Endocrine disruptor & nutritional effects of heavy metals in ovarian hyperstimulation.

PURPOSE: There is increasing concern that environmental chemicals have a direct effect on fertility. Heavy metals such as mercury have been shown to affect various organ systems in humans including nervous system and skin, however they could also act as endocrine disrupting chemicals adversely affecting fertility. Metals such as zinc and selenium are essential micronutrients with diverse functions that may be important for reproductive outcomes. We measured mercury, zinc and selenium levels in the hair, a reliable reflection of long term environmental exposure and dietary status, to correlate with the outcome of ovarian hyperstimulation for in vitro fertilisation (IVF) treatment. METHODS: We analysed the hair of 30 subfertile women for mercury, zinc and selenium using inductively coupled mass spectrometry. Each woman underwent one cycle of IVF treatment. Correlation between the levels of these trace metals and treatment outcomes was investigated. RESULTS: Thirty women were recruited with mean (±SD) age of 32.7(4.4) years and BMI of 25.4(5.0)kg/m(2). Hair mercury concentration showed a negative correlation with oocyte yield (p < 0.05,ßcoefficient 0.38) and follicle number (p = 0.03,ß coefficient0.19) after ovarian stimulation. Zinc and selenium levels in hair correlated positively with oocyte yield after ovarian stimulation (p < 0.05,ß coefficient0.15) and (p = 0.03,ß coefficient0.21) respectively. Selenium levels in hair correlated significantly with follicle number following stimulation (p = 0.04, ßcoefficient0.22). There was no correlation between mercury, zinc and selenium in hair and their corresponding serum levels. CONCLUSION: These data suggest that mercury had a deleterious effect whilst there was a positive effect for zinc and selenium in the ovarian response to gonadotrophin therapy for IVF. Hair analysis offers a novel method of investigating the impact of long-term exposure to endocrine disruptors and nutritional status on reproductive outcomes.

Viewing ultrasound scan images prior to termination of pregnancy: choice for women or conflict for ultrasonographers?

Establishing pregnancy location is key to minimising the risks of abortion, and establishing gestational age optimises women's choice of procedure and timing. There is limited information in UK practice about the views of women having an ultrasound before an abortion with regards to whether they would wish to see the scan image of their fetus. We therefore surveyed the views of women having pre-abortion ultrasound scans and the views of ultrasonographers, using self-completed anonymous questionnaires. Responses were available for analysis from 191 women aged 16 to over 45. A total of 25 (13%) women had seen their scan. Of those who did not see their scan, 40 (24%) said they would have liked to see it, to aid their decision-making, as a right, or out of curiosity. Nine out of 17 ultrasonographers completed their questionnaires. Four ultrasonographers thought that women having scans before an abortion should see their scan images if they wished and another four thought they should not because of possible psychological effects. Their response also highlighted possible effects of such scans on those performing them. Given the choice, a larger number of women would like to see their scan images than actually ask. Women request to see their pre-abortion ultrasound images for their own individual reasons, which should be respected. Ultrasonographers may have conflict or ethical dilemmas when performing pre-abortion scans and they should be supported in identifying women for whom looking at their scan images would be of benefit.

The effect of prostaglandin synthetase inhibitors on human preovulatory follicular fluid prostaglandin, thromboxane, and leukotriene concentrations.

This study evaluates the eicosanoid concentration in luteinized unruptured follicles (LUFs) on the ovaries of patients who had been treated with inhibitors of prostaglandin synthetase. Indomethacin, bromfenac, or azapropazone (or a placebo) was administered orally to 41 women during the periovulatory period. Follicular development was monitored by serial ultrasound examinations, and the onset of ovulation was regulated by an injection of hCG. Follicular fluid was aspirated during sterilization by minilaparotomy, which was performed just before the expected time of ovulation. Prostaglandin E2 and PGF2 alpha levels in the fluid were significantly reduced by indomethacin and bromfenac compared to those after placebo treatment. Bromfenac also reduced the follicular fluid leukotriene B4 level. Therefore, the development of luteinized unruptured follicles after treatment with nonsteroidal antiinflammatory drugs appears to be associated with a significant decrease in the synthesis of ovarian eicosanoids.

Eicosanoids and ovulation.

PGs and probably other eicosanoids play a fundamental role in the process of ovulation, more specifically in the mechanism of follicle wall rupture. Although the nature of this role has yet to be established a number of plausible theories exist. It seems likely that altered PG metabolism is responsible for some cases of human female subfertility. The potential for fertility control by PG inhibition is an exciting possibility for the future.

