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The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders
Abstract
To investigate the effectiveness of treatment with transdermal testosterone gel (TTG) before controlled ovarian stimulation (COS) using GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection (ICSI).
Prospective randomized controlled trial.
University-affiliated infertility clinic.
A total of 110 low responders, who were defined as patients who failed to produce ≤ 3 follicles with a mean diameter of ≥ 16 mm with the result that ≤ 3 oocytes were retrieved despite the use of a high gonadotropin dose (>2,500 IU) in a previous failed IVF/ICSI cycle.
Patients were randomized into TTG pretreatment group or control group. For TTG pretreatment group, 12.5 mg TTG were applied daily for 21 days in the cycle preceding COS for IVF.
COS results and IVF outcome.
There were no differences in patients' characteristics between the two groups. Total dose and days of rhFSH used were significantly fewer in the TTG pretreatment group than in the control group. The numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were significantly higher in the TTG pretreatment group. Embryo implantation rate and clinical pregnancy rate per cycle initiated also were significantly higher in the women pretreated with TTG. No patient reported adverse effects attributed to TTG use.
TTG pretreatment might be beneficial in improving both response to COS and IVF outcome in low responders undergoing IVF/ICSI.
... Kim et al. (6) , in a large RCT including 110 patients showed that testosterone pretreatment (12.5 mg/day for 21 days) significantly increased the number of oocytes retrieved (mean difference: +1.60 COCs, 95% CI: +0.97 to +2.23) in poor responders as compared with no pretreatment. The same author in 2014 (Kim et al., 2014) studied the effect of testosterone pretreatment in 120 poor responders relatively to the duration of its administration (no pretreatment, 2, 3, and 4 weeks of testosterone pretreatment). ...
... Kim et al. (6) , found that the clinical pregnancy rates per cycle initiated and per cycle ET were also significantly higher in the TTG pretreatment group than in the control group (P=. 041 and P=.045, respectively). ...
... The number of patients with ovum retrieval tended to be higher in Group 1 than in Group 2 (80.6% versus 58.1% ,P = 0.09), the difference reaching statistical significance (81.2% versus 41.1%, P < 0.05) when only patients having normal basal FSH levels (16 and 17 patients in Groups 1 and 2, respectively) were considered. He observed six live births in the intervention group (n = 31) compared with four live births in the control group (n = 31), whereas (Kim et al. 2011) reported 15 (n = 55) and seven (n = 55), respectively. ( Kim et al.2014), reported that The numbers live birth rates were significantly higher in 4 weeks TTG treatment group than those in control group in the previous 1,2 and 3 weeks 30.0% ...
... No statistically significant differences were observed after testosterone pretreatment in the current trial and the previous trial without testosterone regarding baseline patient characteristics. 6 Atretic Table (4) shows that there was a higher number of oocytes recruited in the second trial. However, no statistically significant difference was found between first and second trial regarding outcome of ovarian stimulation. ...
... On the contrary of our study, Kim et al. (6) , in a large RCT including 110 patients showed that testosterone pretreatment (12.5 mg/day for 21 days) significantly increased the number of oocytes retrieved (mean difference: +1.60 COCs, 95% CI: +0.97 to +2.23) in poor responders as compared with no pretreatment. The same author in 2014 Kim et al. (7) , studied the effect of testosterone pretreatment in 120 poor responders relatively to the duration of its administration (no pretreatment, 2, 3, and 4 weeks of testosterone pretreatment). ...
... Fábregues et al. (8) observed six live births in the intervention group (n = 31) compared with four live births in the control group (n = 31), whereas Kim et al. (6) reported 15 (n = 55) and seven (n = 55), respectively. ( Kim et al.2014), reported that The numbers live birth rates were significantly higher in 4 weeks TTG treatment group than those in control group in the previous 1,2 and 3 weeks 30.0% ...
... Also, in order to not promote the excessive elevation of serum testosterone concentrations, we chose to use 25 mg every 48 hours (and not daily), associated with COC containing progestin levonorgestrel (Level®), since COCs cause the elevation of SHBG, with a consequent reduction in free concentrations of sex steroids 28 . The choice for the period of use (60 days prior to COS), which is longer than that described in surveys that investigated the effectiveness of transdermal testosterone in poor responders [11][12][13][14][15][16][17][29][30][31] , was due to the fact that studies in non-human primates show a potential beneficial role of testosterone since the beginning of folliculogenesis 6 . ...
... We found that the use of transdermal testosterone at a dose of 25 mg, given as one sachet every 48 hours, caused mild adverse effects, mainly represented by irregular vaginal bleeding, breast tenderness, and oily skin and acne. This dose of transdermal testosterone given in the present study was higher than those used in other studies in potentially poor responders [11][12][13][14][15][16]29,30 and was administered for a longer period of time as compared to previously described in the literature (maximum time of 4 weeks, in the study by Kim et al.) 15 . ...
... Although our findings suggest the possible need for a higher total dose of gonadotropins and longer duration of COS by patients in the Testosterone Cycle, they did not present a statistical difference. These findings differ from some studies, which have shown that transdermal testosterone use requires a lower total dose of gonadotropins and a shorter duration of COS 12,14,15,29 . ...
... Eight randomized controlled studies (Al-Jeborry, 2019; Bosdou et al., 2016;Doan et al., 2017;Hoang et al., 2021;Kim et al., 2014;Kim et al., 2011;Massin et al., 2006;Subirá et al., 2021) published between 2006 and 2021 were eligible for the systematic review, including a total of 797 women. The number of included patients ranged from 50 to 132. ...
... Randomization method and allocation concealment were reported in six (Bosdou et al., 2016;Hoang et al., 2021;Kim et al., 2014;Kim et al., 2011;Massin et al., 2006;Subirá et al., 2021) and in three (Hoang et al., 2021;Kim et al., 2014;Kim et al., 2011) out of the eight studies, respectively. Definition of poor ovarian response, as well as the primary outcome varied among studies. ...
... Randomization method and allocation concealment were reported in six (Bosdou et al., 2016;Hoang et al., 2021;Kim et al., 2014;Kim et al., 2011;Massin et al., 2006;Subirá et al., 2021) and in three (Hoang et al., 2021;Kim et al., 2014;Kim et al., 2011) out of the eight studies, respectively. Definition of poor ovarian response, as well as the primary outcome varied among studies. ...
A systematic review and meta-analysis was performed aiming to identify good quality randomized controlled trials (RCTs) evaluating testosterone pretreatment in poor responders. Eight RCTs were analyzed, evaluating 797 women. Transdermal testosterone gel was used in all studies with a dose ranging from 10 to 12.5 mg/day for 10 to 56 days. The main outcome measure was achievement of pregnancy, expressed as clinical pregnancy or live birth. Testosterone pretreatment was associated with a significantly higher live birth (RR: 2.07, 95% CI: 1.09 to 3.92) and clinical pregnancy rate (RR: 2.25, 95% CI: 1.54 to 3.30), as well as a significant increase in the number of cumulus–oocyte complexes (COCs) retrieved. Significantly less days to complete ovarian stimulation, a lower total dose of gonadotrophins, lower cancellation rate due to poor ovarian response and a thicker endometrium on the day of triggering final oocyte maturation were observed. No significant differences were observed in estradiol levels, in the numbers of follicles ≥17 mm, of metaphase II, of 2-pronuclei oocytes, of embryos transferred and in the proportion of patients with embryo transfer. The current study suggests that the probability of pregnancy is increased in poor responders pretreated with transdermal testosterone undergoing ovarian stimulation for IVF.
... Evidence for the importance of AR during the early stages of folliculogenesis derives from several mammalian species. In humans, the significance of the AR is highlighted by infertility treatment protocols that include androgens to promote follicular growth in women seeking fertility assistance [20][21][22][23][24][25][26][27][28]. In cases of hypoandrogenism, diminished ovarian reserve, premature ovarian aging, and reduced fertility have been observed, indicating that AR is essential for optimal ovarian health and function [29,30]. ...
... In humans, the importance of AR in follicular growth becomes evident with the beneficial effects of androgens in assisted reproductive technology outcomes [20][21][22][23][24][25][26][27]. Although the mechanism remains elusive, it has been suggested that androgen priming of women seeking fertility treatment promotes follicle growth resulting in an increase in the FSH-sensitive follicle pool [82]. ...
... Gene expression studies in human small antral follicles reveal significant association of AR and FSHR levels, suggesting that the increase in follicle growth could be mediated through regulating AR transcription in granulosa cells [79,82]. Epidemiological studies have shown that upon androgen pretreatment, increase in the number of antral follicles and mean follicular diameter were observed [21,28]. This increase supports the hypothesis that androgen receptor signaling is important for early follicle growth. ...
We recently proposed to formally recognize Key Event Relationships (KERs) as building blocks of Adverse Outcome Pathways (AOPs) that can be independently developed and peer-reviewed. Here, we follow this approach and provide an independent KER from AOP345, which describes androgen receptor (AR) antagonism leading to decreased female fertility. This KER connects AR antagonism to reduced granulosa cell proliferation of gonadotropin-independent follicles (KER2273). We have developed both the KER and the two adjacent Key Events (KEs). A systematic approach was used to ensure that all relevant supporting evidence for KER2273 was retrieved. Supporting evidence for the KER highlights the importance of AR action during the early stages of follicular development. Both biological plausibility and empirical evidence are presented, with the latter also assessed for quality. We believe that tackling isolated KERs instead of whole AOPs will accelerate the AOP development. Faster AOP development will lead to the development of simple test methods that will aid screening of chemicals, endocrine disruptor identification, risk assessment, and subsequent regulation.
... 32 This review incorporated four RCTs comparing testosterone with either placebo 73 or no treatment. [74][75][76] All studies included women who had a previous poor response to IVF, but the definition of this was variable. Furthermore, the studies were generally small, incorporating between 50 and 120 participants. ...
... rates. However, three studies were considered to be at high risk of performance bias [74][75][76] and after their removal, the significance of the association between pretreatment with testosterone and either a clinical pregnancy (OR: 2.09, 95% CI: 0.35-12.51) or live birth (OR: 2.00, 95% CI: 0.17-23.49) ...
... In addition to the differences described earlier, the study by Saharkhiz et al utilized testosterone gel only during stimulation and not at all prior to the onset of treatment. 78 Although the summary estimates for five of the six studies favor the use of testosterone in women with predicted or prior POR, [73][74][75][76]78 only one reported a significantly increased clinical pregnancy rate. 75 We undertook a meta-analysis incorporating these six studies that compared testosterone with placebo or no treatment in 443 women with predicted or proven POR (►Figs. ...
Androgen priming with either dehydroepiandrosterone (DHEA) or testosterone has been suggested as an adjunct to improve in vitro fertilization (IVF) outcomes in women with diminished ovarian reserve (DOR). Numerous studies have investigated the effects of both DHEA and testosterone on IVF outcome. The results were inconsistent, and the quality of most studies is substandard. Meta-analyses have consistently reported that DHEA does appear to significantly improve IVF outcome in women with predicted or proven poor ovarian response (POR), but these have included some normal responders and/or nonrandomized studies. Our meta-analyses including randomized controlled trials (RCTs) incorporating only women with DOR or POR suggest that DHEA confers no benefit. While meta-analyses of RCTs on the use of testosterone in women with DOR or POR showed an improved IVF outcome, most studies included are of low quality with high risk of bias. When analysis of data from studies of only low-risk bias was performed, such a benefit with testosterone was not observed. Although recruitment may well be a challenge, a large, well-designed RCT is, however, still warranted to investigate whether or not androgen priming with either DHEA or testosterone should be recommended as an adjuvant treatment for women with DOR or POR undergoing IVF.
... Peak serum T levels are achieved in early adulthood and show a decline with age as AMH 14 . Furthermore, studies have revealed that T supplementation may have a positive effect on antral follicle count (AFC) in poor ovarian responders (PORs) 15,16 and T suppression by oral contraceptives might decrease the number of antral follicles and even serum AMH levels in polycystic ovary syndrome (PCOS) patients 17,18 . ...
... The overall proportions of subjects who met the criteria for diminished ovarian reserve (DOR, AMH < 1.2 ng/mL) and excess ovarian reserve (EOR, AMH ≥ 5.0 ng/mL) were 16 (142/317), respectively (Fig. 2b). Multiple logistic regression analyses revealed that the ORs for the risk of EOR dose-dependently increased across increasing T quartile categories, and the odds for the risk of EOR were 10.41-fold higher in subjects in Q4 than in those in Q1 after adjustment for potential confounders (Table 3). ...
... In a randomized controlled trial of 110 PORs undergoing IVF cycle, Kim et al. reported that pretreatment with transdermal T gel signi cantly increased AFC and reduced the day of stimulation and total dosage of gonadotropins. In addition, the numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were signi cantly higher in the T pretreatment group than in the control group 16 . A metaanalysis of 7 randomized controlled trials conducted by Noventa and colleagues revealed that PORs receiving T therapy demonstrated higher numbers of total oocytes, MII oocytes and total embryos, as well as a higher clinical pregnancy rate and live birth rate than controls 47 . ...
