Spontaneous Premature Ovarian Failure Research Articles

Endometriosis in women undergoing ovarian tissue transplantation due to premature menopause after gonadotoxic treatment or spontaneous premature ovarian failure.

Cryopreservation of ovarian tissue with subsequent transplantation is an efficient option for restoring fertility in women at risk of premature ovarian failure. The association between infertility and endometriosis is well recognized. Although endometriosis usually ends with the onset of natural or iatrogen menopause due to declining estrogen levels, endometriosis can in rare cases occur after menopause. This study aims to investigate women with premature menopause who were diagnosed with endometriosis during laparoscopy for ovarian tissue transplantation, and to address the questions of how endometriotic lesions after cytotoxic treatment and premature menopause might be explained, whether endometriosis affects pregnancy rates, and whether there is an association between endometriosis and the original cancer. Seventeen patients who had undergone ovarian tissue transplantation to restore their fertility and who were diagnosed with endometriosis during transplantation were included in this retrospective study. The endometriosis foci were completely removed and ovarian tissue was transplanted into the pelvic peritoneum. Preexisting conditions, use of hormonal preparations, endometriosis stage pain assessment, as well as pregnancy and live birth rate were evaluated. The mean age of the patients was 29.5 ± 6.3 years (range 14-39) at the time of ovarian tissue harvest and 34.6 ± 4.3 years (range 28-40) at transplantation. Prior to transplantation, four patients had taken hormone replacement therapy, four women oral contraceptives and two patients' tamoxifen. Twelve women had stage I endometriosis and five stage II endometrioses according to the rASRM classification. Four patients reported dysmenorrhea. None of the women complained of general pelvic pain or dyspareunia. The pregnancy rate in the study population was 41.2%, with a live birth rate of 35.3%. The pregnancies occurred in three cases after spontaneous conception, in four women after a natural cycle IVF/ICSI. This study highlights the under-researched association between endometriosis in women entering premature or early menopause either after gonadotoxic treatment or due to primary ovarian insufficiency. As more and more patients seek to have their cryopreserved ovarian tissue transplanted to fulfill their desire to have children, specialists will inevitably encounter women with this condition.

Long non-coding RNA HOTAIR overexpression improves premature ovarian failure by upregulating Notch-1 expression.

The aim of the present study was to investigate the role of long non-coding (lnc)RNA HOTAIR in premature ovarian failure. A total of 69 women with spontaneous premature ovarian failure and 48 healthy women were enrolled in the present study. Ovarian tissues and blood samples were harvested from each participant. The expression of HOTAIR in ovarian tissues and sera was detected using reverse transcription-quantitative polymerase chain reaction. A receiver operator characteristic curve analysis was performed to assess the diagnostic value of HOTAIR expression in ovarian tissues and sera for premature ovarian failure. Hamster ovary cell lines overexpressing HOTAIR were established and cell apoptosis were assessed using an MTT assay. The effect of HOTAIR upregulation on the expression of Notch-1 was measured using western blotting. The expression of HOTAIR in ovarian tissues and serum samples was significantly lower in patients with premature ovarian failure compared with healthy controls. These results suggest that ovarian and serum HOTAIR expression levels may be used to accurately predict the risk of premature ovarian failure. It was also demonstrated that HOTAIR overexpression upregulates Notch-1 protein expression in hamster ovary cells and reduced apoptosis, whereas the Notch inhibitor L685458 ameliorated these effects. In conclusion, the results of the present study suggest that LncRNA HOTAIR overexpression improves premature ovarian failure by upregulating the expression of Notch-1.

Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases.

STUDY QUESTIONCan spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF?SUMMARY ANSWERCNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function.WHAT IS KNOWN ALREADYPOF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown.STUDY DESIGN, SIZE, DURATIONThe current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank.PARTICIPANTS/MATERIALS, SETTING, METHODSDNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis.MAIN RESULTS AND THE ROLE OF CHANCEEleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated.LIMITATIONS, REASONS FOR CAUTIONThis is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause.WIDER IMPLICATIONS OF THE FINDINGSThe present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF.STUDY FUNDING/COMPETING INTERESTThis study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Horizon 2020 innovation programme (WIDENLIFE, 692065), Academy of Finland and the Sigrid Juselius Foundation.

The prevalence and phenotypic characteristics of spontaneous premature ovarian failure: a general population registry-based study.

