My 28 Days - a global digital women's health initiative for evaluation and management of secondary amenorrhea: case report and literature review.

There is a need to close the gap between knowledge and action in health care. Effective care requires a convenient and reliable distribution process. As global internet and mobile communication increase capacity, innovative approaches to digital health education platforms and care delivery are feasible. We report the case of a young African woman who developed acute secondary amenorrhea at age 18. Subsequently, she experienced a 10-year delay in the diagnosis of the underlying cause. A global digital medical hub focused on women's health and secondary amenorrhea could reduce the chance of such mismanagement. Such a hub would establish more efficient information integration and exchange processes to better serve patients, family caregivers, health care providers, and investigators. Here, we show proof of concept for a global digital medical hub for women's health. First, we describe the physiological control systems that govern the normal menstrual cycle, and review the pathophysiology and management of secondary amenorrhea. The symptom may lead to broad and profound health implications for the patient and extended family members. In specific situations, there may be significant morbidity related to estradiol deficiency: (1) reduced bone mineral density, 2) cardiovascular disease, and 3) cognitive decline. Using primary ovarian insufficiency (POI) as the paradigm condition, the Mary Elizabeth Conover Foundation has been able to address the specific global educational needs of these women. The Foundation did this by creating a professionally managed Facebook group specifically for these women. POI most commonly presents with secondary amenorrhea. Here we demonstrate the feasibility of conducting a natural history study on secondary amenorrhea with international reach to be coordinated by a global digital medical hub. Such an approach takes full advantage of internet and mobile device communication systems. We refer to this global digital women's health initiative as My 28 Days®.

Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause.

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.

Hormone replacement therapy in young women with surgical primary ovarian insufficiency.

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.

Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance.

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.

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.

A new approach to primary ovarian insufficiency.

There is a need for a new approach to managing women with primary ovarian insufficiency. This condition is a serious chronic disease that may have far reaching effects on physical and emotional health. An integrative and collaborative approach to management works best. To maintain wellness, most women with primary ovarian insufficiency need to reassess their primary source of meaning and purpose in life and how this diagnosis may have threatened that part of who they are. They also need assessment with regard to bone health, thyroid and adrenal function, determination of FMR1 premutation and karyotype status, and ongoing estradiol-progestin hormone replacement.

Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency.

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 second 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 ß1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF ß2 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.

NLRP5 mediates mitochondrial function in mouse oocytes and embryos.

Unraveling molecular pathways responsible for regulation of early embryonic development is crucial for our understanding of female infertility. Maternal determinants that control the transition from oocyte to embryo are crucial molecules that govern developmental competence of the newly conceived zygote. We describe a series of defects that are triggered by a disruption of maternal lethal effect gene, Nlrp5. Previous studies have shown that Nlrp5 hypomorph embryos fail to develop beyond the two-cell stage. Despite its importance in preimplantation development, the mechanism by which the embryo arrest occurs remains unclear. We confirmed that Nlrp5 mutant and wild-type females possess comparable ovarian germ pool and follicular recruitment rates. However, ovulated oocytes lacking Nlrp5 have abnormal mitochondrial localization and increased activity in order to sustain physiological ATP content. This results in an accumulation of reactive oxygen species and increased cellular stress causing mitochondrial depletion. Compromised cellular state is also accompanied by increased expression of cell death inducer Bax and depletion of cytochrome c. However, neither genetic deletion (Bax/Nlrp5 double knockout) nor mimetic interference (BH4 domain or Bax inhibitory peptide) were sufficient to alleviate embryo demise caused by depletion of Nlrp5. We therefore conclude that lack of Nlrp5 in oocytes triggers premature activation of the mitochondrial pool, causing mitochondrial damage that cannot be rescued by inactivation of Bax.

The time is now for a new approach to primary ovarian insufficiency.

OBJECTIVE: To articulate the need for a new approach to primary ovarian insufficiency. The condition, also known as premature menopause or premature ovarian failure, is defined by the presence of menopausal-level serum gonadotropins in association with irregular menses in adolescent girls or women younger than 40 years. It can be iatrogenic as related to cancer therapy or may arise spontaneously, either alone or as part of a host of ultrarare syndromes. In a large percentage of spontaneous cases no pathogenic mechanism can be identified. DESIGN: Literature review and consensus building at a multidisciplinary scientific workshop. CONCLUSION(S): There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of primary ovarian insufficiency. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about the condition. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency.

A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency.

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.

Bone mineral density in estrogen-deficient young women.

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.

The menstrual cycle: a biological marker of general health in adolescents.

Menstruation is the cyclic, orderly sloughing of the uterine lining on account of the interactions of hormones produced by the hypothalamus, pituitary, and ovaries. There is a tendency among parents and clinicians to view oligo-amenorrhea as a normal variant in the teen years. In fact, the 95th percentile for the time interval between cycles is 90 days. Thus, it is abnormal for an adolescent to be amenorrheic for greater than 3 months, even in the early gynecologic years. Identification of abnormal menstrual patterns throughout adolescence may permit early identification of potential health concerns for adulthood. Few problems in gynecologic endocrinology are as complex or challenging to the clinician as amenorrhea. However, thorough evaluation of menstrual cycle disorders in adolescence provides a window of opportunity for early diagnosis and treatment of conditions affecting the hypothalamic-pituitary-ovarian (HPO) axis. Here we discuss a systematic approach to the evaluation and treatment of amenorrhea in adolescents who do not have androgen excess. There is strong evidence that estrogen deficiency is a risk factor for later development of osteoporosis and hip fracture. Delay in the evaluation and treatment of disordered menses in some cases may contribute to reduced bone density. Both patients and clinicians need to view the ovary as an important endocrine organ that helps maintain health, especially bone health.

Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea.

BACKGROUND: The forkhead transcription factor Foxo3 is a master regulator and potent suppressor of primordial follicle activation. Loss of Foxo3 function in the mouse leads to premature ovarian failure (POF) due to global follicle activation. METHODS AND RESULTS: Here, we show that the mouse Foxo3 locus is haploinsufficient, and that Foxo3-/+ females undergo early reproductive senescence consistent with an increased rate of primordial follicle utilization. Then, to determine if heterozygous or homozygous polymorphisms or mutations of the human orthologue FOXO3 contribute to POF or idiopathic primary amenorrhea (PA), we sequenced the exons and flanking splice sequences of the gene in a large number of women with idiopathic POF (n = 273) or PA (n = 29). A total of eight single-nucleotide polymorphisms (SNPs) were identified, revealing a substantial amount of genetic variation at this locus. Allelic frequencies in control samples excluded several of these variants as causal. For the remaining variants, site-directed mutagenesis was performed to assess their functional impact. However, these rare sequence variants were not associated with significant decreases in FOXO3 activity. CONCLUSIONS: Taken together, our findings suggest that, despite the potential for FOXO3 haploinsufficiency to cause ovarian failure, FOXO3 mutations or common SNPs are not a common cause of either POF or PA.

Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency.

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.

Normalization of serum luteinizing hormone levels in women with 46,XX spontaneous primary ovarian insufficiency.

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.