Summary
Premature ovarian failure (POF) is a disorder with a complicated clinical presentation and course that is poorly defined by its name. A more scientifically accurate term for the disorder is ...primary ovarian insufficiency (POI), a term that can be appropriately modified to describe the state of ovarian function. In recent years, the known aetiologies of POI have expanded, although the cause of POI in a majority of clinical cases remains undefined. The most common aetiologies should be ruled out clinically including chromosomal abnormalities, fragile X premutations and autoimmune causes. Management should be directed at symptom resolution and bone protection, but most importantly should include psychosocial support for women facing this devastating diagnosis.
Objective:
The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS).
Participants:
An Endocrine Society-appointed Task Force of experts, a ...methodologist, and a medical writer developed the guideline.
Evidence:
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.
Consensus Process:
One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence.
Conclusions:
We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study.
Context:
Polycystic ovary syndrome (PCOS) is diagnosed during the reproductive years when women present with 2 of 3 of the following criteria: 1) irregular menstrual cycles or anovulation, 2) ...hyperandrogenism, and 3) PCO morphology. However, there is evidence that PCOS can be identified from early infancy to puberty based on predisposing environmental influences. There is also increasing information about the PCOS phenotype after menopause. The goal of this review is to summarize current knowledge about the appearance of PCOS at different life stages and the influence of reproductive maturation and senescence on the PCOS phenotype.
Evidence:
PubMed, the bibliography from the Evidence-Based PCOS Workshop, and the reference lists from identified manuscripts were reviewed.
Evidence Synthesis:
The current data suggest that daughters of women with PCOS have a greater follicle complement and mild metabolic abnormalities from infancy. PCOS is often diagnosed in puberty with the onset of hyperandrogenism and may be preceded by premature pubarche. During the reproductive years, there is a gradual decrease in the severity of the cardinal features of PCOS. Menopausal data suggest that the majority of women who had PCOS during their reproductive years continue to manifest cardiovascular risk factors. However, the majority do not present an increased risk for cardiovascular morbidity and mortality, perhaps because women with no history of PCOS may catch up after menopause.
Conclusion:
The current data provide a comprehensive starting point to understand the phenotype of PCOS across the lifespan. However, limitations such as a bias of ascertainment in childhood, age-based changes during reproductive life, and the small numbers studied during menopause point to the need for additional longitudinal studies to expand the current knowledge.
Polycystic ovary syndrome (PCOS) is a complex genetic disorder with many genetic loci contributing small risk. Large genome-wide association studies identified 21 genetic risk loci for PCOS in ...European and Han Chinese women. The genetic architecture is similar across PCOS diagnostic categories. The next wave of analysis will incorporate large genotyped datasets linked to medical records, increasing numbers and ethnic subsets. The resulting genetic risk loci can then be used to create robust genetic risk scores enhanced with clinical information, environment and lifestyle data for a precision medicine approach to PCOS diagnosis and treatment.
Abstract
Context
Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing alactogenesis.
Objective
...We hypothesized a heterozygous genetic mutation.
Methods
This was a family-based study. Two generations of women (proband, sister, and niece) with puerperal alactogenesis and one control were studied. Prolactin levels in the 3 women ranged from 0.618 to 1.4 ng/mL (range, 2.8-29.2 ng/mL). All the women had regular menstrual cycles during their reproductive years. The niece required fertility treatment to become pregnant and the proband and sister underwent menopause before age 45 years. Prolactin gene (PRL) exons 1 to 5 were sequenced. We sought a heterozygous, deleterious gene variant with functional consequences.
Results
We identified a heterozygous mutation (c.658C > T) changing CGA to TGA (p.Arg220Ter) in exon 5 of the prolactin gene. Transfection of PRL containing the stop gain mutation resulted in similar intracellular prolactin levels compared to PRL wild type, but little detectable immunoactive or bioactive prolactin in conditioned medium. Prolactin secretion was also impaired by a PRL stop gain mutation deleting both of the terminal cysteine amino acids (c.652A > T; p.Lys218Ter).
Conclusion
This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.
The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause is PCOS. Hirsutism is the ...most common presenting symptom. The woman's concern about her symptoms plays an important role in the management of disease. Although measurement of testosterone is useful in identifying an underlying cause, care must be taken when interpreting the less accurate assays that are available commercially. Surgical resection is curative in tumorous etiologies, whereas medical management is the mainstay for non-tumorous causes.
