The FIGO Ovulatory Disorders Classification System†.

Ovulatory disorders are common causes of amenorrhea, abnormal uterine bleeding and infertility and are frequent manifestations of polycystic ovary syndrome (PCOS). There are many potential causes and contributors to ovulatory dysfunction that challenge clinicians, trainees, educators, and those who perform basic, translational, clinical and epidemiological research. Similarly, therapeutic approaches to ovulatory dysfunction potentially involve a spectrum of lifestyle, psychological, medical and procedural interventions. Collaborative research, effective education and consistent clinical care remain challenged by the absence of a consensus comprehensive system for classification of these disorders. The existing and complex system, attributed to the World Health Organization (WHO), was developed more than three decades ago and did not consider more than 30 years of research into these disorders in addition to technical advances in imaging and endocrinology. This article describes the development of a new classification of ovulatory disorders performed under the aegis of the International Federation of Gynecology and Obstetrics (FIGO) and conducted using a rigorously applied Delphi process. The stakeholder organizations and individuals who participated in this process comprised specialty journals, experts at large, national, specialty obstetrical and gynecological societies, and informed lay representatives. After two face-to-face meetings and five Delphi rounds, the result is a three-level multi-tiered system. The system is applied after a preliminary assessment identifies the presence of an ovulatory disorder. The primary level of the system is based on an anatomic model (Hypothalamus, Pituitary, Ovary) that is completed with a separate category for PCOS. This core component of the system is easily remembered using the acronym HyPO-P. Each anatomic category is stratified in the second layer of the system to provide granularity for investigators, clinicians and trainees using the 'GAIN-FIT-PIE' mnemonic (Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious and Inflammatory, Trauma and Vascular; Physiological, Idiopathic, Endocrine). The tertiary level allows for specific diagnostic entities. It is anticipated that, if widely adopted, this system will facilitate education, clinical care and the design and interpretation of research in a fashion that better informs progress in this field. Integral to the deployment of this system is a periodic process of reevaluation and appropriate revision, reflecting an improved understanding of this collection of disorders.

Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas.

Mediator regulates transcription by connecting gene-specific transcription factors to the RNA polymerase II initiation complex. We recently discovered by exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common in uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and mutations have been detected in uterine leiomyosarcomas, extrauterine leiomyomas and leiomyosarcomas, endometrial polyps, and colorectal cancers. All mutations have been missense changes or in-frame insertions/deletions. Here, we have analyzed 611 samples representing all above-mentioned tumor types for possible exon 1 mutations. Five mutations were observed, all of which were in-frame insertion/deletions in uterine leiomyomas. Transcriptome-wide expression data revealed that MED12 exon 1 and exon 2 mutations lead to the same unique global gene expression pattern with RAD51B being the most upregulated gene. Immunoprecipitation and kinase activity assays showed that both exon 1 and exon 2 mutations disrupt the interaction between MED12 and Cyclin C and CDK8/19 and abolish the mediator-associated CDK kinase activity. These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings.

Maternal hair selenium levels as a possible long-term nutritional indicator of recurrent pregnancy loss.

BACKGROUND: Approximately 1% of all couples trying to conceive will suffer from recurrent pregnancy loss (RPL). Nutritional deficiencies have been postulated as a possible cause of RPL and in particular, selenium deficiency has been associated with reproductive failure in animal studies and more recently, in some human studies. This study was undertaken to assess the maternal hair selenium levels in women with RPL without an identified cause and to compare these results with those of women with successful reproductive histories. METHODS: Twenty four patients with RPL and twenty four control subjects with at least one successful pregnancy and no pregnancy failures, who were matched for age and ethnicity, were recruited. A questionnaire was completed, which included demographic and social information and a dietary history. Hair samples were collected and analyzed for selenium content by inductively coupled plasma mass spectrometry. RESULTS: The control subjects had a higher mean income and had completed more years of education compared with the RPL patients. There was no significant difference in the intake of selenium rich foods between the 2 groups. The patients, however, consumed significantly more fruit, cheese, potatoes and chocolate than the controls. The median (range) selenium content was 0.80 ppm (0.19-4.15) and 0.68 ppm (0.43-3.76) in patients and controls respectively (Mann Whitney U test 209.5 p = 0.74). CONCLUSIONS: While there were significant differences in the 2 groups with regard to resources, education and diet our results show that hair selenium concentrations and dietary selenium intake, were similar in the two groups. Both groups had low levels of this important element.

The FIGO Ovulatory Disorders Classification System.

