Pituitary Desensitization Research Articles

Soft ovarian stimulation protocol in polycystic ovary syndromes women inspired by gonadotropin stimulated intrauterine insemination cycles converted to rescue IVF: time to shift the focus “retrospective study”

BackgroundPolycystic ovary syndrome (PCOs) women usually exhibit a high luteinizing hormone (LH) and hypersensitivity to exogenous gonadotropins stimulation which is a tremendous risk to ovarian hyperstimulation syndrome (OHSS). Since the pathophysiology of PCOS is mysterious, an aetiological approach to the treatment is difficult and should be individually designed. These features affect the outcome of treatment including ovulation and success rate. Also, PCOS women who have difficulty conceiving, frequently experience substantial treatment burden, risk, and psychological distress. Recently, a renewed interest has emerged in patient-friendly, low-risk, and less costly IVF treatments. Our study proposed a new soft protocol in PCOS ovrian stimulation without prior pituitary desensitization followed by fresh embryo transfer. Patients and methods: a retrospective cohort study was conducted between January 2018 to December 2021, including 48 out of 325 women with PCOS who underwent gonadotropin-stimulated intrauterine insemination cycles but due to unexpectedly high response with risk of multiple pregnancies and OHSS, they had been shifted to a rescue IVF and fresh embryo transfer. The primary outcomes were biochemical pregnancy, implantation rate, clinical pregnancy, rate of miscarriage, OHSS, and multiple pregnancies. Secondary outcomes were the endocrinological profiles, gonadotropin dose, and duration of stimulation. This study aims to evaluate the outcomes in the conversion of high-response gonadotropin intrauterine insemination (IUI) cycles to “rescue” in vitro fertilization (IVF/fresh embryo transfer) regarding implantation rates, pregnancy rates, and ovarian hyperstimulation syndrome (OHSS).ResultsThis study used a low dose gonadotropin injections (2.1 ± 1.4) for an average duration of (9.1 ± 1.2) and showed a high success pregnancy rate: biochemical pregnancies (56.2%), implantation rate (50.2%), clinical pregnancy rate (49.9%), and miscarriage rate (8.5%). Multiple pregnancies occurred in (6.6%) and OHSS(4.4%) only in a mild form.ConclusionOur study revealed that ovarian stimulation without prior pituitary suppression in high responders was feasible to improve the implantation rate and alleviate profound OHSS without compromising the pregnancy outcomes. This encourages all fertility specialists to implement this new protocol with expected high responders as an alternative to the conventional cycle segmentation protocol: GnRH agonist-antagonist IVF/freeze-all strategy.

Is it necessary to monitor the serum luteinizing hormone (LH) concentration on the human chorionic gonadotropin (HCG) day among young women during the follicular-phase long protocol? A retrospective cohort study

BackgroundThe normal physiological function of LH requires a certain concentration range, but because of pituitary desensitization, even on the day of HCG, endogenous levels of LH are low in the follicular-phase long protocol. Therefore, our study aimed to determine whether it is necessary to monitor serum LH concentrations on the day of HCG (LHHCG) and to determine whether there is an optimal LHHCG range to achieve the desired clinical outcome.MethodsA retrospective cohort study included 4502 cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) from January 1, 2016, to June 30, 2019, in a single department. The main outcome measures included retrieved eggs, available embryos, and live birth rate.ResultsThe LHHCG was divided into five groups: Group A (LH ≤ 0.5), Group B (0.5 IU/L < LH ≤ 1.2 IU/L), Group C (1.2 IU/L < LH ≤ 2.0 IU/L), Group D (2.0 IU/L < LH ≤ 5.0 IU/L), Group E (LH > 5 IU/L). In terms of the numbers of retrieved eggs (15.22 ± 5.66 vs. 13.54 ± 5.23 vs. 12.90 ± 5.05 vs. 12.30 ± 4.88 vs. 9.6 ± 4.09), diploid fertilized oocytes (9.85 ± 4.70 vs. 8.69 ± 4.41 vs. 8.39 ± 4.33 vs. 7.78 ± 3.96 vs. 5.92 ± 2.78), embryos (7.90 ± 4.48 vs. 6.83 ± 4.03 vs. 6.44 ± 3.88 vs. 6.22 ± 3.62 vs. 4.40 ± 2.55), and high-quality embryos (4.32 ± 3.71 vs. 3.97 ± 3.42 vs. 3.76 ± 3.19 vs. 3.71 ± 3.04 vs. 2.52 ± 2.27), an increase in the LHHCG level showed a trend of a gradual decrease. However, there was no significant difference in clinical outcomes among the groups (66.67% vs. 64.33% vs. 63.21% vs. 64.48% vs. 63.33%). By adjusting for confounding factors, with an increase in LHHCG, the number of retrieved eggs decreased (OR: -0.351 95%CI − 0.453-[− 0.249]).ConclusionIn the follicular-phase long protocol among young women, monitoring LHHCG is recommended in the clinical guidelines to obtain the ideal number of eggs.