Anti-Mullerian hormone (AMH) and testosterone (T) both play distinct roles in the early stages of folliculogenesis. However, the relationship between serum T and AMH levels is poorly understood. This study aimed to investigate the association between serum T and AMH levels in infertile women. A total of 1,935 infertile women aged 20 to 46 years were included in the cross-sectional study and divided into four quartile groups (Q1 to Q4) based on serum T levels. Compared to the subjects in the highest T quartile (Q4), those in the lowest T quartile (Q1) showed significantly lower AMH levels. After adjustment for age, body weight, body mass index and FSH, increasing T quartile categories were associated with higher AMH levels. Binary logistic regression analyses revealed that the odds for the risk of diminished ovarian reserve (DOR) were 11.44-fold higher in Q1 than in Q4 and the odds for the risk of excess ovarian reserve (EOR) were 10.41-fold higher in Q4 than in Q1. Our data show that serum T levels are positively associated with serum AMH levels and suggest that androgen insufficiency may be a potential risk factor for DOR; androgen excess may lead to EOR in infertile women.
... Testosterone plays an important role in maintaining female fertility because it stimulates the recruitment of follicles during their early stages [20,21]. Experimental studies using rhesus macaques have suggested that androgens amplify the effect of FSH on folliculogenesis and have shown that the administration of testosterone in these animals increases the number of FSH receptors in the membranes of the granulosa cells, which, in turn, stimulates the initial follicular growth [22]. ...
... It is important to note that the main objective of hormonal contraceptives is to keep the endogenous levels of estrogens and progestogens constant [28]. Usually, hormonal contraceptive users also show a marked decline in estradiol levels [20]. When women receive an intramuscular shot of CHC, a peak in estradiol level is observed lasting for up to six days. ...
... Error bars represent standard error. that S. libidinosus presents the same physiological alterations as women do when administered with CHC [20]. ...
This study aimed at evaluating the availability of the primate Sapajus libidinosus as an animal model for research assessing the physiological effects of the continuous use of combined hormonal contraceptives. In order to do this, six reproductively active female S. libidinosus from the Primate Research Center of the University of Brasília were selected to take part in this experiment. Every 21 days or so, each female received a single dose of combined hormonal contraceptive (algestone acetophenide and 17-enanthate estradiol) in a total of five doses throughout the experiment. The physiological parameters were accessed by means of 13 blood samples from each female, whereas three were gathered during the baseline and 10 samples were collected during the treatment phase. The results showed that the contraceptive use provoked changes in hematological coagulation factors such as an increase in the amount of platelets ( p=0.039 ) and a reduction in both prothrombin ( p<0.001 ) and thromboplastin coagulation time ( p<0.001 ). These results are similar to what has been observed in human patients; thus, it is concluded that S. libidinosus can be successfully used in studies about the physiological impact of hormonal contraceptives.
... Contrary to DHEA, testosterone is an androgen with a high affinity with androgen receptor that directly binds to the receptor. A systematic review of the literature identified previous small RCTs to increase the reproductive outcomes of IVF patients [32][33][34] ( Table 1). Nevertheless, a significant shortcoming in most of these published studies is the lack of consistency in the mode and duration of administration. ...
... Nevertheless, a significant shortcoming in most of these published studies is the lack of consistency in the mode and duration of administration. Transdermal testosterone has been used in most of the studies in relatively high doses before ovarian stimulation with a duration ranging from 5 to 21 days [33][34][35][36]. Nonetheless, this might not be consistent with the folliculogenesis process in humans, given that the transition from the preantral to antral follicles lasts approximately 65-85 days [37,38]. ...
... On the other hand, doses as high as 12.5 mg per day, that have been adopted in the past [33][34][35], may not be the proper dose needed. Although previous studies have shown that high doses may affect the number of oocytes [33], others failed to demonstrate any impact [34,35]. ...
Purpose of review:
The purpose of this review is to provide an overview of androgen supplementation in ART with the most updated evidence, from animal studies to its clinical applications in poor ovarian responders (POR) and the future studies to be published.
Recent findings:
Animal studies, has shown that testosterone supplementation, can be an option to increase the recruitable follicular pool in POR. However, the potential mechanism of action, dose, and duration of treatment is still under investigation. Early studies in humans reported promising results in favor of androgens [dehydroepiandrosterone (DHEA) or testosterone] in POR. Nevertheless, recent evidence does not appear to follow the initial results, whereas the type, dose, and duration of testosterone administration appear to be crucial for treatment effect.
Summary:
Testosterone seems to play an essential role in regulating ovarian function. However, it is worrisome that androgens are used off-label, despite that the available evidence is weak. Although testosterone supplementation may be beneficial in POR, published studies have used inconsistent doses and duration of administration. An ongoing trial (T-TRANSPORT trial) for the first time aims to provide conclusive evidence on whether transdermal testosterone administration can improve the reproductive outcomes in patients undergoing IVF/ICSI.
... Transdermal testosterone (TT) has been used at different doses and in different stimulation protocols (Bosdou et al., 2016;Kim et al., 2011;Fàbregues et al., 2009;Massin et al., 2006). However, it is difficult to establish its efficacy with sufficient evidence (Polyzos et al., 2018). ...
... Transdermal testosterone has been shown in previous small RCTs to increase the reproductive outcomes of IVF/ICSI patients (González-Comadran et al., 2012). In most of these studies, transdermal testosterone in relatively high doses was administered before ovarian stimulation with a duration varying from 5 to 21 days (Bosdou et al., 2016;Kim et al., 2011;Fàbregues et al., 2009;Massin et al., 2006). ...
... Studies suggest that IGF-I appears to mediate or facilitate the effect of TT on early follicle development, and also improves oocyte and embryo quality (Meldrum et al., 2013). IGF-I stimulation by testosterone may explain the unusually high implantation rates reported in some studies with treatments aimed at increasing the exposure of any kind of testosterone to ovarian follicles in poor responders (Bosdou et al., 2012;Kim et al., 2011). ...
Objective
Transdermal testosterone has been used in different doses and in different stimulation protocols in poor responders. The aim of the present study is to compare the luteal estradiol/GnRH antagonists protocol versus long GnRH agonists in poor responder patients according to the Bologna criteria, in which transdermal testosterone has been used prior to the stimulation with gonadotropins.
Methods
In this retrospective analysis, a total of 141 poor responder patients according to the Bologna criteria were recruited. All patients were treated with transdermal testosterone preceding ovarian stimulation with gonadotropins during 5 days. In 53 patients we used the conventional antagonist protocol (Group 1). In 88 patients (GrH pituitary suppression was achieved by leuprolide acetate according to the conventional long protocol (Group 2). We analyzed the ovarian stimulation parameters and IVF outcomes.
Results
Comparing groups 1 and 2, there were no significant differences between cancellation rates and number of oocytes retrieved. However the total gonadotropin dose used and the mean length of stimulation were significantly lower in group 1 when compared to group 2. There were no significant differences in pregnancy outcomes; however, there was a slight increase in the implantation rate in group 1 vis-a-vis group 2, although statistical significance was not achieved.
Conclusion
TT in poor responder patients can be effective both with the conventional agonist's long protocol and with the conventional antagonist's protocol. However, short regimes with previous estradiol antagonists in the luteal phase facilitate ovarian stimulation by shortening the days of treatment and the consumption of gonadotropins
... We examined the full text of 18 remaining manuscripts, and, of these, we excluded 10 papers-one paper due to the lack of data concerning CPR and/or LBR [27], one trial reported data not analyzable [28], three papers because the design was observational [29][30][31], and six papers because they were review/metaanalysis [11-13, 21, 32, 33]. Finally, 7 manuscripts were included in the meta-analysis [10,[22][23][24][34][35][36]. See Fig. S1. ...
... One study was double-blinded [36], and two were single-blinded [10,24]. The remaining ones were open-label studies [22,23,34,35]. Two studies were placebo-controlled [24,36]; the remaining were treatment versus no treatment [10,22,23,34,35]. ...
... The remaining ones were open-label studies [22,23,34,35]. Two studies were placebo-controlled [24,36]; the remaining were treatment versus no treatment [10,22,23,34,35]. ...
... We examined the full text of 18 remaining manuscripts, and, of these, we excluded 10 papers-one paper due to the lack of data concerning CPR and/or LBR [27], one trial reported data not analyzable [28], three papers because the design was observational [29][30][31], and six papers because they were review/metaanalysis [11-13, 21, 32, 33]. Finally, 7 manuscripts were included in the meta-analysis [10,[22][23][24][34][35][36]. See Fig. S1. ...
... One study was double-blinded [36], and two were single-blinded [10,24]. The remaining ones were open-label studies [22,23,34,35]. Two studies were placebo-controlled [24,36]; the remaining were treatment versus no treatment [10,22,23,34,35]. ...
... The remaining ones were open-label studies [22,23,34,35]. Two studies were placebo-controlled [24,36]; the remaining were treatment versus no treatment [10,22,23,34,35]. ...
Purpose
The aim of the present systematic review and meta-analysis was to summarize evidence on the effectiveness of testosterone supplementation for poor ovarian responders (POR) on IVF outcomes. The primary outcome was live birth rate (LBR); secondary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR), total and MII oocytes, and total embryos.
Methods
This meta-analysis of randomized controlled trials (RCTs) evaluates the effects of testosterone administration before/during COS compared with a control group in patients defined as POR. The primary outcome was live birth rate (LBR); secondary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR), total and MII oocytes, and total embryos. Pooled results were expressed as risk ratio (RR) or mean differences (MD) with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroup analysis. All analyses were performed by using the random-effects model.
Results
Women receiving testosterone showed higher LBR (RR 2.29, 95% CI 1.31–4.01, p = 0.004), CPR (RR 2.32, 95% CI 1.47–3.64, p = 0.0003), total oocytes (MD = 1.28 [95% CI 0.83, 1.73], p < 0.00001), MII oocytes (MD = 0.96 [95% CI 0.28, 1.65], p = 0.006), and total embryos (MD = 1.17 [95% CI 0.67, 1.67], p < 0.00001) in comparison to controls, with no difference in MR (p = ns). Sensitivity and subgroup analysis did not provide statistical changes to the pooled results.
Conclusions
Testosterone therapy seems promising to improve the success at IVF in POR patients. Further RCTs with rigorous methodology and inclusion criteria are still mandatory.
... Jeaheng et al. (2020) indicated that trust is a substantial prerequisite for travelers to choose a tourist destination. Thus, the tourism and hospitality players rely on constructing some solid partnerships between the destination practitioners and tourists (Kim et al., 2011;Jeaheng et al., 2020). Furthermore, destination trust has a significant influence on the psychological mood of tourists where it leads to magnify the travel intention (Wenping and Chunxiao, 2014). ...
... Slovic (1993) pointed out that once trust is lost, it is difficult to re-establish. As it is extensively known that trust plays an important role in forming tourist satisfaction and loyalty to a destination (Orth and Green, 2009;Kim et al., 2011;Artigas et al., 2017), the goal of this study is to continuously build destination trust by using vaccine passports. Tourists are widely preferred to visit places that they perceive to be trustworthy (Al-Ansi and Han, 2019). ...
To ensure a smooth and rapid recovery of tourism, countries around the world are stepping up vaccinations against COVID-19. China, in particular has a very high vaccination rate due to its own vaccine production. Following this trend, many countries have started introducing vaccine passports as an alternative solution to verify valid and vaccinated travelers. This study attempted to understand the fundamental perceptions of travelers’ intentions using vaccine passports. A total of 601 samples were investigated and analyzed. As a result, four factors were identified: perceived usefulness, destination trust, risk perception, and perception of incentives. Also, this study performed means comparisons analysis with the major demographic characteristics of respondents. Based on this study, it is expected that the results will contribute to the revival of the travel industry in the future and provide valuable implications for marketing plans to help the travel industry suffer from COVID-19.
... oocytes were retrieved following standard treatment. 5 Assuming the same rate of retrieval holds good in this study, a sample size of 35 in each group will detect significant difference between testosterone gel and standard with 90% power at 5% level of significance. Considering a dropout rate of 10%, a total of 35 patients in each group were recruited. ...
... In 2011, Kim et al conducted a randomized controlled trial in 110 poor responders and reported an increase in the number of oocytes retrieved and pregnancy rates in the testosterone group. 5 In a similar trial in 2016, Bosdou et al reported no significant difference in the number of cumulus oocyte complexes retrieved, fertilization rates and live birth rates between the testosterone and control groups. 10 One other trial in 2017 by HT Doan et al showed an increase in the number of oocytes retrieved, number of embryos, pregnancy rate, and embryo implantation rate in testosterone gel group compared to control group. ...
