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Study Question: What is the clinical value of anti-Müllerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment?, Summary Answer: AMH as a single test has substantial accuracy for ovarian response prediction in GnRH antagonist treatment for IVF, with a higher accuracy for predicting a high response than for low response., What Is Known Already: The role of AMH and other patient characteristics in ovarian response prediction has been studied extensively in long GnRH agonist protocols; however, little information is available regarding the clinical value in GnRH antagonists., Study Design, Size, Duration: This is an observational (retrospective) substudy as part of an ongoing cohort study. A total of 487 patients scheduled for IVF/ICSI between 2006 and 2011 were included in the study., Participants/materials, Setting, Methods: Patients with a regular cycle who underwent their first IVF/ICSI cycle with GnRH antagonist treatment while receiving a starting dose of 150 or 225 IU recombinant FSH were included in the study. Patients were divided into three subgroups according to the following ovarian response categories: high (>15 oocytes or cycle cancellation), normal (4-15 oocytes) and low (<4 oocytes or cycle cancellation). Serum samples collected prior to IVF treatment were used to determine serum AMH levels., Main Results and the Role of Chance: According to the predefined ovarian response categories, 58 patients were classified as high, 326 as normal and 101 as low responders, and the ongoing pregnancy rates did not differ among groups (19.0, 22.1 and 16.8%, respectively, P = 0.9). For the prediction of high response, AMH had an area under the receiver-operating characteristic curve (AUC) of 0.87. Both female age and BMI had lower accuracy (AUC 0.66 and 0.58, respectively). For low response prediction, again AMH had a better accuracy (AUC 0.79) than female age and BMI (AUC 0.59 and 0.56, respectively). In a multivariate model, including the factors age, AMH, BMI, smoking, type and duration of subfertility, only BMI added some predictive value to AMH for both high and low response prediction. Clinical test characteristics demonstrated that using a specificity of ∼90%, the detection rate of AMH for high and low response, corresponding with a test cut-off of 4.5 and 0.8 µg/l, was ∼60 and ∼45%, respectively., Limitations, Reasons for Caution: The impact of the antral follicle count (AFC) on ovarian response prediction in GnRH antagonists was not assessed; however, previously studies demonstrated that for GnRH antagonists, AMH has a better accuracy than AFC., Wider Implications of the Findings: The current study demonstrates that AMH is an adequate predictor for both high and low response in GnRH antagonist cycles, showing a similar accuracy to GnRH agonists, as reported previously. The optimization and individualization of GnRH antagonist protocols may be improved by using an AMH-tailored approach., Study Funding/competing Interests: This study was funded by the Academic Institutional Resources of the Department of Reproductive Medicine of the UMC Utrecht. O.H., M.J.C.E, E.W.G.L and H.L.T. have nothing to declare. N.S.M. has received fees and/or grant support from the following companies (in alphabetic order): Anecova, Ferring, Informa, Merck Serono and MSD. B.C.J.M.F. has received fees and/or grant support from the following companies (in alphabetic order); Childhealth, CVON, Ferring, Ova-Science, PregLem, Roche and Watson laboratories. F.J.B. has received fees and/or grant support from the following companies (in alphabetic order); Merck Serono and MSD., Trial Registration Number: www.clinicaltrials.gov, Protocol ID 13-109., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In contrast to current approaches, the aim of mild stimulation is to develop safer and more patient-friendly protocols in which the risks of the treatment as a whole are minimized. Mild stimulation is defined as the method when exogenous gonadotropins are administered at lower doses, and/or for a shorter duration in GnRH antagonist co-treated cycles, or when oral compounds (antiestrogens, aromatase inhibitors) are used for ovarian stimulation for IVF, with the aim of limiting the number of oocytes obtained to fewer than eight. In this chapter we discuss the relevant physiology of follicle development, the development of milder stimulation protocols, the implications of mild stimulation, the current state of affairs, and future developments.

Study Question: What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)?, Summary Answer: Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation., What Is Known Already: During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes., Study Design, Size, Duration: This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included., Participants/materials, Setting, Methods: Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6., Main Results and the Role of Chance: There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6)., Limitations, Reasons for Caution: The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice., Wider Implications of the Findings: The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs., Study Funding/competing Interest(s): This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono., Trial Registration Number: www.clinicaltrials.gov, no. NCT00866034.

