Bart C.J.M Fauser

Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture

OBJECTIVEnTo evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of two embryos that had been cultured for 3-5 days.nnnDESIGNnProspective study.nnnSETTINGnAn IVF laboratory at a tertiary referral university hospital.nnnPATIENT(S)nOne thousand seven hundred eighty-seven couples who underwent their first IVF cycle between January 1995 and December 1997.nnnINTERVENTION(S)nIn vitro fertilization and transfer of embryos after 3, 4, or 5 days of culture using a single medium without coculture.nnnMAIN OUTCOME MEASURE(S)nImplantation and pregnancy rates.nnnRESULT(S)nOverall implantation and pregnancy rates were not significantly different with different culture periods. Forty-one percent of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, whereas the implantation rate of eight-cell embryos on day 3 was 18%. Implantation rates for retarded, normal, and advanced embryos were not significantly different with an extended culture period.nnnCONCLUSION(S)nUnder the study conditions, the transfer of embryos after 5 days rather than 3 days of embryo culture did not change the overall implantation and pregnancy rates. The implantation potential of embryos available for transfer can be assessed better after an extended culture period. Five days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.

A prediction model for selecting patients undergoing in vitro fertilization for elective single embryo transfer

OBJECTIVEnConstruction of a prediction model to enable the selection of patients for elective single ET.nnnDESIGNnRetrospective cohort study.nnnSETTINGnFertility center in a tertiary referral university hospital.nnnPATIENT(S)nSix hundred forty-two women undergoing their first IVF treatment cycle in which no more than two embryos were transferred.nnnINTERVENTION(S)nDatabase analysis.nnnMAIN OUTCOME MEASURE(S)nOngoing pregnancy and multiple pregnancy.nnnRESULT(S)nIn multivariate analysis, the best predictors for ongoing pregnancy were female age, the number of retrieved oocytes, the developmental stage score and the morphology score of the two best embryos available for transfer, and the day of transfer. Younger age and high quality of transferred embryos were the best predictors for increased risk of multiple pregnancy. The resulting model enables the calculation of probabilities of pregnancy and twin pregnancy. Depending on embryo quality, there is a threshold age under which the chance of singleton pregnancy is higher if one embryo is transferred compared with two embryos.nnnCONCLUSION(S)nApplication of this model may enable a reduction in the chance of twin pregnancy without compromising singleton pregnancy rates in a subgroup of patients undergoing IVF.

Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency

OBJECTIVEnTo predict the FSH response (threshold) dose in normogonadotropic, anovulatory infertile women undergoing gonadotropin induction of ovulation.nnnDESIGNnProspective longitudinal clinical study.nnnSETTINGnSpecialist academic fertility unit.nnnPATIENT(S)nNormogonadotropic, oligoamenorrheic, infertile women who were resistant to clomiphene citrate or in whom clomiphene citrate therapy had failed.nnnINTERVENTION(S)nDaily exogenous FSH administration in a low-dose, step-up regimen.nnnMAIN OUTCOME MEASURE(S)nThe FSH dose on the day of ovarian response (follicle growth > 10 mm in diameter).nnnRESULT(S)nMultivariate analysis was used to devise the following equation to predict the individual FSH response dose (75 to >187 IU/d) before initiation of therapy: [4 body mass index (in kg/m(2))] + [32 clomiphene citrate resistance (yes = 1 or no = 0)] + [7 initial free insulin-like growth factor-I (in ng/mL)] + [6 initial serum FSH level (in IU/L)] - 51. The SE of the predicted dose is 35 IU.nnnCONCLUSION(S)nThe individual FSH response dose for gonadotropin induction of ovulation in anovulatory infertile women can be predicted on the basis of initial screening characteristics. The prediction model developed in this study may increase the safety and efficiency of low-dose gonadotropin protocols (step-up and step-down) by correctly determining the appropriate starting dose for a given patient.

A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the "follicle-stimulating hormone window" combined with the gonadotropin-releasing hormone antagonist cetrorelix.

OBJECTIVEnTo study whether minimal interference in the process of selection of the single dominant follicle may serve as the basis for a simplified ovarian stimulation regimen for IVF.nnnDESIGNnSingle-center randomized pilot study.nnnSETTINGnTertiary referral fertility center.nnnPATIENT(S)nFifteen normo-ovulatory patients with a regular indication for IVF.nnnINTERVENTION(S)nOvarian stimulation for IVF was begun with 100 or 150 IU/d recombinant FSH starting on cycle day 5. From cycle day 8 or later, cotreatment was begun with 0.25 mg/d GnRH antagonist. No luteal support was provided.nnnMAIN OUTCOME MEASURE(S)nTotal number of dominant follicles and characteristics of the endocrine cycle.nnnRESULT(S)nMultiple follicle development occurred in five of eight patients in the 100-IU group and in all seven women in the 150-IU group. Follicular phase and luteal phase lengths were normal, but the endocrine profile was abnormal.nnnCONCLUSION(S)nA fixed daily dose of 150 IU recombinant FSH starting in the midfollicular phase resulted in ongoing growth of a restricted number of dominant follicles and sufficient oocytes retrieved to lead to ET. A marked reduction in the total amount of gonadotropins administered compared with standard treatment was achieved. Withholding luteal support did not exclude pregnancies.

Follicle-stimulating hormone and advanced follicle development in the human.

