Ian S. Fraser

FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age

There is general inconsistency in the nomenclature used to describe abnormal uterine bleeding (AUB), in addition to a plethora of potential causes—several of which may coexist in a given individual. It seems clear that the development of consistent and universally accepted nomenclature is a step toward rectifying this unsatisfactory circumstance. Another requirement is the development of a classification system, on several levels, for the causes of AUB, which can be used by clinicians, investigators, and even patients to facilitate communication, clinical care, and research. This manuscript describes an ongoing process designed to achieve these goals, and presents for consideration the PALM‐COEIN (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified) classification system for AUB, which has been approved by the International Federation of Gynecology and Obstetrics (FIGO) Executive Board as a FIGO classification system.

3-Dimensional imaging of collagen using second harmonic generation

Collagen is the most important structural protein of the animal body. Its unique triple-helix structure and extremely high level of crystallinity make it exceptionally efficient in generating the second harmonic of incident light, and we show here how this leads to a novel mode of microscopy of immediate practical significance in medicine and biology. In particular, it provides sensitive and high-resolution information on collagen distribution, discriminates between type I and type III collagen, and allows both a greater understanding of and a sensitive test for cirrhosis of the liver. Future research applications could include wound healing and hereditary collagen diseases such as osteogenesis imperfecta.

Randomized Trial of 2 Hormonal and 2 Prostaglandin-inhibiting Agents in Women with a Complaint of Menorrhagia

Summary: A series of 45 ovulatory women with a complaint of menorrhagia were randomized into 3 treatment groups, before receiving therapy with mefenamic acid in 2 cycles and 1 of 3 other agents in 2 cycles: naproxen (group 1; n = 14), a low dose monophasic combined oral contraceptive (group 2; n = 12) or low dose danazol (group 3; n = 12). Menstrual blood loss was measured in 2–4 control cycles and during therapy. Mefenamic acid reduced measured blood loss by 20%; 38%; and 39% in groups 1–3 respectively. Naproxen reduced blood loss by 12%; the oral contraceptive by 43%; and danazol by 49%. There was no statistically significant difference in blood loss reduction (mean of 2 cycles) between any of the treatments, although women on danazol experienced a dramatic and highly significant further reduction in blood loss after the first treatment cycle (p < 0.003). These were all effective therapies in a majority of women, but some ‘non‐responders’ were seen in each group. The ‘non‐responders’ had a significantly lower pretreatment blood loss than responders. Several women in group 1 showed anomalous responses to prostaglandin inhibitors with consistent and substantial exacerbation of menorrhagia during therapy. A number of reasonable therapies exist for the medical treatment of menorrhagia, but because none is suitable for everyone management needs to be individualized for each patient.

Rich innervation of deep infiltrating endometriosis

BACKGROUND Deep infiltrating endometriosis (DIE) is a specific type of endometriosis, which can be associated with more severe pelvic pain than other forms of endometriotic lesions. However, the mechanisms by which pain is generated are not well understood. METHODS DIE (n = 31) and peritoneal endometriotic (n = 40) lesions were sectioned and stained immunohistochemically with antibodies against protein gene product 9.5, neurofilament, nerve growth factor (NGF), NGF receptors tyrosine kinase receptor-A (Trk-A) and p75, substance P, calcitonin gene-related peptide, vesicular acetylcholine transporter, neuropeptide Y, vasoactive intestinal peptide and tyrosine hydroxylase to demonstrate myelinated, unmyelinated, sensory and autonomic nerve fibres. RESULTS There were significantly more nerve fibres in DIE (67.6 +/- 65.1/mm(2)) than in peritoneal endometriotic lesions (16.3 +/- 10.0/mm(2)) (P < 0.01). DIE was innervated abundantly by sensory Adelta, sensory C, cholinergic and adrenergic nerve fibres; NGF, Trk-A and p75 were strongly expressed in endometriotic glands and stroma of DIE. CONCLUSIONS The rich innervation of DIE may help to explain why patients with this type of lesion have severe pelvic pain.

The effects of Implanon on menstrual bleeding patterns.

Objectives To evaluate an integrated analysis of bleeding patterns associated with use of the subdermal contraceptive implant Implanon® (etonogestrel, Organon, part of Schering-Plough) and to provide physician guidance to optimize patient counselling. Methods Data from 11 clinical trials were reviewed (N = 923). Assessments included bleeding-spotting records, dysmenorrhoea, and patient-perceived reasons for discontinuation. Bleeding patterns were analysed via reference period (RP) analyses. Results Implanon® use was associated with the following bleeding irregularities: amenorrhoea (22.2%) and infrequent (33.6%), frequent (6.7%), and/or prolonged bleeding (17.7%). In 75% of RPs, bleeding-spotting days were fewer than or comparable to those observed during the natural cycle, but they occurred at unpredictable intervals. The bleeding pattern experienced during the initial phase predicted future patterns for the majority of women. The group of women with favourable bleeding patterns during the first three months tended to continue with this pattern throughout the first two years of use, whereas the group with unfavourable initial patterns had at least a 50% chance that the pattern would improve. Only 11.3% of patients discontinued owing to bleeding irregularities, mainly because of prolonged flow and frequent irregular bleeding. Most women (77%) who had baseline dysmenorrhoea experienced complete resolution of symptoms. Conclusion Implanon® use is associated with an unpredictable bleeding pattern, which includes amenorrhoea and infrequent, frequent, and/or prolonged bleeding. The bleeding pattern experienced during the first three months is broadly predictive of future bleeding patterns for many women. Effective preinsertion counselling on the possible changes in bleeding patterns may improve continuation rates.

Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study

BACKGROUND Diagnosis of endometriosis currently requires a laparoscopy and this need probably contributes to the considerable average delay in diagnosis. We have reported the presence of nerve fibres in the functional layer of endometrium in women with endometriosis, which could be used as a diagnostic test. Our aim was to assess efficacy of nerve fibre detection in endometrial biopsy for making a diagnosis of endometriosis in a double-blind comparison with expert diagnostic laparoscopy. METHODS Endometrial biopsies, with immunohistochemical nerve fibre detection using protein gene product 9.5 as marker, taken from 99 consecutive women presenting with pelvic pain and/or infertility undergoing diagnostic laparoscopy by experienced gynaecologic laparoscopists, were compared with surgical diagnosis. RESULTS In women with laparoscopic diagnosis of endometriosis (n = 64) the mean nerve fibre density in the functional layer of the endometrial biopsy was 2.7 nerve fibres per mm(2) (+/-3.5 SD). Only one woman with endometriosis had no detectable nerve fibres. Six women had endometrial nerve fibres but no active endometriosis seen at laparoscopy. The specificity and sensitivity were 83 and 98%, respectively, positive predictive value was 91% and negative predictive value was 96%. Nerve fibre density did not differ between different menstrual cycle phases. Women with endometriosis and pain symptoms had significantly higher nerve fibre density in comparison with women with infertility but no pain (2.3 and 0.8 nerve fibre per mm(2), respectively, P = 0.005). CONCLUSIONS Endometrial biopsy, with detection of nerve fibres, provided a reliability of diagnosis of endometriosis which is close to the accuracy of laparoscopic assessment by experienced gynaecological laparoscopists. This study was registered with the Australian Clinical Trials Registry (ACTR) 00082242 (registered: 12/12/2007). The study was approved by the Ethics Review Committee (RPAH Zone) of the Sydney South West Area Health Service (Protocol number X05-0345) and The University of Sydney Human Research Ethics Committee (Ref. No. 10761) and all women gave their informed consent for participation.

Body weight, exercise and menstrual status among ballet dancers in training

Summary. A prospective study of the menstrual pattern and weight changes was made in the first year of training of 29 new female entrants to a professional ballet school. Seventy‐nine per cent of the student girls had menstrual disturbances at entry: primary amenorrhoea, four; secondary amenorrhoea, 11; irregular menses, eight. The incidence of secondary amenorrhoea increase substantially by the end of the year (20), but was not associated with any significant change in body weight. Only three students menstruated regularly during the year. Menstrual regularity improved during periods of injury and long vacation and it appears that deterioration of the menstrual pattern during dancing periods was related to strenuous physical exercise rather than to any change in body weight.

NORPLANT CONSENSUS STATEMENT AND BACKGROUND REVIEW

This review has highlighted the attributes of a very important new method of contraception. The signatories to this document agree that, with the provision of appropriate information and instruction for the user, Norplant is a good contraceptive choice to be made available worldwide in family planning programs that have the resources for appropriate training and counseling. The signatories to this document are acting in their own personal capacity and not as representatives of any particular organization.

Treatment of Ovulatory and Anovulatory Dysfunctional Uterine Bleeding with Oral Progestogens

Summary: Six anovulatory and 10 ovulatory women with dysfunctional uterine bleeding (DUB) were treated with cyclical oral progestogens (norethisterone or medroxypro‐gesterone acetate). Anovulatory women were treated from day 12–25 and ovulatory from day 5–25, in doses of 5–10mg 3 times daily. Measured menstrual blood loss was effectively reduced from control to treatment cycles in both anovulatory (control cycle 131ml; treatment 80 and 64ml) and ovulatory women (control cycles 110 and 113ml; treatment 76 and 71ml). Three women with ovulatory DUB did not show a useful response. Duration of bleeding was reduced in both groups and the pattern of loss changed. These regimens are effective forms of management for most women with ovulatory or anovulatory DUB.

Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of a fixed estrogen step-down and progestin step-up 28-day estradiol (E2) valerate and dienogest oral contraceptive regimen in women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology. METHODS: This double-blind, placebo-controlled study randomized women aged 18 years or older with prolonged, frequent, or heavy menstrual bleeding, objectively confirmed during a 90-day run-in phase, to treatment with E2 valerate and dienogest or placebo (2:1) for 196 days. Data from the last 90 days of treatment and the run-in phase were compared. The primary variable was the “complete response” rate (complete resolution of qualifying abnormal menstrual symptoms, including a 50% or greater reduction in pretreatment menstrual blood loss volume in women with heavy menstrual bleeding). Secondary variables included objective changes in menstrual blood loss volume (alkaline hematin methodology) and iron metabolism parameters. Overall, 180 women were needed to provide 90% power. RESULTS: There were no marked differences in the characteristics of E2 valerate and dienogest (n=120) and placebo (n=70) recipients. The proportion of “complete responders” in the evaluable group was significantly higher in E2 valerate and dienogest (35/80; 43.8%) compared with placebo (2/48, 4.2%, P<.001) recipients. The mean [standard deviation] reduction in menstrual blood loss with E2 valerate and dienogest from the run-in phase to the efficacy phase was substantial (−353 mL [309 mL]; mean −64.2%; median −70.6%) and significantly greater than that in placebo recipients (−130 mL [338 mL]; mean −7.8%; median −18.7%; P<.001). Significant improvements in hemoglobin, hematocrit, and ferritin were seen with E2 valerate and dienogest, but not with placebo. CONCLUSION: Oral E2 valerate and dienogest was highly effective compared with placebo in the treatment of women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00293059. LEVEL OF EVIDENCE: I