Background: Dealing with poor ovarian responders is the newest challenge for the present-day reproductive physicians. Androgens are said to increase pregnancy outcomes due to enhanced oocyte retrieval in poor responders. The aim of the study was to measure the effect of transdermal testosterone gel in women with unexplained poor ovarian response.Methods: It was a prospective randomized controlled trial with active control conducted at ART centre, department of obstetrics and gynaecology, AIIMS, New Delhi from August 2017-August 2018. Seventy women with previously failed IVF/ICSI who had ≤5 oocyte retrieval in previous cycle having normal ovarian reserve with normal or low testosterone levels were randomized. Study arm (N=35) received testosterone gel pre-treatment whereas the control arm (N=35) received standard treatment. GnRH antagonist stimulation protocol was followed. The number of oocytes retrieved and pregnancy outcomes were studied.Results: Of the 70 women in the study, the number of oocytes retrieved was significantly higher (6.5±5.8 vs 3.1±2.1; p=0.002), cycle cancellation rate was lower (8.6% vs 22.9%; p=0.094), implantation rate (8.2% vs 2.6%; p=0.228), clinical pregnancy, ongoing pregnancy, live birth rates (14.7% vs 2.9%; p=0.092) and take home baby rates (17.6% vs 2.9%; p=0.049) were higher in testosterone group compared to controls. One woman in testosterone group developed mild OHSS.Conclusions: The study shows that transdermal testosterone gel is found to improve oocyte retrieval significantly in unexpected poor responders, although there was not a significant improvement in pregnancy outcomes. Hence further studies are of utmost importance to establish the effectiveness of the gel.
... One of the key questions seems to be the duration of the exposure to testosterone before starting ovarian stimulation, especially if the duration of human folliculogenesis (70-80 days) is accounted for, and the fact that androgens seem to be a determinant for the growth of primary follicles into secondary and pre-antral follicles (Walters, 2015). The duration and dose of testosterone used in studies has been heterogeneous, with most only using testosterone during the previous luteal phase of the ovarian stimulation cycle (Balasch et al., 2006;Massin et al., 2006;Fábregues et al., 2009;Kim et al., 2011;Marzal Escriva et al., 2015;Bosdou et al., 2016). It could be argued, however, that considering the prolonged folliculogenesis, short regimens only acting for a few days before starting ovarian stimulation will not be effective in restoring this androgen depletion at the primary follicular level and, therefore, this might be the reason why testosterone has not been proven effective in a number of studies. ...
... Studies published over 10 years ago used heterogenous definitions of POR (before the widespread use of Bologna criteria), and testosterone dose and duration of treatment were not comparable. Some of them reported improvement in number of oocytes retrieved (Balasch et al., 2006;Kim et al., 2011), whereas others only found significant differences in other cycle parameters, such as duration of stimulation or gonadotrophin consumption (Fábregues et al., 2009). Surprisingly, some studies did not report better ovarian response but higher implantation and pregnancy rates (Marzal Escriva et al., 2015), which could mean a beneficial effect not mediated by the number of oocytes, such as oocyte quality. ...
Research Question
Does testosterone administration, either in a long or short-course, prior to IVF increase the number of mature oocytes retrieved in poor ovarian response (POR)?
Design
Single-center, single-blinded randomized controlled trial. POR according to Bologna criteria. Fertility Unit of University Hospital. N=63. Three arms: Group 1 (long-testosterone, N=17) 12.5 mg/day testosterone gel during 56 days before controlled ovarian stimulation (COS), Group 2 (short-testosterone, N=16) 12.5 mg/day testosterone gel during 10 days before COS and Group 3 (control, no intervention). Primary outcome was number of mature oocytes retrieved. Secondary outcomes included other cycle parameters: duration of stimulation, antral follicle count (AFC), number of follicles >16 mm, total oocytes retrieved, testosterone levels.
Results
The number of mature oocytes retrieved did not differ between the 3 groups (2.16, 2.71 and 2.91, p=0.719, groups 1, 2 and 3 respectively). There were no other significant differences in the rest of cycle parameters with the exception of testosterone levels at the beginning of COS, which were higher in both testosterone groups and relatively higher in Group 2 (1.67 and 3.03 respectively versus 0.14 control group, p=0.01). A Poisson regression model showed no significant differences for the primary outcome (group 3 vs group 2: 0.925 (95% CI 0.572-1.508, p-value = 0.753; group 3 vs group 1: 0.873 (95% CI 0.534-1.426, p-value = 0.587)
Conclusions
The use of testosterone, even when applied for a prolonged period of time, does not improve the number of mature oocytes in POR.
... In total, a sample size of 60 patients (30 for each group) was estimated to be sufficient to analyze the efficacy of LPOS compared with FPOS based on previous studies [24,25]. In the study of Kim and colleagues, 24 patients were required to be included in each group in order to detect a difference of 1.5 cumulus-oocyte complexes (COCs), using a two-sided, Mann-Whitney test with 80% power, given a standard deviation (SD) of 1.9 and a significance level of 0.05 [25]. ...
... In total, a sample size of 60 patients (30 for each group) was estimated to be sufficient to analyze the efficacy of LPOS compared with FPOS based on previous studies [24,25]. In the study of Kim and colleagues, 24 patients were required to be included in each group in order to detect a difference of 1.5 cumulus-oocyte complexes (COCs), using a two-sided, Mann-Whitney test with 80% power, given a standard deviation (SD) of 1.9 and a significance level of 0.05 [25]. A difference of 1.5 COCs retrieved, on which the power analysis was performed, is based on the results of a subsequent meta-analysis [24], which showed that testosterone pretreatment increased the number of COCs by 1.5. ...
Background:
In young women with poor ovarian response, luteal-phase ovarian stimulation (LPOS) is a potential method for collecting competent oocytes. The aim of this study was to assess the efficacy of LPOS compared with follicular phase ovarian stimulation (FPOS) in young women with poor ovarian response (POR).
Methods:
This single-center, prospective, randomized pilot study compared LPOS and FPOS in women with POR fulfilling Bologna criteria who underwent in vitro fertilization at the Instituto Bernabeu. The primary outcome was the number of metaphase II (MII) oocytes obtained by follicular puncture.
Results:
Sixty women were included in the study, with 27 women completing LPOS and 30 undergoing FPOS. There was no statistically significant difference in the number of MII oocytes obtained between the LPOS group and the FPOS group (2.1 ± 2.0 vs. 2.6 ± 2.2, p = 0.31). Length of stimulation was also similar in both groups (8.35 ± 2.8 vs. 8.15 ± 4.1 days, p = 0.69). Similarly, there was no significant difference in the follicle-stimulating hormone total dose, number of cumulus-oocyte complexes, survival rate, fertilization rate, or cancellation rate between groups. A significantly higher Ovarian Sensitivity Index was observed in the LPOS group versus the FPOS group (0.96 vs. 0.57, p = 0.037).
Conclusion:
LPOS was comparable with FPOS in terms of efficacy and may improve ovarian responsiveness in young women with POR.
Trial registration:
ClinicalTrials.gov identifier: NCT02625532; EudraCT identifier: 2015-003856-31.
... It can be administered either trans-dermally or orally. Different RCTs report a beneficial effect of TT pre-treatment [16,17] and the meta-analysis from Bosdou et al. [18] analyzing both trials conducted by Massin et al. [16] and Kim et al. [17] reported that pretreatment with transdermal testosterone was associated with an increase in clinical pregnancy (risk difference (RD): +15%, 95% confidence interval (CI): +3 to +26%) and live birth rates (RD: +11%, 95% CI: +0.3 to +22%) in poor responders undergoing ovarian stimulation for IVF. A second meta-analysis conducted by Gonzalez-Comadran et al. [19] also reported that testosterone-treated women achieved a significantly higher live birth rate (risk ratio, RR, 1.91, 95% CI 1.01 to 3.63), clinical pregnancy rate (RR 2.07, 95% CI 1.13 to 3.78) and required significantly lower doses of FSH (RR -461.96, ...
... It can be administered either trans-dermally or orally. Different RCTs report a beneficial effect of TT pre-treatment [16,17] and the meta-analysis from Bosdou et al. [18] analyzing both trials conducted by Massin et al. [16] and Kim et al. [17] reported that pretreatment with transdermal testosterone was associated with an increase in clinical pregnancy (risk difference (RD): +15%, 95% confidence interval (CI): +3 to +26%) and live birth rates (RD: +11%, 95% CI: +0.3 to +22%) in poor responders undergoing ovarian stimulation for IVF. A second meta-analysis conducted by Gonzalez-Comadran et al. [19] also reported that testosterone-treated women achieved a significantly higher live birth rate (risk ratio, RR, 1.91, 95% CI 1.01 to 3.63), clinical pregnancy rate (RR 2.07, 95% CI 1.13 to 3.78) and required significantly lower doses of FSH (RR -461.96, ...
... Barad, 2011;Fabregues et al., 2009). Along with improving ovarian response, androgen pre-treatment has been reported to increase antral follicle, oocyte and embryo numbers, improve embryo quality and increased pregnancy and live births in IVF (Balasch et al., 2006;Wiser et al., 2010;Kim et al., 2011), inferring androgens can mediate their effects on various cells within the follicle, and at different stages of development. ...
... These finding support the current, but still unproven, concept adopted by some IVF clinics of androgen pre-treatment to enhance follicular response to FSH in women having previously exhibited a poor ovarian response to IVF hyperstimulation. Indeed clinical findings from mostly small or uncontrolled case series report improved antral follicle, oocyte and embryo numbers, embryo quality and pregnancy and live birth rates in some women following increased exposure to aromatisable pro-androgens (DHEA, testosterone) or an aromatase inhibitor (letrozole) (Garcia-Velasco et al., 2005;Balasch et al., 2006;Wiser et al., 2010;Kim et al., 2011;Meldrum et al., 2013). Further evidence to support this theory comes from PCOS patients, who exhibit androgen excess and often display an increased sensitivity to gonadotrophins during IVF protocols. ...
It has been well established for decades that androgens, namely testosterone (T) plays an important role in female reproductive physiology as the precursor for oestradiol (E2). However, in the last decade a direct role for androgens, acting via the androgen receptor (AR), in female reproductive function has been confirmed. Deciphering the specific roles of androgens in ovarian function has been hindered as complete androgen resistant females cannot be generated by natural breeding. In addition, androgens can be converted into estrogens which has caused confusion when interpreting findings from pharmacological studies, as observed effects could have been mediated via the AR or estrogen receptor. The creation and analysis of genetic mouse models with global and cell-specific disruption of the Ar gene, the sole mediator of pure androgenic action, has now allowed the elucidation of a role for AR-mediated androgen actions in the regulation of normal and pathological ovarian function. This review aims to summarize findings from clinical, animal, pharmacological and novel genetic AR mouse models to provide an understanding of the important roles androgens play in the ovary, as well as providing insights into the human implications of these roles.
... These findings are further supported by other trials as well. 9,10 Use of testosterone gel resulted in the lower amount of gonadotrophin usage and a lesser number of days to reach our target follicle growth, as documented in other studies 5,9,11,12 This finding further strengthens the concept that androgens increase the sensitivity of the growing follicle to FSH by increasing the FSH receptors on the follicles, thereby reducing the dose of gonadotrophins required to achieve the desired follicle growth. 3,11 Similarly, the implantation and clinical pregnancy rate was also higher in the TTG group than in controls. ...
... 19 In 2010 a study demonstrated that TTG pretreatment can increase the number of oocytes retrieved, number of good quality embryos, clinical pregnancy rate and reduction in the total FSH dose required in poor responders undergoing IVF/ICSI. 20 However, these promising primary studies explored the effect of testosterone management before ovarian stimulus in unfortunate responder females and showed a better live birth rate with testosterone pretreatment. 21 Moreover, a recent study conducted by Bosdou et al. which concluded in their publication in 2016 that pretreatment transdermal testosterone not upsurge the amount of "cumulus-oocyte complexes (COCs)" saved by ≥ 1.5 and they also described that there was no upsurge in LBR. ...
Background: Classically, poor women respond with old maternal age and little ovarian standby. Though, some females unpredictably have little reply to measured ovarian stimulation. Aim of the Study: To evaluate the eff ectiveness of transdermal testosterone gel (TTG) before controlled ovarian stimulation (COS) in poor responders undergoing intracytoplasmic sperm injection (ICSI). Methods: An interventional prospective randomized control trial that included 60 females who were defi nite as unfortunate responders undergoing an intracytoplasmic sperm injection (ICSI) procedure. The population was divided into two groups. Approximately 30 patients received 10 mg TTG that was applied daily for 21 days in the cycle preceding COS for ICSI Transdermal testosterone gel (TTG) pretreatment group, while the other 30 patients are the control group. All patients were assessed for their AFC again and to begin in-vitro futilization (IVF) treatment with the beginning of the menstrual cycle. Serum testosterone was measured again in the study group. The primary outcome is the number of retrieved oocytes while the secondary outcome is the number and quality of embryos transferred, chemical gestation rate. Results: No important diff erences in sociodemographic features between both groups compared. Also there was an increase in total number of oocytes in the study group but again, this diff erence was statically non-signifi cant. Although the total dose of gonadotrophin (GT) and the duration of stimulation days were less in study group but this was statically non-signifi cant. No diff erences experiential regarding number and grading of embryos, chemical pregnancy rate nor clinical pregnancy rate. Conclusion: Pretreatment of transdermal testosterone at a dose of 10 mg/day for 21 days not upsurge the number of oocyte retrieved nor the number of embryos or pregnancy rate to a signifi cant level in poor responders undergoing ICSI
... In human studies, baseline testosterone levels have been positively correlated with number of oocytes obtained after ovarian stimulation, although no direct correlation was noted with pregnancy outcome rates [267,268]. Transdermal testosterone pretreatment on known poor responders was able to increase number of retrieved and fertilized oocytes, good quality embryos, and clinical pregnancy rates [269][270][271]. Reproductive aging has been associated with decreased serum testosterone levels [267,272]. ...