Ovarian follicles during oral contraceptive cycles: their potential for ovulation.

Ovarian follicles of a preovulatory size were encouraged to develop by extending the pill-free period of combine, triphasic oral contraceptive (OC) cycles. Despite recommencement of OC therapy, most follicles continued to grow and then respond to gonadotropin administration by both rupture and luteinization. It is concluded that follicles developing during OC cycles have the potential for ovulation, but this is of doubtful clinical significance for the vast majority of women.

PIP: To determine whether ovarian follicles developing during triphasic oral contraceptive cycles are capable of responding to a gonadotropin surge, follicles developing during the pill-free period were followed by ultrasound in 10 women. The subjects had been taking a triphasic formulation containing 30 mcg ethinyl estradiol (EE) with 50 mcg levonorgestrel for 6 days, 40 mcg EE with 75 mcg levonorgestrel for 5 days, and 30 mcg EE with 125 mcg levonorgestrel for 10 days. For the study, the pill-free period was extended until a 12 mm follicle was seen, and the woman began her pills. When the dominant follicle reached 18 mm, she received 5000 U hCG im. The 10 subjects took 7-16 days to develop a 12-mm follicle. Signs of ovulation judging by EE and progesterone levels and clinical signs and symptoms eventually were recorded in 8 of the 10 women. This study showed the wide individual variation in response in terms of follicle development, but does not suggest that failure of the pill is likely, because of other anti- fertility aspects of the triphasic pill.

Transcervical embryo transfer as a risk factor for ectopic pregnancy.

OBJECTIVE: To evaluate the ease and timing of transcervical ET as risk factors for ectopic pregnancy (EP) after IVF. DESIGN: Retrospective study. SETTING: University-based IVF program in the United Kingdom. PATIENT(S): Eighteen consecutively seen patients with an EP after IVF and 314 patients with an intrauterine pregnancy after transcervical ET performed during the same period. INTERVENTION(S): Additional manipulation with a transfer catheter or the use of other instruments to assist transfer. Embryo transfer on day 2 or 3 after oocyte retrieval. MAIN OUTCOME MEASURE(S): Risk factors for EP (day 2 ET, difficult transfer overall and on days 2 and 3, history of tubal subfertility, and previous EP) presented as odds ratios with 95% confidence intervals. RESULT(S): The risk of EP was 2.26 (0.64-8.01) after day 2 ET, 3.91 (1.49-10.23) after difficult ET, 3.88 (1.34-11.24) after difficult ET on day 2, 2.7 (0.20-13.99) after difficult ET on day 3, 5.73 (1.99-16.62) when there was a history of tubal subfertility, and 5.41 (1.96-14.91) when there was a previous EP. CONCLUSION(S): A difficult ET significantly increases the risk of an EP. The risk is particularly high when the patient has a history of tubal damage or previous EP. The timing of ET is important only if the ET is difficult.

Ovarian function during and after treatment with the new progestagen Org 30659.

OBJECTIVE: To evaluate ovarian function during 21 days of oral administration of different doses of Org 30659, a novel selective progestagenic steroid. DESIGN: Randomized, double-blind, dose-finding study. SETTINGS: Three centers in Austria, Sweden, and the United Kingdom. PARTICIPANTS: Eighty-one healthy women 19-40 years of age with regular ovulatory cycles. INTERVENTION: Daily oral administration of 0.060, 0.120, 0.180, or 0.240 mg of Org 30659, or 0.075 mg desogestrel (reference group), for 21 days. MAIN OUTCOME MEASURE(S): Once-daily measurements of follicular diameter and 17-beta estradiol, progesterone, FSH, and LH levels. RESULT(S): Daily treatment with Org 30659 for 21 days caused dose-dependent suppression of ovarian activity. No ovulation was observed in any study group. On average, ovulation returned 16.5 to 22.1 days after treatment. The effects of desogestrel, 0.075 mg, were similar to those of 0.060 and 0.120 mg of Org 30659. All doses were well tolerated, as shown by the type of side effects that occurred, the absence of an effect on physical and laboratory findings, and the low rate of study discontinuation. CONCLUSION(S): Daily oral administration of 0.060-0.240 mg of Org 30659 suppresses ovarian function to a level sufficient to inhibit ovulation. This effect is dose-dependent, and the suppressive effect is readily reversible at all doses tested. Org 30659 can thus be safely administered orally for 21 days to healthy female volunteers in a dosage of 0.060 mg/d to 0.240 mg/d.