Comparison of Reproductive Outcomes on addition of GnRH agonist for Luteal phase Support in Antagonist IVF cycle

Background: The luteal phase supplementation was reported to be necessary in Controlled Ovarian Hyperstimulation cycles for IVF or ICSI, independently when agonistsor antagonist were used for pituitary desensitization. Theeffectiveness of GnRH agonist in luteal phase supplementation remains controversial.Aims and Objectives: This study aimed at comparing theclinical outcomes of addition of GnRH agonist for lutealphase support in antagonist IVF cycle.Materials and Methods: A cross-sectional study of 150eligible clients who underwent assisted reproduction program in two autonomous IVF centers between 1st January,2017 and 31st December, 2020. Clients were divided intotwo groups; (I) Antagonist stimulation protocol with progesterone and oestradiol valerate and (II) Antagonist Protocol with a single bolus of buserelin in addition to progesterone and oestradiol valerate for luteal phase support. Theprimary outcome was live birth rates while the secondaryoutcomes were clinical pregnancy, miscarriage rates andthe safety for OHSS.Results: There were no statistically significant differencesbetween the number of oocyte received, fertilized, embryosavailability for transfer, duration of infertility, duration ofFSH usage, endometrial thickness and OHSS risk betweenthe groups (p>0.05). The clinical pregnancy and live birthrates were more in group II while the miscarriage rate waslower compared to group I. The differences were statistically significant (p < 0.005).Conclusion: From this study, buserelin addition to the luteal phase of antagonist cycles appears to improve pregnancy outcomes with no associated increase in OHSS risk.Further multi- centered studies with larger sample sizes arerequired to validate these findings.

Can Long-Standing GnRH Therapy Cause a Pituitary Prolactinoma?

Abstract Background: Pituitary adenoma (PA) is the most common cause of sellar masses and accounts for about 10% of all intracranial tumors. Several physiological, pathological, drugs, and rare causes like hypothyroidism can cause PA. We describe a case of long-standing treatment with GnRH analogues possibly contributing to development of PA. Clinical Case: An 86-year-old man with a history of prostate cancer (PC) treated with medical therapy, presented to the hospital with progressively worsening loss of vision in his right eye associated with low-grade headaches over the past few years. Fifteen years prior to presentation, the patient was diagnosed with Gleason 6 (3 + 3) localized PC. He had refused surgical intervention and hence was treated with flutamide, then leuprolide. Labs were significant for an elevated prolactin 34.2 ng/mL [n= 2.5 -17.4], low LH 0.7 mIU/mL [n=1.2-10.6], with normal FSH, TSH, ACTH, IGF, Cortisol, and PTH. CT head and MRI brain identified a 2.7cm x 2.6.3 cm X 1.7 cm mass in the suprasellar region involving the left cavernous sinus and right optic chiasm. These findings were consistent with a diagnosis of Prolactinoma. Patient refused surgery and hence was started on bromocriptine. The findings were suspected to be secondary to long-standing GnRH agonist therapy, and leuprolide was discontinued. DEXA scan confirmed osteoporosis with a T score of --2.5, which was treated with denosumab. Subsequently his vision improved. The patient continues to follow with endocrinology for the management of osteoporosis and prolactinoma. Conclusion: Primary hypothyroidism predisposes to PA due to loss of thyroxine feedback inhibition to hypothalamus with overproduction of TRH with hyperplasia of lactotrophs. We speculate that constant stimulation of the pituitary by GnRH analogues can also lead to enlargement of the anterior pituitary in a similar fashion, and can lead to the development of prolactinoma. LHRH agonists such as Leuprolide, as palliative treatment for advanced prostate cancer, causes desensitization of the anterior pituitary and decreases the production of LH and FSH, which ultimately leads to decreased testosterone in males. Although not standard of care for treatment of locally advance tumors, medical therapy was chosen in this patient’s case due to refusal of surgical intervention. He then developed a clinically significant pituitary adenoma years after the therapy. We suggest that constant stimulation of the pituitary by GnRH analogues can lead to enlargement of the anterior pituitary in a similar fashion, resulting in the development of the prolactinoma. Reference(1) Du J, Ji H, Jin J, Gao S, Yan X, Hu S. Pituitary adenoma secondary to primary hypothyroidism: Two case reports. Medicine (Baltimore). 2020;99(8). https://journals.lww.com/md-journal/Fulltext/2020/02210/Pituitary_adenoma_secondary_to_primary.47.aspx

