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Context: Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD)., Objective: The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women., Design and Setting: This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland)., Participants: Young women with primary ovarian insufficiency participated in the study., Interventions: We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 μg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 μg/d) or placebo., Main Outcome Measure: Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry., Results: At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well., Conclusion: Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.

Objective: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI., Methods: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests., Results: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects., Conclusions: A 150-μg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.

Context: A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI., Objectives: We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI., Design and Setting: We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center., Patients: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study., Main Outcome Measures: The structured clinical interview for DSM-IV was performed., Results: Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events., Conclusions: POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.

Objective: To assess ovarian follicle function in women with 46,XX spontaneous primary ovarian insufficiency., Design: Case-control with nested prospective cohort., Setting: Clinical Research Center, National Institutes of Health., Patient(s): Women with primary ovarian insufficiency without estrogen replacement for 2 weeks (N = 97) and regularly menstruating control women (N = 42)., Intervention(s): Single injection of 300 IU hrFSH., Main Outcome Measure(s): Change in serum estradiol at 24 hours., Result(s): Antral follicles ≥3 mm were detected in 73% (69/95) of patients; both serum estradiol and progesterone levels correlated significantly with maximum follicle diameter in these women. Patients with a maximum follicle diameter ≥8 mm had significantly higher serum estradiol and progesterone levels and significantly lower FSH and LH levels compared with patients without such follicles. In controls estradiol levels increased significantly after FSH administration, but in patients this was not the case despite the presence of an antral follicle ≥8 mm., Conclusion(s): Most women with 46,XX spontaneous primary ovarian insufficiency have antral follicles detectable by ultrasound, suggesting that down-regulation of FSH receptors is not the predominant mechanism of follicle dysfunction. Evidence of progesterone secretion by antral follicles ≥8 mm in these patients is consistent with prior histologic evidence that follicle luteinization is the predominant mechanism of follicle dysfunction in this condition. Prospective controlled investigation designed to improve ovulatory function and fertility in these women is indicated., (Published by Elsevier Inc.)

Objective: To examine factors associated with emotional well-being in women with spontaneous primary ovarian insufficiency., Design: Cross-sectional and case-control study., Setting: Clinical research center, national U.S. health research facility., Patient(s): Women diagnosed with spontaneous 46,XX primary ovarian insufficiency (n = 100) at a mean age of 32.4 years and healthy control women of similar age (n = 60)., Intervention(s): Administration of validated self-reporting instruments., Main Outcome Measure(s): Illness uncertainty, stigma, goal disengagement/re-engagement, purpose in life, Positive and Negative Affect Schedule, Center of Epidemiologic Studies Depression Scale, State-Trait Anxiety Inventory., Result(s): Compared with controls, women with spontaneous primary ovarian insufficiency scored adversely on all measures of affect. Illness uncertainty and purpose in life were significant independent factors associated with anxiety (R(2) = 0.47), stigma and purpose in life were the significant independent factors associated with depression (R(2) = 0.51), and goal re-engagement and purpose in life were significantly and independently associated with positive affect (R(2) = 0.43)., Conclusion(s): This evidence supports the need for prospective studies. Our findings are consistent with the hypothesis that clinicians could improve the emotional well-being of their patients with primary ovarian insufficiency by [1] informing them better about their condition, [2] helping them to feel less stigmatized by the disorder, and [3] assisting them in developing alternative goals with regard to family planning as well as other goals., (Published by Elsevier Inc.)

Objective: To test the hypothesis that women with spontaneous primary ovarian insufficiency differ from control women with regard to perceived social support and to investigate the relationship between perceived social support and self-esteem., Design: Cross-sectional., Setting: Mark O. Hatfield Clinical Research Center, National Institutes of Health., Patient(s): Women diagnosed with spontaneous primary ovarian insufficiency (n = 154) at a mean age of 27 years and healthy control women (n = 63)., Intervention(s): Administration of validated self-reporting instruments., Main Outcome Measure(s): Personal Resource Questionnaire 85 and Rosenberg Self-Esteem Scale., Result(s): Women with primary ovarian insufficiency had significantly lower scores than controls on the perceived social support scale and the self-esteem scale. The findings remained significant after modeling with multivariate regression for differences in age, marital status, and having children. There was a significant positive correlation between self-esteem scores and perceived social support in patients. We found no significant differences in perceived social support or self-esteem related to marital status, whether or not the women had children, or time since diagnosis., Conclusion(s): This evidence supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous primary ovarian insufficiency.