Reproductive aging is characterized by a decline in oocyte quantity and quality, which is directly associated with a decline in reproductive potential, as well as poorer reproductive success and obstetrical outcomes. As women delay childbearing, understanding the mechanisms of ovarian aging and follicular depletion have become increasingly more relevant. Age-related meiotic errors in oocytes are well established. In addition, it is also important to understand how intraovarian regulators change with aging and how certain treatments can mitigate the impact of aging. Individual studies have demonstrated that reproductive pathways involving antimullerian hormone (AMH), vascular endothelial growth factor (VEGF), neurotropins, insulin-like growth factor 1 (IGF1), and mitochondrial function are pivotal for healthy oocyte and cumulus cell development and are altered with increasing age. We provide a comprehensive review of these individual studies and explain how these factors change in oocytes, cumulus cells, and follicular fluid. We also summarize how modifiers of folliculogenesis, such as vitamin D, coenzyme Q, and dehydroepiandrosterone (DHEA) may be used to potentially overcome age-related changes and enhance fertility outcomes of aged follicles, as evidenced by human and rodent studies.
... 66 However, no local or systemic side effects related to the use of transdermal T patches or gel have been reported in most studies. 63,67,68,79,80 Systematic Review Effect of androgens on ovarian response to controlled ovarian stimulation Oocyte yield The impact of androgen pretreatment on the number of oocytes retrieved was compared among 12 RCTs (Figure 4 (Figure 4, B). Embryo yield and embryo quality. ...
Objective
1) To present a narrative review regarding androgens’ production, androgens’ role in folliculogenesis and the available therapeutic approaches for androgen supplementation; 2) To perform a systematic review and meta-analysis regarding impact of androgens (Dehydroepiandrosterone/Testosterone) compared to placebo or no treatment on ovarian response and pregnancy outcomes in patients with diminished ovarian reserve and/or poor ovarian responders.
Data sources
An electronic search of MEDLINE, EMBASE, The Cochrane, The Cochrane Central Register of Controlled Trials (CENTRAL), SCOPUS, the Central Register of Controlled Trials, Current Controlled Trials and the World Health Organization International Clinical Trials Registry was conducted up to September 2021.
Study eligibility criteria
Randomized controlled trials that compared ovarian response and/or pregnancy outcomes between the different IVF protocols using androgens (i.e., dehydroepiandrosterone and testosterone) and conventional IVF stimulation in patients with diminished ovarian reserve and/or poor ovarian responders were included.
Methods
The quality of each study was evaluated with the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). The meta-analysis used random-effects models. All the results were interpreted based on intention-to-treat analysis (defined as the inclusion of all randomized patients in the denominator). Risk ratio (RR) and the 95% confidence intervals (CIs) were used and combined for meta-analysis.
Results
No significant differences were found regarding the number of oocytes retrieved (Mean Difference (MD) 0.76; 95%CI −0.35-1.88), mature oocytes retrieved (MD 0.25; 95%CI −0.27-0.76), clinical pregnancy rate (CPR) (Risk Ratio (RR) 1.17, 95%CI 0.87-1.57), live birth rate (LBR) (RR 0.97, 95%CI 0.47-2.01) or miscarriage rate (MR) (RR 0.80, 95%CI 0.29-2.22) when dehydroepiandrosterone priming was compared to placebo or no treatment. Testosterone pre-treatment yielded a higher number of oocytes retrieved (MD 0.94; 95%CI 0.46-1.42), a higher CPR (RR 2.07, 95%CI 1.33-3.20) and LBR (RR 2.09, 95%CI 1.11-3.95).
Conclusion
While dehydroepiandrosterone did not present a clear effect on assisted reproductive techniques’ outcomes, we found a potentially beneficial effect of testosterone priming on ovarian response and pregnancy outcomes. However, results should be interpreted with caution taking into account the low to moderate quality of the available evidence.
... Considering the effect of androgen in the early stages of follicular development, supplementation can be taken for 1-3 weeks before ovarian stimulation. 12,17,21,22 To evaluate the effect of a longer duration of androgen supplementation, the present RCT compared 4 and 6 week interventions to a control group to evaluate the optimum duration of testosterone supplementation in patients with POR. Our data showed that the duration of FSH administration and the total FSH dose in the 4 week group were significantly lower than those in the 6 week group. ...
Purpose
This study compared the therapeutic effects of transdermal testosterone gel (TTG) application at 4 and 6 weeks before controlled ovarian hyperstimulation (COH) in women with poor ovarian response (POR).
Methods
In this randomized control trial, infertile women with POR who underwent in vitro fertilization (IVF) were recruited and randomly classified into 4 week (n = 42) and 6 week (n = 38) TTG treatment groups and control group (n = 42). The primary outcome was total number of retrieved mature oocytes. The secondary outcomes were the biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate.
Results
No significant differences were observed in the number of oocytes retrieved, mature oocytes and embryos between all groups. Human chorionic gonadotropin (hCG) positive, clinical, and ongoing pregnancy rates were significantly higher in the TTG pretreatment groups than in the control group but no differences were observed between the 4‐ and 6 week groups.
Conclusions
Applying TTG in infertile women with POR may ameliorate the outcomes of IVF. The extended application of TTG to 6 weeks did not improve the response to ovarian stimulation regarding the number of retrieved oocytes nor pregnancy outcomes compared to the 4 week pretreatment.
... In a randomized controlled trial of 110 PORs undergoing IVF cycles, Kim et al. reported that pretreatment with transdermal T gel significantly increased AFC and reduced the day of stimulation and total dosage of gonadotropins. In addition, the numbers of oocytes retrieved, mature oocytes, fertilized oocytes, and good-quality embryos were significantly higher in the T pretreatment group than in the control group 16 . A meta-analysis of 7 randomized controlled trials conducted by Noventa and colleagues revealed that PORs receiving T therapy demonstrated higher numbers of total oocytes, MII oocytes and total embryos, as well as a higher clinical pregnancy rate and live birth rate than controls 47 . ...
Anti-Mullerian hormone (AMH) and testosterone (T) both play distinct roles in the early stages of folliculogenesis. However, the relationship between serum T and AMH levels is poorly understood. This study aimed to investigate the association between serum T and AMH levels in infertile women. A total of 1935 infertile women aged 20–46 years were included in the cross-sectional study and divided into four quartile groups (Q1 to Q4) based on serum T levels. Compared to the subjects in the highest T quartile (Q4), those in the lowest T quartile (Q1) showed significantly lower AMH levels. After adjustment for age, body weight, body mass index and FSH, increasing T quartile categories were associated with higher AMH levels. Binary logistic regression analyses revealed that the odds for the risk of diminished ovarian reserve (DOR) were 11.44-fold higher in Q1 than in Q4 and the odds for the risk of excess ovarian reserve (EOR) were 10.41-fold higher in Q4 than in Q1. Our data show that serum T levels are positively associated with serum AMH levels and suggest that androgen insufficiency may be a potential risk factor for DOR; androgen excess may lead to EOR in infertile women.
... However, a sensitivity analysis removing the studies at high risk of performance bias showed no statistically significant difference in LBR between the testosterone and control groups (OR 2.00; 95% CI, 0.17-23.49; 1 RCT, n= 53). These contradictory results could be explained by the different doses used (10 to 12 mg/ daily), the way of application (patches or gel) and the pretreatment length (5 to 21 days) (Massin et al., 2006;Fàbregues et al., 2009;Kim et al., 2011;Doan et al., 2017). Obviously, only a multicenter randomized study with a large number of patients can definitively clarify the true efficacy of this add-on therapy in ovarian stimulation (Polyzos et al., 2018). ...
Objective:
Follicular Output Rate (FORT) is an efficient quantitative and qualitative marker of ovarian responsiveness to gonadotropins. Transdermal testosterone (TT) has been used as adjuvant therapy to gonadotrophins in order to improve ovarian response in poor responders (PR). The aim of this study was to analyze whether TT can improve follicular sensitivity to gonadotropins using FORT.
Methods:
This retrospective study, held in a tertiary-care university hospital included 90 PR patients, according to the Bologna criteria. Patients in Group 1 (n = 46) received transdermal application of testosterone preceding gonadotrophin ovarian stimulation under pituitary suppression. In Group 2 (n = 44) ovarian stimulation was carried out with high-dose gonadotrophin in association with minidose GnRH agonist protocol. We analyzed ovarian stimulation parameters and IVF outcomes. We determined antral follicle count (AFC) (3-8 mm) before ovarian stimulation, pre-ovulatory follicle count (PFC) (16-22 mm) and the day of hCG administration. We calculated the FORT using the PFCx100/AFC ratio.
Results:
Baseline characteristics and ovarian reserve parameters were similar in both groups. FORT and oocytes retrieved were significantly higher in group 1 vs group 2. There were no significant differences in pregnancy rates. In group 1 there was a significant correlation between FORT and AFC.
Conclusions:
This study suggests that the potential beneficial mechanism of TT in poor responder patients may be based on increasing the antral follicle sensitivity to gonadotrophin. FORT is an excellent tool to demonstrate this.
... Few studies have reported higher clinical pregnancy rate and live birth rate in poor responders undergoing ovarian stimulation for IVF, after pretreatment with transdermal testosterone. [10,11] However more RCTs with larger sample size are needed to reach further conclusions. ...
... Pharmacologic treatment with T has been primarily studied in women who respond poorly to conventional FSH-based gonadotropin stimulation for IVF. Results have been inconsistent (7)(8)(9)(10), but a recent meta-analysis of seven randomized controlled trials concluded that T administration before or during ovarian stimulation for poor responders resulted in a higher live birth rate compared with controls (10). ...
Objective
To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population.
Design
Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial.
Setting
Multicenter university-based clinical practices.
Patient(s)
Nine hundred couples with unexplained infertility were included. Women were 18–40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed.
Intervention(s)
None.
Main Outcome Measure(s)
The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss.
Result(s)
When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes.
Conclusion(s)
In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment.
Clinical Trial Registration Number
NCT 01044862.
... Given the wide variety of their different mechanisms of action, many adjuvant therapies have been proposed to improve pregnancy outcomes by improving follicular development, oocyte maturation and embryo quality or by enhancing endometrial receptivity. Currently, the most frequently proposed adjuvant therapies include androgen supplements [testosterone and dehydroepiandrosterone (DHEA)] (Artini et al., 2012;Bosdou et al., 2016;Fábregues et al., 2009;Kara et al., 2014;Kim et al., 2011;Kotb et al., 2016;Massin et al., 2006;Narkwichean et al., 2017;Saharkhiz et al., 2018;Yeung et al., 2014) or androgenmodulating agents (letrozole, an aromatase inhibitor) (Bastu et al., 2016;Davar et al., 2010;Ebrahimi et al., 2017;Goswami et al., 2004;Lee et al., 2011;Mohsen and El Din, 2013;Ozmen et al., 2009;Schoolcraft et al., 2008;Yu et al., 2018), steroid hormones (oestradiol and progesterone) (Davar et al., 2018;Davar et al., 2013;DiLuigi et al., 2011;Escriva et al., 2015), recombinant LH (rLH) (Barrenetxea et al., 2008;Humaidan et al., 2017;Musters et al., 2012;Younis et al., 2016), clomiphene (Karimzadeh et al., 2011;Pilehvari et al., 2016;Ragni et al., 2012;Revelli et al., 2014;Schimberni et al., 2016;Siristatidis et al., 2017), growth hormone (GH) (Bassiouny et al., 2016;Bayoumi et al., 2015;Bergh et al., 1994;Choe et al., 2018;Dakhly et al., 2018;Kucuk et al., 2008;Suikkari et al., 1996) and coenzyme Q10 (CoQ10) (Xu et al., 2018). ...
Background:
Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine.
Objective and rationale:
The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included.
Search methods:
Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217).
Outcomes:
Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls).
Wider implications:
For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.
... These products are cheap and available, yet their use remains controversial. This is due to lack of sufficient studies for their efficacy and safety [2] [3]. ...
... Testosterone pretreatment was associated to lower total doses of r-FSH and shorter length of COS. The number of oocytes, mature oocytes, fertilized oocytes, and good-quality embryos retrieved and clinical pregnancy rates were also significantly higher in the pretreatment group (Kim et al., 2011). ...
Objective:
This study aimed to assess a novel protocol designed to improve poor ovarian response through intra-ovarian androgenization. The endpoints were: number of oocytes and mature oocytes retrieved, fertilization, cancellation and pregnancy rates.