Effects of Different Exposure Days to Gonadotropin-Releasing Hormone Agonist (GnRH-a) on Live Birth Rates in the Depot GnRH-a Protocol: A Retrospective Analysis of 7007 Cycles.

BackgroundIn controlled ovarian hyperstimulation protocols worldwide, depot gonadotropin-releasing hormone agonist (GnRH-a) pretreatment is generally used for pituitary desensitization. The delay between the GnRH-a administration and starting gonadotropin treatment varies greatly, from 25 to 60 days. However, the association between exposure days to GnRH-a before the onset of gonadotropin administration and the clinical outcomes remains unknown.Material/MethodsThis retrospective study included 7007 patients who underwent fresh embryo transfers between February 2016 and July 2019. The duration of pituitary downregulation was categorized into 3 groups: group 1, ≤30 days; group 2, 31–35 days; and group 3, ≥36 days. The rates of live birth were compared as the main outcome measure. Logistic regression analysis was also performed after controlling for a range of confounders.ResultsThe number of patients in groups 1, 2, and 3 was 2001, 2824, and 2182, respectively. Group 3 (≥36 days) had a noticeably higher live birth rate (48.1%) than the other 2 groups (42.6% and 43.9%, P=0.001). The rate of live birth was remarkably enhanced in group 3 (adjusted odds ratio: 1.264, 95% confidence interval: 1.098, 1.455, P=0.001) after controlling for confounders, while the difference was not found in group 2 (P=0.512) compared with group 1.ConclusionsIn the depot GnRH-a protocol, live birth rates are higher among patients needing a longer time to achieve the goal of pituitary downregulation.

Comparison of clinical efficacy of long- versus short-acting gonadotrophin-releasing hormone agonists for pituitary down regulation in In vitro fertilisation cycles.

Gonadotrophin-Releasing Hormone agonist (GnRHa) - long and short acting - is used for pituitary down regulation prior to ovarian stimulation in in vitro fertilisation (IVF) treatment. However, there are controversies in the literature as to their effectiveness, dose of gonadotrophin needed subsequently for ovarian stimulation and the clinical outcome. The objective of the study was to compare the efficacy of single-dose long-acting GnRHa - goserelin - and daily dose short-acting GnRHa - buserelin - for pituitary down regulation and their clinical outcome in IVF treatment. : This prospective comparative study was undertaken at the IVF centre in National Hospital Abuja, a public tertiary hospital in Nigeria. A total of 114 IVF patients were consecutively allocated into either long-acting GnRHa - goserelin - 3.6 mg single dose (Group A) or short-acting GnRHa - buserelin - 0.5 mg daily (Group B) both starting on day 21 of the cycle preceding the IVF treatment. The effects on pituitary down regulation and treatment outcomes were compared. Time taken (days) to achieve down regulation (22.6 ± 4.3 vs. 26.1 ± 8.0; P = 0.084) and the mean number of human menopausal gonadotrophin (HMG) doses used (57.7 ± 13.7 vs. 54.2 ± 16.7; P = 0.222) were similar in the two groups. Although the number of oocytes retrieved (9.9 ± 6.7 vs. 7.2 ± 5.0; P = 0.02) and fertilised (6.2 ± 4.4 vs. 4.6 ± 3.5; P = 0.04) were significantly higher in Group A, there was no statistically significant difference in the number of embryos (4.4 ± 2.6 vs. 4.0 ± 3.0; P = 0.850) and clinical pregnancy rate at 6 weeks (49.2% vs. 43.6%; odds ratio 1.249; confidence interval = 0.579-2.612; P = 0.578) in both the groups. While group B had a significantly higher number of hospital visits (P = 0.0001) as well as a higher number of injections (P = 0.0001), the mean cost of GnRHa and gonadotrophin used was significantly higher in Group A (P = 0.043). Single-dose long-acting GnRHa is as effective as daily dose short-acting GnRHa for pituitary desensitisation prior to controlled ovarian stimulation in IVF cycles.

