Luca Sabatini

Relevance of basal serum FSH to IVF outcome varies with patient age

Live birth rate (LBR), age and basal serum FSH values were analysed in 1589 women undergoing their first cycle of IVF. Four age groups (<30, 30-34, 35-38, 39-45 years) and three FSH groups (<5, 5-9.9, > or =10 IU/l) were established. Logistic regression analysis was used to determine the effect of age and FSH on live birth. A model to predict the probability of a live birth suggests that an additional 10 years of age reduces the odds for live birth (OR = 0.66, 95% CI 0.48-0.91); an increase of FSH by 5 IU/l reduces the probability of live birth (OR = 0.75, 95% CI 0.61-0.92); women > or =39 years have an additional reduction in probability of live birth (OR = 0.58, 95% CI 0.61-0.92). Analysis by age and FSH categories showed that pregnancy rate (PR) did not change significantly with rising FSH for women <35 years old. In cycles started with serum FSH <5 IU/l, increasing age did not effect PR and LBR. Cycles started with serum FSH > or =10 IU/l had a PR and LBR of 23.6 and 16.9% respectively. The clinical relevance of elevated FSH varies according to age; younger women with elevated FSH and older women with low FSH still have an acceptable LBR.

Does pretreatment with progestogen or oral contraceptive pills in low responders followed by the GnRHa flare protocol improve the outcome of IVF-ET?

AbstractPurpose: Women undergoing in vitro fertilization with lowovarian reserve and poor response to controlled ovarianhyperstimulation (COH) present a management dilemma.In a retrospective observational study, we compared thepretreatment use of the gestogen medroxyprogesterone acetate(10 mg twice daily from day 15 of the cycle for aminimum of 2 weeks) with an oral contraceptive pill (onetablet daily from day 4 of the cycle for a minimum of 3 weeks). Methods: The criteria for inclusion in the study includedone or more of the following: abandoned cycles due topoor response, fewer than four oocytes retrieved followinga standard COH protocol, age >39 years, and elevatedbasal serum follicle-stimulating hormone (FSH).Thirty-eight women received pretreatment with gestogen, and asimilar number of women received pretreatment with thepill. The flare protocol was used in all treatment cyclescombined with an individualized dose of human menopausalgonadotropin (hMG) (4–8 ampoules/day of 75 units FSH/ampoule) depending on previous response, age, and earlyfollicular serum FSH level. Both groups were similar inmean age, duration of infertility, early follicular FSH levels,and the distribution of various aetiologies. Results: Twenty-nine cycles were abandoned before oocyteretrieval, 15 (39.5%) in the pill group and 14 (36.8%) inthe gestogen group, because of an inadequate ovarianresponse. The mean (±SD) number of ampoules (75 IUFSH/ampoule) of hMG used per cycle was similar in thepill and gestogen groups (59.7 ± 19.3 vs. 70.2 ± 29.4,respectively). There also was no difference seen in the numbersof oocytes retrieved (4.4 ± 2.3 vs. 4.2 ± 2.5), totalnumber of embryos (2.5 ± 2.4 vs. 2.2 ± 1.1), or the numberof embryos transferred (1.8 ± 1.2 vs. 2.1 ± 1.0) in the pilland gestogen groups, respectively. One pregnancy in eachgroup resulted following embryo transfer in 22 women inthe pill group and in 24 women in the gestogen group. Conclusions: We conclude that pre-IVF treatment with oralcontraceptive pill or gestogen combined with the flare protocolin women at high risk of or with a history of poor ovarianresponse, as defined in this study, did not appear to resultin an improvement in outcome of IVF-embryo transfer.

Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials

Polycystic ovary syndrome is a common cause of anovulation and infertility, and a risk factor for development of metabolic syndrome and endometrial cancer. Systematic review and meta‐analysis of randomised controlled trials (RCT) that evaluated the effects of inositol as an ovulation induction agent. We searched MEDLINE, EMBASE, Cochrane and ISI conference proceedings, Register and Meta‐register for RCT and WHO trials’ search portal. We included studies that compared inositol with placebo or other ovulation induction agents. Quality of studies was assessed for risk of bias. Results were pooled using random effects meta‐analysis and findings were reported as relative risk or standardised mean differences. We included ten randomised trials. A total of 362 women were on inositol (257 on myo‐inositol; 105 on di‐chiro‐inositol), 179 were on placebo and 60 were on metformin. Inositol was associated with significantly improved ovulation rate (RR 2.3; 95% CI 1.1–4.7; I2 = 75%) and increased frequency of menstrual cycles (RR 6.8; 95% CI 2.8–16.6; I2 = 0%) compared with placebo. One study reported on clinical pregnancy rate with inositol compared with placebo (RR 3.3; 95% CI 0.4–27.1), and one study compared with metformin (RR 1.5; 95% CI 0.7–3.1). No studies evaluated live birth and miscarriage rates. Inositol appears to regulate menstrual cycles, improve ovulation and induce metabolic changes in polycystic ovary syndrome; however, evidence is lacking for pregnancy, miscarriage or live birth. A further, well‐designed multicentre trial to address this issue to provide robust evidence of benefit is warranted.

Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis

OBJECTIVE To systematically review and summarize the existing evidence related to the efficacy and safety of transdermal T in postmenopausal women for the treatment of hypoactive sexual desire disorder (HSDD). DESIGN Systematic reviews and meta-analysis. SETTING Not applicable. PATIENT(S) Seven randomized controlled trials enrolled 3,035 participants; 1,350 women were randomized to treatment with T patch, and 1,379 women were randomized to placebo. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Primary outcome: satisfying sexual episodes. SECONDARY OUTCOMES sexual activity, orgasm, Profile of Female Sexual Function domains (desire), personal distress score, adverse events, acne, increased hair growth, facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction, total adverse events, serious adverse events, withdrawal from study, and follow-up rate. RESULT(S) The T group had significantly more satisfying sexual episodes, sexual activity, orgasms, desire, significant change in Personal Distress Scale score, androgenic adverse events, acne, and hair growth compared with the placebo group. There was no significant difference between the two groups in increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study. CONCLUSION(S) The short-term efficacy in terms of improvement of sexual function and safety of transdermal T in naturally and surgically menopausal women affected by HSDD either on or not on estrogen progestin hormone therapy is evident from this systematic review. The use of transdermal T is associated with increase in androgenic adverse events such as acne but is not associated with any serious adverse events.

Differential Expression of CRH, UCN, CRHR1 and CRHR2 in Eutopic and Ectopic Endometrium of Women with Endometriosis

Endometriosis is considered as a benign aseptic inflammatory disease, characterised by the presence of ectopic endometrium-like tissue. Its symptoms (mostly pain and infertility) are reported as constant stressors. Corticotropin releasing hormone (CRH) and urocortin (UCN) are neuropeptides, strongly related to stress and inflammation. The effects of CRH and UCN are mediated through CRHR1 and CRHR2 receptors which are implicated in several reproductive functions acting as inflammatory components. However, the involvement of these molecules to endometriosis remains unknown. The aim of this study was to examine the expression of CRHR1 and CRHR2 in endometriotic sites and to compare the expression of CRHR1 and CRHR2 in eutopic endometrium of endometriotic women to that of healthy women. We further compared the expression of CRH, UCN, CRHR1 and CRHR2 in ectopic endometrium to that in eutopic endometrium of women with endometriosis. Endometrial biopsy specimens were taken from healthy women (10 patients) and endometrial and endometriotic biopsy specimens were taken from women with endometriosis (16 patients). Τhe expression of CRH, UCN, CRHR1, and CRHR2 was tested via RT-PCR, immunohistochemistry and Western blotting. This study shows for the first time that CRH and UCN receptor subtypes CRHR1β and CRHR2α are expressed in endometriotic sites and that they are more strongly expressed (p<0.01) in eutopic endometrium of women with endometriosis compared to healthy women endometrium at the mRNA and protein level. CRH, UCN, CRHR1 and CRHR2 mRNA were also more highly expressed in ectopic rather than eutopic endometrium (CRH, UCN, CRHR2α: p<0.01, CRHR1β: p<0.05) and protein (CRH and UCN: p<0.05, CRHR1 and CRHR2: p<0.01) in women with endometriosis. These data indicate that CRH and UCN might play an immunoregulatory role in endometriotic sites by affecting reproductive functions such as decidualization and implantation of women with endometriosis.

