Predicting menopausal age with anti-Müllerian hormone: A cross-validation study of two existing models

Objective This study aimed to cross-validate two comparable Weibull models of prediction of age at natural menopause from two cohorts, the Scheffer, van Rooij, de Vet (SRV) cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. It summarizes advantages and disadvantages of the models and underlines the need for achieving correct time dependency in dynamic variables like anti-Müllerian hormone. Methods Models were fitted in the original datasets and then applied to the cross-validation datasets. The discriminatory capacity of each model was assessed by calculating C-statistics for the models in their own data and in the cross-validation data. Calibration of the models on the cross-validation data was assessed by measuring the slope, intercept and Weibull shape parameter. Results The C-statistic for the SRV model on the SRV data was 0.7 (95% confidence interval (CI) 0.7-0.8) and on the TLGS data it was 0.8 (95% CI 0.8-0.9). For the TLGS model on the TLGS data, it was 0.9 (95% CI 0.8-0.9) and on the SRV data it was 0.7 (95% CI 0.6-0.8). After calibration of the SRV model on the TLGS data, the slope was 1, the intercept -0.3 and the shape parameter 1.1. The TLGS model on the SRV data had a slope of 0.3, an intercept of 12.7 and a shape parameter of 0.6. Conclusions Both models discriminate well between women that enter menopause early or late during follow-up. While the SRV model showed good agreement between the predicted risk of entering menopause and the observed proportion of women who entered menopause during follow-up (calibration) in the cross-validation dataset, the TLGS model showed poor calibration. © 2014 International Menopause Society

Follicle development during the normal menstrual cycle

An understanding of the factors which determine initiation of follicle growth, recruitment and dominant follicle selection may increase our understanding of the underlying process of ovarian aging. In this article, these aspects of the normal menstrual cycle are reviewed. The morphological and endocrinological development in the early follicle is described from the primordial follicle stage. The degree of follicle-stimulating hormone (FSH) dependency is discussed, as is the relationship of estradiol (E2) production to follicle diameter. The principles governing mono-follicular selection are outlined, and the FSH 'threshold' and 'window' concepts are highlighted. Maximum FSH levels in the early follicular phase are shown to be variable between individuals. The relevance of this and the means by which individual sensitivity to FSH may be altered at the ovary in the context of ovarian aging are discussed

Impact of ovarian hyperstimulation on the luteal phase

The contemporary approach to ovarian stimulation in IVF treatment results in supraphysiological concentrations of progesterone and oestrogen in the luteal phase. These sex steroids act directly and indirectly to mature the endometrium, thus influencing its receptivity to implantation. The development of endometrial receptivity is a complex process that may be altered by inappropriate exposure to sex steroids. Alterations in the oestrogen to progesterone ratio, growth factor concentrations and cell adhesion molecule profiles may occur after ovarian stimulation, potentially affecting the receptivity of the endometrium. Recent clinical IVF studies have shown that implantation rates and corpus luteum function are influenced by oestrogen concentrations during the early luteal phase. Few comparative studies have been performed, but after ovarian stimulation there is a reduced implantation rate and a higher pregnancy loss rate before pregnancies can be detected clinically compared with natural cycle conceptions. Novel approaches to ovarian stimulation aimed at achieving a more physiological luteal phase endocrinology are now being developed. Data from a recent pilot study by our laboratory, involving minimal ovarian hyperstimulation and no luteal phase support, are discussed

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

Objective: To 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. Design: Single-center randomized pilot study. Setting: Tertiary referral fertility center. Patient(s): Fifteen normo-ovulatory patients with a regular indication for IVF. Intervention(s): Ovarian 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. Main Outcome Measure(s): Total number of dominant follicles and characteristics of the endocrine cycle. Result(s): Multiple 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. Conclusion(s): A 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

Gonadotrophin-releasing hormone antagonists: application in ovary-stimulating and sex-steroid dependent disorders

The hypothalamic gonadotrophin-releasing hormone (GnRH) stimulates synthesis and secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the gonadotrophic cells of the pituitary. The mechanisms of action of GnRH antagonists and of agonists is completely different. Due tot competitive blockage of GnRH receptors by antagonist administration, LH (and to a lesser extent FSH) levels drop rapidly. Moreover pituitary function normalizes immediately following cessation of medication. The direct and rapid action of GnRH antagonists, the dose dependent suppression of LH and FSH and the rapid restoration of hypophyseal function after cessation of the use of antagonists may shorten and simplify in-vitro fertilization, with less chance of side effects or complications. Further studies are required to decide whether antagonists can usefully be applied for other gynecological indications such as the polycystic ovary syndrome. The possibilities of profitable long term treatment will increase considerably if it proves possible to develop a sustained action formulation

Pregnancy at a later age with the help of oocyte donation

An increasing number of women are delaying childbirth until an age when their fertility has significantly declined. Oocyte donation provides the opportunity for women to successfully conceive regardless of age. In The Netherlands, in 1997 the age limit for oocyte donation treatment was set at 45 years. The most important objections to pregnancy in older women are the medical risks for mother and child, the application of fertility treatments beyond the natural reproductive age and the psychosocial consequences for the child. However, based on international experience and recent data concerning the risks of pregnancy after oocyte donation in older women, it is proposed to increase the maximum age limit for this procedure to 50 years

FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility

The patient group with the best step-down profile for ovulation induction exhibited the closest match between the clinically applied and calculated starting dose of gonadotropins. Therefore, this study provides support for the concept that the individual effective FSH starting dose for gonadotropin induction of ovulation in anovulatory infertile patients can be predicted on the basis of initial screening characteristics, such as body mass index, clomiphene resistance or failure, free IGF-I and FSH. This may result in more effective patient treatment protocols, reduced complication rates and health-economic benefits

High dose gonadotrophin-releasing hormone antagonist (ganirelix) may prevent ovarian hyperstimulation syndrome caused by ovarian stimulation for in-vitro fertilization

This case report describes the first attempt to treat imminent ovarian hyperstimulation syndrome (OHSS) by using a gonadotrophin-releasing hormone (GnRH) antagonist. A 33 year old, normo-ovulatory woman undergoing in-vitro fertilization received daily subcutaneous injections of 150 IU of recombinant follicle-stimulating hormone (recFSH) from cycle day 2, together with GnRH antagonist (ganirelix) 0.125 mg from cycle day 7 onwards. On cycle day 10 the patient was found to have a serum oestradiol concentration of 16 500 pmol/l and, on ultrasound examination, four preovulatory (>16 mm) and nine intermediate sized (10-16 mm) follicles. RecFSH injections were discontinued, human chorionic gonadotrophin (HCG) withheld, whereas the ganirelix dose was increased to 2 mg/d. This regimen led to a rapid decrease in serum oestradiol concentrations and the decrease in ovarian size on ultrasound. Since GnRH antagonists will become clinically available for in-vitro fertilization programmes in the near future this suggested regimen might have a role in preventing severe OHSS