Background: Corifollitropin alfa, a fusion protein lacking LH activity, has a longer elimination half-life and extended time to peak levels than recombinant FSH (rFSH). A single injection of corifollitropin alfa may replace seven daily gonadotrophin injections during the first week of ovarian stimulation., Methods: In this large, double-blind, randomized, non-inferiority trial the ongoing pregnancy rates were assessed after one injection of 150 microg corifollitropin alfa during the first week of stimulation and compared with daily injections of 200 IU rFSH using a standard GnRH antagonist protocol., Results: The study population comprised 1506 treated patients with mean age of 31.5 years and body weight of 68.6 kg. Ongoing pregnancy rates of 38.9% for the corifollitropin alfa group and 38.1% for rFSH were achieved, with an estimated non-significant difference of 0.9% [95% confidence interval (CI): -3.9; 5.7] in favor of corifollitropin alfa. Stratified analyses of pregnancy rates confirmed robustness of this primary outcome by showing similar results regardless of IVF or ICSI, or number of embryos transferred. A slightly higher follicular response with corifollitropin alfa resulted in a higher number of cumulus-oocyte-complexes compared with rFSH [estimated difference 1.2 (95% CI: 0.5; 1.9)], whereas median duration of stimulation was equal (9 days) and incidence of (moderate/severe) ovarian hyperstimulation syndrome was the same (4.1 and 2.7%, respectively P = 0.15)., Conclusion: Corifollitropin alfa is a novel and effective treatment option for potential normal responder patients undergoing ovarian stimulation with GnRH antagonist co-treatment for IVF resulting in a high ongoing pregnancy rate, equal to that achieved with daily rFSH. The trial was registered under ClinicalTrials.gov identifier NTC00696800.

Background: Polycystic ovary syndrome (PCOS) is a complex genetic disorder. Multiple functional polymorphisms have been identified in genes that regulate the hypothalamic-pituitary-gonadal (HPG) axis that regulates ovarian function. The present study aims to examine the influence of genetic variants of the HPG-axis on the severity of clinical features of PCOS and disease susceptibility., Methods: We included 518 Caucasian PCOS women and 2996 unselected controls from the general population (the Rotterdam study). Genotype distributions were compared between patients and controls. Subsequently, associations with clinical features of PCOS were studied. Single nucleotide polymorphisms were selected in GnRH (Trp16Ser [rs6185]), the FSH-receptor (FSHR, Ala307Thr [rs6165] and Asn680Ser [rs6166]) and the LH-receptor (18insLQ, Asn291Ser [rs12470652] and Ser312Asn [rs2293275])., Results: FSHR Ser(680) was associated with higher levels of gonadotrophic hormones (FSH: P < 0.01, LH: P = 0.01), and testosterone (P = 0.05) and a higher frequency of hyperandrogenism (P = 0.04). No differences in risk for PCOS in association with the FSH-receptor variants were observed., Conclusion: Genetic variants of the HPG-axis were associated with a modest but significant effect on the phenotype of PCOS. FSHR variants were strongly associated with the severity of clinical features of PCOS, such as levels of gonadotrophic hormones and the presence of hyperandrogenism, but not disease risk.

IVF is performed with oocytes collected in natural and stimulated cycles. Different approaches to ovarian stimulation have been employed worldwide. Following the introduction of GnRH antagonists and strategies to reduce multiple births such as single embryo transfer, there is a genuine scientific interest in the revival of natural cycle and mild approaches to ovarian stimulation in IVF. Recent evidence suggests that application of natural and mild IVF is patient-centred, aimed at reducing the cost of treatment, patient discomfort and multiple pregnancies. However, there seems to be no consistency in the terminology used for definitions and protocols for ovarian stimulation in IVF cycles. Following the recent International Society for Mild Approaches in Assisted Reproduction (ISMAAR) meeting and communication with interested international experts, this article has recommended revised definitions and terminology for natural cycle IVF and different protocols used in ovarian stimulation for IVF. It is proposed that these terms are adopted internationally in order to achieve a consistency in clinical practice, research publications and communication with patients.