Methods:
This prospective crossover study enrolled poor responders from previous ovarian stimulation cycles submitted to a novel protocol called ANDRO-IVF. The protocol included pretreatment with transdermal AndroGel(r) (Besins) 25 mg, oral letrozole 2.5 mg and subcutaneous hCG 2500 IU; cycle control was performed with estradiol valerate and micronized progesterone; ovarian stimulation was attained with gonadotropins FSH/LH 450 IU, GnRH antagonist and hCG 5000 IU.
Results:
Fourteen poor responders were enrolled. One patient did not meet the inclusion criteria. Thirteen patients previously summited to the standard protocol were offered the ANDRO-IVF Protocol.-Standard Protocol: Mean age: 35.30 years; cancellation rate: 61.53%; mean number of MII oocytes retrieved per patient: 1.8; fertilization rate: 33.33%. Only two patients had embryo transfers, and none got pregnant.-ANDRO-IVF Protocol: Mean age: 35.83 years; cancellation rate: 7.69%; mean number of oocytes retrieved per patient: 5.58, MII oocytes: 3.91. ICSI was performed in 84.61% of the patients and a mean of 1.5 embryos were transferred per patient. Fertilization rate: 62.5%; cumulative pregnancy rate: 16.66%; mean duration of stimulation: 9.77 days.
Conclusion:
ANDRO-IVF allows intra-ovarian androgenization by increasing serum and intra-follicular androgen levels and preventing androgen aromatization. This protocol apparently improved clinical outcomes of poor responders in parameters such as number of oocytes retrieved and clinical pregnancy rates. Further randomized controlled trials are needed to confirm these findings.
Study question:
Does 8 weeks of daily low-dose hCG administration affect androgen or inhibin B levels in serum and/or follicular fluid (FF) during the subsequent IVF/ICSI cycle in women with low ovarian reserve?
Summary answer:
Androgen levels in serum and FF, and inhibin B levels in serum, decreased following 8 weeks of hCG administration.
What is known already:
Recently, we showed that 8 weeks of low-dose hCG priming, in between two IVF/ICSI treatments in women with poor ovarian responder (anti-Müllerian hormone (AMH) <6.29 pmol/l), resulted in more follicles of 2-5 mm and less of 6-10-mm diameter at the start of stimulation and more retrieved oocytes at oocyte retrieval. The duration of stimulation and total FSH consumption was increased in the IVF/ICSI cycle after priming. Hypothetically, hCG priming stimulates intraovarian androgen synthesis causing upregulation of FSH receptors (FSHR) on granulosa cells. It was therefore unexpected that antral follicles were smaller and the stimulation time longer after hCG priming. This might indicate a different mechanism of action than previously suggested.
Study design, size, duration:
Blood samples were drawn on stimulation day 1, stimulation days 5-6, trigger day, day of oocyte retrieval, and oocyte retrieval + 5 days in the IVF/ICSI cycles before and after hCG priming (the control and study cycles, respectively). FF was collected from the first aspirated follicle on both sides during oocyte retrieval in both cycles. The study was conducted as a prospective, paired, non-blinded, single-center study conducted between January 2021 and July 2021 at a tertiary care center. The 20 participants underwent two identical IVF/ICSI treatments: a control cycle including elective freezing of all blastocysts and a study cycle with fresh blastocyst transfer. The control and study cycles were separated by 8 weeks (two menstrual cycles) of hCG priming by daily injections of 260 IU recombinant hCG.
Participants/materials, setting, methods:
Women aged 18-40 years with cycle lengths of 23-35 days and AMH <6.29 pmol/l were included. Control and study IVF/ICSI cycles were performed in a fixed GnRH-antagonist protocol.
Main results and the role of chance:
Inhibin B was lower on stimulation day 1 after hCG priming (P = 0.05). Dehydroepiandrosterone sulfate (DHEAS) was significantly lower on stimulation day 1 (P = 0.03), and DHEAS and androstenedione were significantly lower on stimulation days 5-6 after priming (P = 0.02 and P = 0.02) The testosterone level in FF was significantly lower in the study cycle (P = 0.008), while the concentrations of inhibin B and androstenedione in the FF did not differ between the study and control cycles. A lower serum inhibin B in the study cycle corresponds with the antral follicles being significantly smaller after priming, and this probably led to a longer stimulation time in the study cycle. This contradicts the theory that hCG priming increases the intraovarian androgen level, which in turn causes more FSHR on developing (antral up to preovulatory) follicles. However, based on this study, we cannot rule out that an increased intra-follicular androgen level was present at initiation of the ovarian stimulation, without elevating the androgen level in serum and that an increased androgen level may have rescued some small antral follicles that would have otherwise undergone atresia by the end of the previous menstrual cycle. We retrieved significantly more oocytes in the Study cycle, and the production of estradiol per follicle ≥10-mm diameter on trigger day was comparable in the study and control cycles, suggesting that the rescued follicles were competent in terms of producing oocytes and steroid hormones.
Limitations, reasons for caution:
The sample size was small, and the study was not randomized. Our study design did not allow for the measurement and comparison of androgen levels or FSHR expression in small antral follicles before and immediately after the hCG-priming period.
Wider implications of the findings:
The results make us question the mechanism of action behind hCG priming prior to IVF. It is important to design a study with the puncture of small antral follicles before and immediately after priming to investigate the proposed hypothesis. Improved cycle outcomes, i.e. more retrieved oocytes, must be confirmed in a larger, preferably randomized study.
Study funding/competing interest(s):
This study was funded by an unrestricted grant from Gedeon Richter awarded to the institution. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co and payment for participation in an advisory board for Preglem. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S, and equipment and travel support has been given to the institution by Gedeon Richter Nordics AB. The remaining authors have no conflicts of interest to declare.
Trial registration number:
ClinicalTrials.gov Identifier: NCT04643925.
Study question:
Does 8 weeks of continuous low-dose hCG administration increase the proportion of antral follicles that reach the preovulatory state during ovarian stimulation (OS) in women with low ovarian reserve?
Summary answer:
The proportion of antral follicles (2-10 mm) that reached the preovulatory state did not increase.
What is known already:
The administration of androgens prior to OS might upregulate FSH receptor (FSHR) expression on granulosa cells, making follicles more responsive to exogenous FSH stimulation during OS. LH and hCG stimulate the local follicular androgen synthesis in theca cells and may be used as an endogenous androgen priming method. Exogenous priming by testosterone and dehydroepiandrosterone (DHEA) have been shown to increase the number of retrieved oocytes and live birth rate but the studies are small, and their use is associated with side effects.
Study design, size, duration:
A prospective, paired, non-blinded single-center study including 20 women serving as their own controls conducted between January 2021 and July 2021 at The University Hospital Copenhagen Rigshospitalet, Denmark.
Participants/materials, setting, methods:
Participants underwent two identical consecutive IVF/ICSI treatments, a Control cycle and a Study cycle, separated by ∼8 weeks (two menstrual cycles) of daily injections of 260 IU recombinant hCG (rhCG). A freeze-all strategy was applied in the Control cycle. Both IVF/ICSI cycles were performed in a fixed GnRH antagonist protocol using a daily dose of 300 IU recombinant FSH (rFSH) and GnRH antagonist 0.25 mg from stimulation days 5-6.
Main results and the role of chance:
Follicular output rate, defined as the number of follicles >16 mm on hCG trigger day divided by the antral follicle count (2-10 mm) at baseline, did not increase after 8 weeks of hCG priming (P = 0.8). The mean number of oocytes retrieved was significantly higher after the hCG priming being 4.7 (2.8) vs 3.2 (1.7) in the Study and Control cycle, respectively (P = 0.01). The duration of stimulation was longer in the Study versus the Control cycle (P = 0.05), despite the use of identical hCG trigger criterion and similar diameters of the three biggest follicles on hCG trigger day in the two cycles (P = 0.9).
Limitations, reasons for caution:
The sample size was small, and the number of oocytes retrieved was not the primary endpoint. Larger studies are needed to confirm this finding.
Wider implications of the findings:
Long-term, low-dose rhCG administration may increase the number of oocytes retrieved during IVF/ICSI in women with low ovarian reserve, but more research is needed before firm conclusions can be drawn.
Study funding/competing interest(s):
This study was funded by an unrestricted grant from Gedeon Richter. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S and receipt of equipment by the institution from Gedeon Richter Nordics AB is reported. The remaining authors have no conflicts of interest to declare.
Trial registration number:
ClinicalTrials.gov Identifier: NCT04643925.
Objective(s)
Patients with poor ovarian response who have reduced ovarian reserve sometimes despite the maximum dose of gonadotropins do not respond properly. Androgens have been shown to play an important role in the early follicular development and proliferation of granulosa cells. This study aimed to evaluate the effect of androgen administration on IVF outcome in poor responders.
Study Design
In this randomized clinical trial, 60 poor responder women candidate for controlled ovarian stimulation were randomly enrolled in two groups (n= 30/each). In the intervention group testosterone gel added to the interrupted microdose flare protocol. The control group received the conventional microdose flare protocol.
Results
The main outcome was clinical and chemical pregnancy; and the second outcomes were the number of mature oocytes, duration of cycle and total dose of gonadotropins. Basic clinical and demographic features were comparable between the groups. The total gonadotropin consumption were significantly higher in the control group than the intervention group (p= 0.047). In addition, the number of MII oocytes was higher (but not significant) in the intervention group than the control group (p= 0.16). The mean total duration of the cycle was equal in both groups. There were no significant differences in chemical and clinical pregnancy rates between the two groups (p= 0.41, p= 0.67).
Conclusion(s)
The results of the current study showed that androgen administration in poor responders in in vitro fertilization reduces the total dose of gonadotropin, but it does not improve the pregnancy outcomes.
New evidence is indicating a growing role of LH in promoting ovarian follicular growth and maturation, even at the early stages. LH seems to enhance the transition of follicles to the antral stage hence leading to an increase in the so-called functional ovarian reserve (recruitable antral follicles). Hypogonadotropic hypogonadism is characterized by low, and sometimes undetectable, serum LH and FSH levels, which may indeed explain the low anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) found in patients affected by this condition. We report here the cases of two young women affected by hypothalamic amenorrhea (HA) that presented for fertility treatment with very low functional ovarian reserve. The two patients were treated with exogenous LH for 1 and 2 months (extended LH administration: ELHA) at the dose of 187.5 IU LH every day and 150 IU LH every other day, respectively. In both the cases there was an increase in serum AMH levels and in the AFC. In one patient, the AMH and AFC increased from a baseline 1.3 ng/ml and 8 to 2.3 ng/ml and 14 at end of treatment, respectively. In the second case, serum AMH and AFC increased from 0.4 ng/ml and 6 to 1.6 ng/ml and 13, respectively. One patient underwent ovarian stimulation before and after ELHA, showing an increase in the number of mature oocytes recruited (3 versus 8 metaphase II (MII) oocytes before and after, respectively). The second patient underwent an IVF cycle after ELHA resulting in the retrieval of six MII oocytes and an ongoing pregnancy following transfer of a single blastocyst. Women with HA are characterized by chronic, low levels of gonadotrophins, which may impact not only on the cyclic recruitment of follicles but also the progression of small growing follicles through the first stages of folliculogenesis. Some women with HA may in fact show very low serum AMH and AFC. Our case series shows that the administration of LH at a dose of at least 150-187.5 IU every day or every other day may contribute to a clinically evident increase in the functional ovarian reserve (AFC), and probably accounts for a positive effect of LH on the progression of follicles throughout the early stages of folliculogenesis.
Ovarian stimulation is the starting point of reproductive medicine but the procedure can result in adverse reactions particularly the dangerous ovarian hyperstimulation syndrome. Fully revised in line with modern practice of ovarian stimulation, this new edition is divided into six sections that cover mild forms, non-conventional forms, IVF, complications and their management, alternatives, and the practicalities of procedures. All aspects of ovarian stimulation are discussed including the different stimulation protocols from which to choose, the management of poor responders and hyper-responders, as well as stimulation in patients with PCOS. Comprehensively reviewing the modern approach to ovarian stimulation, the alternative procedures are also described, both in IVF and other methods of assisted reproduction. Written by leading experts on reproductive health and fertility, this book will assist infertility specialists, gynecologists, reproductive endocrinologists and radiologists in determining successful treatment for their patients.
The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause is PCOS. Hirsutism is the most common presenting symptom. The woman's concern about her symptoms plays an important role in the management of disease. Although measurement of testosterone is useful in identifying an underlying cause, care must be taken when interpreting the less accurate assays that are available commercially. Surgical resection is curative in tumorous etiologies, whereas medical management is the mainstay for non-tumorous causes.
The management of patients with diminished ovarian reserve (DOR) remains one of the most challenging tasks in IVF clinical practice. Despite the promising results obtained from animal studies regarding the importance of androgens on folliculogenesis, the evidence obtained from clinical studies remains inconclusive. This is mainly due to the lack of an evidence-based methodology applied in the available trials and to the heterogeneity in the inclusion criteria and IVF treatment protocols. In this review, we analyze the available evidence obtained from animal studies and highlight the pitfalls from the clinical studies that prevent us from closing the chapter of this line of research.
