Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter?

STUDY QUESTION: Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles? SUMMARY ANSWER: Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles. WHAT IS ALREADY KNOWN: For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins. STUDY DESIGN, SIZE, DURATION: Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC. PARTICIPANTS/MATERIALS, SETTING, METHODS: EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER). MAIN RESULTS AND THE ROLE OF CHANCE: Mid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13-2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75-1.29). LIMITATIONS, REASONS FOR CAUTION: This was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women. WIDER IMPLICATIONS OF THE FINDINGS: In women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT > 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs. STUDY FUNDING/COMPETING INTEREST(S): The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Netherlands Trial Register, number NTR1449.

A case of loss of heterozygosity in the BRCA2 gene of a borderline ovarian tumor: case report and review of literature.

Germline BRCA1 and BRCA2 mutations highly increase the risk of breast and female adnexal cancer. The role of these genes in the tumorigenesis of other malignancies is still under debate. Borderline ovarian tumors (BOT) are occasionally found in families with a strong history of breast and/or female adnexal cancer with or without proven germline mutations. We investigated whether a BOT arising in a germline BRCA2 mutation carrier could be attributed to this mutation, in which case BOT should be added to the BRCA2 related tumor spectrum. Tumor DNA of a serous borderline ovarian tumor (sBOT) of a 55-year-old female carrier of a pathogenic BRCA2 mutation (6085G>T) was analyzed for loss of heterozygosity (LOH) of BRCA2. The sBOT cells, unexpectedly, revealed loss of the mutant allele of BRCA2, while ovarian stroma cells and peripheral blood lymphocytes contained both wild-type and mutant allele of BRCA2. The finding that no loss of the wild-type BRCA2 allele was found in the tumor tissue but loss of the mutant allele was seen suggests that sBOT are not part of the BRCA2 related tumor spectrum. In the literature BOT's in germline BRCA1 and BRCA2 mutation carriers are described incidentally, while in patients with a BOT a germline BRCA1 or BRCA2 mutation is rarely found. Therefore, we conclude that borderline ovarian tumors are neither part of the BRCA1- nor the BRCA2- related tumor spectrum.

Perspectives in hormone replacement therapy.

Estrogens have been convincingly shown to be highly effective in preventing and reversing menopause-related conditions, such as hot flushes, urogenital complaints, and postmenopausal bone loss. Observational studies report that long-term, estrogen-containing, postmenopausal hormone replacement therapy (HRT) leads to a substantial reduction in hip fractures, myocardial infarction, and possibly colonic cancer, with important consequences for health and quality of life. Estrogen replacement may postpone the onset of Alzheimer's disease and extend life. While many of these effects are biologically plausible, with a variety of cellular mechanisms being involved, only ongoing and future large-scale randomized clinical trials can and should define the effects of HRT more precisely. Long-term compliance is a key issue for long-term benefits, and offering women a choice of administration routes and regimens can only be beneficial in this respect. Pills, patches, gels, and implants are all widely prescribed. Intravaginal or intranasal forms of administration, which are very easy to use and adaptable on an individual level, are among the new options which could improve long-term continuation of HRT use. Fear of breast cancer and recurrence of vaginal bleeding are real concerns for many women considering HRT. This has led to research into lower-dose, estrogen-containing regimens, into continuous combined regimens, and into the potential of estrogen receptor alpha or beta binding molecules that may help to prevent such problems from arising. The prospects for safe and effective postmenopausal HRT with either estrogens or estrogen-like drugs are very promising when these drugs are used in a patient-tailored, risk profile-based manner.

[Lactation-induced amenorrhea as birth control method]. / Lactatieamenorroe als geboorteregelingsmethode.

Improving access to quality care in family planning, a recent document of the World Health Organization, reviews the epidemiological and clinical evidence relevant to medical eligibility of well established contraceptive methods. Breastfeeding is widely regarded as unreliable for individual contraception. The document, however, argues that the lactational amenorrhoea method (LAM) is a safe and effective family planning method. Worldwide, LAM is the most important way of fertility regulation and its efficacy is confirmed in many studies, with a 2% risk of pregnancy in the first six months after birth. Taking into account certain well defined conditions (frequent feedings, no supplementary feeding before 4-6 months, method only to be used in the absence of menstruation), LAM can be relied on for contraceptive protection for up to 1 year post partum.

PIP: In 1966 WHO published a document on improving access to quality care in family planning, which who pronounced to be a fundamental human right. According to this document, despite the assortment of reliable contraceptives worldwide 350 million people have unmet need for contraception because of lack of access or availability. Adequate reproductive health depends not only access to contraceptives, but also on adequate screening and treatment of anemia, sexually transmitted diseases, and cervical carcinoma. Among 8 groups of birth control methods studied, the lactational amenorrhea method (LAM) was dealt with in detail. The underlying mechanism lies in the stimulation that breastfeeding brings about and in breastfeeding's suppression of the release of gonadotropin- releasing hormone and of dopamine (the prolactin inhibiting factor). A 1974 investigation in Rwanda demonstrated that 50% of rural women who breast fed their children frequently got pregnant within 23 months of childbirth and that 50% of city women became pregnant 9 months postpartum. The Bellagio consensus has stated that LAM provides 98% protection against pregnancy in the first 6 months postpartum as long as breast feeding is the exclusive feeding method practiced. A 1992 analysis of 9 prospective studies reported that 6 months postpartum only 0.7% of the women using LAM became pregnant. LAM still plays a crucial role in Africa, where the average number of children per woman is 6. Without breastfeeding the estimated figure would be 10.