Ectopic pregnancy after transmyometrial embryo transfer: case report.

OBJECTIVE: To report a case of ectopic pregnancy after transvaginal transmyometrial ET. DESIGN: Case report. SETTING: University-based IVF program. PATIENT(S): A woman with tubal subfertility and a history of difficult ETs. INTERVENTION(S): Transvaginal transmyometrial ET performed to avoid a difficult transcervical ET. MAIN OUTCOME MEASURE(S): Expected improvement in the pregnancy rate in a selected group of patients. RESULT(S): Tubal pregnancy. CONCLUSION(S): Transmyometrial ET is an attractive alternative to difficult transcervical ET but is not free of complications.

The relative bioavailability of levonorgestrel and ethinylestradiol when administered in tablet and capsule form.

The relative bioavailability of levonorgestrel (LNG) and ethinylestradiol (EE2) administered as a conventional tablet (150/30) or capsule has been assessed in a randomized two-period crossover study in 9 healthy volunteer women. Serum concentrations were monitored for 24h post-dosing. There was no significant difference in any of the pharmacokinetic parameters determined for either steroid. Hence the relative bioavailability is similar after tablet and capsule formulations.

PIP: 9 female volunteers, aged 18-38 years participated in this study contrasting the bioavailability of levonorgestrel (LNG) and ethinylestradiol (EE2). Each subject received a combination of LNG (150mcg) and EE2 (30mcg) in a soft gelatin capsule form and in tablet form, in random sequence on separate occasions in each of 2 consecutive menstrual cycles. Blood samples were drawn at 0, 0.5, 1, 1.5, 1, 1.5, 3, 4, 5, 6, 7, 8, and 24 hours, and measured by radioimmunoassay after clotting and serum. There was no significant difference in the kinetics of either steroid when data for capsule vs. tablet form were compared. LNG is almost completely bioavailable, while EE2 has a bioavailability of 50% with extensive presystemic metabolism occurring principally in the intestinal wall. However, this study demonstrates no significant improvement in the bioavailability when comparing a capsule with a tablet formulation. The capsule formulation therefore offered little potential for reducing the total steroid dose or maintaining a more constant blood level of contraceptive steroid.

Electrical impedance measurements: an objective measure of prelabor cervical change.

OBJECTIVE: To investigate the use of electrical impedance measurements of the pregnant cervix as an objective measure of cervical favorability (Bishop score > or = 5). METHODS: A prospective study of 86 women, investigating electrical impedance measurements of the pregnant cervix at the time of induction of labor. Transfer electrical impedance measurements were made by placing a tetrapolar pencil probe of 8 mm in diameter on the surface of the cervix. A Bishop score was determined simultaneously. RESULTS: A mean resistivity (standard error of the mean) of 7.03 (6.01-8.04) omega(m) was measured for the unfavorable group and 5.34 (4.61-6.07) omega(m) for the favorable group. This was a statistically significant difference (p = 0.016). CONCLUSION: We highlight the ability of this safe, painless technique to differentiate the favorable from the unfavorable cervix at induction of labor.

Hysterosalpingo contrast sonography as a screening test for tubal patency in infertile women.

The most informative method for assessing tubal patency in subfertile women is laparoscopy-and-dye. This investigation, however, puts a large burden on services and a screening test is needed that identifies a high likelihood of occlusion. In our infertility programme we introduced hysterosalpingo contrast sonography for this purpose, operated entirely by ultrasonographers. A series of audits indicated that this innovation speeded the process of investigation by several weeks and reduced the number of laparoscopy-and-dye procedures by 75%. The negative predictive value was 89% and the positive predictive value was 44%. The main limitation of the method was the long period required for training, in those without extensive experience of vaginal ultrasonography.

Obstetrics and gynaecology trainees' knowledge of electrosurgical equipment.

