-
International Journal of Molecular... Mar 2024The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the...
The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the menstrual cycle during the window of implantation. This coincides with a peak in progesterone and estradiol production. We hypothesized that the interplay between hormone-induced changes in the mechanical properties of the endometrial epithelium and stroma supports this process. To study it, we used hormone-responsive endometrial adenocarcinoma-derived Ishikawa cells growing on substrates of different stiffness. We showed that Ishikawa monolayers on soft substrates are more tightly clustered and uniform than on stiff substrates. Probing for mechanical alterations, we found accelerated stress-relaxation after apical nanoindentation in hormone-stimulated monolayers on stiff substrates. Traction force microscopy furthermore revealed an increased number of foci with high traction in the presence of estradiol and progesterone on soft substrates. The detection of single cells and small cell clusters positive for the intermediate filament protein vimentin and the progesterone receptor further underscored monolayer heterogeneity. Finally, adhesion assays with trophoblast-derived AC-1M-88 spheroids were used to examine the effects of substrate stiffness and steroid hormones on endometrial receptivity. We conclude that the extracellular matrix and hormones act together to determine mechanical properties and, ultimately, embryo implantation.
Topics: Female; Humans; Progesterone; Epithelium; Extracellular Matrix; Menstrual Cycle; Estradiol
PubMed: 38612536
DOI: 10.3390/ijms25073726 -
International Journal of Molecular... Mar 2024Despite serum progesterone being a widely accepted method for luteal phase support during embryo transfer cycles, debates persist regarding the optimal strategy for...
Despite serum progesterone being a widely accepted method for luteal phase support during embryo transfer cycles, debates persist regarding the optimal strategy for guiding clinical decisions on progesterone dosages to maximize reproductive outcomes. This retrospective study explored the utility of microRNA (miRNA) biomarkers in guiding personalized progesterone dosage adjustments for frozen embryo transfer (FET) cycles in 22 in vitro fertilization (IVF) patients undergoing hormone replacement therapy. Utilizing MIRA, an miRNA-based endometrial receptivity test, we analyzed patients' miRNA expression profiles before and after progesterone dosage adjustments to determine suitable dosages and assess endometrial status. Despite patients receiving identical progesterone dosages, variations in miRNA profiles were observed in the initial cycle, and all patients presented a displaced window of implantation. Following dosage adjustments based on their miRNA profiles, 91% of patients successfully transitioned their endometrium towards the receptive stages. However, two patients continued to exhibit persistent displaced receptivity despite the adjustments. Given the evident variation in endometrial status and serum progesterone levels among individuals, analyzing miRNA expression profiles may address the challenge of inter-personal variation in serum progesterone levels, to deliver more personalized dosage adjustments and facilitate personalized luteal phase support in IVF.
Topics: Female; Humans; Progesterone; Luteal Phase; Retrospective Studies; MicroRNAs; Embryo Transfer; Endometrium
PubMed: 38612482
DOI: 10.3390/ijms25073670 -
International Journal of Molecular... Mar 2024C19 steroids and C22 steroids are vital intermediates for the synthesis of steroid drugs. Compared with C19 steroids, C22 steroids are more suitable for synthesizing...
C19 steroids and C22 steroids are vital intermediates for the synthesis of steroid drugs. Compared with C19 steroids, C22 steroids are more suitable for synthesizing progesterone and adrenocortical hormones, albeit less developed. 9,22-dihydroxy-23,24-bisnorchol-4-ene-3-one(9-OHBA), due to its substituents at positions C-9 and C-22, is a beneficial and innovative steroid derivative for synthesizing corticosteroids. We focused on the C22 pathway in ATCC 35855, aiming to develop a productive strain that produces 9-OHBA. We used a mutant strain, MFΔ, that knocked out from ATCC 35855 named MFKD in this study as the original strain. Hsd4A and FadA5 are key enzymes in controlling the C19 metabolic pathway of steroids in ATCC 35855. After knocking out , MFKDΔ accumulated 81.47% 9-OHBA compared with 4.13% 9-OHBA in the strain MFKD. The double mutant MFKDΔΔ further improved the selectivity of 9-OHBA to 95.13%, and 9α-hydroxy-4-androstenedione (9-OHAD) decreased to 0.90% from 4.19%. In the end, we obtained 6.81 g/L 9-OHBA from 10 g/L phytosterols with a molar yield of 80.33%, which showed the best performance compared with formerly reported strains.
Topics: Mycobacterium fortuitum; Androstenedione; Molar; Phytosterols; Progesterone
PubMed: 38612391
DOI: 10.3390/ijms25073579 -
Microbial Cell Factories Apr 2024Pregnenolone and progesterone are the life-important steroid hormones regulating essential vital functions in mammals, and widely used in different fields of medicine....
BACKGROUND
Pregnenolone and progesterone are the life-important steroid hormones regulating essential vital functions in mammals, and widely used in different fields of medicine. Microbiological production of these compounds from sterols is based on the use of recombinant strains expressing the enzyme system cholesterol hydroxylase/C20-C22 lyase (CH/L) of mammalian steroidogenesis. However, the efficiency of the known recombinant strains is still low. New recombinant strains and combination approaches are now needed to produce these steroid hormones.