The present review describes, on the basis of the currently available evidence, the consensus reached by a group of experts on the use of gonadotropin-releasing hormone (GnRH) antagonists in ovarian stimulation for IVF. The single or multiple low-dose administration of GnRH antagonist during the late-follicular phase effectively prevents a premature rise in serum luteinizing hormone (LH) levels in most women. Although controversy remains, most comparative studies suggest a slight, not significant reduction in the probability of pregnancy after IVF using GnRH antagonist versus GnRH agonist co-treatment. Published meta-analyses suggest that this slight difference in pregnancy rates is not attributed to chance. Further studies applying varying treatment regimens and outcome measures are required. Data are not in favour of a need to modify the starting dose of gonadotropins. Data are not in favour of increasing gonadotropin dose at GnRH antagonist initiation. The addition of LH from the initiation of ovarian stimulation or from GnRH antagonist administration does not appear to be necessary. Replacement of human chorionic gonadotropin (HCG) by GnRH agonist for triggering final oocyte maturation is associated with a lower probability of pregnancy. The optimal timing for HCG administration needs to be explored further. GnRH antagonist initiation on day 6 of stimulation appears to be superior to flexible initiation by a follicle of 14-16 mm, although earlier GnRH antagonist administration is worth further evaluation. Luteal phase supplementation in GnRH antagonist protocols remains mandatory in IVF. Effects of GnRH antagonist co-treatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a trend is present in favour of the GnRH antagonists. The role of GnRH antagonists in ovarian stimulation for IVF appears to be promising, although many questions regarding preferred dose regimens and effects on clinical outcomes remain.

Elevated LH concentration is a common feature in polycystic ovary syndrome (PCOS). This study was designed to establish whether elevated LH levels in PCOS might be suppressed to normal range values by the administration of different low doses of GnRH antagonist, which subsequently might reverse the anovulatory status of these patients. Twenty-four PCOS patients with elevated endogenous LH concentrations were randomized into 3 different dose groups, receiving either 0.125 mg (Group A), 0.250 mg (Group B) or 0.500 mg (Group C) ganirelix sc daily for 7 subsequent days. During the first day of treatment, LH and FSH levels were assessed at 20 min intervals, during 8 h. Thereafter LH, FSH, androgens, estradiol (E2) and inhibins were assessed daily and frequent ultrasound scans were performed for 7 days to record follicle development. Repeated GnRH antagonist administration induced a significant suppression of LH (and to a lesser extent of FSH) serum levels, which was comparable between the different doses. Six hours after ganirelix administration, endogenous LH was suppressed by 49, 69 and 75%, and endogenous FSH was suppressed by 23, 19 and 25%, respectively. The decrease in serum LH and FSH levels was transient and lasted for 12 h, after which serum levels returned to baseline levels at 24 h after drug administration. Androgen levels were not significantly suppressed using this regimen. E2 levels decreased significantly (p < 0.001) and suppression was most pronounced in Group C. Spontaneous follicle development or ovulations were not recorded during the course of treatment. In conclusion, the present study demonstrates that the GnRH antagonist ganirelix is capable of normalising elevated LH levels in PCOS patients, in doses similar to the ones previously shown to prevent a premature LH rise during ovarian hyperstimulation for in vitro fertilization (IVF). In addition, the transient suppression of elevated endogenous LH levels per se does not re-establish normal follicle development in PCOS. However, follicle development may be insufficiently supported by the accompanied subtle suppression of endogenous FSH. Similarly, a transient decline in E2 levels does not effectively restore normal pituitary ovarian feedback. Moreover, these results support the contention of a limited role of LH in the pathogenesis of PCOS.

