Anders Nyboe Andersen

Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue

BACKGROUND Cryopreservation of the ovarian cortex with subsequent autotransplantation has, on an experimental basis, been performed to preserve fertility in women being treated for a malignant disease. The present study reports ovarian activity and pregnancies following autotransplantation of frozen/thawed ovarian tissue. METHODS One complete ovary was cryopreserved from each of six patients who were 26-35 years old prior to treatment. Tissue from three of the patients was transported 4-5 h on ice prior to cryopreservation. After a period of 17-32 months, orthotopic autotransplantation was performed replacing 20-60% of the tissue. Two patients received additional heterotopic transplants. RESULTS In all cases, the tissue restored menstrual cyclicity 14-20 weeks following transplantation. Four of the six women conceived following assisted reproduction: two women (who had the tissue transported 4-5 h prior to cryopreservation) each, based on the orthotopic transplanted tissue, delivered one healthy child (February 2007 and January 2008); one woman miscarriaged in gestational Week 7; and the other had a positive hCG test but no clinical pregnancy. The remaining two women did not become pregnant. CONCLUSIONS Two additional healthy children have been born as a result of the ovarian cryopreservation procedure. In both cases, the ovarian tissue was transported 4-5 h prior to freezing demonstrating that hospitals may offer cryopreservation without having the necessary expertise locally.

Infant outcome of 957 singletons born after frozen embryo replacement: The Danish National Cohort Study 1995–2006

OBJECTIVE To examine infant outcome of singletons born after cryopreservation of embryos (Cryo). DESIGN National population-based controlled follow-up study. SETTING Denmark, 1995-2007. PATIENT(S) The study population was 957 Cryo singletons (Cryo-IVF, n=660; Cryo-ICSI, n=244; Cryo-IVF/-ICSI, n=53). The first control group was all singletons born after fresh IVF or intracytoplasmic sperm injection (ICSI) during the same period (IVF, n=6904; ICSI, n=3425). The second control group comprised a random sample of non-assisted reproductive technology (ART) singletons (n=4800). INTERVENTION(S) All observations were obtained from national registers. MAIN OUTCOME MEASURE(S) Low birth weight (LBW; <2500 g), preterm birth (PTB; <37 weeks), congenital malformations, mortality, and morbidity. RESULT(S) Birth weight was higher in Cryo (mean=3578 g, SD=625) versus fresh (mean=3373 g, SD=648) and in Cryo versus non-ART (mean=3537 g, SD=572), and this was also the case for first birth only. Lower adjusted risk of LBW (odds ratio [OR]=0.63; 95% confidence interval [CI], 0.45-0.87) and PTB (OR=0.70; 95% CI, 0.53-0.92) was observed in Cryo versus fresh. Similar LBW and PTB rates were observed when comparing Cryo with non-ART, but the perinatal mortality rate was doubled in Cryo (1.6%) compared with non-ART (0.8%) singletons, and the adjusted risks of very preterm birth (<34 weeks) and neonatal admittance were also significantly increased. No significant differences in the prevalence rates of birth defects, neurological sequelae, malignancies, and imprinting-related diseases were observed between the Cryo and the two control groups. However higher malformation and cerebral palsy rates were observed in the total Fresh vs. non-ART group. CONCLUSION(S) Cryo singletons have better neonatal outcome than offspring after fresh ET but poorer compared with non-ART singletons.

Infertility, fertility drugs, and invasive ovarian cancer : a case-control study

OBJECTIVE To assess the risk of invasive ovarian cancer among infertile women treated with fertility drugs. DESIGN A case-control study. SETTING Nationwide data based on public registers. PATIENT(S) All Danish women (below the age of 60 years) with ovarian cancer during the period from 1989 to 1994 and twice the number of age-matched population controls. Included in the analysis were 684 cases and 1,721 controls. MAIN OUTCOME MEASURE(S) Influence of parity, infertility, and fertility drugs on the risk of ovarian cancer after multivariate confounder control. Risk measure(s): odds ratios (OR) with 95% confidence intervals. RESULT(S) Nulliparous women had an increased risk of ovarian cancer compared with parous women: OR 1.5 to 2.0. Infertile, nontreated nulliparous women had an OR of 2.7 (1.3 to 5.5) compared with noninfertile nulliparous women. The OR of ovarian cancer among treated nulliparous women was 0.8 (0.4 to 2.0) and among treated parous 0.6 (0.2 to 1.3), compared with nontreated nulliparous and parous infertile women, respectively. CONCLUSION(S) Nulliparity implies a 1.5- to 2-fold increased risk of ovarian cancer. Infertility without medical treatment among these women increased the risk further. Among parous as well as nulliparous women, treatment with fertility drugs did not increase the ovarian cancer risk compared with nontreated infertile women.

