Impact of 'LH activity' supplementation on serum progesterone levels during controlled ovarian stimulation: a systematic review.

BACKGROUND: The influence of LH on serum progesterone rise during gonadotrophin stimulation is a matter of debate. The purpose of this analysis was to assess the impact of supplementation with 'LH activity' products on serum progesterone changes before hCG administration in GnRH analog-treated women. METHODS: A computerized literature search was performed to identify studies comparing FSH treatment alone to those that provided supplementation with 'LH activity' using hMG, recombinant (r)LH (rLH) or hCG in GnRH analog protocols. Data regarding stimulation regimens were extracted from those that reported serum progesterone levels at the time of hCG in order to assess the specific role of LH activity products. RESULTS: Serum progesterone determination at the time of hCG administration was performed in 34 out of 108 studies comparing the effects of FSH alone or in combination with LH activity products. In a vast majority, no significant difference in serum progesterone could be found between stimulation regimens. However, in four studies where LH activity (three hMG and one rLH) was administered from the beginning of ovarian stimulation, serum P-values were significantly decreased. In contrast, in two studies where LH activity (hCG) was provided during the late follicular phase, serum P-values were significantly increased. Analysis of confounding factors showed that the intensity of ovarian stimulation is the most important determining factor to explain serum progesterone elevation at the time of hCG administration, CONCLUSIONS: This systematic review shows that providing LH activity supplementation in combination with FSH during ovarian stimulation does not have a consistent effect on serum progesterone concentrations at the time of hCG administration. However, these data also suggest that, in accordance with physiological concept, the timing of LH activity administration could influence the impact on serum progesterone changes.

[Views of each member of an Assisted Reproductive Technologies centre on the embryo transfer procedure]. / Points de vue de l'équipe multidisciplinaire d'un centre d'Assistance médicale à la procréation concernant le transfert embryonnaire.

The embryo transfer (ET) is probably the key step of Assisted Reproductive Technologies (ART), end point of the collaboration of a multidisciplinary clinical team and an infertile couple. Thus, a perfect knowledge of available data regarding ET is required to optimize the results of ART. Indeed, numerous published studies demonstrate the impact of defined parameters onto the effectiveness of ET procedure. The aim of this study is to provide views of physicians dealing with ART, i.e. endocrinologist, ultrasound scan specialist, surgeon and biologist to put in perspective questions and answers about ET.

Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation.

BACKGROUND: The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist. METHODS: We employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration. RESULTS: The LH treatment was associated with increased small antral follicles prior to FSH stimulation (P = 0.007), and an increased yield of normally fertilized (2 PN) embryos (P = 0.03). There was no influence of the r-hLH pretreatment upon hormone profiles or ultrasound assessments during the FSH phase. Anti-mullerian hormone increased in both groups during the week prior to FSH stimulation (P = 0.002). CONCLUSIONS: This sequential approach to the use of r-hLH in standard IVF showed a possible modest clinical benefit. The results support other recent work exploring up-regulated androgen drive upon follicular metabolism indicating that clinical benefit may be obtainable after further practical explorations of the concept.

[The use of GnRH antagonists in ovarian stimulation for intrauterine inseminations: is there any interest?]. / Utilisation des antagonistes de la GnRH au cours des stimulations pour inséminations intra-utérines: y a-t-il un intérêt?

The use of the GnRH antagonists during ovarian stimulation for intrauterine insemination is relatively recent. The primary aim was to improve the timing of the inseminations on working days. However, according to published data, the consequences on pregnancy rate remain uncertain. Moreover, the impact of this strategy on stimulation's parameters, specifically on the size of the follicle cohort, should be better assessed.

[Prospective evaluation of elective single-embryo transfer versus double-embryo transfer following in vitro fertilization: a two-year French hospital experience]. / Evaluation prospective du transfert sélectif d'un embryon: deux années d'expérience.