Massive Ovarian Growth in a Woman With Severe Insulin-Resistant Polycystic Ovary Syndrome Receiving GnRH Analogue

Ovarian hyperandrogenism from polycystic ovary syndrome (PCOS) and hyperinsulinemia from insulin resistance are modulators of ovarian follicle development. We report on a woman with PCOS and hyperandrogenism and severe insulin resistance from metabolic syndrome who received long-term GnRH analogue therapy preceding bilateral salpingo-oophorectomy for massive ovarian enlargement. Ovarian histological examination showed proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas, demonstrating a unique link between hyperinsulinemia and granulosa cell mitogenesis. A 30-year-old woman with PCOS with hyperandrogenism, severe insulin resistance from metabolic syndrome, and nonalcoholic steatohepatitis experienced abdominal pain from bilaterally enlarged ovaries. She had previously experienced a pulmonary embolism while taking oral contraceptives and hepatotoxicity from metformin and spironolactone therapies. Long-term GnRH analogue therapy to induce pituitary desensitization to GnRH successfully decreased gonadotropin-dependent steroidogenesis without improving insulin resistance. Despite GnRH analogue therapy, progressive ovarian enlargement in the presence of hyperinsulinemia from worsening metabolic function eventually required bilateral salpingo-oophorectomy for removal of massively enlarged ovaries. Histological examination showed both ovaries contained proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas. In women with PCOS and hyperinsulinemia from severe insulin resistance due to metabolic syndrome, granulosa cell proliferation within antral follicles can occur despite long-term GnRH analogue therapy, implicating hyperinsulinemia as a granulosa cell mitogen in the absence of gonadotropin-dependent ovarian function.

Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial.

STUDY QUESTIONSThe primary objective is to investigate if continuous use of oral contraceptives is non-inferior compared to long-term pituitary desensitization with a GnRH agonist prior to IVF/ICSI in patients with moderate to severe endometriosis with regard to treatment efficacy. Secondary objectives concern treatment safety and cost-effectiveness.WHAT IS KNOWN ALREADYLong-term pituitary desensitization with a GnRH agonist for 3–6 months prior to IVF/ICSI improves clinical pregnancy rates in women suffering from endometriosis. However, discussion about this treatment strategy exists because of its uncomfortable side effects. Alternatively, IVF/ICSI pre-treatment with continuously administered oral contraceptives may offer fewer side-effects and lower (in)direct costs, as well as encouraging IVF outcomes in women with endometriosis. To date, these two different IVF/ICSI pre-treatment strategies in women with endometriosis have not been directly compared.STUDY DESIGN, SIZE, DURATIONAn open-label, parallel two-arm randomized controlled multicenter trial is planned, including patients with moderate to severe endometriosis. To demonstrate an absolute difference of 13% (delta of 10% with non-inferiority margin of 3%) with a power of 80% 137 patients per group are sufficient. Taking into account a withdrawal of patients of 10% and a cancelation rate of embryo transfer after ovarian pick up of 10% (for instance due to fertilization failure), the sample size calculation is rounded off to 165 patients per group; 330 patients in total will be included. After informed consent, eligible patients will be randomly allocated to the intervention or reference group by using web based block randomization stratified per centre. Study inclusion is expected to be complete in 3–5 years.PARTICIPANTS/MATERIALS, SETTING, METHODSThe research population consists of patients with moderate to severe endometriosis (ASRM III/IV) who are scheduled for their first, second or third IVF/ICSI treatment attempt. Women aged over 41 years, younger than 18 years, with a known contraindication for the use of oral contraceptives and/or GnRH agonists or with severe male factor infertility will be excluded from participation. After informed consent patients are allocated to the intervention group (one-phase oral contraceptive continuously during three subsequent months) or the reference group (three Leuprorelin 3.75 mg i.m./s.c. depot injections during three subsequent months). Tibolon 2.5 mg can be given daily as add-back therapy in the reference group. After 3 months of pre-treatment the IVF/ICSI stimulation phase will be started. The primary outcome is live birth rate after fresh embryo transfer. Secondary outcomes are cumulative live birth rate after one IVF/ICSI treatment cycle (including fresh and frozen embryo transfers up to 15 months after randomization), ongoing pregnancy rate and time to pregnancy. In addition, treatment outcome parameters, adverse events, side-effects during the first 3 months, complications, recurrence of endometriosis (complaints), quality of life, patient preferences, safety and costs effectiveness will be reported. Measurements will be performed at baseline and at 3, 6, 9, 12 and 15 months after randomization.STUDY FUNDING/COMPETING INTEREST(s)All authors have no conflict of interest related to this manuscript. The department of reproductive medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work.TRIAL REGISTRATION NUMBERThe trial is registered as the COPIE trial (Continuous use of Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) in the Dutch Trial Register (Ref. No. NTR6357, http://www.trialregister.nl).TRIAL REGISTRATION DATE16 March 2017.DATE OF FIRST PATIENT’S ENROLMENTEnrollment is planned for November 2018.

