Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

Urological and colorectal complications following surgery for rectovaginal endometriosis.

OBJECTIVES: To report the short- and medium-term complications of laparoscopic laser excisional surgery for rectovaginal endometriosis. DESIGN: Retrospective cohort study. SETTING: University teaching hospital, UK. POPULATION: A total of 128 women with histologically confirmed rectovaginal endometriosis who underwent laparoscopic laser surgery between May 1999 and September 2006. METHODS: Women were identified from operative database, and a case note review was performed. Data for surgical outcome and surgical complications were collected. MAIN OUTCOME MEASURES: Rates of urinary tract and colorectal complications. RESULTS: A total of 128 women underwent surgery. Of these, 32 required intraoperative closure of a rectal wall defect, including 3 segmental rectosigmoid resections. There were three rectovaginal fistulae and one ureterovaginal fistula. Ureteric damage occurred in two women, and five women suffered postoperative urinary retention. The risk of intraoperative bowel intervention was increased in women who complained of cyclical rectal bleeding. CONCLUSION: Laparoscopic laser excision of rectovaginal endometriosis is a safe procedure with similar, if not lower, complication rates to other published surgical series.

An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage.

When trying to conceive 1% of couples have recurrent miscarriages, defined as three or more consecutive pregnancy losses. This is not accounted for by the known incidence of chromosomal aneuploidy in miscarriage, and it has been suggested that there is an immunological aetiology. The endometrial mucosa is populated by a variety of immune cells which in addition to providing host pathogen immunity must facilitate pregnancy. Here we characterise the endometrial CD8-T cell population during the embryonic window of implantation and find that the majority of cells are tissue resident memory T cells with high levels of CD69 and CD103 expression, proteins that prevent cells egress. We demonstrate that unexplained recurrent miscarriage is associated with significantly decreased expression of the T-cell co-receptor CD8 and tissue residency marker CD69. These cells differ from those found in control women, with less expression of CD127 indicating a lack of homeostatic cell control through IL-7 signalling. Nevertheless this population is resident in the endometrium of women who have RM, more than three months after the last miscarriage, indicating that the memory CD8-T cell population is altered in RM patients. This is the first evidence of a differing pre-pregnancy phenotype in endometrial immune cells in RM.

Endometriosis: aetiology, pathogenesis and treatment.

Endometriosis, which may be defined as the presence and proliferation of endometrial tissue outside the uterine cavity, causes pain and infertility for millions of women worldwide. Studies suggest a prevalence of 0.5 to 5% in fertile and 25 to 40% in infertile women. The most widely accepted aetiological theory is that retrograde flow of menstrual fluid through the Fallopian tubes deposits viable endometrial tissue, which implants on the peritoneal surface. Increasingly, the aetiology of endometriosis is being studied at the immunological and genetic levels. The aim of treatment of endometriosis is to remove or diminish disease deposits. This may be attempted through medical or surgical means. It has long been recognised that endometriotic glands are hormonally sensitive. Medical therapies work by inducing a hypoestrogenic, anovulatory state to induce atrophy within the glandular tissue. Conception is generally not possible during medical therapy and has not been demonstrated to increase afterwards. Medical treatment of endometriosis should be discouraged when infertility is the primary problem. In this situation surgery or an assisted reproduction treatment such as in vitro fertilisation may be more appropriate. Medical treatment of pain caused by endometriosis is generally effective. There is little difference in efficacy between the different medications but their adverse effect profiles differ greatly. It appears that gonadotropin-releasing hormone agonists, particularly when used with add-back estrogen, may be more acceptable to women than other treatments. Laparoscopic surgical treatment of minimal and mild endometriosis has been demonstrated to increase fecundity. Surgical treatment has also been shown to decrease pain scores compared with expectant management. Ongoing and future research examining the aetiology of endometriosis at the immunological and genetic levels should usher in new treatments directed at the actual cause of the disease. More randomised trials examining the role of surgery, and comparing surgical and medical treatments, are also required and are necessary if we are to continue in our attempts to adopt an evidence-based approach to treatment.

Sequential bilateral adnexal torsion after a single cycle of gonadotropin ovulation induction with intrauterine insemination.