OBJECTIVE: Multiple embryo transfer is responsible for a high rate of multiple pregnancies (ICSI), with subsequent risks of premature birth and perinatal death. This prospective non randomized study aimed to assess the ability of an elective single-embryo transfer (eSET) policy to reduce the twin pregnancy rate, compared to a double embryo transfer (DET) approach. PATIENTS AND METHODS: Between March 2005 and May 2006, 180 eligible women were proposed to benefit from an eSET transfer rather than a DET. Inclusion criteria were (i) age less than 37 years old; (ii) at least two good quality embryos available (three to five cells at day 2 or six to nine cells at day 3; less than 20% fragmentation and the absence of multinucleates blastomeres), after IVF or ICSI and (iii) no more than one previous failed treatment cycle. Outcome analysis included cycles with frozen-thawed embryo transfer (FET). RESULTS: According to patients' decision, 107 and 73 women had an eSET (59.4%) and a DET (40.6%) respectively. No differences were found between eSET and DET groups regarding demographics and biologicals parameters. The clinical pregnancy rate (PR) per transfer was 43.9% in eSET group and 57.5% in DET group (p=0.07). The twin pregnancy rates were 0 and 14.3%, in eSET and DET groups, respectively (p=0.007). The cumulative PR per patient, including the outcome of performed FET cycles, was 63.6% in eSET group and 61.6% in DET group. In this case, the cumulative twin pregnancy rates were 2.9 and 15.6% in eSET and DET groups, respectively (p=0.02). DISCUSSION AND CONCLUSION: Our data show that in a selected population of women, transferring one fresh embryo and then, if required, one or two frozen-thawed embryos significantly reduces the twin pregnancy rate without decreasing the overall pregnancy rate. This study supports the policy of eSET in this subgroup of patients.

[Hypothyroidism: from the desire for pregnancy to delivery]. / Hypothyroïdie: du désir de grossesse à l'accouchement.

The link between hypothyroidism and infertility is still a matter of debate. Hypothyroidism can result in cycle disturbances, such as oligomennorhea and functional bleeding. Additionally, several studies have shown that thyroid autoimmunity (detection of anti peroxydase antibodies) may account for the occurrence of repetitive miscarriages. In infertility work-up, screening thyroid function should be specifically recommended for women with clinical hypothyroidism, with a personal, familial history of thyroid or other auto immune diseases (such as type I diabetes) as well as for women with unexplained anovulation or functional bleeding. Moreover, detection of thyroid antibody seems to be worthwhile for the assessment of recurrent miscarriages, due to the potential benefit of thyroid supplementation. In pregnant women, assessment of thyroid function seems specifically crucial to ensure adequate foetal development. Indeed, it has been well established that untreated maternal hypothyroidism may be associated with disturbances of brain development and low intellectual quotient. Additionally, other foetal (growth deficiency, premature birth, low birth weight) as well as maternal (gestational hypertension, pre-eclampsia...) complications have been also reported in pregnant women with untreated hypothyroidism. Consequently, screening of thyroid function should be performed in every woman at risk of thyroid disease. Recent studies even advocate that thyroid screening should be extended to the overall pregnant population. The objective is to adjust L-thyroxin supplementation to maintain serum TSH concentrations below the threshold of 2.5 mUI/l. Finally, iodine deficiency, currently observed in pregnant women, should be prevented by iodine supply prior to conception, during pregnancy and during breast feeding as well.

[Follicle-stimulating hormone receptor polymorphism and ovarian function]. / Polymorphisme du gène du récepteur de la FSH et fonction ovarienne.

The FSH receptor presents several polymorphisms. Two of them, located at codon 307 and 680, are the most frequent. Threonine can be substituted by alanine at position 307 and serine can be substituted by asparagine at position 680. The two most frequent allelic combinations are Thr(307) -Asn (680) (60%) and Ala(307) -Ser (680) (40%). As the allelic variants at codon 307 and 680 are almost invariably associated, most of the studies assessed only one codon (680) and classified the women as homozygous (Ser/Ser ou Asn/Asn) or heterozygous (Asn/Ser). Several studies aimed to correlate the follicle-stimulating hormone receptor polymorphism and ovarian function. Women homozygous for the Ser (680) variant have higher follicular FSH levels and longer follicular phase length, which suggest a lower sensitivity to FSH. The FSH receptor genotype would also influence the sensitivity to exogenous FSH: as regards ovarian stimulation, higher recombinant FSH doses are needed for Ser/Ser homozygous women. The analysis of polymorphism in women with premature ovarian failure did not show a link with any particular allelic variant. In women with polycystic ovaries, the distribution of the allelic variants greatly varies from one study to another.

[Ovarian hyperstimulation syndrome: is there a place for surgery?]. / Hyperstimulation ovarienne: place de la chirurgie.

Ovarian hyperstimulation syndrome is a iatrogenic complication that could happen during ovulation induction. Metabolic modifications can lead to a third sector and organic failure. Medical treatment, undertaken in first line, may be insufficient. In these cases, invasive treatment, using surgical techniques, in association with reanimation principles becomes necessary. From the simple drainage to final measures for the patient's rescue, this review describes the different solutions and their respective place. Several means exist, but serious evaluation is lacking. Their use should be indicated specifically. Medico-surgical associations seemed to offer interesting results.