In a randomized multicenter study, the efficacies of two different GnRH agonists were compared with that of hCG for triggering final stages of oocyte maturation after ovarian hyperstimulation for in vitro fertilization. Ovarian stimulation was conducted by recombinant FSH (Puregon), and the GnRH antagonist ganirelix (Orgalutran) was coadministered for the prevention of a premature LH rise. Luteal support was provided by daily progestin administration. Frequent blood sampling was performed at midcycle in the first 47 eligible subjects included in the current study, who were randomized for a single dose of 0.2 mg triptorelin (n = 17), 0.5 mg leuprorelin (n = 15), or 10,000 IU hCG (n = 15). Serum concentrations of LH, FSH, E2, and progesterone (P) were assessed at variable intervals. LH peaked at 4 h after both triptorelin and leuprorelin administration, with median LH levels of 130 and 107 IU/liter (P < 0.001), respectively. LH levels returned to baseline after 24 h. Subjects receiving hCG showed peak levels of 240 IU/liter hCG 24 h after administration. A rise in FSH to 19 IU/liter (P < 0.001) was noted in both GnRH agonist groups 8 h after injection. Within 24 h the areas under the curve for LH and FSH were significantly higher (P < 0.001) in both GnRH agonist groups compared with that for hCG. E2 and P levels were similar for all groups up to the day of oocyte retrieval. Luteal phase areas under the curve for P and E2 were significantly elevated (P < 0.001) in the hCG group. The mean (+/-SD) numbers of oocytes retrieved were 9.8 +/- 5.4, 8.7 +/- 4.5, and 8.3 +/- 3.3; the percentages of metaphase II oocytes were 72%, 85%, and 86%; and fertilization rates were 61%, 62%, and 56% in the triptorelin, leuprorelin, and hCG group, respectively (P = NS for all three comparisons). These findings support the effective induction of final oocyte maturation in both GnRH agonist groups. In summary, after treatment with the GnRH antagonist ganirelix for the prevention of premature LH surges, triggering of final stages of oocyte maturation can be induced effectively by a single bolus injection of GnRH agonist, as demonstrated by the induced endogenous LH and FSH surge and the quality and fertilization rate of recovered oocytes. Moreover, corpus luteum formation is induced by GnRH agonists with luteal phase steroid levels closer to the physiological range compared with hCG. This more physiological approach for inducing oocyte maturation may represent a successful and safer alternative for in vitro fertilization patients undergoing ovarian hyperstimulation.

The contemporary approach to ovarian stimulation for IVF treatment results in supraphysiological concentrations of steroids during the follicular and luteal phases of the menstrual cycle. These sex steroids act directly and indirectly to mature the endometrium, influencing receptivity for implantation. Corpus luteum function is distinctly abnormal in IVF cycles, and therefore luteal support is widely used. Various reasons may underlie the defective luteal phase, including (i) ovarian hyperstimulation per se, (ii) gonadotrophin-releasing hormone (GnRH) analogue co-treatment and (iii) the use of human chorionic gonadotrophin (HCG) to induce final oocyte maturation. The recent introduction of GnRH antagonist co-treatment for the prevention of a premature LH rise during the late follicular phase allows for different approaches to ovarian stimulation for IVF. However, a recent meta-analysis showed that implantation rates may be compromised by using GnRH antagonists in currently employed regimens. The development of endometrium receptive to embryo implantation is a complex process and may be altered by inappropriate exposure to sex steroids in terms of timing, duration and magnitude. New approaches to the assessment of endometrial receptivity are now required. Novel approaches to ovarian stimulation aimed at adjusted GnRH antagonist regimens and achieving a more physiological luteal phase endocrinology are now appearing in the literature and may represent an important step in the improvement of the overall health economics of IVF.

Objective: To investigate relations between dose of GnRH antagonist and follicular phase characteristics., Design: Randomized controlled multicenter trial., Setting: Tertiary referral fertility centers., Patient(s): Three hundred and twenty-nine IVF patients., Intervention(s): Ovarian 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., Main Outcome Measure(s): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations., Result(s): In 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., Conclusion(s): Follicular 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.

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.

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.