The great majority of human oocytes is destined to undergo atresia. Only follicles able to respond to stimulation by follicle-stimulating hormone (FSH) will enter the final stage of development and ovulate. While the role of FSH in early follicle development is unclear, late follicular development is FSH-dependent. FSH levels increase during the luteo-follicular transition and give rise to continued growth of a cohort of follicles. In the normo-ovulatory cycle, one follicle achieves a diameter of >8 mm and produces high concentrations of estradiol. In response to negative feedback from rising estradiol and inhibin levels, FSH levels fall in the late follicle phase. The dominant follicle has increased sensitivity to the falling FSH levels and continues growing. Follicles that initiate the latter stages of development after FSH levels begin to fall undergo atresia. The duration of this FSH window during which FSH levels are above the threshold required to stimulate ongoing development determines the number of follicles that can develop to the pre-ovulatory stage. Recognition of this concept has resulted in new approaches in ovulation induction treatment and ovarian hyperstimulation therapy for in vitro fertilization (IVF).

Dynamics of the development of multiple follicles during ovarian stimulation for in vitro fertilization using recombinant follicle-stimulating hormone (Puregon) and various doses of the gonadotropin-releasing hormone antagonist ganirelix (Orgalutran/Antagon)

OBJECTIVEnTo investigate relations between dose of GnRH antagonist and follicular phase characteristics.nnnDESIGNnRandomized controlled multicenter trial.nnnSETTINGnTertiary referral fertility centers.nnnPATIENT(S)nThree hundred and twenty-nine IVF patients.nnnINTERVENTION(S)nOvarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist.nnnMAIN OUTCOME MEASURE(S)nNumber of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations.nnnRESULT(S)nIn 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E(2) levels showed a GnRH antagonist dose-related decrease (P<0.05). Late follicular phase E(2) levels correlated with total follicular surface area, AD, LH, and FSH (all P<0.001). Increasing GnRH antagonist doses exhibited additional suppressive action on E(2) levels.nnnCONCLUSION(S)nFollicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E(2) levels could not be exclusively attributed to suppression of LH.

Gonadotropin-releasing hormone antagonist: new tools vs. old habits

Until recently, the only GnRH analogues available were GnRH agonists. Their range of indications is now well established and includes the suppression of gonadotropin-dependent disorders. The first antagonist analogue is now available in Europe (cetrorelix), and its use is thus far limited to the suppression of the LH surge in ovarian stimulation protocols for assisted reproductive techniques (IVF).

Tibolone and its effects on bone: a review

This review examines the evidence for the effects of tibolone on bone. Tibolone is a synthetic steroid with a mixed (estrogenic–progestogenic–androgenic) hormonal profile. Data suggest a complex receptor-mediated as well as metabolic regulation of the activity of tibolone at target tissue level. It has been shown that tibolone can prevent axial and appendicular bone loss induced by ovariectomy and/or a low calcium diet in young and mature rats. In addition, tibolone increases trabecular and cortical bone mineral density in rats with established osteopenia. In the rat, treatment with tibolone results in an increased strength of the femoral neck and of the vertebral body, similar to that found with estrogens. The protective effect on bone can be blocked by antiestrogens, indicating that the effect is estrogen receptor-mediated. Clinical trials have shown that loss of bone in the spine and proximal hip can be prevented with tibolone 2.5 mg/day in early- and late-postmenopausal women. In addition, a dose of 1.25 mg/day seems also to be effective, especially in late-postmenopausal women. In women with established osteoporosis, bone density of the axial and appendicular skeleton increases with tibolone. In comparative studies, tibolone 2.5 mg/day seems to be as effective as conventional hormone replacement therapy regimens. There are no direct comparative studies between tibolone and bisphosphonates or raloxifene. Furthermore, to establish the efficacy of tibolone for prevention of osteoporotic fractures, studies of the magnitude of reduction in fracture risk remain to be conducted. Finally, tibolone seems to be effective in preserving bone density in patients treated with gonadotropin-releasing hormone agonist.

Pregnancy and Birth After GnRH Agonist Treatment for Induction of Final Oocyte Maturation in a Woman Undergoing Ovarian Stimulation for ICSI, Using a GnRH Antagonist (Orgalutran/Antagon) to Prevent a Premature LH Surge: A Case Report

In the normal menstrual cycle, the endogenous midcycle luteinizing hormone (LH) surge induces resumption of oocyte meiosis and dissociation of the cumulus, which leads to rupture of the follicular wall and ovulation of the oocyte from the Graafian follicle (1). In conventional in vitro fertilization (IVF) programs, gonadotropin-releasing hormone (GnRH) agonists are used for pituitary ‘‘down-regulation’’ to prevent a premature LH surge. Because of its LH-like properties, human chorionic gonadotropin (hCG) is given to induce final oocyte maturation. However, the increased carbohydrate content of hCG in comparison to LH results in a longer circulating half-life and a longer biological effect (2). In contrast to GnRH agonists, GnRH antagonists

Gonadotropin therapy for the treatment of anovulation and for ovarian hyperstimulation for IVF.

Knowledge of the mechanisms of single dominant follicle selection has led to the development of a novel and effective ovulation induction regimen for anovulatory women; the step down protocol. This commences with a fixed high gonadotropin dose followed by several decremental steps. For some patients the initial dose is too high, risking ovarian hyperstimulation syndrome. A major improvement to this approach would, therefore, be the ability to use initial screening characteristics to assess the individual FSH threshold beforehand. For IVF treatment, interfering in the process of single dominant follicle selection in ovulatory women by late follicular phase administration of low doses of FSH may result in a significantly reduced duration of stimulation and amounts of exogenous FSH preparations used. Less monitoring would be required and chances for short-term complications or long term risks may be reduced.