[Laparoscopy in ART?]. / Y a-t-il une place pour la cœlioscopie dans le parcours en assistance médicale à la procréation ?

The use of laparoscopy in infertility is currently controversial. However, laparoscopic treatment of tubal and peritoneal disease, or endometriosis improves natural fecundity and ART results. The use of laparoscopy in unexplained infertility can be considered because of underestimated pelvic pathology. The result of laparoscopy may help the practitioner for choosing spontaneous pregnancy or ART postoperative management. Although there is a lack of randomized study, laparoscopy is useful for a high overall pregnancy rate (surgery and ART treatment). Rather than opposing ART and laparoscopy, the integrated approach seems better for personal management.

[Endometriosis Fertility Index, or classification of the American Society of Reproductive Medicine for postoperative endometriosis patients with infertility: Which is more relevant?]. / Endometriosis Fertility Index ou classification de l'American Society of Reproductive Medicine pour les patientes infertiles endométriosiques opérées. Lequel est le plus pertinent ?

The revised American Fertility Society classification system has been most used after surgery by all consensus on endometriosis fertility. However, it does not predict pregnancy. The EFI score has been recently developed to aim at predicting clinical pregnancy after surgery. Several study performed its external validation. It may be a useful new tool to counsel couples for personalized postoperative management.

Delivery rates after elective single cryopreserved embryo transfer related to embryo survival.

OBJECTIVE: The objective of this study was to assess if eSCET (elective Single Cryopreserved Embryo Transfer) outcome is related to blastomere survival rate. The final objective was to avoid multiple pregnancies and offer the best chances to women to achieve pregnancy even during their frozen-thawed embryo transfer (FET) cycles. STUDY DESIGN: Patients were included in this prospective observational study if they met the following criteria: (i) women age <37 years old; (ii) IVF of ICSI cycle rank ≤2, (iii) eSET proposed during fresh embryo transfer cycle and (iv) ≥1 good quality cryopreserved embryos available (<20% fragmentation and 4-5 blastomeres at day-2 or 7-9 blastomeres at day-3). Live birth rates (LBR) were compared into eSCET groups according to embryo survival (partially damaged or intact transferred embryo). RESULTS: We observed among selected patients, that partial loss of blastomeres (1 blastomere for day-2 embryos, 1 or 2 blastomeres for day-3 embryos) following FET cycles did not affect LBR compared with intact embryo. CONCLUSION: These results underline the relevance of eSCET as a strategy to reduce multiple pregnancies frequency without reducing LBR.

Sensitivity of thyrotropin (TSH) secretion to 3,5,3'-triiodothyronine and TSH-releasing hormone in rat during starvation.

The mechanisms by which plasma T3 and TSH decrease after a 3-day starvation period are not completely understood. In this study we tested the hypothesis of a possible modification in the sensitivity of thyrotroph cell to T3 and/or TRH. For that purpose, TRH tests were performed before and after a 3-day starvation in euthyroid, thyroidectomized, and T3-treated (75 or 175 ng/100 g BW) thyroidectomized male Wistar rats. TRH (10 to 500 ng/100 g BW) was injected iv through a chronically-implanted catheter. In another set of experiments, hypophyseal TSH content was also determined. Our results showed that after a 3-day-starvation plasma TSH decreased in all except hypothyroid rats; TSH responsiveness to TRH was unchanged in euthyroid rats but was increased in hypothyroid rats; and the T3-dependent increase in TSH responsiveness to TRH was significantly amplified. Moreover, there was a significant positive correlation between TSH responsiveness to TRH and hypophyseal TSH content. These results suggest that starvation induces an increased sensitivity of thyrotroph cell to T3.

Evidence of a thyrotropin-releasing hormone-dependent increase in plasma thyrotropin during refeeding of starved rats.

After 3 days of starvation, refeeding with carbohydrate (CHO) leads to a rapid increase in plasma T4 and T3, suggesting increased TSH secretion. The aim of the present study was to describe the time course of plasma TSH changes during refeeding with CHO and fat. Repetitive blood samples were obtained from freely moving animals by indwelling jugular venous catheters. Refeeding was performed on the fourth day of starvation at either 1100 or 1900 h, and blood was sampled during the preceding hour and during the following 3 h. In control experiments, blood was sampled over 4 h without refeeding. Refeeding with CHO and fat induced a significant increase in plasma TSH in the first hour. This increase could be abolished by a previous injection of an anti-TRH serum, while normal rabbit serum was without effect. Plasma corticosterone, measured hourly, also showed a tendency to increase with refeeding. It is concluded that refeeding of starved rats represents a reproducible stimulus for TSH secretion.

