Abstract Human chorionic gonadotropin (hCG) is the first hormonal message from the placenta to the mother. It is detectable in maternal blood two days after implantation and behaves like an agonist ...of LH stimulating progesterone secretion by the corpus luteum . hCG has also a role in quiescence of the myometrium and local immune tolerance. Specific to humans, hCG is a complex glycoprotein composed of two glycosylated subunits. The α-subunit is identical to the pituitary gonadotropin hormones (LH, FSH, TSH), contains two N-glycosylation sites, and is encoded by a single gene ( CGA ). By contrast the β-subunits are distinct in each of the hormones and confer receptor and biological specificity. The hCG β-subunit contains two sites of N-glycosylation and four sites of O-glycosylation and is encoded by a cluster of genes ( CGB ). In this review, we will stress the importance of hCG glycosylation state, which varies with the stage of pregnancy, its source of production and in the pathology. It is well established that hCG is mainly secreted by the syncytiotrophoblast into maternal blood where it peaks around 8–10 weeks of gestation (WG). The invasive extravillous trophoblast also secretes hCG, and in particular like choriocarcinoma cells, hyperglycosylated forms of hCG (hCG-H). In maternal blood hCG-H is high during early first trimester. In addition to its endocrine role, hCG has autocrine and paracrine roles. It promotes formation of the syncytiotrophoblast and angiogenesis through LHCG receptor. In contrast, hCG-H stimulates trophoblast invasion and angiogenesis by interacting with the TGFβ receptor 2. hCG is largely used in antenatal screening and hCG-H represents a serum marker of early trophoblast invasion. Other abnormally glycosylated hCG are described in aneuploidies. In conclusion, hCG is the major pregnancy glycoprotein hormone, whose maternal concentration and glycan structure change all along pregnancy. Depending on its source of production, glycoforms of hCG display different biological activities and functions that are essential for pregnancy outcome.
Le mitotane (o.p’DDD, Lysodren® ) est utilisé pour traiter corticosurrénalomes et syndromes de Cushing. Il est catabolisé en o.p’DDA et o.p’DDE, se lie peu aux protéines, mais beaucoup aux lipides et ...présente des effets secondaires digestifs. Les patients sous mitotane sont décrits comme ayant une T4L diminuée sans signe d’hypothyroïdie. Nous avons voulu savoir si cela était dû à une interférence analytique dans le dosage de T4L ou une action du mitotane sur l’axe thyréotrope. Les sérums de 31 patients (22 corticosurrénalomes, 9 syndromes de Cushing) ont été analysés rétrospectivement en dosant : o.p’DDD et o.p’DDE ; TSH, T4L, T3L, rT3, TBG ; albumine, cholestérol, triglycérides (analyse statistique, logiciel Statview Spearman rho, p significatif si < 0,005). In vitro, l’addition de quantités croissantes d’ o.p’DDD (1–40 mg/L) et o.p’DDE n’a pas d’influence sur la T4L ou TSH sérique. In vivo, nous confirmons une diminution isolée mais non significative (−0,16, p = 0,24) de la T4L sous mitotane. La mitonanémie est négativement corrélée à la rT3 (−0,36, p = 0,013) mais positivement à la TBG (+ 0,43, p = 0,0016). Nos résultats montrent que ni le mitotane ni son métabolite l’o.p’DDE n’ont d’influence sur le dosage de la T4L ou de la TSH. L’absence de corrélation T4L/TSH n’est pas en faveur d’une production hypophysaire de TSH diminuée. L’augmentation de la TBG peut entraîner une diminution de la T4L. La diminution de la rT3 alors que la T3L reste inchangée suggère que le mitotane modulerait les désiodases voir le catabolisme hépatique de la T4L.
Le suivi biochimique de la fonction ovarienne sous stimulation se limite aux dosages sériques d’estradiol et de progestérone, sans étudier leurs précurseurs. Notre objectif est d’analyser la ...stéroïdogénèse ovarienne complète sous stimulation. Cette étude inclut rétrospectivement 50 femmes (26 FIV, 24 ICSI) (groupe induction PMA) et 11 femmes suivies pour IIU (groupe contrôle). Les concentrations des estrogènes (estrone, estradiol, estriol), des androgènes (D4-androstènedione, testostérone), des progestatifs (progestérone, 17 hydroxyprogestérone) ont été mesurées tous les 2 jours. Les profils stéroïdiens ont été caractérisés par spectrométrie de masse et les résultats exprimés en médiane. La sécrétion basale stéroïdienne se situe dans la normale physiologique (FIV, ICSI et IIU respectivement) : estradiol (534, 640, 314 pmol.L−1 ), testostérone (1,2, 1,2, 1,6 nmol.L−1 ), D4-androstènedione (4,4, 4,5, 5,6 nmol.L−1 ), 17 hydroxyprogestérone (1,7, 2,4, 2,3 nmol.L−1 ), progestérone (2,0, 1,8, 2,9 nmol.L−1 ). À j12, nous observons une augmentation significative ( p < 0,05) uniquement en œstradiol (4040, 4139 and 951 pmol.L−1 ) et en D4-androstènedione (6,2, 7,8, 6,1 nmol.L−1 ). La cinétique d’augmentation sous 48 h est significativement différente entre le groupe contrôle et le groupe PMA pour l’œstradiol (facteur 1,5 à 1,9) et pour la D4-androstènedione. Pour la testostérone et la 17 hydroxyprogestérone, elle n’est significative qu’au sein du groupe PMA. Dans ce groupe, il n’y a pas de différence de cinétique d’augmentation de ces stéroïdes entre FIV et ICSI, exceptée pour la D4-androstenedione. La stimulation par rFSH conduit à une hyperplasie ovarienne globale avec des variations individuelles qui ont été caractérisées par spectrométrie de masse.
