Zephne M van der Spuy

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.

Prospective study of hormonal and semen profiles in marathon runners

OBJECTIVE To investigate the effect of marathon training on hormonal and semen profiles in male athletes. DESIGN Prospective longitudinal study over 1 year. SETTING Department of Obstetrics and Gynaecology, University of Cape Town, South Africa. PARTICIPANTS Twenty-four healthy male marathon runners, 25 to 54 years of age. MAIN OUTCOME MEASURES Hormonal evaluation included determination of plasma concentrations of total T, LH, FSH, PRL, E2, and P. Semen analyses included an evaluation of count, motility, morphology, and volume. These profiles were correlated with training intensity. RESULTS The intensity of training increased significantly in the first 5 months of the study. This was accompanied by a significant rise in serum PRL levels and a fall in P levels. No other significant hormonal changes were identified. The semen volume and sperm motility and morphology fell significantly during training, but there was no significant alteration in the sperm count. CONCLUSION This longitudinal study demonstrates that endurance training can modify significantly hormonal profiles and semen parameters in long-distance runners.

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.

Zoladex (goserelin acetate) and the anemic patient: results of a multicenter fibroid study * † ‡ § ∥

OBJECTIVE To compare the effects of goserelin acetate treatment with or without iron with iron alone. DESIGN Multinational, multicenter, prospective, randomized, double-blind study. PATIENTS Premenopausal women with menorrhagia or metrorrhagia and anemia associated with uterine leiomyomata awaiting hysterectomy. INTERVENTION Patients were randomized to one of three 12-week treatment groups namely goserelin acetate 3.6 mg once monthly plus placebo iron; 3.6 mg goserelin acetate once monthly plus 600 mg/d iron; or sham injection once monthly plus 600 mg/d iron. MAIN OUTCOME MEASURE Preoperative hemoglobin concentration; preoperative uterine and fibroid volumes and operative blood loss. RESULTS Considering the entry and preoperative hemoglobin concentrations, there was a difference in least square means of just over 1 g/dL between the goserelin acetate plus iron and iron only groups and 2.6 g/dL between the goserelin acetate plus iron and goserelin acetate only group. These differences were both statistically significant. Uterine and fibroid volumes were decreased in the goserelin acetate-treated patients by between 37% and 40% and 44% and 47%, respectively, compared with 7% decreases for both in the iron only group. The differences in absolute changes were statistically significant for both the goserelin acetate-treated groups versus the iron-treated group. The least square geometric mean operative blood loss was greatest in the iron only group. CONCLUSION In the patient with uterine leiomyomata and anemia, goserelin acetate in combination with iron therapy has shown significant advantages over the iron alone in restoring hematologic normality, decreasing uterine and fibroid volumes, and reducing operative blood loss.

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

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.

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.

Definition of a minimal region of deletion of chromosome 7 in uterine leiomyomas by tiling-path microarray CGH and mutation analysis of known genes in this region

Somatic interstitial deletions of chromosome segment 7q22–q31 in uterine leiomyomas are a frequent event, thought to be indicative of a tumor suppressor gene in the region. Previous LOH and CGH studies have refined this region to 7q22.3–q31, although the target gene has not been identified. Here, we have used tiling‐path resolution microarray CGH to further refine the region and to identify homozygous deletions in fibroids. Furthermore, we have screened all manually annotated genes in the region for mutations. We have refined the minimum deleted region at 7q22.3–q31 to 2.79 Mbp and identified a second region of deletion at 7q34. However, we identified no pathogenic coding variation.

The effect of morphine and naloxone administration on maternal oxytocin concentration in late pregnancy

OBJECTIVE Modification of the inhibitory control of oxytocin secretion by endogenous opiates in late pregnancy may be one of the factors involved in the onset of labour. The interrelationships between exogenously administered opioids and oxytocin may demonstrate activity of this control mechanism.

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome

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. Thirty-seven 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 AGREEII 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

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

To evaluate knowledge and use of contraception among pregnant teenagers in the Cape Town metropolitan area.