Frozen thawed embryo transfer cycles; A comparison of pregnancy outcomes with and without prior pituitary suppression by GnRH agonists: An RCT

To perform an in-vitro fertilization cycle, pretreatment with gonadotropin-releasing hormone (GnRH) agonist is widely used as a part of controlled ovarian hyper-stimulation protocols to prevent endogenous luteinizing hormone surge and spontaneous ovulation. GnRH agonist pretreatment is relatively costly and there is a risk of hypo estrogenic side effect. It would also lengthen the preparation period until pituitary desensitization occurs. Our study is aimed at evaluating the pregnancy outcome rate of frozen thawed embryo transfer with and without GnRH agonists pretreatment. Women with documented infertility who were candidate for frozen thawed embryo transfer were recruited and randomly assigned to two groups. In group A (n=100), patients received GnRH agonist, Buserelin, to induce pituitary desensitization prior to endometrial preparation and embryo transfer. Individuals in group B (n=100) received steroid manipulation without prior down-regulation of the pituitary. Chemical pregnancy, implantation rate, clinical pregnancy and ongoing pregnancy were measured and statistically compared between the two groups. None of the outcome measures including clinical and chemical pregnancy rates, implantation rate, and ongoing pregnancy rate showed significant difference between the two groups. Similarly, the rate of miscarriage did not vary between the two groups. In this study, we found that removing the GnRH agonists pretreatment from the programmed cycles did not negatively influence the pregnancy outcome or implantation rate. Moreover, it will cause a considerable reduction in cost of assisted reproductive technology as well as adverse effects related to GnRH agonists, while having a favorable implantation and pregnancy outcomes.

The Effect of Metformin on the Endometrium of Women with Polycystic Ovary Syndrome

Objectives: To investigate the effect of metformin on endometrial receptivity in women with polycystic ovary syndrome (PCOS). Methods: Twenty volunteer women with polycystic ovaries and oligomenorrhea were prospectively investigated. All women were treated with exogenous estradiol and progesterone to simulate a normal menstrual cycle (28-day duration) after GnRH-induced pituitary desensitization. Ten of the women received no other medication (group A, control), while the remaining 10 received metformin (group B, metformin). Endometrial biopsy was performed in all women on day 21 of the 2 simulated cycles. Results: The expression of corticotropin – releasing hormone and urocortin in the endometrium was investigated. There was no significant difference between the 2 groups. A 3-day delay in the secretory maturation of the glandular epithelium relatively to the stroma was observed in 7 out of 10 women of group B (70%) as compared to only 1 out of 10 women of group A (10%, p = 0.02). Conclusions: It is shown for the first time that metformin administration to women with PCOS did not affect the expression of endometrial receptivity markers but delayed histological glandular maturation. It is suggested that metformin may have an impact on the function of the endometrium in PCOS.

Effect of Growth Hormone on Uterine Receptivity in Women With Repeated Implantation Failure in an Oocyte Donation Program: A Randomized Controlled Trial

Background and Objective:Administration of growth hormone (GH) during ovarian stimulation has been shown to improve success rates of in vitro fertilization. GH beneficial effect on oocyte quality is shown in several studies, but GH effect on uterine receptivity is not clear. To assess it, we studied whether GH administration can improve the chance of pregnancy and birth in women who experienced repeated implantation failure (RIF) using donated oocyte programs.Design and Study Population:A total of 105 infertile women were enrolled in the randomized controlled trial: 70 women were with a history of RIF with donated oocytes, and 35 infertile women underwent the first oocyte donation attempt. Women receiving donated oocytes were treated with progressively increasing doses of oral estradiol, followed by intravaginal progesterone after previous pituitary desensitization with gonadotropin-releasing hormone agonist. Thirty-five RIF patients were treated with GH (GH patients), whereas the rest of the 35 RIF patients (non-GH patients) and 35 first-attempt patients (positive control group) were not.Results:RIF patients receiving GH showed significantly thicker endometrium and higher pregnancy and live birth rates as compared with RIF patients of non-GH study group, although these rates remained somewhat lower as compared with the non-RIF patients of the positive control group. No abnormality was detected in any of the babies born.Conclusion:Our data of improved implantation, pregnancy, and live birth rates among infertile RIF patients treated with GH indicate that GH improves uterine receptivity.