Genome-wide association studies and replication analyses have identified (n = 5) or replicated (n = 10) DNA variants associated with risk for polycystic ovary syndrome (PCOS) in European women. ...However, the causal gene and underlying mechanism for PCOS risk at these loci have not been determined. We hypothesized that analysis of phenotype, gene expression and metformin response as a function of genotype would identify candidate genes and pathways that could provide insight into the underlying mechanism for risk at these loci. To test the hypothesis, subjects with PCOS (n = 427) diagnosed according to the NIH criteria (< 9 menses per year and clinical or biochemical hyperandrogenism) and controls (n = 407) with extensive phenotyping were studied. A subset of subjects (n = 38) underwent a subcutaneous adipose tissue biopsy for RNA sequencing and were subsequently treated with metformin for 12 weeks with standardized outcomes measured. Data were analyzed according to genotype at PCOS risk loci and adjusted for the false discovery rate. A gene variant in the THADA locus was associated with response to metformin and metformin was a predicted upstream regulator at the same locus. Genotype at the FSHB locus was associated with LH levels. Genes near the PCOS risk loci demonstrated differences in expression as a function of genotype in adipose including BLK and NEIL2 (GATA4 locus), GLIPR1 and PHLDA1 (KRR1 locus). Based on the phenotypes, expression quantitative trait loci (eQTL), and upstream regulatory and pathway analyses we hypothesize that there are PCOS subtypes. FSHB, FHSR and LHR loci may influence PCOS risk based on their relationship to gonadotropin levels. The THADA, GATA4, ERBB4, SUMO1P1, KRR1 and RAB5B loci appear to confer risk through metabolic mechanisms. The IRF1, SUMO1P1 and KRR1 loci may confer PCOS risk in development. The TOX3 and GATA4 loci appear to be involved in inflammation and its consequences. The data suggest potential PCOS subtypes and point to the need for additional studies to replicate these findings and identify personalized diagnosis and treatment options for PCOS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The measurement of adrenal and ovarian androgens in women with PCOS has been difficult based on poor specificity and sensitivity of assays in the female range.
Women with PCOS (NIH criteria; n = 52) ...and control subjects with 25-35 day menstrual cycles, no evidence of hyperandrogenism and matched for BMI (n = 42) underwent morning blood sampling. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to simultaneously measure 13 steroids from a single blood sample to measure adrenal and ovarian steroids. Androgen and progesterone results were compared in the same samples using RIA.
Testosterone, androstenedione, progesterone and 17OH progesterone levels were higher when measured using RIA compared to LC-MS/MS, although the testosterone RIA demonstrated the best agreement with the LC-MS/MS using a Bland-Altman analysis. Results using LC-MS/MS demonstrated that the concentration of androgens and their precursors were higher in women with PCOS than controls median (2.5, 97.5th %ile); 1607 (638, 3085) vs. 1143 (511, 4784) ng/dL; p = 0.03. Women with PCOS had higher testosterone 49 (16, 125) vs. 24 (10, 59) ng/dL, androstenedione 203 (98, 476) vs. 106 (69, 223) ng/dL and 17OH progesterone levels 80 (17, 176) vs. 44 (17, 142) ng/dL compared to controls (all P<0.02), but no differences in serum concentrations of the adrenal steroids DHEAS, cortisol, corticosterone and their 11 deoxy precursors. Women with PCOS also had an increase in the product:precursor ratio for 3β-hydroxysteroid dehydrogenase 22% (6, 92) vs. 20% (4, 43); p = 0.009.
LC-MS/MS was superior to RIA in measuring androstenedione, progesterone and 17OH progesterone levels, while testosterone measurements were better matched in the two assays. Androgen levels were higher in women with PCOS in the absence of a difference in adrenal-predominant steroids. These data support previous findings that the ovary is an important source for the androgen excess in women with PCOS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
What is known about health-related quality of life (HR-QoL) in women with idiopathic primary ovarian insufficiency (POI)?
Women with POI have a range of unmet psychosocial needs relating to three ...interrelated themes: 'diagnostic odyssey', 'isolation and stigma' and impaired 'ego integrity'.
Prior studies have reported increased depressive symptoms, diminished sexual function and altered body image/self-concept in women with POI.
A systematic scoping review (11 databases) on HR-QoL in POI including published quantitative, qualitative and mixed-methods studies as well as unpublished gray literature (i.e. unpublished dissertations) through June, 2021.
After removing duplicates, 1244 articles underwent title and abstract review by independent reviewers. The remaining 72 relevant articles underwent dual full text review to determine inclusion criteria yielding 24 articles (100% concordance) for data extraction. Findings were summarized in tables by methodology and recurrent HR-QoL themes/sub-themes were mapped to define key aspects of HR-QoL in POI. Promoters of active coping were charted at the individual, interpersonal and healthcare system levels. Targets for tailored interventions supporting active coping and improved HR-QoL were mapped to the Theory of Planned Behavior (TPB).
Three interrelated themes affecting HR-QoL in POI emerged from the data synthesis. First, the theme 'diagnostic odyssey' comprised sub-themes of uncertainty, lack of control, knowledge gaps, discontinuous care and negative clinical interactions. The second theme 'isolation and stigma' included sub-themes of guilt, shame, concealment, feeling labeled as infertile, lack of social support and unsympathetic clinicians. The third theme, impaired 'ego integrity' captured sub-themes of decreased sexual function, altered body image, psychological vulnerability and catastrophizing. Targets promoting active coping at the individual (n = 2), interpersonal (n = 1) and healthcare system (n = 1) levels were mapped to the TPB to inform development of tailored interventions supporting active coping and improved HR-QoL in POI (i.e. narrative intervention, co-creating patient-facing materials, peer-to-peer support and provider resources).
No studies using a POI-specific HR-QoL instrument were identified. No interventional studies aimed at improving HR-QoL in POI were identified. Only articles published in English were included in the study.
Women with POI frequently have impaired HR-QoL related to the life-altering infertility diagnosis. The range of unmet psychosocial needs may be relevant for informing interventions for other populations with infertility.
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 'Massachusetts General Hospital-Harvard Center for Reproductive Medicine' (1 P50 HD104224-01 NICHD). The authors have no conflicts to declare.
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