Ovulatory disorders are common causes of amenorrhea, abnormal uterine bleeding, and infertility, and are frequent manifestations of polycystic ovary syndrome (PCOS). There are many potential causes and contributors to ovulatory dysfunction that challenge clinicians, trainees, educators, and those who perform basic, translational, clinical, and epidemiological research. Similarly, therapeutic approaches to ovulatory dysfunction potentially involve a spectrum of lifestyle, psychological, medical, and procedural interventions. Collaborative research, effective education, and consistent clinical care remain challenged by the absence of a consensus comprehensive system for classification of these disorders. The existing and complex system, attributed to WHO, was developed more than three decades ago and did not consider more than 30 years of research into these disorders in addition to technical advances in imaging and endocrinology. This manuscript describes the development of a new classification of ovulatory disorders performed under the aegis of the International Federation of Gynecology and Obstetrics (FIGO) and conducted using a rigorously applied Delphi process. The stakeholder organizations and individuals who participated in this process comprised specialty journals, experts at large, national, specialty obstetrical and gynecological societies, and informed lay representatives. After two face-to-face meetings and five Delphi rounds, the result is a three-level multi-tiered system. The system is applied after a preliminary assessment identifies the presence of an ovulatory disorder. The primary level of the system is based on an anatomic model (Hypothalamus, Pituitary, Ovary) that is completed with a separate category for PCOS. This core component of the system is easily remembered using the acronym HyPO-P. Each anatomic category is stratified in the second layer of the system to provide granularity for investigators, clinicians, and trainees using the "GAIN-FIT-PIE" mnemonic (Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious and Inflammatory, Trauma and vascular; Physiological, Idiopathic, Endocrine). The tertiary level allows for specific diagnostic entities. It is anticipated that, if widely adopted, this system will facilitate education, clinical care, and the design and interpretation of research in a fashion that better informs progress in this field. Integral to the deployment of this system is a periodic process of reevaluation and appropriate revision, reflecting an improved understanding of this collection of disorders.

The FIGO ovulatory disorders classification system.

Ovulatory disorders are common causes of amenorrhea, abnormal uterine bleeding, and infertility, and are frequent manifestations of polycystic ovary syndrome (PCOS). There are many potential causes and contributors to ovulatory dysfunction that challenge clinicians, trainees, educators, and those who perform basic, translational, clinical, and epidemiological research. Similarly, therapeutic approaches to ovulatory dysfunction potentially involve a spectrum of lifestyle, psychological, medical, and procedural interventions. Collaborative research, effective education, and consistent clinical care remain challenged by the absence of a consensus comprehensive system for classification of these disorders. The existing and complex system, attributed to WHO, was developed more than three decades ago and did not consider more than 30 years of research into these disorders in addition to technical advances in imaging and endocrinology. This manuscript describes the development of a new classification of ovulatory disorders performed under the aegis of the International Federation of Gynecology and Obstetrics (FIGO) and conducted using a rigorously applied Delphi process. The stakeholder organizations and individuals who participated in this process comprised specialty journals, experts at large, national, specialty obstetrical and gynecological societies, and informed lay representatives. After two face-to-face meetings and five Delphi rounds, the result is a three-level multi-tiered system. The system is applied after a preliminary assessment identifies the presence of an ovulatory disorder. The primary level of the system is based on an anatomic model (Hypothalamus, Pituitary, Ovary) that is completed with a separate category for PCOS. This core component of the system is easily remembered using the acronym HyPO-P. Each anatomic category is stratified in the second layer of the system to provide granularity for investigators, clinicians, and trainees using the "GAIN-FIT-PIE" mnemonic (Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious and Inflammatory, Trauma and Vascular; Physiological, Idiopathic, Endocrine). The tertiary level allows for specific diagnostic entities. It is anticipated that, if widely adopted, this system will facilitate education, clinical care, and the design and interpretation of research in a fashion that better informs progress in this field. Integral to the deployment of this system is a periodic process of reevaluation and appropriate revision, reflecting an improved understanding of this collection of disorders.

A survey to assess knowledge and acceptability of the intrauterine device in the Family Planning Services in Cape Town, South Africa.

INTRODUCTION: Despite reliable evidence of the safety and effectiveness of intrauterine devices (IUDs), this contraceptive method remains under-utilised in many countries due to persistent fears that it causes pelvic infection. The aim of this study was to assess the knowledge and acceptability of IUDs among clients and providers in our family planning services and to attempt to identify barriers to use. METHODS: A descriptive cross-sectional survey was conducted at eight family planning clinics in Cape Town, South Africa. A total of 216 clients and 30 providers from the same clinics were interviewed using structured questionnaires. RESULTS: Awareness of the IUD among clients was low: 41% (n = 88) had heard of this contraceptive method. Ever and current use were very low. Only 4% (n = 9) had ever used an IUD, and three women were still using this method. Lack of knowledge was cited by many women as an obstacle to use. Among providers, factual knowledge about IUDs was limited, and infection (47%, n = 14) and increased menstrual bleeding (40%, n = 12) were frequently mentioned as disadvantages of the method. DISCUSSION AND CONCLUSIONS: Although the IUD is available free of charge in our public sector services, it is not being utilised. Clients lacked knowledge of this method, and research evidence had not impacted on the knowledge and practice of providers. Ongoing education of both clients and providers is essential in order to improve accessibility and acceptability of this safe and effective contraceptive method.