The clinical application of gonadotrophin-releasing hormone (GnRH) antagonists instead of GnRH agonists, to prevent spontaneous premature luteinizing hormone surge during ovarian stimulation for assisted reproduction treatment has been advocated. A recent, double-blind, dose-finding study, including six dosages of the GnRH antagonist ganirelix, in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (FSH), has indicated that high doses of GnRH antagonist (1 or 2 mg once daily) are associated with a low implantation rate. This follow-up study reports on the pregnancy rate after replacement of cryopreserved embryos obtained in stimulation cycles of the above-mentioned trial. Ovarian stimulation was initiated on day 2 of the cycle, with daily injections of 150 IU recombinant FSH. Ganirelix (0.0625, 0.125, 0.25, 0.5, 1.0 or 2.0 mg) was administered once daily from stimulation day 6 onwards, up to and including the day of human chorionic gonadotrophin. Retrieved oocytes were fertilized by in-vitro fertilization (IVF) or intracytoplasmic sperm injection and a maximum of three fresh embryos was transferred. Excess embryos were frozen, and subsequently used in either natural or programmed cycles. Until June 1998, 11 ongoing pregnancies (12-16 weeks after embryo transfer) were achieved from 46 cycles in which embryos had been first frozen (23.9% per transfer). Six of these 11 patients had been treated with a high dose of ganirelix (1.0 or 2.0 mg) during the IVF cycles in which the embryos were obtained. In conclusion, our data suggest that high dosages of ganirelix do not adversely affect the potential of embryos to establish clinical pregnancy in freeze-thaw cycles.

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.

This chapter has focused on the step-down principle for gonadotrophin induction of ovulation in women suffering from clomiphene-resistant anovulation. The physiological rationale of this approach has been highlighted. Under normal conditions, FHS levels surpassing the FSH threshold initiate gonadotrophin-dependent growth of a cohort of follicles (this process is referred to as 'recruitment'). Due to negative feedback actions, the FSH levels decrease and FSH is above the threshold for only a limited number of days (the 'FSH window'). Around the mid-follicular phase, selection of a dominant follicle takes place; in addition to relatively low serum FSH concentrations, intraovarian regulation appears to be important for this process. In the conventional step-up or low dose step-up protocols for gonadotrophin induction of ovulation, administered doses are kept constant once an 'adequate' ovarian response is observed, resulting in high FSH serum levels in the late follicular phase and a broad FSH window. This contradicts normal circumstances and may give rise to unintended interference with the selection process by continuously stimulating follicles to enter the growing pool. This may result in multiple follicle development which, in turn, may be related to higher rates of multiple pregnancies and ovarian hyperstimulation. Potential mechanisms underlying arrested follicle maturation in PCOS are also discussed since they appear to be of relevance for the induction of ovulation. Disturbed selection can be overcome in the majority of cases by elevating the serum FSH concentrations through the administration of exogenous gonadotrophins to surpass the elevated FSH threshold in these patients. Data obtained by our group so far suggest that in PCOS patients treated with gonadotrophins in a step-down fashion, follicles continue to mature and can be stimulated to ovulation. Moreover, the number of functionally active medium-sized follicles seems to be reduced. If monofollicular development is observed in these patients, growth rates and oestrogen serum levels are indistinguishable from unstimulated normal development of the dominant follicle. In our initial series of over 200 cycles of gonadotrophin treatment according to the step-down principle in clomiphene-resistant anovulatory patients, 84% of cycles were ovulatory and pregnancy was achieved in 18% of the cycles (giving a cumulative pregnancy rate of 51%). Moreover, the overall complication rate appears to be low. The potential advantages and critical points of adjuvant treatment with GnRH analogues is also discussed. It has been clearly demonstrated that premature luteinization can be prevented effectively. Various other potential advantages of cotreatment seems to justify adjuvant medication with GnRH agonists.(ABSTRACT TRUNCATED AT 400 WORDS)

Meta-analysis of all randomised trials published so far, was performed to compare the effect of additional gonadotropin releasing hormone (GnRH)-agonist treatment to exogenous gonadotropins for ovulation induction in clomiphene-resistant polycystic ovary syndrome (PCOS) patients. Five clinical studies were included, of which only one showed significant differences in pregnancy rate. In addition, pretreatment with GnRH-agonist was once reported to lead more often to cancellation of medication. Combining the results of all five trials, a significant difference in favour of additional GnRH-agonist administration could only be observed for pregnancy rate. No significant differences in ovulation rate could be found. Due to the relative small number of patients in each separate group, no conclusions could be drawn concerning the influence of GnRH-agonist treatment on gonadotropin doses necessary to induce ovulation, and the incidence of multiple pregnancy, abortion and ovarian hyperstimulation.