Assisted conception following radical trachelectomy

BACKGROUND Radical trachelectomy (RT) has been established as a valuable fertility-preserving treatment in women with early stage cervical cancer. A number of these women will require assisted conception which may bring certain challenges to those managing treatment. An awareness of those challenges is essential to maximize outcome in terms of live birth rates. METHODS All women who had undergone assisted conception following RT were assessed with respect to treatment management and pregnancy outcome. RESULTS Pregnancy rates were good, with nine pregnancies in seven women treated. Difficulties in treatment were essentially related to isthmic stenosis. There was a clear need for trial embryo transfer (ET) prior to treatment and dilatation of the isthmus where necessary. The premature delivery rate was high (75% at <37 weeks), highlighting the importance of single ET to avoid multiple pregnancy. CONCLUSIONS Assisted conception following RT is associated with a good pregnancy rate, although there is a high miscarriage and premature delivery rate. Treatment outcome should be maximized by careful patient preparation in terms of assessing the need for isthmic dilatation, and ET should be performed by an experienced operator.

The correlation between basal serum follicle-stimulating hormone levels before embryo cryopreservation and the clinical outcome of frozen embryo transfers

OBJECTIVE To evaluate the correlation between basal serum FSH level before the fresh IVF/intracytoplasmic sperm injection (ICSI) cycle and the clinical outcome of the subsequent frozen embryo replacement cycles. DESIGN Retrospective observational study. SETTING University tertiary referral center, London, United Kingdom. PATIENT(S) Five hundred four consecutive frozen embryo transfer (FET) cycles where serum FSH levels were obtained, on days 1-4 of the cycle before the fresh IVF +/- ICSI cycles. INTERVENTION(S) Frozen-thawed embryo transfer. MAIN OUTCOME MEASURE(S) Clinical pregnancy (CP) and live birth (LB). RESULT(S) Basal serum FSH in 127 women (25.2%) who had a CP was significantly lower compared with that in women who did not have a CP. Multivariate regression analysis showed significant correlation between basal serum FSH levels and clinical pregnancy and a low significance to LB, but there was no statistical significant differences between women who had a CP and those who did not with regard to age, treatment protocol (natural or hormone treatment cycle), or the freeze-thaw interval. The LB rate was higher in natural cycles (n = 71; 21.2%) than in hormone treatment cycles (n = 28; 16.7%). Conceiving in the fresh cycle had a positive influence on the FET outcome. CONCLUSION(S) Basal serum FSH level before fresh IVF/ICSI cycle is inversely correlated to a CP outcome in FET cycles. A trend was present between FSH levels and LB, but this failed to reach statistical significance.

Galectin-1 Overexpression in Endometriosis and Its Regulation by Neuropeptides (CRH, UCN) Indicating Its Important Role in Reproduction and Inflammation

Endometriosis is an inflammatory disease of women of reproductive age featured by the presence of ectopic endometrium and is strongly related to infertility. Galectins, carbonhydrate-binding proteins, have been found to have pro- or anti-inflammatory roles in the reproductive tract and in pathological conditions concerning infertility. Galectin-1, which is expressed at endometrium and decidua, plays a major role in implantation and trophoblast invasion. Also, the neuropeptides, corticotropin releasing hormone (CRH) and urocortin (UCN) and their receptors are expressed in eutopic and ectopic endometrium showing a differential expression pattern in endometriotic women compared to healthy ones. The aim of this study was to examine the galectin-1 expression in endometriotic lesions and compare its expression in eutopic endometrium of endometriotic and healthy women. Furthermore, we examined the effect of CRH and UCN in galectin-1 expression in Ishikawa cell line and macrophages and investigated the implication of CRHR1 in these responses. Eutopic and ectopic endometrium specimens, Ishikawa cell line and mice macrophages were used. Immunohistochemistry and western blot analysis were performed in order to identify galectin-1 expression in ectopic and eutopic endometrium of women with and without endometriosis and the regulatory effect of CRH and UCN on galectin-1 expression. This study presents for the first time that galectin-1 is overexpressed in endometriotic lesions compared to eutopic endometrium of endometriotic women and is more abundantly expressed in eutopic endometrium of disease women compared to healthy ones. Furthermore, it is shown that CRH and UCN upregulate galectin-1 expression in Ishikawa cell line and macrophages and this effect is mediated through CRHR1. These results suggest that galectin-1 might play an important role in endometriosis pathology and infertility profile of women suffering from endometriosis by being at the same time regulated by CRH and UCN interfering in the immune disequilibrium which characterizes this pathological condition.