HIV and reproductive health: a South African experience.

Acquired immune deficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), disproportionately affects Africa whereby the majority of new infections and deaths occur in sub-Saharan Africa. It is the leading cause of death in Africa and a major cause of maternal mortality. HIV/AIDS impacts on every aspect of reproductive health and presents considerable challenges to healthcare systems. Fertility is particularly valued in Africa and voluntary childlessness is unusual. AIDS results in a reduction in both fecundity and fertility, as well as compromising the outcome of pregnancy. The stigma of childlessness is quite profound and impacts both social life and social standing within the community, particularly of the women who are affected. Unfortunately, treatment for infertility is often inadequate and, because of limited resources, is frequently denied to HIV-positive couples. Undoubtedly the challenges in dealing with the HIV/AIDS pandemic in Africa are enormous; however, appropriate solutions are available and these need to be put in place. It is essential that the management of the HIV patient is holistic and takes all needs, including that of fertility, into account.

Medical conditions associated with recurrent miscarriage-Is BMI the tip of the iceberg?

BACKGROUND: In contrast to sporadic miscarriage, recurrent miscarriage (RM) is a rare entity which affects 1% of couples attempting conception. It is distressing for couples and healthcare professionals as the aetiology is unclear with limited treatment options. Apart from anti-phospholipid syndrome (APS), the strength of associations between RM and commonly investigated endocrine, autoimmune, thrombophilic and uterine structural abnormalities remains uncertain and variable. OBJECTIVES: To assess the prevalence of commonly investigated medical conditions associated with RM. STUDY DESIGN: A 9-year retrospective analysis of a prospectively collected database was conducted for 592 patients seen between 2008 and 2016, in tertiary level RM clinic in South Africa. RESULTS: In this period, 592 patients were assessed. The mean age was 29.73±5.46 (mean±SD), gravidity 4.6±1.82 and parity 0.98±1.05. The mean number of miscarriages per patient was 3.34±1.63, of which two-thirds (61.3%) were in the first trimester, a third (33%) in the second trimester and intrauterine fetal deaths (IUFDs) constituted 6% of total losses. Of the 50% of patients with no identified associated disorders, 15% were unexplained (investigations complete but no associations found), 10% became pregnant during investigation (investigations incomplete) and 25% were lost to follow-up (investigations incomplete). Nearly forty percent (38%) of patients had an associated endocrine disorder (22% PCOS, 11% IGT, 3% Diabetes Mellitus and 2% Thyroid Dysfunction) and 10% a uterine factor (4% Cervical Incompetence, 2% Fibroids, 2% Synechiae and 2% Anomalies). APS and Thrombophilias constituted 3% and 2% of patients respectively. The BMI (mean±SD) amongst patients with Unexplained RM, PCOS and IGT were 28.85±5.95, 30.86±7.79 and 33.40±6.47 respectively. Patients with IGT had significantly higher mean BMI in comparison to those with Unexplained RM (p<0.0001)*** and PCOS (p<0.001)**. CONCLUSION: PCOS, IGT and Type II Diabetes are all likely surrogates for elevated BMI and constitute 70% of those women with RM and identified associated medical disorders. In our population, BMI seems to have a substantial impact on recurrent pregnancy loss and future studies should interrogate its effect on recurrent miscarriage.

Contraception usage and timing of pregnancy among pregnant teenagers in Cape Town, South Africa.

OBJECTIVE: To evaluate knowledge and use of contraception among pregnant teenagers in the Cape Town metropolitan area. METHODS: A cross-sectional study enrolled women aged 16 to 19 years who were pregnant and attending prenatal clinics, and prenatal and labor wards at regional hospitals and midwife-run obstetric clinics in the Cape Town area between March 1, 2011 and September 30, 2011. Data were collected using an administered questionnaire. RESULTS: The study enrolled 314 participants. Of the participants, 240 (76.4%) felt their pregnancies had occurred at the "wrong time" but only 38 (12.1%) were using contraception at the time of conception. The form of contraception that participants most commonly had knowledge of was injectable hormonal contraception (274 [87.3%]). Contraception use was low, with 126 (40.1%) participants having never used contraception. The forms of contraception used most commonly were the male condom (106 [33.8%]) and injectable contraception (98 [31.2%]). The majority of participants found it easy to get contraception (192 [61.1%]) and felt that information regarding contraception was readily available (233 [74.2%]). CONCLUSION: Contraception use is suboptimal but this may not simply be a reflection of ineffective family-planning services. Further research is needed to fully explain the lack of contraceptive use in this population.