OBJECTIVE: To report a rare case of sequential bilateral adnexal torsion in a pregnant woman after a single cycle of gonadotropin ovulation induction with IUI. To review the literature with regards to the causation and aspects of the management of adnexal torsion, particularly after assisted conception. DESIGN: Case report. SETTING: Fertility department within a teaching hospital. PATIENT(S): A 35-year-old woman with a twin pregnancy after a cycle of gonadotropin ovulation induction and IUI. INTERVENTION(S): Gonadotropin ovulation induction with IUI; two laparotomies, salpingo-oophorectomy, stabilization of adnexa with stay suture. RESULT(S): Continuation of pregnancy until 37 weeks gestation with the abdominal delivery of healthy twins. CONCLUSION(S): The case of a woman with a multiple pregnancy and ovarian hyperstimulation syndrome after ovulation induction and IUI who developed sequential bilateral adnexal torsion is used to illustrate the risk factors and management options for adnexal torsion. Physicians should be aware of the increased incidence of adnexal torsion in the rising number of women undergoing ovulation induction in order to effect early surgical intervention and adnexal salvage. Consideration should be given to the anchoring of bulky adnexae to prevent torsion recurrence.

In vitro maturation and fertilization of oocytes from unstimulated normal ovaries, polycystic ovaries, and women with polycystic ovary syndrome.

OBJECTIVE: To investigate differences in immature oocyte maturation, fertilization, and pregnancy rates among women with unstimulated normal ovaries, polycystic ovaries (PCOs), or PCOS. DESIGN: Prospective observational study. SETTING: University fertility clinic. PATIENT(S): One hundred forty-four women undergoing 180 in vitro oocyte maturation treatment cycles. INTERVENTION(S): Transvaginal immature oocyte recovery from unstimulated ovaries 36 hours after hCG priming. In vitro oocyte maturation and fertilization. Fresh embryo transfer. MAIN OUTCOME MEASURE(S): Immature oocytes collected, metaphase II oocytes, and embryos produced. Implantation and pregnancy rates. RESULT(S): The overall oocyte maturation and fertilization rates attained were 80.3% (1,222 of 1,522) and 76.5% (935 of 1,222), respectively. Significantly fewer immature oocytes were retrieved from normal ovaries (5.1 +/- 3.7) compared with the PCO (10.0 +/- 5.1) or PCOS (11.3 +/- 9.0) groups. Fertilization and cleavage rates were comparable among the three groups. The implantation, pregnancy, and live birth rates per transfer for normal ovaries were 1.5%, 4.0%, and 2.0%, respectively; for PCOs 8.9%, 23.1%, 17.3%, respectively; and for women with PCOS 9.6%, 29.9%, and 14.9%, respectively. CONCLUSION(S): Immature oocytes retrieved from normal ovaries, PCOs, or women with PCOS, when using hCG priming before oocyte retrieval, have a similarly high maturation, fertilization, and cleavage potential. In vitro maturation is a useful treatment option, particularly for women with PCOs.

An intra-articular method for assessing topical application to a synovial joint.

Intra-articular injection of drugs is increasingly used in human medicines. We report a method for the direct administration of a test substance to the synovial fluid of the canine stifle joint. This method caused little distress or pathology, making it suitable for pre-clinical assessment of new drugs in dogs and other species.

Strategies to prevent multiple pregnancies in assisted conception programmes.

All assisted conception techniques are associated with an increase in the multiple pregnancy rate. Iatrogenic multiple births are increasing as the use of these technologies expands. The cornerstone of safe ovulation induction is careful ultrasound monitoring, with cancellation of cycles if excessive ovulation is expected. In in vitro fertilization (IVF) cycles, the main determinant of multiple pregnancy risk is the number of embryos replaced. The current move in IVF clinics is to reduce the risk of multiple pregnancy by reducing the number of embryos transferred. We would suggest a maximum of two embryos transferred to women under, for example, 39 years of age. Women of 39 years or over have a reduced chance of embryo implantation; they should be allowed the transfer of up to three embryos (the UK legal maximum).

Across-channel masking of changes in modulation depth for amplitude- and frequency-modulated signals.

This study examines a form of masking that can take place when the signal and masker are widely separated in frequency and cannot be explained in terms of the traditional concept of the auditory filter or critical band. We refer to this as across-channel masking. The task of the subject was to detect an increment in modulation depth of a 1000-Hz sinusoidal carrier. The carrier could either be sinusoidally amplitude modulated or sinusoidally frequency modulated at a 10-Hz rate. Modulation increment thresholds of this "target" signal were measured for the target alone, and in the presence of two interfering sounds with carrier frequencies of 230 and 3300 Hz. When the interfering sounds were unmodulated, they had no effect on modulation increment thresholds. When the interfering sounds were either amplitude or frequency modulated, thresholds increased. Amplitude modulation (AM) increment thresholds were affected by both amplitude-modulated and frequency-modulated interference. Similarly, frequency modulation (FM) increment thresholds were affected by both amplitude-modulated and frequency-modulated interference. For both types of signal, the interference was tuned for modulation rate; across-channel masking was greatest when the interfering sounds were modulated at rates close to 10 Hz, and declined for higher or lower rates. However, the tuning was rather broad. When the target and interfering sounds were modulated at the same rate, there was no effect of the relative phase of the modulators. Two possible explanations for the results are discussed. One is based on the idea that carriers that are modulated in a similar way tend to be perceptually "grouped". The other is based on the idea that there are "channels" in the auditory system tuned for AM and FM rate. Neither explanation appears completely satisfactory.