The management of hydrosalpinges: tubal surgery or salpingectomy?

Purpose of review The clinical management of hydrosalpinges in infertile patients remains a contentious issue. This review aims to provide a critical analysis on the available treatments for hydrosalpinges, which have recently created a fierce debate between the promoters of salpingectomy and in-vitro fertilization and those who endorse tubal surgery. Recent findings Hydrosalpinges have a detrimental effect on the outcome of in-vitro fertilization yet their mechanism is still unclear. Salpingectomy prior to in-vitro fertilization restores the likelihood of a successful outcome in a well defined group of patients with ultrasound-visible hydrosalpinges. However, not every woman with large hydrosalpinges should undergo salpingectomy as some fallopian tubes may be amenable to surgical repair. Preserved tubal mucosa indicates a good prognosis for tubal surgery, therefore an appropriate mucosal assessment should be routine prior to deciding upon further management. Summary As salpingectomy is a definitive procedure it should be performed when the hydrosalpinges are beyond repair or in cases of in-vitro fertilization failure. Tubal surgery should be preferred to salpingectomy in mild to moderate tubal disease. A comparative study of restorative tubal surgery versus salpingectomy and in-vitro fertilization in selected women with hydrosalpinges is needed and will significantly help this debate. Prophylactic salpingectomy prior to in-vitro fertilization and tubal surgery is not competing but complementary in the treatment of hydrosalpinges-related infertility.

Can the fall in serum FSH during coasting in IVF/ICSI predict clinical outcomes?

This retrospective cohort study determined whether the total falls in serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection could predict clinical outcomes. Ninety-nine cycles, with gonadotrophin-releasing hormone-agonist down-regulation where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of severe ovarian hyperstimulation syndrome, were consecutively included. The primary clinical outcome was live-birth rate (LBR); other outcomes measured were number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates. LBR for FSH fall>10 IU/l compared with 5-10 and<5 IU/l were 45.4% versus 22.0% and 25.0%, respectively. Mean serum FSH fall was similar with and without live birth (8.4 ± 6.2 versus 7.3 ± 5.0 IU/l) as were mean oestradiol and FSH concentrations on HCG administration, oestradiol fall, percentage fall in FSH/oestradiol and duration of coasting. None of the variables efficiently predicted live birth on regression analysis. The AUC of FSH fall was 0.53 at 11.0 IU/l. Basal FSH, starting and total gonadotrophin dose and duration of coasting were positively correlated with FSH fall. A potentially clinically important association between live birth and FSH fall during coasting was apparent, which requires further evaluation. The purpose of this retrospective cohort study was to determine whether the magnitude of fall in the serum FSH and oestradiol concentrations from start to end of coasting in IVF/intracytoplasmic sperm injection cycles could predict the clinical outcomes. Gonadotrophin-releasing hormone-agonist down-regulated cycles (n=99), where coasting with serial serum oestradiol and FSH monitoring was adopted due to risk of ovarian hyperstimulation, were consecutively included. Live birth was the primary clinical outcome measured; number of oocytes retrieved and fertilization, implantation and clinical pregnancy rates were the other outcomes examined. Live-birth rate tended to be high when FSH fall was >10 IU/l, compared with 5-10 IU/l and <5 IU/l, although not statistically significantly. Mean serum FSH fall were similar in live-birth and no-live-birth cycles (8.4 ± 6.2 versus 7.3 ± 5.0) as were mean oestradiol and FSH concentrations on hCG administration, oestradiol fall, percentage fall in FSH and oestradiol and duration of coasting. None of the variables efficiently predicted live birth. The area under the curve of FSH fall was 0.53. FSH fall of <11.0 IU/l was found to be more likely to predict negative outcome (specificity 84.72%) than predicting positive outcome when FSH fall was >11 IU/l (sensitivity 34.48%). Womens basal FSH, starting and total gonadotrophin dose of ovarian stimulation and duration of coasting had direct positive correlation with the magnitude of FSH fall. A potentially clinically important rise in live birth in association with greater FSH fall during coasting was apparent, which requires further evaluation.