Can Elevated Levels of Basal Follicle Stimulating Hormone Predict a Decrease in Fertility in Young Women Undergoing ART Cycles?

Background: The determination of ovarian reserve is often measured in normal cycling women through day 3 basal FSH. This determination will help to choose patients who are eligible for starting assisted reproductive technique (ART) cycles. Female age and basal FSH level are independently associated with IVF outcome. Objective:This study aims’ at evaluating the impact of basal FSH level associated with female age on IVF outcome. Methods: A retrospective study that included 367 patients undergoing ICSI cycles. Basal FSH levels were measured using the same immunoenzymatic method for all patients. The age of women was checked before they were undergoing pituitary desensitization. Patients were divided into 4 groups according to their age and basal FSH levels. Then its correlation with IVF outcome was evaluated. Results:The increase of FSH levels was associated significantly with reduced oocytes retrieved, and embryos obtained in young women. Nevertheless, there was no significant difference in terms of fertilization or pregnancy rate. Cancellation rates were significantly higher among patients with high day 3 FSH levels compared to patients having normal FSH levels in all age groups. Loss rates were affected by FSH levels among patients < 38 years old. However, they were significantly higher in older patients having elevated day 3 FSH levels. Younger women with high FSH levels produced less but better quality embryos resulting in acceptable pregnancy rate. Conclusion: Female age is the most important prognostic factor. The basal FSH should be used to identify women who are purveyors of poor response to ART and should not be used to exclude them from fertility treatment.

WITHDRAWN: Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome.

Background Approximately 15% of women with PCOS remain anovulatory despite treatment with oral anti-oestrogen medications such as citrate. In addition, about half of women with PCOS ovulating on anti-oestrogen treatment fail to conceive. Gonadotrophin stimulation is the next step in treatment for women who are clomiphene resistant, however, results of gonadotrophin stimulation in women with PCOS are less successful. In PCOS associated with hypersecretion of LH, purified urinary follicle-stimulating hormone (u-FSH) preparations have theoretical advantages over the use of human menopausal gonadotrophin (hMG) preparations (containing both FSH and LH) , but whether this claimed advantage extends into clinical practice remains uncertain. In addition, the use of gonadotrophin-releasing hormone analogues (GnRH-a) to produce pituitary desensitisation prior to ovulation induction in PCOS has been claimed to increase the success rates of treatment as well as reduce complications such as OHSS and multiple pregnancy. Gonadotrophin preparations have also been administered via different routes (intramuscular or subcutaneous), or using different stimulation regimens and protocols (step-up or standard) in an attempt to improve efficacy. Objectives To determine the effectiveness of urinary-derived gonadotrophins as ovulation induction agents in patients with PCOS trying to conceive. In particular, to assess the effectiveness of (1) different gonadotrophin preparations, (2) the addition of a gonadotrophin-releasing hormone agonist (GnRH-a) to gonadotrophin stimulation and (3) different modalities of gonadotrophin administration. Search methods The search strategy to identify RCTs consisted of (1) the Group's Specialised Register of Controlled Trials using the search strategy developed for the Menstrual Disorders and Subfertility Group as a whole (see the Review Group details for more information), (2) additional specific electronic MEDLINE searches and (3) bibliographies of identified studies and narrative reviews. Selection criteria RCTs in which urinary-derived gonadotrophins were used for ovulation induction in patients with primary or secondary subfertility attributable to PCOS. Data collection and analysis Twenty three RCTs were identified, nine of which were excluded from analysis. The data were extracted independently by two authors. The following criteria were assessed: (1) the methodological characteristics of the trials (2) the baseline characteristics of the studied groups and (3) the outcomes of interest: pregnancy rate (per cycle), ovulation rate (per cycle), miscarriage rate (per pregnancy), multiple pregnancy rate (per pregnancy), overstimulation rate (per cycle) and ovarian hyperstimulation syndrome (OHSS) rate (per cycle). Where suitable, meta-analysis was performed using Peto's OR with 95% CI with the fixed effect Mantel-Haentszel equation. Main results (1) A reduction in the incidence of OHSS with FSH compared to hMG in stimulation cycles without the concomitant use of a GnRH-a (OR 0.20; 95% CI 0.08-0.46) and (2) a higher overstimulation rate when a GnRH-a is added to gonadotrophins (OR 3.15; 95% CI 1.48-6.70). Authors' conclusions Although 14 RCTs were included in this review, few dealt with the same comparisons, all were small to moderate size and their methodological quality was generally poor. Any conclusions, therefore, remain tentative as they are based on a limited amount of data and will require further RCTs to substantiate them. In none of the comparisons was there a significant improvement in pregnancy rate but this may be due to the lack of power (i.e. insufficient patients randomised to demonstrate a significant difference between treatments). There was a trend towards better pregnancy rates with the addition of a GnRH-a to gonadotrophin stimulation and these interventions warrant further study. Despite theoretical advantages, urinary-derived FSH preparations did not improve pregnancy rates when compared to traditional and cheaper hMG preparations; their only demonstrable benefit was a reduced risk of OHSS in cycles when administered without the concomitant use of a GnRH-a. No conclusions can be drawn on miscarriage and multiple pregnancy rates due to insufficient reporting of these outcomes in the trials.