Context: Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density., Objective: The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model., Design and Setting: We conducted a cross-sectional study at a tertiary care research center., Participants: We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353)., Primary Outcome Measure: We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry., Results: Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score <-2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (<32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below -2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density., Conclusions: Women with POI have lower bone density compared to regularly menstruating women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.

Objective: To assess sexual function in women with spontaneous 46,XX primary ovarian insufficiency after at least 3 months of a standardized hormone replacement regimen., Design: Cross-sectional cohort, controlled., Setting: National Institutes of Health Clinical Research Center., Patient(s): Women with primary ovarian insufficiency (n = 143) and regularly menstruating controls (n = 70)., Intervention(s): Self-administered questionnaires, 100 microg/day E(2) patch, oral medroxyprogesterone acetate 10 mg for 12 days each month for patients., Main Outcome Measure(s): Derogatis Interview for Sexual Function Self-Report (DISF-SR)., Result(s): Women with primary ovarian insufficiency had significantly lower DISF-SR composite scores compared with control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score, although this accounted for only 4% of the variance in this measure. Patients with testosterone levels below normal tended to have lower DISF-SR composite scores. Of patients with primary ovarian insufficiency, 9 of 127 (7%) scored below the second percentile on the composite sexual function score, compared with 1 of 49 control women (2%)., Conclusion(s): As assessed by the DISF-SR, sexual function is in the normal range for most young women with 46,XX spontaneous primary ovarian insufficiency who are receiving physiologic E(2) replacement. However, as a group, these young women score significantly lower on this sexual function scale than control women.

Objective: To determine the proportion of women with primary ovarian insufficiency who achieve normal serum LH levels on transdermal E(2) therapy., Design: Prospective., Setting: Clinical research center at a national US health research facility., Patient(s): Women with spontaneous primary ovarian insufficiency (n = 137) and 70 regularly menstruating control women (n = 70)., Intervention(s): Blood sampled from controls in the midfollicular phase and from patients while they were off E(2) for 2 weeks, then again 3 months later during the E(2)-only phase of hormone therapy (E(2) patch [100 microg/d] and oral medroxyprogesterone acetate [10 mg for 12 d/mo])., Main Outcome Measure(s): Serum LH., Result(s): While on transdermal E(2) therapy, significantly more women (51.1%, 70/137; 95% confidence interval, 42%, 60%) had serum LH levels in the normal range (5/137, 3.9% at baseline). Mean (SD) serum E(2) level significantly increased on therapy to 95.4 (84.9) pg/mL., Conclusion(s): A regimen of 100 microg/d of transdermal E(2) therapy achieves normal serum LH levels in approximately one half of women with spontaneous primary ovarian insufficiency. Theoretically, by avoiding inappropriate luteinization, physiologic E(2) therapy may improve follicle function in these women. Controlled studies to assess the effect of transdermal E(2) therapy on follicle function in these women are warranted.

Objective: To examine the relationship between spiritual well-being and functional well-being in women who have spontaneous premature ovarian failure., Design: Cross-sectional., Setting: The Mark O. Hatfield Clinical Research Center at the US National Institutes of Health., Patient(s): Women diagnosed with spontaneous premature ovarian failure (N = 138) at a median age of 28 years., Intervention(s): Administration of validated self-reporting instruments., Main Outcome Measure(s): Functional Well-Being, Spiritual Well-Being, Meaning/Peace, and Faith scores., Result(s): We found a significant positive correlation between overall spiritual well-being and functional well-being scores. The Meaning/Peace subscale strongly correlated with functional well-being, explaining approximately 62% of the variance. In contrast, the Faith subscale was less strongly correlated with functional well-being, explaining only 7% of the variance. In multiple regression analysis evaluating the relative subscale contributions to functional well-being, only Meaning/Peace remained statistically significant. We found no significant associations between either spiritual well-being or functional well-being and age; age at diagnosis; time since diagnosis; or partner, children, or racial status., Conclusion(s): This study provides cross-sectional data supporting the need for prospective controlled studies. Strategies to improve spiritual well-being in the domains of meaning, purpose, and inner peace may provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of premature ovarian failure.

