Primary Ovarian Insufficiency

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Lawrence M. Nelson - One of the best experts on this subject based on the ideXlab platform.

  • fragile x associated Primary Ovarian Insufficiency fxpoi case report and literature review
    Frontiers in Genetics, 2018
    Co-Authors: Dorothy A. Fink, Lawrence M. Nelson, Stephanie L Sherman, Reed Pyeritz, Josh Johnson, Yoram Cohen, Shai E. Elizur
    Abstract:

    Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated Primary Ovarian Insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

  • Table_2_Fragile X Associated Primary Ovarian Insufficiency (FXPOI): Case Report and Literature Review.DOCX
    2018
    Co-Authors: Dorothy A. Fink, Lawrence M. Nelson, Stephanie L Sherman, Reed Pyeritz, Josh Johnson, Yoram Cohen, Shai E. Elizur
    Abstract:

    Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated Primary Ovarian Insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

  • hormone replacement therapy in young women with surgical Primary Ovarian Insufficiency
    Fertility and Sterility, 2016
    Co-Authors: Philip M Sarrel, Shannon D Sullivan, Lawrence M. Nelson
    Abstract:

    Bilateral oophorectomy performed in women before they are menopausal induces surgical Primary Ovarian Insufficiency, an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy (HRT) most of these women develop severe symptoms of estrogen (E) deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal E2 replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal HRTs has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of E therapy, even in women in whom HRT is clearly indicated. Discussion of possible Ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective HRT for women who will experience surgical Primary Ovarian Insufficiency is clearly indicated.

  • hormone replacement therapy in young women with Primary Ovarian Insufficiency and early menopause
    Fertility and Sterility, 2016
    Co-Authors: Shannon D Sullivan, Philip M Sarrel, Lawrence M. Nelson
    Abstract:

    Primary Ovarian Insufficiency (POI) is a rare but important cause of Ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of Ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal Ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or Ovarian cancer, women approaching the age of natural menopause, and breastfeeding women.

  • psychosocial vulnerability resilience resources and coping with infertility a longitudinal model of adjustment to Primary Ovarian Insufficiency
    Annals of Behavioral Medicine, 2016
    Co-Authors: Mary A. Driscoll, Mary C. Davis, Leona S. Aiken, Ellen W. Yeung, Evelina W. Sterling, Vien H. Vanderhoof, Karim A. Calis, V. Popat, Sharon N. Covington, Lawrence M. Nelson
    Abstract:

    The infertility associated with Primary Ovarian Insufficiency (POI) presents significant emotional challenges requiring psychosocial adjustment. Few investigations have explored the longitudinal process of adaptation to POI. This longitudinal investigation tests a model of adjustment to POI that includes separate psychosocial vulnerability and resilience resource factors. Among 102 women with POI, personal attributes reflective of vulnerability and resilience were assessed at baseline. Coping strategies were assessed 4 months later and measures of distress and well-being 12 months later. As hypothesized, confirmatory factor analysis yielded separate, inversely correlated vulnerability and resilience resource factors at baseline, and distress and well-being factors at 12 months. Contrary to predictions, maladaptive and adaptive coping strategies were not bi-factorial. Moreover, a single stand-alone strategy, avoidance (i.e., refusing to acknowledge stress), mediated the association between baseline vulnerability and 12-month distress. For women with POI, interventional studies targeted to reduce avoidance are indicated.

Vien H. Vanderhoof - One of the best experts on this subject based on the ideXlab platform.

  • psychosocial vulnerability resilience resources and coping with infertility a longitudinal model of adjustment to Primary Ovarian Insufficiency
    Annals of Behavioral Medicine, 2016
    Co-Authors: Mary A. Driscoll, Mary C. Davis, Leona S. Aiken, Ellen W. Yeung, Evelina W. Sterling, Vien H. Vanderhoof, Karim A. Calis, V. Popat, Sharon N. Covington, Lawrence M. Nelson
    Abstract:

    The infertility associated with Primary Ovarian Insufficiency (POI) presents significant emotional challenges requiring psychosocial adjustment. Few investigations have explored the longitudinal process of adaptation to POI. This longitudinal investigation tests a model of adjustment to POI that includes separate psychosocial vulnerability and resilience resource factors. Among 102 women with POI, personal attributes reflective of vulnerability and resilience were assessed at baseline. Coping strategies were assessed 4 months later and measures of distress and well-being 12 months later. As hypothesized, confirmatory factor analysis yielded separate, inversely correlated vulnerability and resilience resource factors at baseline, and distress and well-being factors at 12 months. Contrary to predictions, maladaptive and adaptive coping strategies were not bi-factorial. Moreover, a single stand-alone strategy, avoidance (i.e., refusing to acknowledge stress), mediated the association between baseline vulnerability and 12-month distress. For women with POI, interventional studies targeted to reduce avoidance are indicated.