Abstract Background Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large ...inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. Patients and methods This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin ) and 3-month PSA response. Results From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, confidence interval {CI} 95% 50–78). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4–15.6) versus 8.0 ng/mL (CI 95% 5.8–11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 CI 95% 1.01–1.25, P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, CI 95% 0.31–0.99, 12.2 CI 95% 9.2–19.5 versus 7.4 CI 95% 5.5–14.7 months otherwise, P = 0.044). Conclusions We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.
Is there a significant intra-individual variability of serum progesterone levels on the day of single blastocyst Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) between two consecutive ...cycles?
No significant intra-individual variability of serum progesterone (P) levels was noted between two consecutive HRT-FET cycles.
In HRT-FET cycles, a minimum P level on the day of embryo transfer is necessary to optimise reproductive outcomes. In a previous study by our team, a threshold of 9.8 ng/ml serum P was identified as significantly associated with the live birth rates in single autologous blastocyst transfers under HRT using micronized vaginal progesterone (MVP). Such patients may benefit from an intensive luteal phase support (LPS) using other routes of P administration in addition to MVP. A crucial question in the way towards individualising LPS is whether serum P measurements are reproducible for a given patient in consecutive HRT-FET cycles, using the same LPS.
We conducted an observational cohort study at the university-based reproductive medicine centre of our institution focusing on women who underwent at least two consecutive single autologous blastocyst HRT-FET cycles between January 2019 and March 2020.
Patients undergoing two consecutive single autologous blastocyst HRT-FET cycles using exogenous oestradiol and vaginal micronized progesterone for endometrial preparation were included. Serum progesterone levels were measured on the morning of the Frozen Embryo Transfer (FET), by a single laboratory. The two measurements of progesterone levels performed on the day of the first (FET1) and the second FET (FET2) were compared to evaluate the intra-individual variability of serum P levels. Paired statistical analyses were performed, as appropriate.
Two hundred and sixty-four patients undergoing two consecutive single autologous blastocyst HRT-FET were included. The mean age of the included women was 35.0 ± 4.2 years. No significant intra-individual variability was observed between FET1 and FET2 (mean progesterone level after FET1: 13.4 ± 5.1 ng/ml vs after FET2: 13.9 ± 5.0; P = 0.08). The characteristics of the embryo transfers were similar between the first and the second FET. Forty-nine patients (18.6%) had discordant progesterone levels (defined as one progesterone measurement > and one ≤ to the threshold of 9.8 ng/ml) between FET1 and FET2. There were 37/264 women (14.0%) who had high intra-individual variability (defined as a difference in serum progesterone values >75th percentile (6.0 ng/ml)) between FET1 and FET2. No specific clinical parameter was associated with a high intra-individual variability nor a discordant P measurement.
This study is limited by its retrospective design. Moreover, only women undergoing autologous blastocyst HRT-FET with MVP were included, thereby limiting the extrapolation of the study findings to other routes of P administration and other kinds of endometrial preparation for FET.
No significant intra-individual variability was noted. The serum progesterone level appeared to be reproducible in >80% of cases. These findings suggest that the serum progesterone level measured on the day of the first transfer can be used to individualize luteal phase support in subsequent cycles.
No funding or competing interests.
N/A.
Abstract
STUDY QUESTION
Which factors are associated with low serum progesterone (P) levels on the day of frozen embryo transfer (FET), in HRT cycles?
SUMMARY ANSWER
BMI, parity and non-European ...geographic origin are factors associated with low serum P levels on the day of FET in HRT cycles.
WHAT IS KNOWN ALREADY
The detrimental impact of low serum P concentrations on HRT-FET outcomes is commonly recognized. However, the factors accounting for P level disparities among patients receiving the same luteal phase support treatment remain to be elucidated, to help clinicians predicting which subgroups of patients would benefit from a tailored P supplementation.
STUDY DESIGN, SIZE, DURATION
Observational cohort study with 915 patients undergoing HRT-FET at a tertiary care university hospital, between January 2019 and March 2020.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Patients undergoing single autologous blastocyst FET under HRT using exogenous estradiol and vaginal micronized progesterone for endometrial preparation. Women were only included once during the study period. The serum progesterone level was measured in the morning of the FET, in a single laboratory. Independent factors associated with low serum P levels (defined as ≤9.8 ng/ml, according to a previous published study) were analyzed using univariate and multivariate logistic regression models.