Introduction: Poor ovarian responders are the most challenging patients in reproductive medicine and no successful treatment has been proposed. Androgens are thought to play an important role during early folliculogenesis and diminished levels are associated with decreased ovarian sensitivity to follicle-stimulating hormone. This study aimed to determine whether pretreatment with testosterone improves the results in poor responders undergoing in vitro fertilisation (IVF).
Materials and methods: This observational pilot study enrolled 33 poor responders undergoing IVF. Eleven patients were pretreated with 250 mg intramuscular testosterone and compared to a control group of 22 patients. The participants were tested for free testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and anti-mullerian hormone (AMH).
Results: The two groups had similar baseline characteristics. Significant improvement was reached in the hormones free testosterone, dehydroepiandrosterone sulfate, and sex hormone binding globulin in the testosterone-pretreatment group. No difference was detected in antral follicle count (5.06 versus 4.24); AMH (0.51 versus 0.53), mature oocytes (2.2 versus 2.32), and the number of embryos (1.2 versus 1.33) between the study and control groups, respectively. There was a slow improvement in fertilisation rate but without any significance (62.97% versus 57.61%). However, the cancellation rate of the ovarian stimulation was much greater in the control group (18.18%) in comparison with the study group (0.0%). Pregnancy rate (PR) in the testosterone group was higher than controls (PR per cycle: 27.3% versus 4.6; p=0.09).
Conclusion: Based on the limited number of patients studied, pretreatment with testosterone seems to improve PR and cancellation rate in poor responders but failed to affect antral follicle count, AMH, and the number of mature oocytes and embryos. Given these results, further research would provide more certainty.
Androgen receptors are expressed by all stages of growing follicles, and follicular fluid androgen levels are positively correlated to granulosa cell androgen receptor and follicle-stimulating hormone (FSH) receptor expression. Thus, androgens may promote follicular growth, accumulation and/or responsiveness to gonadotropins. This is explored therapeutically in the concept of androgen priming, to improve the ovarian response to stimulation in assisted reproduction. Androgen effects may be achieved in two different ways, either directly by providing exogenous androgen or by providing luteinizing hormone (LH) activity [i.e., LH or human chorionic gonadotropin (hCG)] to stimulate local ovarian production of androgen. The androgen concentrations in follicular fluid by far exceed the levels in female circulation and it has recently been shown that there was no correlation between serum testosterone levels and follicular fluid androgen levels. There is some evidence that administration of exogenous dehydroepiandrosterone or testosterone increases live birth rates, but an optimal protocol has not been established and such adjuvant treatment should be considered experimental. Furthermore, studies exploring long-term administration of LH activity, achieving LH levels comparable to those seen in women with polycystic ovary syndrome, are awaited. The aim of the present review is to discuss critically the most suitable approach for androgen priming from a biological and clinical standpoint, and to evaluate current approaches and results obtained in clinical trials.
The intriguing role of androgens in follicular physiology and their therapeutic potential in female infertility have drawn a great deal of attention in the last decade. Dehydroepiandrosterone or testosterone supplementation prior to ovarian stimulation and aromatase inhibitors as an adjunct to gonadotropins have been tested to enhance follicle growth in women with poor ovarian reserve and premature ovarian failure. However, a critical appraisal of the available evidence shows that the proposed regimens failed to live up to the hype. In the absence of robust data on clinical efficacy and safety, their use should be regarded as empirical.
Letrozole is used for the treatment of subfertility in women undergoing ovarian superstimulation, but the mechanism of action has not been investigated critically. The objective was to test the hypothesis that treatment with letrozole will potentiate the superstimulatory response following gonadotropin treatment by increasing the number of follicles present at ovarian follicular wave emergence in cattle. In Experiment 1, ovarian follicular wave emergence was synchronized among beef heifers (n = 8) by transvaginal ultrasound-guided follicle ablation. On Day 0 (wave emergence), a letrozole-releasing device (LRD) was placed intravaginally for 5 days, followed again by transvaginal follicle ablation on Day 5. The number of follicles ≥3 mm was recorded by transrectal ultrasonography on Days 0 and 6.5 (i.e., pre-vs. post-LRD treatment). In Experiment 2, non-lactating dairy cows were assigned randomly to one of two groups (n = 15/gp) after follicle ablation-induced synchronization of wave emergence (Day 0), and given either an LRD or sham device for 5 days. Superstimulatory treatment was initiated on Day 0, consisting of 8 doses of 50 mg of porcine FSH im at 12 h intervals, and luteolytic doses of prostaglandin on Days 3 and 3.5. The LRD/sham devices were removed on Day 3.5, GnRH was given im on Day 5, estrus response was determined on Days 5 and 6, and the ovarian response was recorded by ultrasonography on Days 0, 3.5, 5, 6.5, and 12. In Experiment 1, no difference was detected in the number of antral follicles at wave emergence pre-vs. post-LRD treatment (23.2 ± 3.2 vs. 23.5 ± 3.8 follicles; P = 0.67; mean ± SEM). In Experiment 2, the interval from prostaglandin treatment to estrus was longer (50.3 ± 1.1 vs. 40.7 ± 2.0 h; P < 0.001) and less variable (residuals: 3.1 ± 0.5 vs. 6.7 ± 0.9 h; P < 0.01) in the LRD vs. sham group. The proportion of ovulations (number of CL on Day 12 over the number of follicles ≥3 mm on Day 0) did not differ (0.65 ± 0.02 vs. 0.70 ± 0.02; P = 0.15) nor did the number of CL on Day 12 (15.9 ± 2.5 vs. 19.0 ± 2.0; P = 0.32) between the LRD and sham groups. In summary, treatment with letrozole did not increase the number of antral follicles at wave emergence or the superstimulatory response, but increased precision in the interval to estrus and may be useful for artificial insemination at a fixed time in superstimulatory protocols.
Ein geringeres Ansprechen der Ovarien auf die FSH-Stimulation ist mit zunehmendem Alter der Normalfall aufgrund der physiologischen Erschöpfung der Eierstöcke. Die entscheidende Voraussetzung für die polyfollikuläre Reifung und somit Gewinnung mehrerer Eizellen für die In-vitro-Fertilisation ist eine noch hinlängliche ovarielle Reserve. Eine geringe Anzahl an Follikeln oder Eizellen trotz intensiver ovarieller Stimulation wird in der Literatur als „poor response“ oder „low response“ bezeichnet. Verschiedene Maßnahmen im Kontext der ovariellen Stimulation wurden in klinischen Studien überprüft, die die Eizellzahl und/oder -qualität und im Gefolge die Schwangerschaftswahrscheinlichkeit für Patientinnen mit verringerter ovarieller Reserve verbessern sollen. In diesem Kapitel wird der Zusammenhang zwischen Stimulationsintensität und ovarieller Antwort erläutert. Ebenso wird der Stellenwert verschiedener Stimulationsprotokolle, die zusätzliche LH-Verabreichung, die Vorbehandlung mit Sexualsteroiden, die Androgenvorbehandlung, die adjuvante Gabe von Wachstumshormon sowie das Konzept der Doppelstimulation erörtert.
Excess testosterone levels affect up to 20% of the female population worldwide and are a key component in the pathogenesis of polycystic ovary syndrome. However, little is known about how excess testosterone affects the function of the human fallopian tube—the site of gamete transport, fertilization, and early embryogenesis. Therefore, this study aimed to characterize alterations caused by long‐term exposure to male testosterone levels. For this purpose, the Fallopian tubes of nine female‐to‐male transsexuals, who had been undergoing testosterone treatment for 1–3 years, were compared with the tubes of 19 cycling patients. In the ampulla, testosterone treatment resulted in extensive luminal accumulations of secretions and cell debris which caused ciliary clumping and luminal blockage. Additionally, the percentage of ciliated cells in the ampulla was significantly increased. Transsexual patients, who had had sexual intercourse before surgery, showed spermatozoa trapped in mucus. Finally, in the isthmus complete luminal collapse occurred. Our results imply that fertility in women with elevated levels of testosterone is altered by tubal luminal obstruction resulting in impaired gamete transport and survival. Excess testosterone levels affect up to 20% of the female population worldwide yet little is known about how it impacts the function of the human fallopian tube. Our results show that in the ampulla, exposure to male levels of testosterone resulted in luminal blockage, while in the isthmus complete luminal collapse occurred. Our results suggest that reduced fertility in women with elevated levels of testosterone—when ovulation has occurred—may be linked to tubal luminal obstruction resulting in impaired gamete transport and survival.
Women with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation present a challenge for reproductive specialists. The primary reasons relate to the still limited knowledge about the POR pathophysiology and the lack of practical solutions for the management of these conditions. Indeed, clinical trials using the current standards to define POR failed to show evidence in favor of a particular treatment modality. Furthermore, critical factors for reproductive success, such as the age-dependent embryo aneuploidy rates and the intrinsic ovarian resistance to gonadotropin stimulation, are not taken into consideration by the current POR criteria. As a result, the accepted definitions for POR have been criticized for their inadequacy concerning the proper patient characterization and for not providing clinicians a guide for therapeutic management. A novel system to classify infertility patients with “expected” or “unexpected” inappropriate ovarian response to exogenous gonadotropins—the POSEIDON criteria—was developed to provide a more nuanced picture of POR and to guide physicians in the management of such patients. The new standards are provoking as they challenge the current terminology of POR in favor of the newly defined concept of “low prognosis.” This article provides readers a critical appraisal of the existing criteria that standardize the definition of POR and explains the primary reasons for the development of the POSEIDON criteria.
Objective:
The aim of this project was to investigate if the AR (androgen receptor) polymorphism could be used to identify patients at risk for POR and that will benefit from androgens pretreatment.
Study design:
To evaluate the POR risk we performed a cohort study including 231 patients (54 POR and 177 control). Moreover, we included 88 IVF-cycles performed by 44 POR-patients to assess the effect on ovarian response. All patients performed two cycles: a standard ovarian stimulation and a second one with androgen preparation. We compare the results in pair from each.
Results:
POR showed the highest frequency of CAG repeats at 24 vs 22 in controls. Only 33% of POR have alleles with a repeat number below 23, compared with 50% of controls (p < 0.05). According to AR polymorphism ovarian response differences were shown. Patients that carried CAG repeats in AR gene between 22 and 24 showed an increased in the number of oocytes (2.61 in cycles without androgens vs 5.11 when they were pretreated with androgens; p < 0.05). For the patients that carried repeats lower than 22 and higher than 24, no differences were reported in the number of oocytes obtained in the cycle with or without androgens (2.94 vs 2.56; p = 0.88). Similar results were obtained for mature oocytes in patients that carry a number of CAG repeats between 22 and 24 (1.86 MII in cycles without androgens vs 4.04 MII when they were pretreated with androgens; p < 0.05). No differences in the number of MII oocytes were found in patients that get out of 22 and 24 repeats between the two cycles (2.31 vs 2.13; p = 0.88).
Conclusion:
The AR polymorphism is associated with POR risk, patients with repeats greater than 22 show a higher risk. Our data suggest that AR genotype could play a role in natural ovarian aging. Furthermore, the use of androgens in POR remains controversial. Our data suggest that the AR genotype could clarify the effectiveness of the androgen pretreatment. AR genotyping could help us to identify patients at risk of POR and POR patients that could benefit from transdermal testosterone pretreatment.
Endogenous androgen production is essential for women’s reproductive function and nonreproductive health. The primary sources of androgens are the ovaries and the adrenal glands. The amount of androgen produced by these sources varies across a woman’s life span. It is well documented that circulating androgen levels decline with age from the middle of the fourth decade of life. This decline appears to affect reproductive capacity and impacts nonreproductive health. This review summarizes what is known about androgen physiology in women, the impact of the age-related decline, and the potential benefits and risks of androgen therapy.
The study was conducted on 110 poor responders undergoing in vitro fertilization (IVF) from October 2015 to July 2016 at the IVF Center of Millitary Medical University, Vietnam. Its aim is to investigate the effectiveness of transdermal androgel before using controlled ovarian stimulation on patients undergoing IVF. A prospective, descriptive study was conducted to compare between the group of patients who used testosterone gel and the group of those who did not in terms of the following indicators: the number of oocytes retrieved, MII oocytes, fertilization rate, number of embryos, pregnancy rate, and embryo implantation rate. The number of oocytes retrieved, number of embryos, pregnancy rate, and embryo implantation rate of the group of patients using transdermal androgel before Controlled Ovarian Stimulation (COS) were found higher than those of the control group, with statistical significance. The use of androgel before stimulating ovarian can improve the responsiveness of poor responders when undergoing IVF.
Studies in macaques have indicated that androgens have some synergistic effects with FSH on folliculogenesis. This study investigated the usefulness of pretreatment with transdermal testosterone in low-responder IVF patients.