  • Psychosocial Vulnerability, Resilience Resources, and Coping with Infertility: A Longitudinal Model of Adjustment to Primary Ovarian Insufficiency.
    Annals of behavioral medicine : a publication of the Society of Behavioral Medicine, 2015
    Co-Authors: Mary A. Driscoll, Mary C. Davis, Leona S. Aiken, Ellen W. Yeung, Evelina W. Sterling, Vien H. Vanderhoof, Karim A. Calis, V. Popat, Sharon N. Covington, Lawrence M. Nelson
    Abstract:

    Background The infertility associated with Primary Ovarian Insufficiency (POI) presents significant emotional challenges requiring psychosocial adjustment. Few investigations have explored the longitudinal process of adaptation to POI.

  • effects of physiologic testosterone therapy on quality of life self esteem and mood in women with Primary Ovarian Insufficiency
    Menopause, 2014
    Co-Authors: Gioia M Guerrieri, Vien H. Vanderhoof, Karim A. Calis, V. Popat, Sophia N Kalantaridou, Nazli Haq, Deloris E Koziol, Pedro E Martinez, Summer P Klug, David R Rubinow
    Abstract:

    Objective Low androgen levels occur in women with Primary Ovarian Insufficiency(POI) and could contribute to mood and behavioral symptoms in this condition. We examined the effects of physiologic testosterone (T) replacement therapy added to standard estrogen/progestin replacement therapy (EPT) on quality of life, self-esteem, and mood in women with POI.

  • bone mineral density in young women with Primary Ovarian Insufficiency results of a three year randomized controlled trial of physiological transdermal estradiol and testosterone replacement
    The Journal of Clinical Endocrinology and Metabolism, 2014
    Co-Authors: V. Popat, Vien H. Vanderhoof, Karim A. Calis, Sophia N Kalantaridou, James Troendle, Deloris E Koziol, James C Reynolds, Lawrence M. Nelson
    Abstract:

    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 doub...

  • autoimmune disorders in women with turner syndrome and women with karyotypically normal Primary Ovarian Insufficiency
    Journal of Autoimmunity, 2012
    Co-Authors: Vladimir K Bakalov, Vien H. Vanderhoof, Lawrence M. Nelson, Liat Gutin, Clara M Cheng, Jian Zhou, Puja Sheth, Kavita Shah, Sruthi Arepalli, Carolyn A Bondy
    Abstract:

    The higher prevalence of autoimmune diseases in women compared to men could be due to effects of Ovarian hormones, pregnancy and/or the presence of a 2nd X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with Primary Ovarian Insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n=244) and women with karyotypically normal (46,XX) Primary Ovarian Insufficiency (POI, n=457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto’s) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P<0.0001); HT prevalence in both Ovarian Insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves’ disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF β1 levels (p<0.0001 for both), and lower anti-inflammatory IL10 and TGF β2 levels (p<0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with Ovarian Insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS.

Karim A. Calis - One of the best experts on this subject based on the ideXlab platform.

Stephanie L Sherman - One of the best experts on this subject based on the ideXlab platform.

  • fragile x associated Primary Ovarian Insufficiency fxpoi case report and literature review
    Frontiers in Genetics, 2018
    Co-Authors: Dorothy A. Fink, Lawrence M. Nelson, Stephanie L Sherman, Reed Pyeritz, Josh Johnson, Yoram Cohen, Shai E. Elizur
    Abstract:

    Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated Primary Ovarian Insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

  • Table_2_Fragile X Associated Primary Ovarian Insufficiency (FXPOI): Case Report and Literature Review.DOCX
    2018
    Co-Authors: Dorothy A. Fink, Lawrence M. Nelson, Stephanie L Sherman, Reed Pyeritz, Josh Johnson, Yoram Cohen, Shai E. Elizur
    Abstract:

    Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated Primary Ovarian Insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

  • reproductive and gynecologic care of women with fragile x Primary Ovarian Insufficiency fxpoi
    Menopause, 2016
    Co-Authors: Heather S Hipp, Krista Charen, Jessica B Spencer, Emily G Allen, Stephanie L Sherman
    Abstract:

    OBJECTIVE Approximately 20% of women with a premutation in the FMR1 gene experience Primary Ovarian Insufficiency (POI). We explored diagnostic patterns, frequency of appropriate hormone replacement, obstetric outcomes, fertility treatment, reproductive decisions, and counseling of women with fragile X-associated POI (FXPOI). METHODS Semistructured interviews with 79 women with FXPOI were conducted by a single interviewer. FMR1 cytosine-guanine-guanine repeat size was determined from a blood, saliva, or buccal sample. RESULTS The median age of POI onset for women in our study was 33 years. Seventy-two percent of the women had an FMR1 cytosine-guanine-guanine repeat length of 80 to 100. Mean length of time from symptom onset to POI diagnosis was 1.12 years, longer in women with a younger age of POI onset and shorter in women who knew they were carriers. After diagnosis, 52% of women never took hormone therapy, started it years after POI diagnosis, or stopped it before 45 years of age. Forty-nine percent of the women had infertility, but 75% had had at least one genetically related child. Obstetric outcomes were similar to the general population. Forty-six percent of women had a diagnosis of low bone mineral density or osteoporosis, and an additional 19% had never had a bone density assessment. CONCLUSIONS Women with FXPOI are at significant risk for delayed POI diagnosis and undertreatment with hormone therapy. Although approximately 50% of women had infertility, most were able to conceive at least one child and had no elevated risk of adverse obstetric outcomes.

  • fragile x premutation rna is sufficient to cause Primary Ovarian Insufficiency in mice
    Human Molecular Genetics, 2012
    Co-Authors: Li Lin, Stephanie L Sherman, Fei Gao, Huiping Tan, Peng Jin, Dahua Chen
    Abstract:

    Spontaneous 46,XX Primary Ovarian Insufficiency (POI), also known as 'premature menopause' or 'premature Ovarian failure', refers to Ovarian dysfunction that results in a range of abnormalities, from infertility to early menopause as the end stage. The most common known genetic cause of POI is the expansion of a CGG repeat to 55-199 copies (premutation) in the 5' untranslated region in the X-linked fragile X mental retardation 1 (FMR1) gene. POI associated with the FMR1 premutation is referred to as fragile X-associated POI (FXPOI). Here, we characterize a mouse model carrying the human FMR1 premutation allele and show that FMR1 premutation RNA can cause a reduction in the number of growing follicles in ovaries and is sufficient to impair female fertility. Alterations in selective serum hormone levels, including FSH, LH and 17β-estradiol, are seen in this mouse model, which mimics findings in humans. In addition, we also find that LH-induced ovulation-related gene expression is specifically altered. Finally, we show that the FMR1 premutation allele can lead to reduced phosphorylation of Akt and mTOR proteins. These results together suggest that FMR1 premutation RNA could cause the POI associated with FMR1 premutation carriers, and the Akt/mTOR pathway may serve as a therapeutic target for FXPOI.

  • Ovarian histopathological and ubiquitin immunophenotypic features in fragile x associated Primary Ovarian Insufficiency a study of five cases and selected controls
    Histopathology, 2011
    Co-Authors: Martin C Chang, Stephanie L Sherman, John J Decaro, Mei Zheng, Marla Gearing, Lisa Shubeck, Corrine K Welt
    Abstract:

    Sir: The fragile X premutation, an expansion of a CGG triplet repeat in the 5′-untranslated region of the FMR1 gene (55–200 repeats), is one of the most common aetiologies of Primary Ovarian Insufficiency: fragile X-associated Primary Ovarian Insufficiency (FXPOI).1–3 Men who carry the premutation are at increased risk for a late-onset neurodegenerative disorder termed fragile X tremor/ataxia syndrome (FXTAS).4 In premutation carriers, FMR1 is transcribed at increased levels, and the large rCGG tracks may cause disease by acting in a toxic gain of function manner.5–8

Shannon D Sullivan - One of the best experts on this subject based on the ideXlab platform.

  • hormone replacement therapy in young women with surgical Primary Ovarian Insufficiency
    Fertility and Sterility, 2016
    Co-Authors: Philip M Sarrel, Shannon D Sullivan, Lawrence M. Nelson
    Abstract:

    Bilateral oophorectomy performed in women before they are menopausal induces surgical Primary Ovarian Insufficiency, an acute and chronic deficiency of the hormones normally produced by the ovaries. Without hormone replacement therapy (HRT) most of these women develop severe symptoms of estrogen (E) deficiency and are at increased risk for osteoporosis, cardiovascular disease, cognitive decline, dementia, and the associated increases in morbidity and mortality. In cases in which a hysterectomy has been performed at the time of bilateral oophorectomy transdermal or transvaginal E2 replacement therapy without cyclic progestin replacement is the optimum hormonal management for these women. There is substantial evidence this approach even reduces the risk for breast cancer. Unfortunately, unwarranted fear of all menopausal HRTs has become widespread following the reports of the Women's Health Initiative studies. This fear has led to a steep decline in use of E therapy, even in women in whom HRT is clearly indicated. Discussion of possible Ovarian conservation in women who are premenopausal is an integral part of the preoperative planning for any women undergoing hysterectomy. Timely and effective HRT for women who will experience surgical Primary Ovarian Insufficiency is clearly indicated.