RESULTS
Based on Mycolicibacterium smegmatis, a recombinant strain was created that expresses the steroidogenesis system (CYP11A1, adrenodoxin reductase, adrenodoxin) of the bovine adrenal cortex. The recombinant strain transformed cholesterol and phytosterol to form progesterone among the metabolites. When 3-methoxymethyl ethers of sterols were applied as bioconversion substrates, the corresponding 3-ethers of pregnenolone and dehydroepiandrosterone (DHEA) were identified as major metabolites. Under optimized conditions, the recombinant strain produced 85.2 ± 4.7 mol % 3-methoxymethyl-pregnenolone within 48 h, while production of 3-substituted DHEA was not detected. After the 3-methoxymethyl function was deprotected by acid hydrolysis, crystalline pregnenolone was isolated in high purity (over 98%, w/w). The structures of steroids were confirmed using TLC, HPLC, MS and H- and C-NMR analyses.
CONCLUSION
The use of mycolicybacteria as a microbial platform for the expression of systems at the initial stage of mammalian steroidogenesis ensures the production of valuable steroid hormones-progesterone and pregnenolone from cholesterol. Selective production of pregnenolone from cholesterol is ensured by the use of 3-substituted cholesterol as a substrate and optimization of the conditions for its bioconversion. The results open the prospects for the generation of the new microbial biocatalysts capable of effectively producing value-added steroid hormones.
Topics: Cattle; Animals; Progesterone; Pregnenolone; Sterols; Steroids; Cholesterol; Cholesterol Side-Chain Cleavage Enzyme; Phytosterols; Mammals; Ethers
PubMed: 38594656
DOI: 10.1186/s12934-024-02385-2 -
BMC Pregnancy and Childbirth Apr 2024Preterm birth is a leading cause of infant morbidity and mortality worldwide. The burden of prematurity underscores the need for effective risk reduction strategies. The...
BACKGROUND
Preterm birth is a leading cause of infant morbidity and mortality worldwide. The burden of prematurity underscores the need for effective risk reduction strategies. The purpose of this study is to evaluate the efficacy of progesterone therapy, both intramuscular 17-α-hydroxyprogesterone caproate (IM 17-OHPC) and vaginal progesterone, in the prevention of recurrent spontaneous preterm birth (sPTB). The co-primary outcomes included: recurrent spontaneous PTB < 37 and < 34 weeks' gestation.
METHODS
This retrospective cohort study included 637 pregnant patients that delivered at any of the three hospitals within the Los Angeles County healthcare system between October 2015 and June 2021. We compared frequencies of measured variables between each of the progesterone treated groups to no treatment using Pearson chi-squared tests and independent t-tests for categorical and continuous variables, respectively. We estimated crude and adjusted associations between each specific treatment (versus no treatment) and primary outcomes using logistic regression.
RESULTS
Recurrent sPTB < 37 weeks' gestation occurred in 22.3% (n = 64) of those in the no treatment group, 29.1% (n = 86, p = .077) in the 17-OHPC group, and 14.3% (n = 6, p = 0.325) in the vaginal progesterone group. Recurrent sPTB < 34 weeks' gestation was 6.6% (n = 19) in the no treatment group, 11.8% (n = 35, p = .043) in the 17-OHPC group, and 7.1% (n = 3, p = 1) in the vaginal progesterone group. Among all participants, neither 17-OHPC nor vaginal progesterone was significantly associated with a reduction in recurrent sPTB at any time point. Among those with a short cervix, IM 17-OHPC was positively associated with recurrent sPTB < 37 weeks' gestation (aOR 5.61; 95% CI 1.16, 42.9).
CONCLUSIONS
Progesterone therapy of any type did not reduce the risk of recurrent sPTB < 34 or < 37 weeks' gestation compared to no progesterone therapy.
Topics: Pregnancy; Female; Humans; Infant, Newborn; Progesterone; Retrospective Studies; Premature Birth; 17 alpha-Hydroxyprogesterone Caproate; Infant, Premature
PubMed: 38589796
DOI: 10.1186/s12884-024-06471-6 -
Global Health, Science and Practice Apr 2024Couple-years of protection (CYP) is an indicator that allows for monitoring and evaluating of family planning (FP) program performance through simple calculations. The... (Review)
Review
BACKGROUND
Couple-years of protection (CYP) is an indicator that allows for monitoring and evaluating of family planning (FP) program performance through simple calculations. The CYP for each contraceptive method is calculated by multiplying the number of contraceptive commodity units distributed to clients over a 1-year period by a conversion factor that quantifies the duration of contraceptive protection provided per unit distributed. CYP calculations across methods were previously updated in 2000 and 2011, resulting in changes in methodology, factor inclusion, and specific methods. Since the 2011 update, changes and additions to the modern contraceptive method mix required new CYP conversion factors for 4 methods of contraception: Levoplant implant, progestin-only pills (POPs), Caya diaphragm, and the hormonal intrauterine device.