Source of circulating levels of inhibin A, pro alpha C-containing inhibins and activin A in early pregnancy.

It is now established that the glycoprotein hormone inhibin is produced by primate granulosa cells, corpus luteum and trophoblast of human placenta. This study was designed to investigate the major source of inhibins and activin A in early pregnancy using a novel panel of assays with high specificity and sensitivity. A total of 12 women (aged 20-35 years) with singleton pregnancy undergoing first trimester (group 1: 6-8; group 2: 8-10; group 3: 10-12 weeks of gestation) termination of pregnancy (TOP) was recruited for the study. Blood samples were taken before TOP, every 15 min for the first hour and hourly for the next 3 h after TOP (total of 4 h of measurements). Circulating concentrations of inhibin A, pro alpha C, activin A, human chorionic gonadotrophin (HCG), oestradiol and progesterone were higher in early pregnancy than at any stage of the menstrual cycle. Peripheral concentrations of inhibin A and activin A were significantly decreased within the first hour in all three groups and gradually decreased to even lower concentrations within the study period. Pro alpha C concentrations decreased within the first hour and then remained unaltered during the next 3 h. Similarly, HCG, oestradiol and progesterone concentrations in circulation decreased substantially within 4 h of TOP. Correlation analyses showed a significant positive correlation (P < 0.001) between inhibin A, activin A, HCG, and oestradiol concentrations throughout the study period. In summary, this study shows that the feto-placental unit is the major source of increased circulating concentrations of inhibin A in early pregnancy. Activin A is produced by the feto-placental unit and the corpus luteum. Pro alpha C-containing inhibins are mainly secreted by the corpus luteum in early pregnancy.

A comparative study of surgical and medical procedures: 932 pregnancy terminations up to 63 days gestation.

The aim of this retrospective study was to compare the efficacy and complications associated with early medical and surgical pregnancy termination. The study population comprised 932 consecutive women undergoing pregnancy termination at gestations of 63 days or less. There were no age or parity differences between the study groups. Medical termination was performed with mifepristone 200 mg orally and misoprostol 800 microgram vaginally; surgical aspiration termination was performed under general anaesthesia. Outcome measures were: surgical curettage for presumed retained products of conception; ongoing pregnancy; and planned and emergency review in the unit. Early medical and surgical termination were associated with a 90.2 and 94.5% complete abortion rate respectively (P = 0.025). The complete abortion rate with medical termination decreased significantly with increasing parity; no such relationship with surgical abortion was found. Women of parity three or more were less likely to have a complete abortion following a medical (83.3%) compared to surgical procedure (97.7%) (P = 0.028). The ongoing pregnancy rate was 0.9% with medical and 0.5% with surgical termination (P = NS). Medical termination was associated with a lower complete abortion rate than surgical termination, particularly for women of higher parity. However, early medical termination allows over 90% of women to avoid the risks of surgical instrumentation of the uterus and anaesthesia.

Morbidity of first trimester aspiration termination and the seniority of the surgeon.

Vacuum aspiration is a safe, acceptable, and efficacious method of first trimester pregnancy termination. The success and complication rates are thought to be partially dependent on operator experience and gestation. We examined this further by studying the outcome of 828 consecutive surgical abortions up to 13 weeks gestation in our hospital. The following outcomes were measured: surgical curettage for presumed retained products of conception; continuing pregnancy; uterine perforation; pelvic sepsis requiring intravenous antibiotics; and blood transfusion required. The complete abortion rate was 94.6% and the rate of continuing pregnancy 0.24%. There was a significant relationship between efficacy and seniority of the surgeon; consultants, senior registrars, registrars, and senior house officers had complete abortion rates of 97.8, 92.8, 94.7, and 88.4% respectively (P = 0.039). Parity did not affect efficacy. Terminations at 12-13 weeks gestation were associated with a significantly lower complete abortion rate. The rates of uterine perforation, blood transfusion, pelvic sepsis requiring intravenous antibiotics, and overnight hospital admission were 0.24, 0, 0.97, and 1.69% respectively. Thus, the only significant factors affecting outcome of surgical abortion are grade of operating surgeon or terminations performed at later gestations of 12-13 weeks. It is vital that physicians performing surgical terminations are adequately trained.