MAIN RESULTS AND THE ROLE OF CHANCE
Two hundred and twenty-six patients (24.7%) had a low serum P level, on the day of the FET. Patients with a serum P level ≤9.8 ng/ml had a lower live birth rate (26.1% vs 33.2%, P = 0.045) and a higher rate of early miscarriage (35.2% vs 21.5%, P = 0.008). Univariate analysis showed that BMI (P < 0.001), parity (P = 0.001), non-European geographic origin (P = 0.001), the duration of infertility (P = 0.018) and the use of oral estradiol for endometrial preparation (P = 0.009) were significantly associated with low serum P levels. Moreover, the proportion of active smokers was significantly lower in the ‘low P concentrations’ group (P = 0.002). After multivariate analysis, BMI (odds ratio (OR) 1.06 95% CI (1.02–1.11), P = 0.002), parity (OR 1.32 95% CI (1.04–1.66), P = 0.022), non-European geographic origin (OR 1.70 95% CI (1.21–2.39), P = 0.002) and active smoking (OR 0.43 95% CI (0.22–0.87), P = 0.018) remained independent factors associated with serum P levels ≤9.8 ng/ml.
LIMITATIONS, REASONS FOR CAUTION
The main limitation of this study is its observational design, leading to a risk of selection and confusion bias that cannot be ruled out, although a multivariable analysis was performed to minimize this.
WIDER IMPLICATIONS OF THE FINDINGS
Extrapolation of our results to other laboratories, or other routes and/or doses of administering progesterone also needs to be validated. There is urgent need for future research on clinical factors affecting P concentrations and the underlying pathophysiological mechanisms, to help clinicians in predicting which subgroups of patients would benefit from individualized luteal phase support.
STUDY FUNDING/COMPETING INTEREST(S)
No funding/no conflicts of interest.
TRIAL REGISTRATION NUMBER
N/A.
Abstract STUDY QUESTION Do women with endometriosis who achieve a live birth (LB) after HRT-frozen embryo transfer (HRT-FET) have different progesterone levels on the day of transfer compared to ...unaffected women? SUMMARY ANSWER In women achieving a LB after HRT-FET, serum progesterone levels on the day of the transfer did not differ between patients with endometriosis and unaffected patients. WHAT IS KNOWN ALREADY In HRT-FET, several studies have highlighted the correlation between serum progesterone levels at the time of FET and LB rates. In the pathophysiology of endometriosis, progesterone resistance is typically described in the eutopic endometrium. This has led to the hypothesis that women with endometriosis may require higher progesterone levels to achieve a LB, especially in HRT-FET cycles without a corpus luteum. STUDY DESIGN, SIZE, DURATION We conducted an observational cohort study at the university-based reproductive medicine center of our institution, focusing on women who underwent a single autologous frozen blastocyst transfer after HRT using exogenous estradiol and micronized vaginal progesterone for endometrial preparation between January 2019 and December 2021. Women were included only once during the study period. Serum progesterone levels were measured on the morning of the FET by a single laboratory. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients were divided into groups based on whether they had endometriosis or not and whether they achieved a LB. The diagnosis of endometriosis was based on published imaging criteria (transvaginal sonography/magnetic resonance imaging) and/or confirmed histology. The primary outcome was progesterone levels on the day of the HRT-FET leading to a LB in patients with endometriosis compared to unaffected women. Subgroup analyses were performed based on the presence of deep infiltrating endometriosis or adenomyosis. MAIN RESULTS AND THE ROLE OF CHANCE A total of 1784 patients were included. The mean age of the women was 35.1 ± 4.1 (SD) years. Five hundred and sixty women had endometriosis, while 1224 did not. About 179/560 (32.0%) with endometriosis and 381/1224 (31.2%) without endometriosis achieved a LB. Among women who achieved a LB after HRT-FET, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (13.6 ± 4.3 ng/ml vs 13.2 ± 4.4 ng/ml, respectively; P = 0.302). In the subgroup of women with deep infiltrating endometriosis (n = 142) and adenomyosis (n = 100), the mean progesterone level was 13.1 ± 4.1 ng/ml and 12.6 ± 3.7 ng/ml, respectively, with no significant difference compared to endometriosis-free patients. After adjusting for BMI, parity, duration of infertility, tobacco use, and geographic origin, neither the presence of endometriosis (coefficient 0.38; 95% CI: −0.63 to 1.40; P = 0.457) nor the presence of adenomyosis (coefficient 0.97; 95% CI: −0.24 to 2.19; P = 0.114) was associated with the progesterone level on the day of HRT-FET. Among women who did not conceive, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (P = 0.709). LIMITATIONS, REASONS FOR CAUTION The primary limitation of our study is associated with its observational design. Extrapolating our results to other laboratories or different routes and/or dosages of administering progesterone also requires validation. WIDER IMPLICATIONS OF THE FINDINGS This study shows that patients diagnosed with endometriosis do not require higher progesterone levels on the day of a frozen blastocyst transfer to achieve a LB in hormonal replacement therapy cycles. STUDY FUNDING/COMPETING INTEREST(S) None declared. TRIAL REGISTRATION NUMBER N/A.