METHODS
We conducted literature reviews of both published and gray literature and consulted with experts to identify updated data on continuation rates, duration of efficacy, and method effectiveness for the 4 methods. New CYP conversion factors were calculated for the 4 methods either by using the same calculation used previously for the method considering new data or, for new methods, using calculations for similar methods.
RESULTS
New CYP conversion factors were assigned to the 4 methods of contraception covered in this update: Levoplant, 2.5 CYP per implant inserted; POPs, 0.0833 CYP per pack (i.e., 12 cycles per CYP); Caya diaphragm, 1 CYP per device, and hormonal intrauterine device, 4.8 CYP per device inserted.
CONCLUSIONS
CYP is an important indicator for FP programs. As new methods of contraception are developed and new evidence is generated for current methods, the indicator may need to be updated. A standard process for updating and documenting future CYP updates is recommended.
Topics: Humans; Female; Contraception; Family Planning Services; Intrauterine Devices
PubMed: 38589048
DOI: 10.9745/GHSP-D-23-00388 -
Advanced Science (Weinheim,... Jun 2024The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond...
The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond well to initial therapy, progestin-refractory disease inevitably emerges, and the molecular basis underlying progestin resistance has not been comprehensively elucidated. Herein, they demonstrated progestin results in p38-dependent IDH1 Thr 77 phosphorylation (pT77-IDH1). pT77-IDH1 translocates into the nucleus and is recruited to chromatin through its interaction with OCT6. IDH1-produced α-ketoglutarate (αKG) then facilitates the activity of OCT6 to promote focal adhesion related target gene transcription to confer progestin resistance. Pharmacological inhibition of p38 or focal adhesion signaling sensitizes endometrial cancer cells to progestin in vivo. The study reveals p38-dependent pT77-IDH1 as a key mediator of progestin resistance and a promising target for improving the efficacy of progestin therapy.
Topics: Female; Humans; Endometrial Neoplasms; Progestins; Drug Resistance, Neoplasm; Mice; Isocitrate Dehydrogenase; Animals; Phosphorylation; Cell Line, Tumor; Disease Models, Animal
PubMed: 38582508
DOI: 10.1002/advs.202310208 -
Reproductive Biology Jun 2024Women may be more susceptible to infections in the luteal phase, supposedly as a consequence of the hormone progesterone and its immunosuppressive action. While...
Women may be more susceptible to infections in the luteal phase, supposedly as a consequence of the hormone progesterone and its immunosuppressive action. While immunosuppression may be important for successful oocyte implantation and pregnancy, it makes women more vulnerable to pathogens. According to theory, to compensate for reduced immunocompetence, women in the luteal phase exhibit proactive behavioral responses, such as disgust and avoidance of disease-associated stimuli, to minimize contagion risk. However, previous studies yielded inconsistent results, and did not account for accompanying proactive immune responses, like the increase of secretory immunoglobin A (sIgA). Here, we assessed the proactive immune response and feelings of disgust associated with disease cues in the comparison of 61 woman with a natural menstrual cycle (31 in the follicular and 30 in the luteal phase) and 20 women taking hormonal contraception (HC). Women rated disease vulnerability and disgust propensity, watched a video displaying people with respiratory symptoms, which was evaluated for its disgust-evoking potential and contagiousness, and provided saliva samples for hormone and sIgA analysis. Women with HC reported a heightened vulnerability to disease compared to naturally cycling women, whereas both the feeling of disgust and the sIgA increase elicited by the disease video were similar across groups, regardless of progesterone. We found a u-shaped relationship between progesterone and baseline sIgA in naturally cycling women, with its nadir during ovulation. Overall, our data do not support a compensatory relationship between the proposed progesterone-induced immunosuppression and heightened disgust or a proactive sIgA response.
Topics: Humans; Female; Adult; Progesterone; Young Adult; Saliva; Immunoglobulin A, Secretory; Luteal Phase; Menstrual Cycle; Disgust
PubMed: 38581902
DOI: 10.1016/j.repbio.2024.100880 -
Toxicology and Applied Pharmacology May 2024Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line...
BACKGROUND
Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues.
METHODS
Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA.
RESULTS
Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands.
CONCLUSION
These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.
Topics: Animals; Female; Topiramate; Rats, Sprague-Dawley; Acetazolamide; Endocrine Disruptors; Rats; Estrus; Luteinizing Hormone; Fructose; Pituitary Gland; Progesterone; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Estradiol; Ovary
PubMed: 38580201
DOI: 10.1016/j.taap.2024.116919 -
Frontiers in Endocrinology 2024Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in...
Micronized natural progesterone (Seidigestan) vs GnRH antagonists for preventing the LH surge during controlled ovarian stimulation (PRO_NAT study): study protocol of a randomized clinical trial.
INTRODUCTION
Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome.
METHODS
We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes.
DISCUSSION
The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier, NCT05954962.
Topics: Female; Humans; Pregnancy; Gonadotropin-Releasing Hormone; Hormone Antagonists; Ovulation Induction; Progesterone; Progestins; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 38577571
DOI: 10.3389/fendo.2024.1350154