Serum concentrations of dimeric inhibins, activin A, gonadotrophins and ovarian steroids during the menstrual cycle in older women.

The transition from regular ovarian cyclicity to menopause is associated with a rise in the circulating concentrations of follicle stimulating hormone (FSH), despite the maintenance of serum oestradiol concentrations during the perimenopause. The aim of this study was to compare the pattern of secretion of dimeric inhibins, activin A, gonadotrophins and steroids in regularly cycling women of 40-50 years with normal and raised early follicular phase serum FSH concentrations and young women (25-33 years) during the menstrual cycle. Blood samples were taken prospectively almost daily throughout the menstrual cycle. Women recruited were classified into three groups: (i) older women with normal FSH [(ON-FSH), day 3 FSH <8 mIU/ml, n = 10]; (ii) older women with raised FSH [(R-FSH), day 3 FSH >8 mIU/ml, n = 6] and (iii) young normal FSH (YN-FSH) women, age 25-32 years (n = 6). Cyclic patterns of serum inhibins and activin A were similar in the ON-FSH and YN-FSH groups. The R-FSH group had significantly lower concentrations of inhibin A prior to the luteinizing hormone (LH) surge and in the mid-luteal phase and lower concentrations of inhibin B in the early follicular phase compared with the ON-FSH group. Serum concentrations of activin A, progesterone and oestradiol were similar in all three groups. It is concluded from this study that the rise in early follicular phase serum FSH in older women is associated with a decrease in circulating concentrations of inhibin B in the early follicular phase. However, lower circulating concentrations of inhibin A in the luteal phase of the R-FSH group may also contribute to the rise in early follicular phase FSH concentrations during the menstrual cycle, although further studies with larger numbers are required to confirm this observation.

Ongoing twin pregnancy after ICSI of PESA-retrieved spermatozoa into in-vitro matured oocytes: case report.

The recovery of immature oocytes from unstimulated ovaries followed by in-vitro maturation (IVM) is an attractive alternative to conventional IVF in the treatment of female infertility. Similarly, surgical recovery of spermatozoa from the epididymis by percutaneous sperm aspiration (PESA) has simplified the retrieval of the male gamete in treatment of men with obstructive azoospermia. We report the first ongoing clinical twin pregnancy resulting from intracytoplasmic sperm injection (ICSI) of spermatozoa retrieved by PESA into IVM oocytes. In the treatment of a 24-year old woman, 12 immature oocytes were retrieved. Six oocytes matured (maturation rate 50%) after 24-hour incubation and were inseminated by ICSI. Four oocytes had two pronuclei (fertilization rate 67%) and 3 good quality embryos were transferred. A viable twin pregnancy was confirmed by ultrasound scan. This report illustrates the use of a combination of less invasive assisted reproductive techniques in overcoming barriers to infertility.

Immunocytogenetic detection of normal and abnormal oocytes in human fetal ovarian tissue in culture.

This study aimed to: (i) determine whether oocytes are present in cultures of human fetal ovary; (ii) identify whether meiotic anomalies are evident; and (iii) assess whether preparation or culture conditions influence oocyte survival and meiotic progression. Ovaries were collected from fetuses after termination at 13-16 weeks. Oocyte assessment utilized antibodies specific for synaptonemal complex proteins (associated with chromosomes only during meiosis), and antibodies to centromeric proteins. Fragments of tissue were cultured in minimal essential medium + 10% serum +/- follicle stimulating hormone (100 mIU/ml). The sera were fetal calf serum (FCS), FCS for embryonic stem cells (ES-FCS) and human female serum. The numbers and stages of oocytes were assessed after 7-40 days, and particular arrangements of chromosome synapsis identified. Results in fresh tissue included oocytes at leptotene, zygotene, pachytene and diplotene in three of five samples. Four specimens remained viable in vitro, and three had detectable oocytes after culture. The numbers of oocytes and the proportions of zygotene and pachytene cells increased with time in culture. The proportion of degenerate cells in culture was initially higher than in fresh samples, but declined subsequently. More oocytes were detected in ES-FCS and human serum than in FCS. We conclude that human oocytes survive in culture and that progression through prophase I continues.