Electrosurgical energy is potentially dangerous but is a very useful surgical tool. A survey was planned to assess the knowledge of electrosurgery among obstetrics and gynaecology trainees in the Yorkshire Deanery (training region). Questionnaires were given to trainees attending the Modular training programme and were collected on the same day. A total of 71 questionnaires were collected, which represents 62% of the 113 trainees in Yorkshire region: 39 participants were registrars; 27 senior house officers (SHO); four senior SHOs, and one Clinical Fellow. A total of 52% of trainees had only MRCOG Part 1 and 36% of trainees had MRCOG Part 2; 53% of trainees had attended a Basic Surgical Skills course and 10% of trainees were not aware that the 'blue pedal' is used for coagulation (all were SHO except one Specialist Registrar, SpR). A total of 71% of trainees answered incorrectly that coagulating current provides an initial high voltage peak that quickly dissipates, while cutting current provides a constant high energy waveform. Trainees who had attended a Basic Surgical Skills (BSS) course did not demonstrate better knowledge. Knowledge of electrosurgery therefore was found to be poor among obstetrics and gynaecology trainees. Attending a BSS course did not seem to improve it significantly. This study outlines a training need. Perhaps a refresher course in electrosurgery and more focussed training might be useful for trainees with a particular interest in operative gynaecology, to acquire the necessary information and skills.

Ultrasound appearance of the uterus in women over 60 years of age on tibolone: is it a SERM?

OBJECTIVES: To evaluate the effects of long-term tibolone on the endometria of asymptomatic women over the age of 60 years. METHODS: An observational study of the ultrasound appearance of the endometria of women aged 60 years or older taking long-term tibolone. Those found to have a double-layer endometrial thickness greater than 4 mm were offered endometrial biopsy. RESULTS: Seventeen asymptomatic patients with a mean age of 61 years (range 60-73 years) and an average duration of tibolone use of 5 years (range 3-12 years) were recruited. Seven patients (41%) showed a thickened endometrium of more than 4 mm. Three of these had an area of translucency in the subendometrial space. Of the ten women with an endometrial thickness of less than 4 mm, four showed the presence of subendometrial fluid. Hysteroscopy was performed in five out of the seven women, as two did not accept further investigations. In all five women, the endometrial cavity was reported as atrophic and the histology showed an inactive basal type. In two of the five cases examined histologically, there were additional changes suggesting endometrial polyp, although the samples were from macroscopically non-polypoid endometrium. DISCUSSION: Endometrial thickness is increased in 41% of elderly women on long-term treatment with tibolone. However, at hysteroscopy, the endometrium was uniformly atrophic. Similar finding have been described in women using selective estrogen receptor modulators and a similar mechanism of action of these drugs on the uterus should be considered.

Is previous aberrant reproductive outcome predictive of subsequently reduced fecundity?

BACKGROUND: Effect of past reproductive performance on subsequent fecundity is uncertain. METHODS: A total of 2983 consecutive pregnant women self-completed questionnaires about time to pregnancy (TTP), pregnancy planning, previous pregnancies, contraceptive use, age, and individual/lifestyle variables. Outcome measures were: TTP, conception rates (CR) and, subfecundity odds ratio (OR; with 95% confidence intervals) before and after each outcome of last pregnancy. RESULTS: After miscarriage, TTP was longer than before miscarriage [2.1 (1.4-3.0), P < 0.001] and than TTP after livebirth [OR = 2.1 (1.6-2.6), P < 0.001]. Also subfecundity OR after miscarriage increased [1.7 (1.2-2.4), 1.8 (1.2-2.5), P = 0.001, 0.002 respectively]. This effect was more evident in older and obese women. Compared with livebirth, time to ectopic pregnancy (EP) was longer [OR = 13.8 (1.8-108.5), P = 0.001] but TTP after EP was not significantly different. Subfecundity OR relative to livebirth were 12.8 (3.6-45.0) (P<0.001) before, and 3.9 (1.4-11.0) (P=0.01) after, EP. The CR after EP increased 3-fold (1.1-8.3) over those prior to EP. Time to the terminated pregnancies even without contraceptive failures was shorter than that to livebirth [OR = 0.5 (0.3-0.7), P = 0.001] and than TTP after termination [0.35 (0.1-0.8), P = 0.001]. Also subfecundity OR increased after termination [7.2 (1.8-29.7), P = 0.02]. CONCLUSIONS: Miscarriers should be counselled about short-term reduction in subsequent fecundity, and earlier investigations should be considered in those who have other potential risk factors for reduced fertility. Further studies are required to clarify the relatively favourable effect on fecundity following EP and the relative reduction in fecundity after termination of pregnancy.

Patient education and understanding: a critical review.

In the United Kingdom, family planning services are readily available to all women, regardless of economic status. Oral contraceptives play an important role in this effort, yet studies suggest that many patients still do not understand how to use these agents appropriately. Specifically, poor patient compliance is much more prevalent than initially thought. Factors influencing compliance in UK populations include age, socioeconomic group, education, side effects, packaging, and health care delivery. In order for these medications to be effective among various female populations, there is a need for greater emphasis on patient education about oral contraception. Several possible approaches are discussed.