Gonadotrophin‐Releasing Hormone Release into the Hypophyseal Portal Blood of the Ewe Mirrors Both Pulsatile and Continuous Intravenous Infusion of Kisspeptin: An Insight into Kisspeptin's Mechanism of Action

Recent studies have demonstrated that kisspeptin (Kp) administration, given as a slow constant infusion of Kp10 (the shortest endogenous form of the Kp molecules which carries biological activity), is able to stimulate gonadotrophin secretion and induce ovulation in anoestrus acyclic ewes. Detailed analysis of peripheral luteinising hormone (LH) concentrations, obtained at 10-min intervals, suggested that this Kp10 treatment induced the continuous release of gonadotrophins. Whether this apparent constant secretion of LH resulted from a continuous elevation of GnRH or discrete high-frequency pulses could not be determined. In the present study, we monitored the patterns of gonadotrophin-releasing homrone (GnRH) secreted into hypophyseal portal blood (HPB) and LH in the peripheral circulation when Kp10 was administered either as discrete pulses or by means of a continuous infusion. Samples of HPB and peripheral blood were obtained at 2 and 10-min intervals, respectively, over a 6-h period, from anoestrous acyclic ewes that received an i.v. bolus injection of Kp10 at 1h and an infusion of Kp10 between hours 2 and 6. GnRH release following Kp10 administration appeared to be dose-dependent, with larger responses being seen to the 20 μg bolus and 20μg/h infusion than to the 10μg bolus and 10μg/h infusion, with the latter being marginally effective in inducing LH release. Bolus injections of Kp10 (either 20 or 10μg) induced a sharp GnRH pulse in HPB and a discrete LH pulse in peripheral blood. By contrast, constant infusion of Kp10 (either 20 or 10μg/h for 4h) induced a sustained increase in baseline GnRH secretion with no convincing evidence of strictly episodic release. Values remained continuously elevated in HPB. No sign of pituitary desensitisation was observed at either concentration. Finally, i.v. injection of a large bolus (500μg) of Kp10 produced immediate pharmacological concentrations of Kp10 in the peripheral circulation but were not associated with detectable levels of the peptide in the cerebrospinal fluid. In summary, our results demonstrate that the mode of Kp10 administration (pulsatile versus continuous) is important in shaping the pattern of GnRH secretion and suggests that this regulatory effect is most likely exerted at the level of the terminals of GnRH neurones. Moreover our data also suggest that Kp is involved in, rather than having a permissive role in, the control of endogenous GnRH pulsatility.

ART outcome in young women with premature ovarian aging.

Background:Young women with signs of ovarian aging are a matter of concern as far as their reproductive performance is concerned. With more women approaching infertility centers with this problem, it becomes necessary to understand what reproductive outcomes are possible in such cases. Female age and basal Follicle stimulating hormone (FSH) level, both are strong independent predictors of In Vitro Fertilization (IVF) outcome.Objective:To correlate age-related basal FSH with IVF outcome in women with premature ovarian aging in gonadotropins-induced cycles.Materials and Methods:Between January 2011 and October 2012, a total of 135 women undergoing IVF and ICSI cycles with antagonist protocol were included in this retrospective cohort study. Basal FSH concentrations were measured and the women's ages were calculated before they were undergoing pituitary desensitization and its correlation with assisted reproduction technique (ART) outcome was evaluated.Results:Increasing FSH was associated significantly with reduced number of oocytes retrieved, and embryos obtained. Young women with high FSH up to 20 produced less but good quality embryo's resulting in sound pregnancy rate.Conclusion:FSH is a quantitative and age is a qualitative measure of ovarian reserve. Both are equally important in predicting IVF outcome. Basal FSH concentration should be restricted to counseling of patients on probability of achieving pregnancy, but should not be used to exclude them from fertility treatment.