Randomized clinical trial including 62 infertile women who had a background of the first IVF treatment cycle cancelled because of poor follicular response. Patients were randomized in two treatment groups in their second IVF attempt. In patients in Group 1 (n = 31), transdermal application of testosterone preceding standard gonadotrophin ovarian stimulation under pituitary suppression was used. In Group 2 (n = 31 patients), ovarian stimulation was carried out with high-dose gonadotrophin in association with a minidose GnRH agonist protocol. The primary end-point was the incidence of low-responder patients. The main secondary outcome was the incidence of patients reaching ovum retrieval.
The percentage of cycles with low response was significantly lower in Group 1 than in Group 2 (32.2 versus 71% 95% confidence interval for the difference, 15.7-61.6; P < 0.05). The number of patients with ovum retrieval tended to be higher in Group 1 than in Group 2 (80.6 versus 58.1% P = 0.09), the difference reaching statistical significance (81.2 versus 41.1%; P < 0.05) when only patients having normal basal FSH levels (16 and 17 patients in Groups 1 and 2, respectively) were considered.
Pretreatment with transdermal testosterone may improve the ovarian sensitivity to FSH and follicular response to gonadotrophin treatment in previous low-responder IVF patients. This approach leads to an increased follicular response compared with a high-dose gonadotrophin and minidose GnRH agonist protocol.
This systematic review and meta-analysis aimed to answer the following clinical question: among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth per randomized patient dependent on the type of analogue used? Eligible studies were randomized controlled trials (RCTs), published as a full manuscript in a peer-reviewed journal, that contained sufficient information to allow ascertainment of whether randomization was true and whether equality was present between the groups compared. A literature search identified 22 RCTs comparing GnRH antagonists and GnRH agonists that involved 3176 subjects. Where live birth was not reported in a study that fulfilled the inclusion criteria, an effort was made to contact the corresponding authors to retrieve the missing information. If this was not possible, the reported outcome measure, clinical pregnancy or ongoing pregnancy was converted to live birth in 12 studies using published data (Arce et al., 2005). No significant difference was present in the probability of live birth between the two GnRH analogues [odds ratio (OR), 0.86; 95% confidence intervals (CI), 0.72 to 1.02]. This result remains stable in subgroup analysis that ordered the studies by type of population studied, gonadotrophin type used for stimulation, type of agonist protocol used, type of agonist used, type of antagonist protocol used, type of antagonist used, presence of allocation concealment, presence of co-intervention and the way the information on live birth was retrieved. In conclusion, the probability of live birth after ovarian stimulation for IVF does not depend on the type of analogue used for pituitary suppression.
In a spontaneous menstrual cycle, during the follicular phase, only one follicle out of a cohort of 10-20 usually completes maturation and ovulates to release a mature oocyte. The aim of ovarian stimulation in assisted reproductive technology (ART) protocols is to overcome the selection of a dominant follicle and to allow the growth of a cohort of follicles. This strategy leads to an increase in the number of oocytes and hence embryos available for transfer, thereby increasing the chance of transferring up to three viable embryos. However, the chance of pregnancy and also live birth begins to dramatically decline after the age of 35, and successful treatment for these patients continues to be a major challenge in ART programs. Preimplantation genetic screening studies over the last decade have identified a dramatic increase in the rate of aneuploidy as a major contributor to the reduction in embryo viability in older patients. It has also been demonstrated that women of advanced maternal age may have oocytes that are compromised by a significant reduction in the amount of mitochondrial DNA in their cytoplasm. The strategies outlined in this review may provide a means of augmenting follicular recruitment and cytoplasmic integrity by utilizing pharmacogenomics and manipulating endocrinology to improve the prognosis for these women. Recent studies indicate that androgen supplementation may be one area to explore further. The availability of recombinant human leutinizing hormone (rhLH) has made it possible to investigate the role of LH in the endocrinology of follicular recruitment: it appears that a defect in the balance of LH/ follicle-stimulating hormone (FSH) might be involved in the subtle age-related decline in follicular recruitment, and patients of older reproductive age undergoing ART might benefit from the addition of LH and/or hGH. Further studies are required to investigate the physiological mechanisms behind this observation and to assess the possible effect of LH and/or hGH supplementation on the age-related decline in pregnancy rate.
OBJECTIVE: [1] To examine the effects of body mass index (BMI), age, cigarette smoking, cause of infertility, and use of oral contraceptives on baseline serum testosterone (T), and [2] to examine associations between baseline serum T and IVF outcomes such as pre-hCG serum E(2), number of oocytes retrieved, oocyte fertilization rate, and pregnancy outcome in regularly cycling women. DESIGN: Prospective, cohort study. SETTING: Three IVF programs in eastern Massachusetts. PATIENT(S): Four hundred twenty-five regularly cycling women planning to undergo IVF. Women with polycystic ovary syndrome, ovulatory infertility, or irregular cycles were excluded from this study. INTERVENTION(S): Collection of epidemiological data and baseline serum in women undergoing IVF. MAIN OUTCOME MEASURE(S): Baseline serum total T, sex hormone binding globulin (SHBG), and calculation of free androgen index. RESULT(S): Body mass index >26 kg/m(2) was associated with a significant increase in serum T (P<.01) and free androgen index (P<.0001). Serum T decreased significantly throughout the fourth decade of life (P<.03). A history of cigarette smoking >10 pack years was associated with increased serum T (P<.01). A diagnosis of endometriosis was associated with decreased serum T. Serum T correlated positively with pre-hCG serum E(2) and number of oocytes retrieved. However, serum T did not significantly influence fertilization or pregnancy rates. CONCLUSION(S): In cycling infertile women, increasing BMI and cigarette smoking are associated with increased serum T. Advancing age and endometriosis are associated with decreased serum T
To assess the endocrine and clinical responses to microdose GnRH agonist (GnRH-a) that was administered in the early follicular phase before controlled ovarian hyperstimulation to poor responders who were candidates for IVF-ET.
Prospective nonrandomized trial with historical controls.
Tertiary care university-affiliated infertility practice.
Thirty-four IVF-ET candidates with a prior poor response to a standard long-protocol GnRH-a controlled ovarian hyperstimulation regimen (cycle A). Patients were divided into two groups based on their age at the initiation of cycle A (Group 1: < or = 39 years, n = 15; Group 2: > or = 40 years, n = 19).
Low-dose oral contraceptive (x 21 d) followed by GnRH-a (leuprolide acetate; 40 micrograms s.c. b.i.d.) flare and urofollitropin initiated on day 3 of GnRH-a administration (cycle B).
Comparative analysis of clinical responses (total urofollitropin dose used and number of oocytes retrieved as well as fertilization and clinical and ongoing pregnancy rates) and endocrine responses (serum E2, FSH, LH, T, and P levels) between cycles A and B in the two groups. Early follicular phase serum E2 and FSH changes in groups 1 and 2 were compared with changes in nine normal responder controls who were receiving a standard long-protocol GnRH-a/urofollitropin regimen (group 3).
Maximal E2 levels as well as clinical and ongoing pregnancy rates were higher in cycle B patients receiving microdose GnRH-a. Cancellation rates in cycle B were lower than in cycle A. Statistically significant increases in treatment day 6 serum FSH levels were noted during cycle B in both groups 1 and 2 but not in group 3 controls. No abnormal rises in LH, P, or T were noted in any of the groups.
Microdose GnRH-a enhances urofollitropin response and clinical outcome in poor responders undergoing IVF-ET. This may be due to enhanced release of early follicular phase endogenous FSH without concomitant deleterious rises in androgen levels or corpus luteum rescue.
This prospective randomized study was performed to compare the efficacy of GnRH antagonist multiple-dose protocol (MDP) with or without oral contraceptive pill (OCP) pretreatment and GnRH agonist low-dose long protocol (LP) in 82 patients undergoing IVF/intracytoplasmic sperm injection (ICSI). GnRH antagonist MDP with OCP pretreatment was at least as effective as GnRH agonist low-dose LP in low responders, and can benefit the low responders by reducing the amount of FSH and the number of days of stimulation required for follicular maturation.
To investigate the effectiveness of minidose GnRH agonist (GnRH-a) + hMG in poor responders with elevated basal level FSH.
Retrospective analysis of IVF cycles.
IVF Unit, Golda Medical Center, Petah Tikva, Israel.
One hundred six patients who were defined as poor responders on two previous IVF attempts. Three treatment protocols of midluteal Decapeptyl (D-Trp6) were compared: [1] a single-dose of 3.75 mg; [2] 0.5 mg daily until menstruation, followed by 0.1 mg daily; and [3] 0.1 mg daily until menstruation, followed by 0.05 mg daily.
Comparisons were made among the three protocols regarding basal FSH levels, number of oocytes retrieved and fertilized, number of days of stimulation, follicular phase, P levels, and pregnancy and miscarriage rates.
Treatment with minidose GnRH-a resulted in higher E2 levels and lower P levels on the day of hCG and lower cancellation rates. Furthermore, a higher number of oocytes recovered and fertilized and embryos transferred were recorded. The trend indicated improved pregnancy and implantation rates with a lower miscarriage rate.
Minidose GnRH-a is a better choice than regular GnRH-a strategies in poor-responder patients undergoing IVF treatment.
To analyze the effect of high dose human FSH in combination with hMG with a flare-up leuprolide acetate (LA) protocol in patients undergoing IVF at risk for a poor response.
Prospective.
Free-standing ambulatory IVF center.
Two hundred eighty-four patients underwent a LA screening test for IVF. Patients with a lack of flare response were considered at risk for a poor response and underwent ovarian stimulation with the flare-up LA protocol in combination with high dose human FSH and hMG.
The poor responder group was compared with the good responders on the flare-up LA protocol and to patients undergoing ovulation induction with a luteal phase LA protocol. There were 53 poor responder flare-up LA cycles, 177 good responder flare-up LA cycles, and 54 luteal phase LA cycles. The cancellation rate was higher in poor flare-up LA responders (11.3 percent) compared with good flare-up LA responders (1.1 percent) and luteal phase LA cycles (1.8 percent). Peak E2 levels, number of oocytes, and number of embryos were significantly higher in the good flare-up LA responders. Fertilization rate was similar in all groups. Ongoing pregnancy rate per retrieval was 28 percent in good responders, 29 percent in poor responders, and 33 percent in luteal phase LA patients. Only one patient (0.4 percent) was hospitalized for severe ovarian hyperstimulation.
The flare-up protocol with high-dose human FSH and hMG is a very good alternative for patients who are at high risk for a poor response. Although peak E2 and number of oocytes were significantly lower in this group, the patients who responded had the same fertilization and pregnancy rate as the good responders. Cancellation rate remains high in poor responders.
We studied 98 in-vitro fertilization (IVF) patients with a high basal follicle stimulating hormone (FSH;>6.5 IU/I) concentration
on day 3 who were treated with a low dose gonadotrophin-releasing hormone agonist (GnRHa) protocol and who had received in
the previous 6 months a long protocol with GnRHa in a depot formula. The evaluation was made using the previous IVF cycle
of the same patient as a control. The mean ± SD age of the patients was 34.1 ± 4.2 years. The use of a low dose agonist protocol
ended with significantly less ampoules (37.5 versus 46.1), a shorter duration of stimulation (10.7 versus 12.3 days), a higher
oestradiol concentration on day 8 (1068 versus 495 pg/ml), a higher number of mature oocytes (5.9 versus 4.4) and a higher
number of good quality embryos (3.3 versus 2.3). The cancellation rate was lower (11 versus 24%). A GnRHa low dose protocol
may be the protocol of choice for patients with high FSH concentrations on day 3. Larger randomized studies are needed to
confirm these data.
The concept that androgens are atretogenic, derived from murine ovary studies, is difficult to reconcile with the fact that hyperandrogenic women have more developing follicles than normal-cycling women. To evaluate androgen's effects on primate follicular growth and survival, normal-cycling rhesus monkeys were treated with placebo-, testosterone-(T), or dihydrotestosterone-sustained release implants, and ovaries were taken for histological analysis after 3-10 d of treatment. Growing preantral and small antral follicles up to 1 mm in diameter were significantly and progressively increased in number and thecal layer thickness in T-treated monkeys from 3-10 d. Granulosa and thecal cell proliferation, as determined by immunodetection of the Ki67 antigen, were significantly increased in these follicles. Preovulatory follicles (> 1 mm), however, were not increased in number in androgen-treated animals. Follicular atresia was not increased and there were actually significantly fewer apoptotic granulosa cells in the T-treated groups. Dihydrotestosterone treatment had identical effects, indicating that these growth-promoting actions are mediated by the androgen receptor. These findings show that, over the short term at least, androgens are not atretogenic and actually enhance follicular growth and survival in the primate. These new data provide a plausible explanation for the pathogenesis of "polycystic" ovaries in hyperandrogenism.
Excess androgens are associated with a characteristic polyfollicular ovarian morphology; however, it is not known to what extent this problem is due to direct androgen action on follicular development vs. interference with gonadotropin release at the level of the pituitary or hypothalamus. To elucidate potential androgen effects on the ovary, we investigated the cellular localization of androgen receptor (AR) messenger ribonucleic acid (mRNA) in rhesus monkey using in situ hybridization. To investigate the regulation of ovarian AR gene expression, we compared the relative abundance of AR transcripts in monkeys during follicular and luteal phases of the menstrual cycle and in monkeys treated with testosterone. To assess potential functional consequences of AR expression in the primate ovary, we compared AR mRNA levels with indexes of follicular cell proliferation and apoptosis in serial sections from individual follicles.