What is the measured prevalence and phenotype of spontaneous premature ovarian failure (POF) in the general population? Spontaneous POF occurs in ∼1% of the general population with unique phenotype of post-menopausal ageing distinct from surgically induced premature menopause. POF is multifactorial ovarian quiescence before the age of 40. The clinical features of POF are diverse and the population prevalence of POF is still not known. This population-depictive registry-based case-cohort study included 34 041 women from the Estonian Genome Center registered between 2003 and 2013. Spontaneous POF was selected retrospectively by excluding other causes for premature menopause under the age of 40 (N = 310) and women with surgically induced premature menopause participated as a reference group (N = 242). The prevalence of spontaneous POF was 0.91% (0.81-1.02%) among women of the general population in Estonia. In women with POF, menarche occurred a few months later than in the reference group and a significantly higher number of live births during their reproductive life was recorded. Women with POF also consumed less alcohol and had smaller waist-to-hip ratios than those in the reference group, although both groups of women were similar in body mass index a decade after menopause. The prevalence of concomitant diseases was similar between two groups of women by their fifties, but the pattern of onset of these diseases was different. Surgically induced premature menopause associated with faster development of osteoporosis, hypertension, and connective tissue diseases, but slower development of allergies, compared with spontaneous POF. The age of menopause was determined by irregular menstrual cycles, but not by the length of regular menstrual cycles, the age of menarche, the number of pregnancies or live births, smoking or alcohol consumption, or the use of oral contraceptives for some time during the reproductive period. POF is rarely stated in medical records and cannot be diagnosed retrospectively by standard procedures. Therefore the data on all cases of women with primary amenorrhea or premature menopause before the age of 40 were requested from the registry and spontaneous POF was predicted retrospectively by excluding other extraovarian causes for premature menopause. Since the current study is retrospective registry-based data analysis, no genetic evaluation concerning possible candidate genes and no blood analysis concerning immunologic disorders could be performed to describe etiopathogenesis of POF. Spontaneous POF most likely comprises several diseases with different etiopathologies and there may be a unique phenotype of post-menopausal ageing distinct from that in surgically induced premature menopause. Irregular menstrual cycles may be a prospective risk for developing spontaneous POF. Compared with spontaneous POF, surgically induced premature menopause associates with faster development of age-related diseases. The data point to new ideas and hypotheses for further studies on etiopathologies and treatment options for spontaneous POF. The study was funded by grant SF0180044s09, SF0180027s10 and IUT20-43 from the Estonian Ministry of Education and Research, Enterprise Estonia, grant no EU30020, Eureka's EUROSTARS programme grant (NOTED, EU41564). No competing interests are declared.

Protein-losing enteropathy and premature ovarian failure in a young woman with systemic lupus erythematosus

Protein-losing enteropathy (PLE) and autoimmune oophoritis are unusual manifestations of systemic lupus erythematosus (SLE). Autoimmune oophoritis may result in menstrual disturbance and spontaneous premature ovarian failure. However, there is no validated examination to confirm the diagnosis and it is easily neglected in patients with ovarian insufficiency. A 31-year-old woman with SLE presented with PLE and autoimmune oophoritis during the long course of flares and remissions in her lupus activity. The synchronism implied the association between the two. Moreover, both conditions simultaneously had a good response to cyclosporine A (CsA) therapy.

Xq;autosome translocation in POF: Xq27.2 deletion resulting in haploinsufficiency for SPANX

Premature ovarian failure (POF), also called primary ovarian insufficiency (POI), is defined as irregular menses in women younger than 40 years with menopausal-level serum gonadotropins [1]. Spontaneous onset POF may result from numeric and structural chromosomal abnormalities, fragile X premutations, autoimmune disorders and rare syndromes, though in most cases the etiology remains unknown [2]. Structural chromosomal abnormalities, such as deletions and translocations of specific regions on the X chromosome, have been associated with POF. This association may be due to the haploinsufficiency of genes necessary for normal ovarian function. Standard karyotypes and deletion mapping have identified three regions of interest for POI, one in Xp and two in X (POF1: X26-28 and POF2: X13.3-22) [3, 4]. Several candidate genes in X have been proposed by mapping genes interrupted by the breakpoints in X;autosome translocations. These candidate genes include DIAPH2, XPNEP2, DACH2, POF1B, CHM and NXF5, though none of these genes have a well-defined role in POF [5]. Introduction of high-resolution microarray CGH has refined the ability to detect cryptic chromosomal deletions and duplications in the X POF regions, potentially facilitating identification of candidate genes [6]. We present a patient with infertility and primary ovarian insufficiency having a balanced Xq;autosome translocation near the POF2 region, with a cryptic deletion at Xq27.2, identified with array CGH and confirmed by fluorescent in situ hybridization (FISH). The deletion corresponds to the loci for SPANX (sperm protein associated with the nucleus, X-linked), which play roles in spermatogenesis and may represent candidate genes for POF.

Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene

Spontaneous premature ovarian failure (POF) occurs in 1% of women and has major implications for their fertility and health. Besides X chromosomal aberrations and fragile X premutations, no common genetic risk factor has so far been discovered in POF. Using high-density single nucleotide polymorphism (SNP) arrays, we set out to identify new genetic variants involved in this condition. A genome-wide association study involving 309 158 SNPs was performed in 99 unrelated idiopathic Caucasian POF patients and 235 unrelated Caucasian female controls. A replication study on the most significant finding was performed. We specifically focused on chromosomal areas and candidate genes previously implicated in POF. Suggestive genome-wide significant association was observed for rs246246 (allele frequency P = 6.0 x 10(-7)) which mapped to an intron of ADAMTS19, a gene known to be up-regulated in the female mouse gonads during sexual differentiation. However, replication in an independent Dutch cohort (60 POF patients and 90 controls) could not confirm a clear association (P = 4.1 x 10(-5) in a joint analysis). We did not observe strong evidence for any of 74 selected POF candidate genes or linkage regions being associated with idiopathic POF in Caucasian females, although suggestive association (P < 0.005) was observed for SNPs that mapped in BDNF, CXCL12, LHR, USP9X and TAF4B. We observed a possible association between POF and a SNP in a biologically plausible candidate gene. Although limited by sample size, this proof-of-principle study's findings reveal ADAMTS19 as a possible candidate gene for POF and thus a larger follow-up study is warranted.

Factors associated with bone density in young women with karyotypically normal spontaneous premature ovarian failure

To evaluate bone density and associated factors in women with premature ovarian failure (POF) compared to age-matched women with normal ovarian function. A cross-sectional study of 50 patients with POF undergoing bone mineral densitometry was conducted, compared to 50 women paired by age who menstruated regularly. In women with POF, the mean bone mineral density measured was 1.22 g/cm(2) at the spine and 0.92 g/cm(2) at the femur, values which were significantly lower than in the control group (P < 0.0001). Factors directly associated with bone density of the lumbar spine were age and with bone density of the femur were BMI and reproductive age. Young women with POF have a decrease in lumbar spine and femoral bone density. Age, reproductive age and BMI were the factors associated with BMD. These women need early investigation and treatment to prevent bone loss and minimize fracture risk in the future.

THE PRESENCE OF ANTI THYROID AND ANTI OVARIAN AUTO-ANTIBODIES IN FAMILIAL PREMATURE OVARIAN FAILURE

Background: Premature ovarian failure (POF) is a disorder of multi causal etiology. Autoimmunity has been proposed as a mechanism for some cases of ovarian follicle dysfunction which is evident in POF. The aim of this study was to identify the level of auto-antibodies in POF and familial POF patients. Materials and Methods: In this study, auto-antibodies including anti-ovarian antibody (AOA), anti thyroid peroxidase (TPO) and anti thyroglobulin (TG) antibodies were assessed in the sera of 43 cases with spontaneous POF including 12 cases affected by familial POF. The control samples were obtained from sera of 39 women with normal ovulatory or post menopause women. Results: AOA were detected in 46.5% of the POF group, 41.7% of the familial POF group and 41% of the control group without significant statistical difference between the three groups. Thyroid peroxidase (TPO) antibody was found in 32.6% of the POF group, 41.6% of the familial POF group and 10.3% of the control group. Anti TPO was detected significantly high in both POF and familial POF groups (p<0.02 and p<0.01, respectively). Thyroglobulin (TG) antibody was found in 48.8% of the POF group, 75% of the familial POF group and 23.1% of the control group with meaningful difference (p<0.02 and p<0.001, respectively). TG antibody was significantly higher in familial POF group in comparison to POF group (p<0.03). Conclusion: Although measurement of AOA is not a reliable method for diagnosis of auto-immune POF, but existence of anti thyroid antibodies in familial POF (mainly anti TG) can potentially represent an autoimmune mechanism. It is possible to propose a genetic component for developing autoimmune POF supported by presence of anti thyroid antibodies in familial POF.