Clinical Evaluation of Deslorelin to Induce Oestrus, Ovulation and Pregnancy in the Bitch

The aim of this study was to evaluate the practical use of Deslorelin in a clinical setting to induce oestrus and ovulation and to assess pregnancy rates. Sixteen anoestrus bitches that were brought into the clinic were implanted subcutaneously in the ventral abdomen with Deslorelin. Implants were removed after ovulation was assumed to have occurred. All bitches came into oestrus and 13 ovulated. 11 of 16 bitches became pregnant (68.8%) and all continued to term. Average litter size was 7.6 puppies. On average, the implant was in place for 13.8 days.

An investigational ovarian stimulation protocol increased significantly the psychological burden in women with premature ovarian failure

To assess the psychological impact (Hospital Anxiety and Depression Scale) of an investigational ovarian stimulation protocol in women with premature ovarian failure (POF). Prospective longitudinal study. Ten women with POF. Women with idiopathic POF were placed on three consecutive treatment cycles consisting of gonadotropin ovarian stimulation after estrogen priming, gonadotropin-releasing hormone agonist pituitary desensitization, and corticosteroid immune suppression. Median anxiety and depression scores increased significantly from baseline following three consecutive treatment cycles from 4.0 (range 2.0-8.0) to 11.0 (range 10.0-14.0) (p-value 0.041) and from 1.5 (range 0-6.0) to 9.0 (range 7.0-10.0) (p-value 0.039), respectively. There were nine "probable" anxiety (90%) and three "probable" depression (30%) cases on the final treatment cycle compared with none (0%) on baseline (p-value 0.004 and 0.250, respectively). The use of investigational ovarian stimulation protocols in women with idiopathic POF was associated with excessive psychological strain. Women with POF should be cautioned against the potentially harmful aspect of similar treatments of unproven benefit.

GnRH antagonist for pituitary desensitization in IVF: Is it a time for a change of practice?

GnRH antagonist for pituitary desensitization in IVF: Is it a time for a change of practice?

A novel long protocol of GnRH agonist: a dramatical increase in pregnancy rate by induction of diminished but significant mid-cycle LH surge

In long protocol of GnRH agonist regime, pituitary desensitization prevents premature LH surge and thus it has been believed that mid-cycle LH surge cannot be induced. But serendipitously we found a novel protocol to induce diminished but significant LH surge, increasing dramatically pregnancy rates.

Evaluation of two doses of recombinant human luteinizing hormone supplementation in down-regulated women of advanced reproductive age undergoing follicular stimulation for IVF: a randomized clinical study

Objectives To evaluate the effects of mid-follicular recombinant human luteinizing hormone (rhLH) supplementation in down-regulated women of advanced reproductive age undergoing in vitro fertilization (IVF). Study design This was a prospective, randomized parallel-group study (allocation 1:1) including 187 normogonadotrophic infertile patients aged ≥35 years. Subcutaneous triptorelin was used for pituitary desensitization, and ovarian stimulation was achieved with recombinant human follicle-stimulating hormone (rhFSH) either alone (Group 1) or in combination with rhLH in one of two daily doses: 37.5 IU (Group 2) or 75 IU (Group 3). Ovarian stimulation characteristics and IVF outcome were evaluated. The main outcome was pregnancy rate. Results A total of 62, 62 and 63 patients were randomized to groups 1, 2 and 3 respectively, and 56, 54 and 55 patients respectively were available for final analysis of the results. Follicular development and oocyte yield were significantly higher in group 1 patients compared with patients in groups 2 and 3. Oocyte maturity and number of oocytes fertilized were also higher in group 1 patients; this difference almost reached statistical significance. No significant difference in implantation and clinical pregnancy rates was found among the three treatment groups. Conclusions rhLH supplementation is not a useful tool for patients of advanced reproductive age in ovarian stimulation protocols using an appropriate gonadotrophin-releasing hormone agonist and a step-down regimen of rhFSH.