Hypothalamo-pituitary regulation of thyrotrophin secretion in chronically catheterized Brattleboro rats.

Plasma TSH rhythms were measured in Brattleboro (DI) and control Long-Evans (LE) rats with an intracardiac catheter allowing repeated sampling in conscious unstressed animals. The TSH response to thyrotrophin-releasing hormone (TRH; 500 ng/100 g body weight) was also determined. Finally, hypothalamic and pancreatic TRH concentrations and TRH-degrading activity (TRH-DA) were measured by specific radioimmunoassay. Long-Evans rats had a 24-h rhythm with a major modulatory 8-h component. In DI rats, only the 24-h rhythm was detected. The mean 24-h rhythm-adjusted mean TSH level was higher in DI than in LE rats (1.38 +/- 0.05 and 1.14 +/- 0.06 micrograms/l respectively, P less than 0.01). The peak TSH response to TRH was significantly increased in DI rats while the pituitary concentration of TSH was also higher (0.93 +/- 0.09 vs 0.39 +/- 0.06 micrograms/mg wet weight in LE, P less than 0.001). Hypothalamic TRH and TRH-DA were similar in both strains. The response to propylthiouracil-induced hypothyroidism was identical in both strains. We conclude that DI rats have a normal pituitary sensitivity to tri-iodothyronine but a central dysfunction in the pituitary environment leading to some alterations of TSH secretion.

Differential effects of passive immunization with somatostatin antiserum on adenohypophysial hormone secretions in starved rats.

The role of somatostatin (SRIF) on adenohypophysial hormone secretion in starved rats was reassessed by passive immunization. Because of the absence of pulsatile GH secretion in starved rats, the effects of the injection of SRIF antiserum on GH levels can be clearly demonstrated. To determine whether starvation modifies the sensitivity of the adenohypophysis to SRIF, we measured 125I-labelled iodo-N-Tyr-SRIF binding. There was no difference in the dissociation constant (Kd) nor in the maximal binding capacity (Bmax) in fed (n = 15) and starved (n = 15) animals (Kd = 0.38 +/- 0.09 (S.E.M.) and 0.45 +/- 0.09 nmol; Bmax = 204 +/- 39 and 205 +/- 30 fmol/mg protein respectively). Administration of SRIF antiserum resulted in a dose-dependent increase in plasma concentrations of GH, TSH and prolactin. The minimal effective dose of SRIF antiserum was 50 microliters for GH, 100 microliters TSH and 200 microliter for prolactin. Our results show that: starvation does not modify adenohypophysial SRIF-binding sites, in starved male rats endogenous SRIF exerts a negative control on prolactin secretion in vivo and sensitivity to endogenous SRIF seems to be different for each hypophysial cell type.

Local control of Leydig cell arginine vasopressin receptor by naloxone.

Arginine vasopressin (AVP) and beta-endorphin are present within the testis where they could act as paracrine effectors of steroidogenesis. In this study we investigated the effect of naloxone, an opioid receptor antagonist on Leydig cell AVP receptor. Intratesticular injection of increasing doses of naloxone (0.1-100 micrograms) resulted 24 h later in a dose-dependent increase in Leydig cell AVP binding capacity. This effect occurred locally since s.c. injection of similar doses of naloxone did not alter the testicular AVP receptor content and intratesticular injection enhanced AVP receptor density only in the naloxone-treated testis but not in the contralateral vehicle-treated testis. Scatchard plot analysis of the data revealed that naloxone locally injected altered AVP binding capacity without change in affinity. These results suggest that in addition to their known paracrine effects in the testis, endogenous opioid peptides may locally control the testicular AVP system by modulating AVP receptor capacity.

Presence in mouse Sertoli cell-conditioned medium of a factor that expresses AVP-like inhibition of steroidogenesis by mouse Leydig cells in long-term culture.

The influence of spent medium from immature mouse Sertoli cells (SCM) on testosterone production by purified Leydig cells was investigated and compared to that of AVP, a potent local modulator of Leydig cell steroidogenesis. SCM inhibited in a dose-dependent manner the hCG-stimulated testosterone production, but was ineffective in basal conditions. As is known for AVP, (i) a lag period of 72 h was prerequisite for SCM to inhibit Leydig cell function; (ii) the main effect of SCM was located at a step beyond the receptor-adenylate cyclase system, since the hCG- and 8-bromo-cAMP-stimulated testosterone productions were similarly affected. The possibility that the effect of SCM may be related to AVP-like molecule(s) is also supported by the observations that at maximal concentrations the inhibitory effects of AVP and SCM were not additive and that the inhibition of testosterone production was largely (65%) reversed by the presence of [(beta-mercapto-beta, beta-cyclopentamethylenepropionyl, O-Me-Tyr2,Arg8)-vasopressin], a selective vasopressor antagonist. These data indicate that Sertoli cells produce in vitro potent inhibitory factors of Leydig cell steroidogenesis. They provide additional evidence that one of these bioactive factors has an effect on Leydig cell function similar to that of AVP.