Neonatal outcome in a Danish national cohort of 8602 children born after in vitro fertilization or intracytoplasmic sperm injection: the role of twin pregnancy.

Background.  In Denmark, 4% of all infants are born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and 40% of these children are twins.

Radiotherapy at a young age reduces uterine volume of childhood cancer survivors

Background.  In contrast to chemotherapy, previous irradiation of the uterus carries an increased risk of an adverse pregnancy outcome. Conflicting results exist as regards the ability of the uterus to increase in volume following radiotherapy‐induced damage. We measured uterine volume in a cohort of childhood cancer survivors, and assessed uterine response to a high‐dose estrogen replacement regimen.

Mild ovarian stimulation for IVF: 10 years later

Ovarian stimulation to achieve multiple follicle development has been an integral part of IVF treatment. In the context of improved laboratory performance, the need for a large number of oocytes as an integral part of a successful IVF programme may be questioned. The aim of the current debate is to summarize the studies performed during the last decade to develop the concept of mild stimulation aiming to obtain fewer than eight oocytes. Here we examine the balance between IVF success and patient discomfort, and complications and cost, and how these might improve by simpler ovarian stimulation protocols aimed at retrieving fewer oocytes. We intend to analyse why progress has been rather slow and why there is much resistance to mild stimulation. Finally, presumed useful directions for future research will be discussed.

Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients

OBJECTIVE To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol. DESIGN Secondary analysis of data prospectively collected in a randomized, assessor-blind trial comparing two different gonadotropin preparations with respect to ongoing pregnancy rate. SETTING Twenty-five centers in seven countries. PATIENT(S) 749 women, aged 21 to 34 years, with primary diagnosis of infertility being unexplained infertility or mild male factor infertility and with serum follicle-stimulating hormone (FSH) level 1-12 IU/L and antral follicle count (AFC) ≥10. INTERVENTION(S) Controlled ovarian stimulation with highly purified human menopausal gonadotropin (hphMG) or recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer and potential subsequent 1-year cryopreserved blastocyst replacement in natural cycles. MAIN OUTCOME MEASURE(S) Relationships between AMH at start of stimulation and ovarian response and treatment outcome. RESULT(S) Serum AMH concentration was strongly correlated with oocyte yield: AMH accounted for 85%, FSH for 14%, and inhibin B and AFC for <1% each of the explained variation in oocyte yield. Also, AMH showed a high accuracy for the prediction of poor (≤3 oocytes) and high response (≥15 oocytes), which was statistically significantly better than basal FSH, AFC, or inhibin B. AMH was statistically significantly positively associated with ongoing pregnancy rate in the fresh cycle as well as with the 1-year cumulative ongoing pregnancy and live-birth rates. CONCLUSION(S) There is a positive relationship between AMH and oocyte yield in GnRH antagonist cycles, and AMH is the best predictor for identifying patients with poor and high ovarian response. The positive association between AMH and cumulative live-birth rates after fresh and cryopreserved cycles reflects the availability of more oocytes/blastocysts, not higher quality. CLINICAL TRIAL REGISTRATION NUMBER NCT00884221.