Objective: To determine whether women with 46,XX spontaneous premature ovarian failure have lower serum free-T levels than do control women., Design: Cross-sectional., Setting: National Institutes of Health Clinical Research Center., Patient(s): Women with 46,XX spontaneous premature ovarian failure (n = 130)., Intervention(s): Evaluation while off any estrogen therapy and then again after receiving a standardized hormone regimen. Regularly menstruating control women (n = 65) were sampled during the midfollicular phase., Main Outcome Measure(s): Serum total T by RIA after extraction and column chromatography, free T by equilibrium dialysis, and sex hormone-binding globulin by immunoradiometric assay., Result(s): While off estrogen therapy patients had a median serum free-T concentration that was statistically significantly lower than controls (2.2 vs. 3.3 pg/mL). This dropped significantly lower to 1.9 pg/mL while the patients were on physiologic transdermal E(2) therapy. This is despite the fact that sex hormone-binding globulin levels did not change. While on E(2) therapy, 13% of women (95% confidence interval, 7.9%-20.3%) had serum free-T levels below the lower limit of normal (<1.1 pg/mL)., Conclusion(s): As a group, young women with 46,XX spontaneous premature ovarian failure have reduced circulating free-T levels, both during an interval off of estrogen therapy and while on physiologic transdermal E(2) therapy.

Objective: To investigate mutations in the human KIT ligand gene (KITLG) gene as a mechanism of 46,XX spontaneous premature ovarian failure. The human KIT ligand gene, known also as human stem cell factor, is the ligand of the c-kit transmembrane tyrosine kinase receptor (KIT). This ligand-receptor interaction is known to play important roles in mouse germ cell migration and proliferation., Design: Cross-sectional study., Setting: Clinical research center., Patient(s): Forty women with 46,XX spontaneous premature ovarian failure., Intervention(s): None., Main Outcome Measure(s): Single-stranded conformational polymorphism analysis and DNA sequencing., Result(s): We found one nucleotide change of the KITLG coding region (811G-->T) that led to an alteration of the amino acid composition of the KITLG protein in one Caucasian patient (Asp210Tyr). However, we found the same alteration in two normal control Caucasian samples. Three nucleotide substitutions were found in the noncoding exon of KITLG (exon 10). We also identified two intronic polymorphisms. Thus, we did not identify a single significant mutation in the coding region of the KITLG gene in any of 40 patients (upper 95% confidence limit is 7.2%)., Conclusion(s): Mutations in the coding regions of the KITLG gene appear not to be a common cause of 46,XX spontaneous premature ovarian failure in North American women.

Objective: To inform clinicians about a reproductive risk associated with spontaneous premature ovarian failure and the fragile X mental retardation 1 gene (FMR1)., Design: Case report., Setting: National Institutes of Health Clinical Center., Patient(s): A 35-year-old woman with confirmed spontaneous premature ovarian failure., Intervention(s): FMR1 genetic testing., Main Outcome Measure(s): Number of CGG trinucleotide repeats in the 5' untranslated region of FMR1., Result(s): Despite having ovarian failure the woman subsequently conceived and delivered a son with fragile X syndrome (>200 CGG repeats). She was then found to carry an FMR1 premutation (85 CGG repeats)., Conclusion(s): This is a real-life manifestation of a theoretical risk; a woman conceived subsequent to the diagnosis of spontaneous premature ovarian failure and has a child who manifests mental retardation due to fragile X syndrome. Women with spontaneous premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Should an FMR1 premutation be uncovered, this will allow patients to make informed reproductive decisions and help clinicians to properly diagnose family members who may have menstrual irregularity, developmental delay, or neurologic symptoms.