Spontaneous premature ovarian failure: Management challenges

Premature ovarian failure (POF) generally describes a syndrome consisting of amenorrhea, sex steroid deficiency, and elevated/menopausal levels of ganadotropins in a woman aged more than two standard deviations below the mean age at menopause estimated for the reference population. Numerous questions relating to this condition remain unanswered, and several important management issues are yet to be addressed. The challenges posed by this important condition range from difficulties with nomenclature to the absence of standardized diagnostic criteria and management guidelines. In the present paper we discuss the management of spontaneous premature ovarian failure, highlight the challenging issues, review the current literature and propose a practical management outline based on our local practice. Women with POF have unique needs that require special attention. There is an urgent need for a more suitable terminology and evidence-based guidelines on which to establish the diagnosis and manage this difficult condition.

Functional well-being is positively correlated with spiritual well-being in women who have spontaneous premature ovarian failure

To examine the relationship between spiritual well-being and functional well-being in women who have spontaneous premature ovarian failure. Cross-sectional. The Mark O. Hatfield Clinical Research Center at the US National Institutes of Health. Women diagnosed with spontaneous premature ovarian failure (N = 138) at a median age of 28 years. Administration of validated self-reporting instruments. Functional Well-Being, Spiritual Well-Being, Meaning/Peace, and Faith scores. 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. 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.

Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure

To determine whether women with 46,XX spontaneous premature ovarian failure have lower serum free-T levels than do control women. Cross-sectional. National Institutes of Health Clinical Research Center. Women with 46,XX spontaneous premature ovarian failure (n = 130). 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. Serum total T by RIA after extraction and column chromatography, free T by equilibrium dialysis, and sex hormone-binding globulin by immunoradiometric assay. 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). 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.

O-110: Genetic testing for the FMR1 premutation in young women with spontaneous premature ovarian failure

To assess the informational needs of women with spontaneous premature ovarian failure regarding genetic testing for the FMR1 premutation. Fragile X syndrome, a cause of mental retardation, occurs when the CGG repeat number in the 5′ untranslated region of the FMR1 gene exceeds 200. Although carriers of the FMR1 premutation (more than 55 but less than 200 unmethylated CGG repeats) were previously thought to be unaffected, women who have the premutation are at increased risk for spontaneous premature ovarian failure. The FMR1 premutation has been found in about 2% of women with no family history of either fragile X syndrome or of premature ovarian failure. This low prevalence, combined with the significant implications of a positive test, creates uncertainty as to the best approach to FMR1 testing in these women. Retrospective. We recruited women with a diagnosis of spontaneous premature ovarian failure. Women seen between June 2004 and March 2006 comprised the study subjects. All women received a 30 minute genetic counseling session that informed them about the relationship between premature ovarian failure and the FMR1 premutation, the availability of FMR1 premutation testing, and the potential implications of a positive test result for the patient and her family. About a month after their visit we telephoned patients to discuss results. Later, under an approved protocol, an individual not involved with the genetic counseling telephoned patients to administer a 15 minute structured interview. Patients were informed that once the interview was completed their name would not be associated with the answers. Thus, responses were anonymous to the team evaluating the findings. Of the 121 patients who received FMR1 counseling during the study period 93 participated in the interview (93/121, 77%). Prior to their visit a majority of women (56/93, 60%) had never heard of the fragile X syndrome or the FMR1 gene. A majority did not know that abnormalities in the fragile X gene could be a cause of the premature ovarian failure (65/93, 70%). Most (84/93, 90%) did not recall ever having been advised to be tested for an abnormality in the FMR1 gene to determine if this could be the cause of their premature ovarian failure. Most women (74/93, 80%) reported that the amount of information provided by the 30 minute genetic counseling session was about right; 7/93 (7.5%) reported that it was more information than they wanted and 8/93 (8.6%) reported that it was less than they wanted. Most women (71/93, 76%) reported that 30 minutes was about the right amount of time for the genetic counseling session; 8/93 (8.6%) reported that it was more and 9/93 (9.7%) reported that this was less time than they wanted. After the 30 minute counseling session nearly all women 90/93 (97%) elected to be tested for FMR1 premutation. None regretted having the test done, including 4 women who had an abnormality detected. Most women cited wanting to know the cause of their premature ovarian failure as the most important reason to be tested (54/93, 58%). Nearly all women with spontaneous premature ovarian failure elect to be tested for premutations in the FMR1 gene when genetic counseling and testing is provided to them at no cost. Most women are satisfied with the amount of information that can be provided in a 30 minute genetic counseling session.