The Brattleboro rat: normal growth hormone secretion, decreased hepatic growth hormone receptors and low plasma somatomedin activity.

Three-month-old male Brattleboro rats with hereditary diabetes insipidus (DI) present a growth defect; Brattleboro rats were studied together with age-matched Long-Evans (LE) rats. Pituitary growth hormone (GH) content was comparable in both groups of rats. Pulsatile GH release and mean 6 h GH plasma levels did not appear significantly different in chronically catheterized DI and control animals. In parallel with the growth defect, the plasma somatomedin bioactivity was significantly lower in DI than in LE rats. The specific binding of [125I]iodo-hGH to liver microsomal membranes of DI rats was 59.7% that of controls. The number of the GH binding sites rather than the affinity of the binding was decreased. The specific binding of [125I]iodo-insulin was oppositely affected by the DI state: it was 1.5 times higher in liver membranes of DI rats than in membranes of LE rats. These findings make a non-specific effect of the DI state on liver membrane proteins unlikely. The Brattleboro rats present a growth failure without reduction of their GH secretion. The decreased number of the hepatic GH receptors and the subsequent low plasma somatomedin activity could explain the growth retardation of the DI rats.

Somatostatin and regulation of prolactin secretion.

In addition to its classical growth hormone (GH) inhibiting action, somatostatin (SRIF) inhibits prolactin (PRL) secretion in man and rat under specific endocrine conditions. Furthermore, SRIF counteracts the thyrotropin releasing hormone (TRH) and vasoactive intestinal peptide (VIP) stimulated prolactin release from rat adenohypophysis in vitro. Two criteria are needed to demonstrate a physiological role of SRIF in PRL control: specific receptors must be present on prolactin secreting cells, and antagonization of endogenous SRIF must affect PRL secretion in vitro. In fact [125I]N--Tyr--SRIF binds to membranes not only of human GH-secreting adenomas, but also of prolactinomas. Specific binding characteristics are comparable in both cell types, but the density of sites in PRL-secreting adenomas is only one-quarter that in GH-secreting adenomas. In contrast, non-PRL-secreting chromophobe adenomas are devoid of specific binding. On the other hand, administration of SRIF antisera (SRIF-AS) affects both GH and PRL secretion in starved rats (a model in which pulsatile GH secretion is abolished); a marked increase in PRL plasma levels occurs, but the needed SRIF-AS concentration is higher than that for GH disinhibition. This demonstrates that endogenous SRIF may exert a negative control over PRL secretion, although lactotroph cells appear less sensitive to SRIF than somatotrophs. Since the apparent affinity of SRIF binding sites is similar on both GH and PRL secreting cells, at least in human tumor tissues, a lower density of SRIF receptors on PRL cells could account for this reduced responsiveness. Alternatively, different coupling mechanisms may be involved in the two cell types.

Recombinant human follicle-stimulating hormone: a scientific step to clinical improvement.

Urinary-derived follicle-stimulating hormone (FSH) preparations have been used clinically for many years. Although effective, these have a number of disadvantages, not least of which is their variable composition. The availability of recombinant human FSH (r-hFSH), produced from CHO cells, with its constant composition and exceptionally high purity, has, therefore, aroused great interest. This review focuses on the use of r-hFSH for ovarian stimulation in assisted reproduction technology protocols and the treatment of World Health Organization Group I and II anovulation. The use of r-hFSH has been shown to lead to improvements in efficacy over urinary-derived preparations, particularly in assisted reproductive treatment, and a recent meta-analysis has shown higher ongoing pregnancy rates with the recombinant product. Although the two available recombinant products from CHO cells (follitropin alpha [Gonal-F((R))] and beta [Puregon((R))]) are similar from a physicochemical perspective, some minor advantages have been reported for follitropin alpha in relation to pregnancy rates and better local tolerance to injections. The apparent higher bioactivity of r-hFSH has led to reduced total FSH consumption over shorter treatment periods compared with conventional preparations, thus reducing overall exposure for patients. This is likely to confer not only safety benefits, but also cost-effectiveness as demonstrated through pharmaco-economic modelling.