Dynamics and mechanisms of chemotherapy-induced ovarian follicular depletion in women of fertile age

OBJECTIVE To study ovarian follicular dynamics during chemotherapy to understand the mechanisms behind chemotherapy-induced ovarian follicular depletion and to evaluate whether pretreatment levels of ovarian reserve markers were predictive of the posttreatment levels. DESIGN Prospective clinical study. SETTING University hospital fertility center. PATIENT(S) Seventeen women (median age 30 years; range 19-35 years) undergoing chemotherapy. INTERVENTION(S) Patients were seen before, frequently during, and after chemotherapy, until 1 year after the end of treatment. Antral follicle count and levels of FSH, LH, E(2), anti-Müllerian hormone (AMH), and inhibin A and B were monitored at each visit. MAIN OUTCOME MEASURE(S) The dynamics of the ovarian reserve markers during chemotherapy and factors predictive of posttreatment ovarian function. RESULT(S) Anti-Müllerian hormone level (mean +/- 2 SEM) dropped from 2.7 +/- 1.0 to 1.1 +/- 0.6 and to 0.4 +/- 0.4 ng/mL immediately after one and two series of chemotherapy, respectively. Inhibin B and antral follicle count decreased after three series whereas FSH reached menopausal levels after four series. High pretreatment AMH levels predicted higher posttreatment AMH levels. CONCLUSION(S) Anti-Müllerian hormone and inhibin B levels immediately declined in response to chemotherapy, and the follicular target of chemotherapy appeared to be growing follicles. High pretreatment AMH levels were predictive of a higher posttreatment AMH level.

Orthotopic autotransplantation of cryopreserved ovarian tissue to a woman cured of cancer–follicular growth, steroid production and oocyte retrieval

Cryopreservation of human ovarian tissue is now an option for cancer patients facing treatment with gonadotoxic regimes, as a means of preserving their fertility. So far, there have been only a few reports on autotransplantation of frozen-thawed tissue with regard to restoration of ovarian function. The present report describes a 32-year-old woman diagnosed with Hodgkins lymphoma, who had cryopreserved ovarian tissue transplanted orthotopically after secondary ovarian failure due to chemotherapy. Only 8 weeks after transplantation, ultrasonography of the remaining ovary revealed two follicles with diameters of 10 and 15 mm. Concomitantly, circulating concentrations of oestradiol increased, while concentrations of gonadotrophins decreased. In the following months, the patient menstruated three times. Subsequent pituitary down-regulation with a gonadotrophin-releasing hormone (GnRH) agonist and ovarian stimulation resulted in development of one pre-ovulatory follicle from which a metaphase II oocyte was retrieved; however, this oocyte was unable to sustain further development after intracytoplasmic sperm injection (ICSI). Intrafollicular concentrations of oestradiol and progesterone suggested a normal luteinizing response of the follicle to human chorionic gonadotrophin stimulation. A 7-month follow-up revealed continued vivid follicular activity and normal oestradiol concentrations. In conclusion, cryopreserved human ovarian tissue restored ovarian function for several cycles and sustained development of mature oocytes in a woman cured of cancer.

Trends in the use of intracytoplasmatic sperm injection marked variability between countries

BACKGROUND ICSI is used increasingly often compared with standard IVF. The aim of the present study was to analyse the changes in the use of ICSI, and discuss possible causes and consequences. METHODS Data from National and Regional registers were analysed for trends in the use of ICSI and indications for assisted reproductive technology (ART). RESULTS The use of ICSI increased from 39.6% of ART cycles in 1997 to 58.9% in 2004 (USA 57.5%, Australia/New Zealand 58.6%, Europe 59.3%). The Nordic countries, the Netherlands and the UK used ICSI to a low extent (40.0-44.3%), whereas Austria, Belgium and Germany (68.5-72.9%) and the southern European countries like Greece, Italy and Spain used ICSI frequently (66.0-81.2%). The marked increase in the proportion of ICSI cycles seems primarily due to an increased use in couples classified as having mixed causes of infertility, unexplained infertility and advanced age together with a relative decline in tubal factor infertility. An absolute increase in the prevalence of couples with impairment in semen quality remains a possibility. CONCLUSIONS ICSI is used increasingly, but huge differences exist between countries within Europe. It is not possible to determine specific factors that explain the differences. As ICSI does not give higher pregnancy rates than IVF in couples without male factors, and as it adds additional costs, infertile couples and society may benefit from a less frequent use of ICSI in some countries.