Provider Conscientious Refusal of Abortion, Obstetrical Emergencies, and Criminal Homicide Law.

Catholic doctrine's strict prohibition on abortion can lead clinicians or institutions to conscientiously refuse to provide abortion, although a legal duty to provide abortion would apply to anyone who refused. Conscientious refusals by clinicians to end a pregnancy can constitute murder or reckless homicide under American law if a woman dies as a result of such a refusal. Such refusals are not immunized from criminal liability by the constitutional right to the free exercise of religion or by statutes that confer immunity from criminal homicide prosecution. Core principles of the rule of law require the state to protect the lives of all persons equally and to place the life and health of persons above any the interests of providers have in moral integrity or in respecting the moral status of prenatal humans. In some states criminal liability related to conscientious objection also applies to corporate hospital officials.

Psychosocial Vulnerability, Resilience Resources, and Coping with Infertility: A Longitudinal Model of Adjustment to Primary Ovarian Insufficiency.

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. PURPOSE: This longitudinal investigation tests a model of adjustment to POI that includes separate psychosocial vulnerability and resilience resource factors. METHODS: 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. RESULTS: 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. CONCLUSIONS: For women with POI, interventional studies targeted to reduce avoidance are indicated.

Update on primary ovarian insufficiency in adolescents.

PURPOSE OF REVIEW: We provide an overview of new insights into the genetic causes of primary ovarian insufficiency (POI) and address the challenges faced by clinicians who care for adolescents with this condition. RECENT FINDINGS: In most cases, the cause of POI remains a mystery after appropriate clinical testing has been completed. Large-scale genomic sequencing approaches are uncovering new mechanisms underlying the disorder. Gene variants that affect the normal processes of primordial germ-cell proliferation and migration, oocyte meiosis, and ovarian follicle formation/activation are plausible mechanisms. Whole exome sequencing has been used to associate many of these variants with human POI. POI is a serious chronic condition with no cure. It qualifies as a rare disease and as such presents special challenges to patients, parents, and clinicians. Although the diagnosis of POI is often delayed because of the assumption that irregular menses are common among adolescents, early detection is critical for the maintenance of bone and cardiovascular health. Treatment options have focused on hormonal therapy and fertility preservation. However, many studies prove the increasing need to incorporate mental health support and a family systems approach into the management plan. SUMMARY: Large-scale genomic sequencing has recently identified new mechanisms of POI. However, at present this testing is not clinically indicated as routine. Practice will change as genomic medicine is integrated into standard care. Adolescents with POI are best served by an integrated personal care approach centered on the patient and provided by a primary care clinician who has support from a multidisciplinary team.

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®.

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.

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.

Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency.

CONTEXT: A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE: We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. DESIGN: The study was an observational study. SETTING: Subjects were recruited at academic institutions. PATIENTS: Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION: We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. MAIN OUTCOME: Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. RESULTS: Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). CONCLUSIONS: Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

Venous thromboembolic disease in trauma and surveillance ultrasonography.

BACKGROUND: The literature reports a wide variation in the incidence of venous thromboembolic (VTE) disease in trauma patients. The performance of routine surveillance venous duplex ultrasound of bilateral lower extremities is controversial. Furthermore, recent examinations of the national trauma databank registry have suggested that routine duplex surveillance is associated with higher deep venous thrombosis (DVT) detection rates. MATERIALS AND METHODS: We examined the incidence and risk factors for VTE disease in 2827 trauma patients admitted over a 2-y period to a state-verified level I trauma center. Detailed chart review was carried out for patients with VTE disease. We then evaluated the effects of a routine bilateral lower extremity duplex surveillance guideline on VTE detection in the subset of injury patients admitted to the trauma service. RESULTS: We found an approximately 2% incidence of venous thromboembolic disease in a mostly blunt trauma population. Amongst patients with VTE disease, the most common risk factors were obesity and significant head injury. We then evaluated the 998 patients with injury who were admitted to the trauma service 1 y before and after surveillance guideline implementation. Despite a nearly 5-fold increase in the number of duplex scans, with a substantial increase in cost, we found no significant difference in the incidence of DVT. CONCLUSIONS: Our preliminary data argue against the use of routine duplex surveillance of lower extremities for DVT in trauma patients. A larger, prospective analysis is necessary to confirm these findings.

Optimizing Fertility in Primary Ovarian Insufficiency: Case Report and Literature Review.

Primary ovarian insufficiency (POI) is a clinical spectrum of ovarian dysfunction. Overt POI presents with oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. Overt POI involves chronic health problems to include increased morbidity and mortality related to estradiol deficiency and the associated osteoporosis and cardiovascular disease as well as psychological and psychiatric disorders related to the loss of reproductive hormones and infertility. Presently, with standard clinical testing, a mechanism for Overt POI can only be identified in about 10% of cases. Now discovery of new mechanisms permits an etiology to be identified in a research setting in 25-30% of overt cases. The most common genetic cause of Overt POI is premutation in FMR1. The associated infertility is life altering. Oocyte donation is effective, although many women prefer to conceive with their own ova. Surprisingly, the majority who have Overt POI still have detectable ovarian follicles (70%). The major mechanism of follicle dysfunction in Overt POI has been histologically defined by a prospective NIH study: inappropriate follicle luteinization due to the tonically elevated serum LH levels. A trial of physiologic hormone replacement therapy, clinically proven to suppress the elevated LH levels in these women, may improve follicle function and increase the chance of ovulation. Here, we report the case of a woman with Overt POI diagnosed at age 35 years. To attempt pregnancy, she elected a trial of intrauterine insemination (IUI) in conjunction with follicle monitoring and physiologic hormone replacement therapy. She conceived on the eighth cycle of treatment and delivered a healthy baby. Our report calls for a concerted effort to define the best methods by which to optimize fertility for women who have POI.

BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein.

Bone morphogenetic protein-15 (BMP15) is selectively synthesized by oocytes as a pre-proprotein and is considered an ovarian follicle organizer whose adequate function is critical for female fertility. Missense mutations were reported in primary ovarian insufficiency (POI) but their biological impact remained unexplored. Here, screening of 300 unrelated idiopathic overt POI women with primary or secondary amenorrhea (SA) led to the identification of six heterozygous BMP15 variations in 29 of them. All alterations are nonconservative and include one insertion of three nucleotides (p.L262_L263insL) and five missense substitutions. Except for the p.S5R located in the signal sequence, the other variants (p.R68W, p.R138H, p.L148P, and p.A180T) localize in the proregion, which is essential for the processing and secretion of bioactive dimers. The mutations p.R68W, p.L148P, and the novel p.R138H lead to marked reductions of mature protein production. Their biological effects, evaluated by a novel luciferase-reporter assay in a human granulosa cell (GC) line, were significantly reduced. Cotransfection experiments of defective mutants with equal amounts of wild-type BMP15 cDNA, thus reproducing the heterozygous state seen in patients, did not generate a complete recovery of wild-type activity. No or minor deleterious effects were detected for the variants p.L262_L263insL, p.A180T, or p.S5R. In conclusion, heterozygous BMP15 mutations associated with the early onset of overt POI lead to defective secretion of bioactive dimers. These findings support the concept that an adequate amount of BMP15 secreted in the follicular fluid is critical for female fertility. We propose to consider the screening of BMP15 mutations among the analyses for the prediction of POI risk.

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.

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.