is Associated with a Preserved Pool of Functioning Follicles J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 3816 - 3823. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, P < 0.001, idiopathic POI vs. postmenopausal women and P < 0.01, idiopathic POI vs. healthy control; 
, P < 0.001, healthy control vs. postmenopausal women; 
, P < 0.001, autoimmune POI vs. idiopathic POI, autoimmune POI vs. postmenopausal women, and P < 0.05, autoimmune POI vs. healthy control; *, P < 0.001, idiopathic POI vs. postmenopausal women; 
, P < 0.001, autoimmune POI vs. idiopathic POI and autoimmune POI vs. postmenopausal women.