Objective: To use a pilot study to investigate markers of the age-related decline in ovarian function of regularly menstruating normal women., Design: Prospective., Setting: Tertiary research center., Patient(s): Healthy volunteers (n = 42) aged 18 to 50 years who had regular ovulatory menstrual cycles and a prior pregnancy., Intervention(s): A single 300-IU dose of human recombinant FSH on day 3 of the menstrual cycle., Main Outcome Measure(s): Antral follicle count by transvaginal ultrasound and basal and FSH-stimulated serum markers., Result(s): Age correlated most strongly with FSH-stimulated inhibin B (r = -0.660), followed by antral follicle count (r = -0.578), basal FSH (r = 0.509), basal Müllerian inhibiting substance (MIS; r = -0.468), and basal inhibin B (r = -0.358). Total antral follicle count correlated most strongly with basal MIS level (r = 0.642)., Conclusion(s): Of the parameters tested, FSH-stimulated serum inhibin B level had the strongest correlation with age. Basal serum MIS level had the strongest correlation with total antral follicle count. We confirm a previous report that in normal women, the antral follicle count as determined by transvaginal ultrasound examination correlates better with age than do basal FSH and basal inhibin B levels.

Objective: To assess the association between serum adrenal cortex autoantibodies and histologically confirmed autoimmune lymphocytic oophoritis., Design: Controlled, prospective., Setting: Tertiary research center., Patient(s): Two hundred sixty-six women with 46,XX spontaneous premature ovarian failure., Intervention(s): Ovarian biopsy in 10 women., Main Outcome Measure(s): Serum adrenal cortex autoantibodies assessed by indirect immunofluorescence and autoimmune oophoritis assessed by immunohistochemical lymphocyte markers., Result(s): We obtained a histologic diagnosis of autoimmune oophoritis in four women who tested positive for adrenal cortex autoantibodies and excluded this diagnosis in ovarian biopsies from six women who tested negative for adrenal cortex autoantibodies (4/4 vs. 0/6). Women with histologically confirmed autoimmune oophoritis had a greater total ovarian volume as assessed by transvaginal sonography (11.4 +/- 5.6 mL vs. 1.5 +/- 0.4 mL) (mean +/- SEM). They were also more likely to have subclinical adrenal insufficiency and clinical signs of androgen deficiency (3/4 vs. 0/6). Overall, 10/266 women tested positive for adrenal cortex autoantibodies (3.8%, 95% confidence interval: 1.8%-6.5%)., Conclusion(s): In women who present with 46,XX spontaneous premature ovarian failure as their primary concern there is a clear association between serum adrenal cortex autoantibodies and the presence of histologically confirmed autoimmune oophoritis.

BACKGROUND: Premature Ovarian Failure (POF), defined as the development of hypergonadotropic amenorrhea before the age of 40 years, occurs in about 1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. Recently, in seven patients who presented with POF and white matter abnormalities on MRI (ovarioleukodystrophy) eight mutationswere found in EIF2B2, 4 and 5. METHODS: To further test the involvement of known mutations of EIF2B genes in POF, we screened 93 patients with POF who did not have identified leukodystrophy or neurological symptoms. We evaluated these eight mutations and two additional mutations that had been found in patients with milder forms of eIF2B-related disorders. We used restriction enzymes and direct sequencing. RESULTS: None of the known mutations in EIF2B genes, either homozygous or heterozygous, were identified in our 93 patients with pure 46,XX POF. The upper 95 % confidence limit of the proportion 0/93 is 3.2%. CONCLUSIONS: We conclude that eIF2B mutations, already described in cases of POF associated with white matter abnormalities, are an uncommon cause of pure spontaneous premature ovarian failure.