Basal serum gonadotropin levels in 11 oligospermic men were significantly higher than in 9 euspermic control subjects, although most were still in the normal range. Basal serum testosterone (T), 17-hydroxyprogesterone (17-OHP), and estradiol levels and their ratios did not differ significantly. Continuous luteinizing hormone-releasing hormone (LH-RH) infusion (1 microgram/minute for 180 minutes) during integrated blood sampling evoked similar gonadotropin responses in both groups but had a differential effect on T: in the control subjects T increased (P less than 0.01) within 15 minutes to 1.5 times baseline, whereas in the oligospermic men T decreased (P less than 0.01). From 60 minutes on, however, T also significantly rose in the oligospermic men, but the maximum increment was about half lower (P less than 0.01) than in the euspermic men, despite virtually similar rises in 17-OHP. Only in the oligospermic men did the 17-OHP/T ratio increase (P less than 0.02) during LH-RH, which is compatible with the occurrence of a 17,20-lyase block. Serum estradiol did not increase in either group. In conclusion, continuous LH-RH infusion uncovers an intrinsic difference in acute Leydig cell stimulation between euspermic and oligospermic men.

In 22 potentially fertile men, pituitary gonadotropin secretion was investigated by intravenous luteinizing hormone-releasing hormone (LH-RH) administration. LH-RH was administered continuously (1 microgram/minute) and in a pulsatile fashion (20 micrograms at 20-minute intervals, 20 micrograms at 60-minute intervals, and 60 micrograms at 60-minute intervals), for 3 hours, under standardized conditions. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration after any type of pulsatile administration rose significantly more than after continuous LH-RH administration. The mean increase in LH after pulsatile LH-RH administration with a 60-micrograms dose and 60-minute intervals was significantly greater than after pulsatile administration with a 20-micrograms dose and 20- or 60-minute intervals. No differences were observed in follicle-stimulating hormone responses after any type of LH-RH administration. These data confirm the existence of a self-priming effect for LH in the men; and maximum pituitary stimulation, within the dosage range tested, is reached after pulsatile LH-RH stimulation with an interval of 60 minutes.

Exogenous luteinizing hormone-releasing hormone (LH-RH) was intravenously administered as a single-bolus injection to 26 healthy normal men. LH-RH doses were selected at 1, 2.5, 5, and 20 micrograms for exploration of the optimum LH-RH dose to obtain adequate pituitary stimulation. Blood samples (for LH-RH and LH determinations) were collected at frequent intervals from 10 minutes before to 60 or 90 minutes after injection. LH-RH peak levels varied, in a dose-dependent way, between 119 +/- 16 and 517 +/- 70 ng/l. Peak values were all reached between 1 and 3 minutes after injection, and elimination occurred rapidly, with half-lives between 2.6 +/- 0.4 and 5.2 +/- 1.0 minutes. The area under the curves increased significantly (P less than 0.01) if the doses of LH-RH had been augmented from 1 to 20 micrograms. Maximum LH values were reached more rapidly in the low-dose (1 and 2.5 micrograms) experiments (between 13.5 and 16.3 minutes), with an obvious decline afterwards. The area under the LH curves increased (P less than 0.01) if the doses of LH-RH had been elevated from 1 to 2.5 micrograms, but no further increase of LH release occurred (P greater than or equal to 0.21) if LH-RH doses were further elevated from 2.5 to 20 micrograms. The current study demonstrates that a 2.5-micrograms intravenous LH-RH dose is best suited for an adequate pituitary stimulation in normal men.

In 14 healthy, potentially fertile men, pituitary gonadotropin responses were studied under standardized conditions. Luteinizing hormone-releasing hormone (LH-RH) was given as a continuous infusion of 1 microgram/minute for 4 hours or in a pulsatile fashion with 20 micrograms as an intravenous bolus at intervals of 20 minutes for 4 hours. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration showed an oscillating pattern around a plateau level reached within 45 minutes during continuous LH-RH administration. During pulsatile infusion, an identical pattern for the first 45 minutes was observed with, thereafter, a continuous increase from 105 minutes until the end of the infusion. The mean increase in the serum LH level during pulsatile administration was significantly higher (P = 0.00001) than the mean increase seen during continuous infusion. The follicle-stimulating hormone concentration revealed a gradual progressive increase after both methods of stimulation, without a significant difference in the mean increase between the two types of administration. This study demonstrates the existence of a self-priming effect of LH after pulsatile LH-RH administration in the man like that in the woman.