A profile of family planning audit in England 1994-1997.

Audit has been entered into enthusiastically by most of the multidisciplinary teams giving family planning services but the nature of the subject makes audit particularly difficult in this field. In many cases it has been used as a tool for determining standards rather than a tool for determining compliance to them. If family planning audit and evaluation is to substantially improve in quality, a great deal of work needs to be done, particularly in the formation of appropriate guidelines and in the increased utilisation of audit/research specialists to advise on methodology. It is hoped that the new clinical effectiveness committee of the faculty will take a lead in this; if so it will undoubtedly gain support from faculty members.

PIP: The British government invested considerable resources in clinical audit during 1994-97. While by 1993/94, 83% of consultants and 86% of general practitioners had contributed to 20,000 different audit projects, few data were available on the participation of other health care professionals. Recognizing that a sizeable percentage of these latter practitioners work in the field of family planning, the National Coordinating Unit (NCU) for Clinical Audit in Family Planning established a national database of unpublished clinical audits in the field of family planning and reproductive health care, which was subsequently passed onto the Faculty of Family Planning Effective Health Care Unit. Since late 1994, practitioners have been encouraged to submit audits for inclusion in the database as a resource for faculty members and others interested in auditing their own services. The national family planning audit database is now comprised of over 300 unpublished audits of varying complexity. Findings are presented from an analysis of the database with regard to the number of audits submitted annually, the choice of topics for audit, progression around the audit cycle, the disciplines involved in conducting audits, and the challenges of family planning audit. Work remains to be done in order to substantially improve the quality of family planning audit and evaluation.

A national study examining the effect of making emergency hormonal contraception available without prescription.

BACKGROUND: In January 2001, emergency hormonal contraception was made available for women over the age of 16 years directly from a pharmacist without prescription. It is of interest whether this change in the UK has led to any improvements or deterioration in the service provided for the women who need it. METHODS: Self- completed, anonymous questionnaires were distributed to women requesting emergency hormonal contraception through a single group of pharmacies located throughout England, Wales and Scotland. RESULTS: A total 419 women returned completed questionnaires. A greater proportion of women were able to take emergency contraception within 24 h when they obtained their tablets directly from a pharmacy without a prescription (64% versus 46%, P = 0.029). Women who obtained their drugs directly from the pharmacist were just as well informed, just as likely to arrange regular follow-up and generally preferred this system, although they disliked having to pay. CONCLUSION: Making emergency hormonal contraception available without prescription has improved services to women who need them, but these improvements are quantitatively minimal, preventing only five additional pregnancies per 10,000 users.

A comparison of prostaglandin E2 pessaries and laminaria tents for ripening the cervix before termination of pregnancy.

Forty primigravid women aged 15-45 years were randomly allocated to receive either an intravaginal pessary of 3 mg prostaglandin E2 (PGE2) or an intracervical 5-mm laminaria tent (LT) 12-16 h before termination of pregnancy at 6-14 weeks gestation. The degree of dilatation of the cervix at operation and its resistance to further dilatation during the procedure were assessed by a 'blind' operator. Laminaria tents were more effective in achieving dilatation and softening of the cervix than were PGE2 pessaries and in 40% of women no further dilatation was necessary. There were no associated side-effects or complications. A cervical tear occurred in two of 20 patients treated with PGE2 pessaries and all 20 required further dilatation of the cervix. Laminaria tents provide a simple, safe, acceptable and effective means of 'ripening' the cervix prior to termination of early pregnancy.

PIP: 40 primigravid women ages 15-45 were randomly allocated to receive either an intravaginal pessary of 3 mg prostaglandin E2 (PGE2) or an intracervical 5 mm laminaria tent (LT) 12-16 hours before termination of pregnancy at 6-14 weeks gestation. The degree of dilatation during the procedure was assessed by a "blind" operator. LTs were more effective in achieving dilatation and softening of the cervix than were PGE2 pessaries, and in 40% of the women, no further dilatation was necessary. There were no associated side effects or complications. A cervical tear occurred in 2 of 20 patients treated with PGE2 pessaries and all 20 required further dilatation of the cervix. LTs provide a simple, safe, acceptable, and effective means of ripening the cervix prior to termination of early pregnancy.