Nature Communications 6: Article number: 7502 (2015); Published: 18 August 2015; Updated: 12 February 2016 In the original version of this Article the genetic locus 8p23.1 was incorrectly referred to ...as 8p32.1 throughout. For example, in the Abstract, the sentence beginning ‘Three loci reach genome-wide significance in the case-control meta-analysis…' originally read ‘Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p32.
The investigation and management of hirsutism Franks, Stephen
The Journal of Family Planning and Reproductive Health Care,
07/2012, Letnik:
38, Številka:
3
Journal Article, Book Review
Recenzirano
Excess male-pattern body hair in women is a very common and psychologically damaging condition. Although its cause is usually a chronic and benign disorder (most commonly polycystic ovary syndrome) ...it may rarely be an indication of a more serious endocrine disease such as Cushing syndrome or an androgen-secreting tumour. Investigations do not usually need to be extensive, but effective management is important, irrespective of cause, for what can be a debilitating symptom. Specific treatment of any underlying disease is important but in most cases treatment is empirical; it may simply involve physical hair removal, ideally by electrolysis or laser treatment. However, endocrine therapy to suppress androgen production and/or action is desirable in many, if not most, cases.
Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of ...global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS).
The aim of this paper was to present an evidence base for the management of anovulatory PCOS.
The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus.
Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m
and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed.
This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS.
Abstract
Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common ...cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFβ superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFβ signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.
We examined androgen effects on mouse preantral follicles in culture. Testosterone and DHT stimulated growth, augmented FSH action, and induced significant changes in the TGFβ signaling pathway.
Anovulation in polycystic ovary syndrome (PCOS) is characterised by arrest of antral follicles, a phenotype that can be rescued by increasing circulating concentrations of follicle stimulating ...hormone (FSH). Abnormalities of gonadotropin regulation, secretion and action have been implicated in the aetiology of anovulation, as well as local, intraovarian factors. Recent studies have implicated both central and intraovarian actions of anti-Mullerian hormone (AMH) in the aetiology of PCOS and in the mechanism of anovulation. It is likely that more than one pathway is involved, whether extrinsic or intrinsic to the ovary, but there appears to be an important role for androgen programming of both neuroendocrine and ovarian effects on ovarian follicular function.
Successful in vitro maturation (IVM) of oocytes obtained from medium-sized antral follicles could avoid the need for superovulation
for in vitro fertilization. The wide range of doses of FSH used in ...IVM prompted us to study the effect of varying concentrations
of FSH on the dynamics of nutrient uptake and production by individual maturing mouse cumulus-oocyte complexes (COCs). COCs
isolated from the antral follicles of unprimed, prepubertal B6CBF 1 mice were cultured individually in increasing concentrations of FSH (0â2000 ng/ml). Following culture, pyruvate, glucose,
and lactate uptake or production by individual complexes were noninvasively assessed and compared with the stage of nuclear
maturation of the enclosed oocyte. FSH significantly increased oocyte maturation and produced a two- to threefold increase
in glucose uptake and lactate production by COCs in which the enclosed oocyte completed maturation. In these COCs, pyruvate
was taken up under control conditions but was produced in progressively higher quantities in increasing concentrations of
FSH. In COCs where the oocyte failed to complete maturation, pyruvate was taken up (rather than produced) and glucose uptake
and lactate production were lower and unaffected by the presence or absence of FSH. This suggests that there is dialogue between
cumulus cells and the maturing oocyte that influences FSH responsiveness and substrate metabolism of the whole COC. Finally,
inhibition of FSH-stimulated glucose uptake by the PI3-kinase inhibitor LY294002 and the finding of GLUT4 protein in granulosa
cells suggest that FSH increases glucose uptake by PI3-kinase-mediated translocation of GLUT4 to the granulosa cell membrane.
Obesity has a negative impact on reproductive health, particularly in women with polycystic ovarian syndrome (PCOS). Obesity itself is the product of both genetic and environmental influences, ...although the current ‘epidemic’ of obesity is largely related to changes in diet and lifestyle. Single gene defects leading to obesity and disordered reproductive function are rare but can are informative about metabolic pathways involved in appetite regulation. There is good evidence that PCOS has an important genetic background, which probably involves the interaction of several genes. The phenotype of PCOS and its impact on reproductive function is profoundly affected by obesity, which, in turn has both genetic and environmental influences. Understanding the genetic basis of PCOS is important but improvements in diet and lifestyle are the best means of improving reproductive function.
Polycystic ovary syndrome (PCOS) is the most common cause of anovulation. A key feature of PCOS is arrest of follicles at the small- to medium-sized antral stage.
To provide further insight into the ...mechanism of follicle arrest in PCOS, we profiled (i) gonadotropin receptors; (ii) characteristics of aberrant steroidogenesis; and (iii) expression of anti-Müllerian hormone (AMH) and its receptor in granulosa cells (GCs) from unstimulated, human small antral follicles (hSAFs) and from granulosa lutein cells (GLCs).
GCs from hSAFs were collected at the time of cryopreservation of ovarian tissue for fertility preservation and GLCs collected during oocyte aspiration before in vitro fertilization/intracytoplasmic sperm injection.
We collected hSAF GCs from 31 women (98 follicles): 10 with polycystic ovaries (PCO) and 21 without. GLCs were collected from 6 women with PCOS and 6 controls undergoing IVF.
Expression of the following genes: LHCGR, FSHR, AR, INSR, HSD3B2, CYP11A1, CYP19, STAR, AMH, AMHR2, FST, INHBA, INHBB in GCs and GLCs were compared between women with PCO and controls.
GCs in hSAFs from women with PCO showed higher expression of LHCGR in a subset (20%) of follicles. Expression of FSHR (P < 0.05), AR (P < 0.05), and CYP11A1 (P < 0.05) was lower, and expression of CYP19A1 (P < 0.05), STAR (P < 0.05), HSD3B2 (P = NS), and INHBA (P < 0.05) was higher in PCO GCs. Gene expression in GL cells differed between women with and without PCOS but also differed from that in GCs.
Follicle arrest in PCO is characterized in GCs by differential regulation of key genes involved in follicle growth and function.
Abstract
STUDY QUESTION
What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer ...preference?
SUMMARY ANSWER
International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.
WHAT IS KNOWN ALREADY
Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist.
STUDY DESIGN, SIZE, DURATION
International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels.
MAIN RESULTS AND THE ROLE OF CHANCE
The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management.
LIMITATIONS, REASONS FOR CAUTION
Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided.
WIDER IMPLICATIONS OF THE FINDINGS
The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.
STUDY FUNDING/COMPETING INTEREST(S)
The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.
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