In 18 healthy normal men Leydig cell response was examined following intravenous luteinizing hormone-releasing hormone (LH-RH) administration under standardized conditions. The same total amount of LH-RH was administered for 3 hours both in a continuous (1 microgram/min; C (1,1)) and in a pulsatile fashion, by giving a 20 micrograms dose at 20 minutes intervals, P (20, 20), and a 60 micrograms dose at 60 minutes intervals, P (60, 60). Following the different modes of LH-RH administration which all caused 3-4 fold elevations of the mean endogenous luteinizing hormone (LH) concentrations and 1.7-2 fold elevations of the mean follicle-stimulating hormone (FSH) serum levels, an overt increase of the mean testosterone (T) levels was noticed up to 1.5 X the baseline value. No difference was observed in the total amount of T release among the investigated groups. The patterns of the T response, however, clearly differed from one another with a rapid increase, during the C (1, 1) and the P (20, 20) LH-RH administration, and a delayed but persistent T increase in the P (60, 60) experiment. The mean 17-hydroxyprogesterone (17-OHP) concentrations demonstrated a similar course to T in the P (60,60) experiment, while significant increases of the oestradiol (E 2) levels were never observed in all three experiments. In view of the comparable LH and FSH increments in response to LH-RH administration in either experiment the differences in T responses may be explained by assuming a direct effect of LH-RH on Leydig cell steroidogenesis in the men.

Serum levels of luteinizing hormone-releasing hormone (LH-RH), LH, and follicle-stimulating hormone (FSH) were measured for 60 minutes after 5- and 20-micrograms bolus doses of LH-RH given either intravenously or subcutaneously to 20 healthy men, for the study of LH-RH pharmacokinetics and the corresponding pituitary gonadotropin release. Intravenous (5- and 20-micrograms) LH-RH administration revealed much sharper LH-RH pulses, with significantly higher levels between 1 and 5 minutes (P less than 0.001) but lower levels between 30 and 60 minutes (P less than 0.05), compared with the subcutaneous route. No statistically significant differences were observed in the magnitude and time occurrence of maximum LH release or in the area under the LH response curves between intravenous and subcutaneous LH-RH administration, either in the 5-micrograms or in the 20-micrograms group. FSH responses were small and insignificant in all the performed tests. The intravenous route of administration seems preferential in therapeutic regimens that use pulsatile exogenous LH-RH, because the conditions of intermittent pituitary stimulation are more adequately fulfilled and the risk of dose accumulation is reduced. Furthermore, LH-RH doses of 5 micrograms are capable of producing adequate pituitary LH release, whereas increases in the pulse dose up to 20 micrograms seem to have no additional effects.

In four normal men with a history of long standing infertility, severely disturbed sperm qualities (determined in at least three spermiograms), normal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels (measured over a time period of 90 minutes), and lack of evidence of further andrological or other obvious endocrine disorders the effectiveness of luteinizing hormone-releasing hormone (LH-RH) treatment was investigated. LH-RH was administered subcutaneously with a portable, comterized infusion pump (Zyclomat) for 3 months, with administration intervals of 90 minutes and bolus dosages of 5 micrograms (three patients) and 20 micrograms (one patient). Semen qualities during and after LH-RH treatment, as compared to pretreatment values, showed no improvement in volume of ejaculate, number of sperms per milliliter and motility. During or at the end of the treatment period no evident differences were observed in serum LH, FSH and testosterone levels (measured over a 90 minutes period) compared with hormonal values before LH-RH therapy, nor at the low-dose (5 micrograms) neither at the high-dose (20 micrograms) administration schedule. It is concluded that pulsatile subcutaneous LH-RH treatment in normogonadotropic, oligozoospermic men does not seem to improve the therapeutical arsenal.