O-218: A structured educational program for young women with spontaneous premature ovarian failure

To assess patient satisfaction with a structured educational program directed to the special needs of women with spontaneous premature ovarian failure. Premature ovarian failure is characterized by the development of amenorrhea, sex hormone deficiency, infertility, and menopausal symptoms in women under the age of 40. Evidence has demonstrated that a structured teaching program can improve outcomes in diabetes management. This report is an initial step towards developing such a program for women with premature ovarian failure.

O-128: Symptoms of depression and their impact on daily functioning in women with spontaneous premature ovarian failure

To assess symptoms of depression in women with spontaneous premature ovarian failure and determine the perceived impact of these symptoms on their daily functioning. Learning the diagnosis of premature ovarian failure can induce sadness and grief at the loss of childbearing capacity, which in some cases can spiral into clinical depression.

Investigation of the human stem cell factor KIT ligand gene, KITLG, in women with 46,XX spontaneous premature ovarian failure

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. Cross-sectional study. Clinical research center. Forty women with 46,XX spontaneous premature ovarian failure. None. Single-stranded conformational polymorphism analysis and DNA sequencing. 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%). 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.

A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome

To inform clinicians about a reproductive risk associated with spontaneous premature ovarian failure and the fragile X mental retardation 1 gene (FMR1). Case report. National Institutes of Health Clinical Center. A 35-year-old woman with confirmed spontaneous premature ovarian failure. FMR1 genetic testing. Number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. 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). 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.

Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure

To assess the association between serum adrenal cortex autoantibodies and histologically confirmed autoimmune lymphocytic oophoritis. Controlled, prospective. Tertiary research center. Two hundred sixty-six women with 46,XX spontaneous premature ovarian failure. Ovarian biopsy in 10 women. Serum adrenal cortex autoantibodies assessed by indirect immunofluorescence and autoimmune oophoritis assessed by immunohistochemical lymphocyte markers. 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%). 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.

A Pilot Study of an Investigational Testosterone Transdermal Patch System in Young Women with Spontaneous Premature Ovarian Failure

Evidence suggests that young women with spontaneous premature ovarian failure (sPOF) have significantly lower androgen levels than age-matched regularly menstruating women. The objective of the study was to evaluate an investigational testosterone transdermal patch (TTP) designed to deliver the normal ovarian production rate of testosterone. This was an open-label study (2-month baseline period followed by 2-month treatment period). Nine women with sPOF and a history of regular bleeding patterns on standard estrogen/progestogen cyclic treatment participated in the study. One subject with abnormal baseline levels was excluded. Four consecutive 28-d cycles of transdermal estradiol (E2; 0.1 mg/d) and sequential oral medroxyprogesterone acetate (MPA; 10 mg/d for the last 12 d of each cycle). During cycles 3 and 4, an investigational TTP (nominal delivery 150 microg/d) was applied twice weekly to the abdomen. Steady-state pharmacokinetic profiles of free and total testosterone and scheduled vaginal bleeding patterns were studied. The mean (95% confidence interval) of the time-average free testosterone levels during TTP treatment was 7.5 (4.9-9.9) pg/ml; 26.0 (17.2-34.6) pmol/liter (with E2), and 6.9 (4.9-8.8) pg/ml; 23.9 (17.2-30.5) pmol/liter (with E2 and MPA). The confidence intervals of the means include the upper limit of normal for premenopausal women, i.e. 6.8 pg/ml (23.5 pmol/liter), although the mean values are slightly above this. The addition of TTP to cyclic E2/MPA therapy in women with sPOF produced mean free testosterone levels that approximate the upper limit of normal. A 3-yr study to assess safety and effectiveness in this population is in progress.

Women With Spontaneous Premature Ovarian Failure Have Reduced Self-Esteem and Perceived Social Support

Women With Spontaneous Premature Ovarian Failure Have Reduced Self-Esteem and Perceived Social Support