  • hormone replacement therapy in young women with Primary Ovarian Insufficiency and early menopause
    Fertility and Sterility, 2016
    Co-Authors: Shannon D Sullivan, Philip M Sarrel, Lawrence M. Nelson
    Abstract:

    Primary Ovarian Insufficiency (POI) is a rare but important cause of Ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of Ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal Ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or Ovarian cancer, women approaching the age of natural menopause, and breastfeeding women.

  • fmr1 and the continuum of Primary Ovarian Insufficiency
    Seminars in Reproductive Medicine, 2011
    Co-Authors: Shannon D Sullivan, Corrine K Welt, Stephanie L Sherman
    Abstract:

    Abstract Spontaneous 46,XX Primary Ovarian Insufficiency (POI) is a term that describes Ovarian dysfunction resulting in a range of abnormalities, from infertility to early menopause as the end stage (overt POI). The most common known genetic cause of 46,XX POI is the expansion of a CGG repeat to 55 to 199 copies in the 5' untranslated region in the X-linked FMR1 gene. This "premutation" is associated with overt POI (FXPOI) in ~20% of carrier women. Greater than 200 CGG copies results in methylation of the CGG repeats and subsequent silencing of the FMR1 gene, causing fragile X syndrome. This "full" mutation is not associated with FXPOI. Even in the absence of overt FXPOI, women who carry the premutation may exhibit Ovarian dysfunction along a continuum of severity. Evidence also suggests that the severity of FXPOI depends on the CGG repeat length, background modifier genes, and environmental factors (e.g., smoking). This review explores the range of Ovarian dysfunction, the mechanisms behind the dysfunction, and the reasons for the variability in presentation in women who carry the FMR1 premutation. Understanding the mechanisms responsible for development of FXPOI is paramount to providing these women with the best overall health care.

  • insights into Primary Ovarian Insufficiency through genetically engineered mouse models
    Seminars in Reproductive Medicine, 2011
    Co-Authors: Shannon D Sullivan, Diego H Castrillon
    Abstract:

    Primary Ovarian Insufficiency (POI), also known as premature Ovarian failure, is a form of hypergonadotropic hypogonadism that causes infertility in ~1% of women <40 years of age. POI has important health consequences for affected patients; however, the mechanisms that cause Ovarian dysfunction are poorly understood. Elucidating these mechanisms is paramount to developing better testing and treatment strategies for affected girls and women. For obvious reasons, studies looking directly at the human ovary are extremely limited. Recently, numerous genetically engineered mouse models have been developed to investigate the molecular mechanisms that may be involved in the pathogenesis of POI. Two potential mechanisms may be involved in the development of POI: (1) abnormalities in primordial follicle activation and (2) increased rates of apoptosis of oocytes. Each of these mechanisms may lead to early depletion of Ovarian follicular reserve, and thus be a contributing factor in POI. This review addresses current knowledge of molecular mechanisms controlling primordial follicle activation and oocyte apoptosis, as evidenced from various genetic mouse models. Translation of these data into clinically effective treatments or even prevention strategies may improve fertility and quality of life for women with this form of reproductive dysfunction.

  • five mutations of mitochondrial dna polymerase gamma polg are not a prevalent etiology for spontaneous 46 xx Primary Ovarian Insufficiency
    Fertility and Sterility, 2010
    Co-Authors: Zhibin Tong, Vien H. Vanderhoof, Shannon D Sullivan, Lindsey M Lawless, Keith Zachman, Lawrence M. Nelson
    Abstract:

    The study objective was to determine if mutations in mitochondrial DNA polymerase gamma (POLG) are associated with spontaneous 46,XX Primary Ovarian Insufficiency (sPOI) using restriction fragment length polymorphism analysis of genomic DNA. Of 201 women with 46,XX sPOI analyzed, we found only one case (0.5%, 95% confidence interval 0-3%) of heterozygosity for a POLG mutation, suggesting that this is not a common genetic etiology for this form of infertility.

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