Labor induction abortion utilizing trilostane, a 3beta-hydroxysteroid dehydrogenase inhibitor.

Labor induction abortion in the second trimester is a difficult problem in developing countries because antiprogestins are either not available or unaffordable. When prostaglandins are used alone for labor induction abortion without antiprogestin pretreatment, the induction to delivery interval and the treatment failure rate increase. Trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase enzyme system, was given to 93 women between 13 and 19 weeks gestation. The trilostane dosage used was 120 mg twice daily for the first 24 h, and then 240 mg twice daily for the next 24 h. The women returned after 48 h for hospital admission. The women were randomized to three different misoprostol regimens: low-dose vaginal group (200 microg every 4 h), high-dose vaginal group (initial dose of 400 microg followed by 200 microg every 4 h) and vaginal-oral group (400 microg vaginally followed by 200 microg orally every 4 h). The median induction to abortion times were 17, 8.3 and 9.4 h, respectively. The latter two groups had significantly shorter induction to delivery times (p<.05). The most common side effects were a burning feeling in the face (47.7%) and nausea (13.3%). Overall, trilostane side effects were mild and self-limiting and did not interfere with therapy. In conclusion, trilostane can be given as out-patient therapy prior to admission for prostaglandin administration in labor induction abortion.

The pathogenesis of infertility and early pregnancy loss in polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) frequently present with reproductive dysfunction. Ovarian function might be disturbed, with resultant abnormal folliculogenesis and steroidogenesis and, although it is difficult to define the exact pathogenesis of anovulation, many possible mechanisms have been postulated. Folliculogenesis in anovulatory women with PCOS is characterized by failure of dominance and the ovary has multiple small follicles, which are arrested but capable of steroidogenesis. Abnormalities in gonadotrophin and insulin secretion and disordered paracrine function have been identified. Women with PCOS have an increased prevalence of miscarriage, both after spontaneous and induced ovulation. Hypersecretion of LH, hyperandrogenaemia and hyperinsulinaemia have all been investigated as possible causes of PCOS. It is likely that these factors are interlinked and together might result in disordered ovarian and endometrial function. Multiple other possible abnormalities have been postulated as contributory factors in the reproductive failure. These include decreased plasminogen activator inhibitor activity, endothelial dysfunction and obesity. Ideally, therapy should target the underlying disorders but at present data are inadequate and further investigations are essential before therapeutic recommendations are truly based on an understanding of the pathophysiology.

The gynaecological subspecialties: advances in women's health.

Under Professor Dennis Davey's leadership, the Department of Obstetrics and Gynaecology recognised the need for subspecialist expertise and training. Thus, the gynaecological subspecialties were developed, the first of which was gynaecological oncology. We review the research, and subsequent clinical application, which has evolved from the subspecialist units.

An audit of indications and complications associated with elective hysterectomy at a public service hospital in South Africa.

OBJECTIVE: To assess relationships between clinical indication for hysterectomy and postoperative histologic findings, and to audit complications of hysterectomy at the gynecologic surgical unit of a public-service hospital in South Africa. METHODS: Surgical indications and details, histologic findings, and postoperative course were reviewed and analyzed for 335 patients who underwent hysterectomy at Groote Schuur Hospital, Cape Town, South Africa, in 2007. RESULTS: Hysterectomy was performed abdominally in 265 patients (79.1%) and vaginally in 70 (20.9%) patients (5 of these procedures were laparoscopically assisted). The most common indication was fibroid-related menorrhagia (23%), followed by abnormal uterine bleeding (14.9%). The incidence of intraoperative complications was 6-fold greater among patients with malignant disease than among those with a benign condition (P=0.001). The incidence of postoperative complications was greater following abdominal rather than vaginal surgery, whether traditional or laparoscopic (P=0.02). CONCLUSION: Most hysterectomies were carried out abdominally rather than vaginally, in part because many patients presented with advanced cancer or other condition that warranted this approach. Because of resource constraints, patients with benign conditions were more likely to be offered surgery if they had a clearly defined condition.

MED12 exon 2 mutations are common in uterine leiomyomas from South African patients.

Uterine leiomyomas, or fibroids, are extremely common tumors. Regardless of their benign nature, fibroids can cause considerable morbidity. Women with African ancestry have a threefold increased risk of developing uterine leiomyomas with a greater symptom severity when compared to white women. Recently, we demonstrated that exon 2 of the MED12 gene is somatically altered in up to 70 per cent of uterine leiomyomas in a series of Finnish (Caucasian) patients. To validate these results in other populations, we sequenced a set of 28 uterine leiomyomas for MED12 exon 2 mutations from 18 different Black African or Coloured South African patients. We observed 14 mutation positive lesions (50%). When corrected by tumor size, these results are very similar to those derived in the Finnish material. This study confirms a major role of MED12 in the genesis of leiomyomas, regardless of ethnicity.