AR mRNA expression was most abundant in granulosa cells of healthy preantral and antral follicles in the primate ovary. Theca interna and stromal cells also expressed AR mRNA, but to a lesser degree than granulosa cells. No significant cycle stage effects were noted in AR mRNA levels; however, larger numbers of animals would be necessary to definitively establish a cycle stage effect. AR mRNA level was significantly increased in granulosa cells and was decreased in theca interna and stromal cells of testosterone-treated monkeys. Importantly, granulosa cell AR mRNA abundance was positively correlated with expression of the proliferation-specific antigen Ki-67 (r = 0.91; P < 0.001) and negatively correlated with granulosa cell apoptosis (r = −0.64; P < 0.001).
In summary, these data show that primate ovary AR gene expression is most abundant in granulosa cells of healthy growing follicles, where its expression is up-regulated by testosterone. The positive correlation between granulosa AR gene expression and cell proliferation and negative correlation with programmed cell death suggests that androgens stimulate early primate follicle development.
To assess the ovarian content of selectable (2-5 mm) follicles using three-dimensional ultrasonography in low responders to ovarian stimulation for IVF.
Prospective case-control study.
IVF program at the Instituto Valenciano de Infertilidad.
Ten low responders < or =35 years of age with normal basal serum FSH and eight control patients with normal response in a previous cycle.
Blood was drawn under basal (day 3) conditions. Three-dimensional ultrasound was performed in both ovaries using a vaginal probe.
Basal serum E2 and FSH measurements. The ovarian volume and the number of follicles > or =2 mm in each ovary were recorded and compared between the groups.
Low-responder women had significantly higher serum FSH levels than controls despite having FSH values within the normal range. The number of selectable follicles and the total number of follicles with an antrum were significantly decreased in low responders as compared with normal responders. Ovarian volume did not differ between the groups.
This study introduces three-dimensional ultrasound as a novel method for the evaluation of low responders. The results show that the most plausible explanation for low response in young women with normal serum FSH is diminished ovarian reserve.
In the study reported here, we investigated the effect of androgens on recruitment of resting, primordial follicles into the actively growing pool. Healthy, random-cycling female rhesus monkeys were treated with testosterone, dihydrotestosterone (DHT), or vehicle for 3-10 days, after which ovaries were collected for histological analysis. The first stage of follicle growth is the formation of the primary follicle, consisting of an oocyte surrounded by a single layer of cuboidal granulosa cells. The number of primary follicles was significantly increased over time in testosterone-treated animals. In situ hybridization showed that androgen treatment resulted in an increase to 3-fold in insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes. DHT effects were comparable to those of testosterone, showing that these are androgen receptor-mediated phenomena. These data show that androgens promote initiation of primordial follicle growth and implicate oocyte-derived IGF-I in this activation process.
To confirm the value of a single dose of 3 mg of cetrorelix in preventing the occurrence of premature LH surges.
Multicenter randomized, prospective study.
Reproductive medicine units.
Infertile patients undergoing ovarian stimulation for IVF-ET.
A single dose of 3 mg of cetrorelix (Cetrotide; ASTA Medica, Frankfurt, Germany) (115 patients) was administered in the late follicular phase. A depot preparation of triptorelin (Decapeptyl; Ipsen-Biotech, Paris, France) was chosen as a control agent (39 patients). Ovarian stimulation was conducted with hMG (Menogon; Ferring, Kiel, Germany).
Premature LH surges (LH level >10 IU/L), progesterone level greater than 1 ng/L, and IVF results.
No LH surge occurred after cetrorelix administration. The patients in the cetrorelix group had a lower number of oocytes and embryos. The percentage of mature oocytes and fertilization rates were similar in both groups, and the pregnancy rates were not statistically different. The length of stimulation, number of hMG ampules administered, and occurrence of the ovarian hyperstimulation syndrome were lower in the cetrorelix group. Tolerance of cetrorelix was excellent.
A cetrorelix single-dose protocol prevented LH surges in all patients studied. It compares favorably to the "long protocol" and could be a protocol of choice in IVF-ET.
In patients with poor response to ovarian stimulation with gonadotrophins, growth hormone (GH) is sometimes used to increase paracrine insulin-like growth factor-1 (IGF-1) effect. We postulated that dehydroepiandrosterone (DHEA) administration to poor responders would augment gonado-trophin effect via a similar mechanism. Baseline ovarian stimulation response to a cycle with DHEA in five healthy non-smoking women <41 years old was compared with day 3 FSH <20 mIU/ml. All had documented poor response to vigorous gonadotrophin administration. After day 2 ultrasounds, DHEA-sulphate (DHEA-S), FSH, human chorionic gonadotrophin (HCG), and testosterone were measured, and the women were given 80 mg/day of oral micronized DHEA for 2 months. While still on DHEA, they underwent ovarian stimulation with FSH given i.m. twice a day, and HCG (10 000 IU) at follicular maturity, followed by intrauterine insemination. Cycle parameters assessed were peak oestradiol, and peak oestradiol/ampoule. The DHEA/ovarian stimulation cycles occurred between 4 and 24 months after the control cycles. After 2 months DHEA treatment, DHEA-S increased to 544 +/- 55 microg/dl, and testosterone increased to 67.3 +/- 6.1 ng/dl. All five subjects (six cycles; one subject had two DHEA cycles) had increased responsiveness; peak oestradiol concentrations increased from 266.3 +/- 69.4 pg/ml to 939.8 +/- 418.9 pg/ml. The oestradiol/ampoule ratio increased in all six cycles, by a mean of 2.94 +/- 0.50 fold (P = 0.012). One of the cycles resulted in a delivered twin pregnancy. In this small series, DHEA improved response to ovarian stimulation even after controlling for gonadotrophin dose. Supplemental DHEA treatment during ovarian stimulation may represent a novel way to maximize ovarian response.
Transdermal testosterone (T) delivery represents an effective alternative to injectable androgens. We studied 163 hypogonadal men who applied 5, 7.5, or 10 g AndroGel (T gel) 1% CIII per day for up to 42 months. Efficacy data were presented in 123 subjects considered evaluable. Continuous AndroGel treatment normalized mean serum T and free T levels. Mean serum 5alpha-dihydrotestosterone concentrations and 5alpha-dihydrotestosterone/T ratio slightly increased, mean serum estradiol/T ratio doubled, and mean serum FSH and LH levels were suppressed by T replacement. Sexual function and mood parameters improved rapidly and were maintained throughout T treatment. Lean body mass increased (P = 0.0001) and fat mass decreased (P = 0.0001), and these changes were maintained with treatment but were not accompanied by significant increases in muscle strength. Increases in serum bone markers suggestive of increased bone formation were followed by gradual and progressive increases in bone mineral density more in the spine (P = 0.0001) than the hip (P = 0.0004). Mild local skin irritation occurred in 12 subjects, resulting in discontinuation in only one subject. Except for the anticipated increase in hematocrit and hemoglobin, there were no clinically significant changes in blood counts or biochemistry. In three subjects with elevated serum prostate-specific antigen, prostate biopsies showed cancer. We conclude that continued application of AndroGel resulted in beneficial effects similar to those with injectables and other transdermal preparations. This study was neither placebo controlled nor powered to determine the effects of T treatment on prostate cancer risk. Thus, monitoring for prostatic disease and assessment for erythrocytosis are strongly advised to reduce the risk of adverse events with T treatment of hypogonadal men.
Serum androgens have a negative correlation with some IVF stimulation parameters. Day 3 T levels <or=20 ng/dL are associated with poor IVF success rates.
[1] To examine the effects of body mass index (BMI), age, cigarette smoking, cause of infertility, and use of oral contraceptives on baseline serum testosterone (T), and [2] to examine associations between baseline serum T and IVF outcomes such as pre-hCG serum E(2), number of oocytes retrieved, oocyte fertilization rate, and pregnancy outcome in regularly cycling women.
Prospective, cohort study.
Three IVF programs in eastern Massachusetts.
Four hundred twenty-five regularly cycling women planning to undergo IVF. Women with polycystic ovary syndrome, ovulatory infertility, or irregular cycles were excluded from this study.
Collection of epidemiological data and baseline serum in women undergoing IVF.
Baseline serum total T, sex hormone binding globulin (SHBG), and calculation of free androgen index.
Body mass index >26 kg/m(2) was associated with a significant increase in serum T (P<.01) and free androgen index (P<.0001). Serum T decreased significantly throughout the fourth decade of life (P<.03). A history of cigarette smoking >10 pack years was associated with increased serum T (P<.01). A diagnosis of endometriosis was associated with decreased serum T. Serum T correlated positively with pre-hCG serum E(2) and number of oocytes retrieved. However, serum T did not significantly influence fertilization or pregnancy rates.
In cycling infertile women, increasing BMI and cigarette smoking are associated with increased serum T. Advancing age and endometriosis are associated with decreased serum T.
Testosterone replacement in hypogonadal men improves body composition, mood, and sexual functioning. In this 90-d study, we compared the pharmacokinetics and treatment effectiveness of a topical testosterone gel (AA2500) at two concentrations, 50 mg/d and 100 mg/d, to a testosterone patch and placebo gel in 406 hypogonadal men. Pharmacokinetic profiles were obtained, body composition was measured, and mood and sexual function were monitored. AA2500 treatments resulted in dose-dependent improvements in all pharmacokinetic parameters, compared with testosterone patch and placebo. Mean average concentrations at d 90 T were 13.8, 17.1, 11.9, and 7.3 nmol/liter for 50 mg/d AA2500, 100 mg/d AA2500, testosterone patch, and placebo, respectively. At d 90, the 100 mg/d AA2500 treatment improved lean body mass by 1.7 kg and percentage of body fat by 1.2% to a significantly greater degree than either control treatment. Significant improvements in spontaneous erections, sexual desire, and sexual motivation were also evidenced with the 100 mg/d AA2500 dose in comparison with placebo. Testosterone gel was well tolerated; however, the testosterone patch resulted in a high rate of application site reactions. Overall, AA2500 is an effective, well tolerated treatment for hypogonadism.
The aim of this study was to investigate the effect of treatment with dehydroepiandrosterone (DHEA) on fertility outcomes among women with diminished ovarian reserve.
This is a case-control study in an academically affiliated private infertility centre. Twenty-five women with significantly diminished ovarian reserve had one IVF cycle before and after DHEA treatment, with otherwise identical hormonal stimulation. Women received 75 mg of DHEA daily (25 mg three times daily) for an average of 17.6 +/- 2.13 weeks. We performed a comparison of IVF outcome parameters, before and after DHEA treatment, including peak estradiol (E(2)) levels, oocyte and embryo numbers, oocyte and embryo quality and embryo transfer statistics.
Paired analysis of IVF cycle outcomes in 25 patients, who underwent cycles both before and after DHEA supplementation, demonstrated significant increases in fertilized oocytes (P < 0.001), normal day 3 embryos (P = 0.001), embryos transferred (P = 0.005) and average embryo scores per oocyte (P < 0.001) after DHEA treatment.
This study confirms the previously reported beneficial effects of DHEA supplementation on ovarian function in women with diminished ovarian reserve.
The study Received C-H.K. has nothing to disclose. C.M.H. has nothing to disclose. H-A.L. has nothing to disclose. Presented at the 23rd meeting of the European Society of Human Reproduction and Embryology
- Center
- Seoul
- South
- Korea
Our prospective randomized study was performed at a university-based infer-tility clinic at the Asan Medical Center, Seoul, South Korea. The study Received March 2, 2010; revised June 9, 2010; accepted July 22, 2010; published online August 30, 2010. C-H.K. has nothing to disclose. C.M.H. has nothing to disclose. H-A.L. has nothing to disclose. Presented at the 23rd meeting of the European Society of Human Reproduction and Embryology, Lyon, France, July 1–4, 2007. Reprint requests: Chung-Hoon Kim, M.D., Ph.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, College of Medicine, University of Ulsan, Asan Medical Center, 388–1, Poognap-dong, Songpa-gu, Seoul, South Korea (FAX: 82-2-476-7331; E-mail: chnkim@amc.seoul.kr).
Use of the flare-up protocol with high dose human menopausal gonadotrophins for in vitro fertilization in poor responders
- Sl Padilla
- K Dugan
- V Maruschak
- S Shalika
- R Smith
Padilla SL, Dugan K, Maruschak V, Shalika S,
Smith R. Use of the flare-up protocol with high dose
human menopausal gonadotrophins for in vitro fertilization in poor responders. Fertil Steril 1996;65:796–9.
Testosterone gel for low responders
- Kim
Kim et al.
Testosterone gel for low responders
Vol. 95, No. 2, February 2011
Use of the flare-up protocol with high dose human menopausal gonadotrophins for in vitro fertilization in poor responders
- Padilla