Objective: To examine whether women with premature ovarian failure (POF) have abnormal findings in ocular surface or tear parameters and whether they report symptoms of ocular discomfort compared with age-matched controls., Methods: Sixty-five patients with POF and 36 age-matched healthy controls were examined for signs and symptoms of dry eye. The Ocular Surface Disease Index questionnaire and the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) were administered to the participants. Assessments of ocular surface damage (Oxford and van Bijsterveld scores of vital dye staining) and tear status (Schirmer tests 1 [without anesthesia] and 2 [with anesthesia] and tear breakup time) were performed., Results: Women with POF scored significantly worse than controls on all ocular surface damage parameters: Oxford score (3.2 vs 1.7; P =.001), conjunctival lissamine green (2.1 vs 1.3; P =.02), corneal fluorescein staining (1.2 vs 0.4; P =.005), and van Bijsterveld score (2.1 vs 1.3; P =.02). Further, the proportion of patients with POF meeting the dry eye diagnostic criterion of a van Bijsterveld score greater than or equal to 4 was significantly greater among women with POF than among controls (20% vs 3%; P =.02). The POF group also tended to have worse scores than controls on self-reported symptoms, as measured by the overall Ocular Surface Disease Index (12.5 vs 2.1; P<.001) and the overall NEI-VFQ (94 vs 98; P =.001) after adjustment for age and race. Schirmer test scores and tear breakup time did not differ., Conclusions: Women with POF were more likely to exhibit ocular surface damage and symptoms of dry eye than age-matched controls. They were not, however, more likely to have reduced tear production. To our knowledge, this association between ocular surface disease and POF has not been previously reported. These data provide further evidence of the multifaceted role of sex hormones in the health and disease of the ocular surface.

BACKGROUND: Spontaneous premature ovarian failure presents most commonly with secondary amenorrhea. Young women with the disorder are infertile and experience the symptoms and sequelae of estrogen deficiency. The mechanisms that give rise to spontaneous premature ovarian failure are largely unknown, but many reports suggest a genetic mechanism in some cases. The small family size associated with infertility makes genetic linkage analysis studies extremely difficult. Another approach that has proven successful has been to examine candidate genes based on known genetic phenotypes in other species. Studies in mice have demonstrated that c-kit, a transmembrane tyrosine kinase receptor, plays a critical role in gametogenesis. Here we test the hypothesis that human KIT mutations might be a cause of spontaneous premature ovarian failure. METHODS AND RESULTS: We examined 42 women with spontaneous premature ovarian failure and found partial X monosomy in two of them. In the remaining 40 women with known 46,XX spontaneous premature ovarian failure we evaluated the entire coding region of the KIT gene. We did this using polymerase chain reaction based single-stranded conformational polymorphism analysis and DNA sequencing. We did not identify a single mutation that would alter the amino acid sequence of the c-KIT protein in any of 40 patients (upper 95% confidence limit is 7.2%). We found one silent mutation at codon 798 and two intronic polymorphisms. CONCLUSION: Mutations in the coding regions of the KIT gene appear not to be a common cause of 46,XX spontaneous premature ovarian failure in North American women.

Background: Auto-immune adrenal insufficiency is a potentially fatal disorder. Young women with spontaneous premature ovarian failure (POF) are at increased risk of developing this condition., Methods: We further characterized auto-immune adrenal insufficiency in this population by conducting an in-depth cross-sectional evaluation of adrenal function in a series of 123 women., Results: We uncovered a new diagnosis of adrenal insufficiency in four women [3.2%, 95% confidence interval (CI) 0.2-6.4%]. All four tested positive for adrenal antibodies as detected by a clinically available indirect immunofluorescence assay. A positive adrenal antibody test was highly associated with adrenal insufficiency while a negative test was associated with normal adrenal function in all cases (P < 0.001). Adrenal antibodies increased the pretest probability of adrenal insufficiency from 3.2 to 67%. As a screening method the cortisol response during a standard adrenocorticotrophic hormone (ACTH) stimulation test gave two false positive results (1.7%, upper 95% confidence limit 5.0%)., Conclusions: Our findings suggest that measuring adrenal antibodies would be an effective screening method by which to detect auto-immune adrenal insufficiency in young women with spontaneous POF. The standard ACTH stimulation test should be reserved to confirm adrenal insufficiency in women with adrenal antibodies, or those with signs and symptoms of adrenal insufficiency.